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Sample records for retinoblastoma susceptibility gene

  1. Alteration of the retinoblastoma gene locus in radium-exposed individuals

    International Nuclear Information System (INIS)

    Hardwick, J.P.; Schlenker, R.; Huberman, E.

    1991-01-01

    This study was performed to determine if the retinoblastoma suppressor gene was altered in individuals exposed to radium. We analyzed the Rb gene in 30 individuals, 17 of whom were exposed to radium either occupationally or iatrogenically. In the kidney DNA from four of nine radium-exposed individuals, the Rb gene was deleted. Three of these alterations in the Rb gene were internal deletions, which resulted in the absence of Rb mRNA accumulation. These results imply that the Rb gene is susceptible to radium-induced damage and confirm previous showing that radiation preferentially causes genomic deletions. The pronounced alterations in the non-tumorigenic femurs from radium-exposed individuals suggests that in the many years of exposure there was a selection of cells with alterations, presumably because of their growth advantage. Also it implies that deletions of one of the Rb alleles can be one of the events (perhaps an initial one) in the progression of radium-induced sarcomas. 11 refs., 2 figs

  2. Genetics and Molecular Diagnostics in Retinoblastoma--An Update.

    Science.gov (United States)

    Soliman, Sameh E; Racher, Hilary; Zhang, Chengyue; MacDonald, Heather; Gallie, Brenda L

    2017-01-01

    Retinoblastoma is the prototype genetic cancer: in one or both eyes of young children, most retinoblastomas are initiated by biallelic mutation of the retinoblastoma tumor suppressor gene, RB1, in a developing retinal cell. All those with bilateral retinoblastoma have heritable cancer, although 95% have not inherited the RB1 mutation. Non-heritable retinoblastoma is always unilateral, with 98% caused by loss of both RB1 alleles from the tumor, whereas 2% have normal RB1 in tumors initiated by amplification of the MYCN oncogene. Good understanding of retinoblastoma genetics supports optimal care for retinoblastoma children and their families. Retinoblastoma is the first cancer to officially acknowledge the seminal role of genetics in cancer, by incorporating "H" into the eighth edition of cancer staging (2017): those who carry the RB1 cancer-predisposing gene are H1; those proven to not carry the familial RB1 mutation are H0; and those at unknown risk are HX. We suggest H0* be used for those with residual <1% risk to carry a RB1 mutation due to undetectable mosaicism. Loss of RB1 from a susceptible developing retinal cell initiates the benign precursor, retinoma. Progressive genomic changes result in retinoblastoma, and cancer progression ensues with increasing genomic disarray. Looking forward, novel therapies are anticipated from studies of retinoblastoma and metastatic tumor cells and the second primary cancers that the carriers of RB1 mutations are at high risk to develop. Here, we summarize the concepts of retinoblastoma genetics for ophthalmologists in a question/answer format to assist in the care of patients and their families. Copyright 2017 Asia-Pacific Academy of Ophthalmology.

  3. Regional and temporal differences in gene expression of LH(BETA)T(AG) retinoblastoma tumors.

    Science.gov (United States)

    Houston, Samuel K; Pina, Yolanda; Clarke, Jennifer; Koru-Sengul, Tulay; Scott, William K; Nathanson, Lubov; Schefler, Amy C; Murray, Timothy G

    2011-07-23

    The purpose of this study was to evaluate by microarray the hypothesis that LH(BETA)T(AG) retinoblastoma tumors exhibit regional and temporal variations in gene expression. LH(BETA)T(AG) mice aged 12, 16, and 20 weeks were euthanatized (n = 9). Specimens were taken from five tumor areas (apex, anterior lateral, center, base, and posterior lateral). Samples were hybridized to gene microarrays. The data were preprocessed and analyzed, and genes with a P 2.5 were considered to be differentially expressed. Differentially expressed genes were analyzed for overlap with known networks by using pathway analysis tools. There were significant temporal (P regional differences in gene expression for LH(BETA)T(AG) retinoblastoma tumors. At P 2.5, there were significant changes in gene expression of 190 genes apically, 84 genes anterolaterally, 126 genes posteriorly, 56 genes centrally, and 134 genes at the base. Differentially expressed genes overlapped with known networks, with significant involvement in regulation of cellular proliferation and growth, response to oxygen levels and hypoxia, regulation of cellular processes, cellular signaling cascades, and angiogenesis. There are significant temporal and regional variations in the LH(BETA)T(AG) retinoblastoma model. Differentially expressed genes overlap with key pathways that may play pivotal roles in murine retinoblastoma development. These findings suggest the mechanisms involved in tumor growth and progression in murine retinoblastoma tumors and identify pathways for analysis at a functional level, to determine significance in human retinoblastoma. Microarray analysis of LH(BETA)T(AG) retinal tumors showed significant regional and temporal variations in gene expression, including dysregulation of genes involved in hypoxic responses and angiogenesis.

  4. Structure and expression of the Xenopus retinoblastoma gene.

    Science.gov (United States)

    Destrée, O H; Lam, K T; Peterson-Maduro, L J; Eizema, K; Diller, L; Gryka, M A; Frebourg, T; Shibuya, E; Friend, S H

    1992-09-01

    We have cloned a Xenopus homology (XRb1) of the human retinoblastoma susceptibility gene. DNA sequence analysis shows that the XRb1 gene product is highly conserved in many regions. The leucine repeat motif and many of the potential cdc2 phosphorylation sites, as well as potential sites for other kinases, are retained. The region of the protein homologous to the SV40 T antigen binding site and the basic region directly C-terminal to the E1A binding site are all conserved. XRb1 gene expression at the RNA level was studied by Northern blot analysis. Transcripts of 4.2 and 10-kb are present as maternal RNA stores in the oocyte. While the 4.2-kb product is stable until at least the mid-blastula stage, the 10-kb transcript is selectively degraded. Between stages 11 and 13 the 10-kb transcript reappears and also a minor product of approximately 11 kb becomes apparent. Both the 4.2- and the 10-kb transcripts remain present until later stages of development and are also present in all adult tissues examined, although at differing levels. Antibodies raised against human p105Rb which recognize the protein product of the XRb1 gene, pXRb1, detect the Xenopus 99-kDa protein prior to the mid-blastula stage, but at lower levels than at later stages in development.

  5. Characterization and Expression Analysis of a Retinoblastoma-Related Gene from Chinese Wild Vitis pseudoreticulata.

    Science.gov (United States)

    Wen, Zhifeng; Gao, Min; Jiao, Chen; Wang, Qian; Xu, Hui; Walter, Monika; Xu, Weirong; Bassett, Carole; Wang, Xiping

    2012-01-01

    Retinoblastoma-related (RBR) genes, a conserved gene family in higher eukaryotes, play important roles in cell differentiation, development, and mammalian cell death; however, little is known of their function in plants. In this study, a RBR gene was isolated from the Chinese wild grape, Vitis pseudoreticulata W. T. Wang clone "Baihe-35-1", and designated as VpRBR . The cDNA sequence of VpRBR was 3,030 bp and contained an open reading frame of 3,024 bp. Conceptual translation of this gene indicated a composition of 1,007 amino acids with a predicted molecular mass of 117.3 kDa. The predicted protein showed a retinoblastoma-associated protein domain A from amino acid residues 416 to 579, and domain B from residues 726 to 855. The result of expression analysis indicated that VpRBR was expressed in tissues, leaves, stem, tendrils, flower, and grape skin at different expression levels. Further quantitative reverse transcription-PCR (qRT-PCR) data indicated that VpRBR levels were higher in Erysiphe necator-treated "Baihe-35-1" and "Baihe-13-1", two resistant clones of Chinese wild V. pseudoreticulata , than in E. necator-treated "Hunan-1", a susceptible clone of V. pseudoreticulata . Furthermore, the expression of VpRBR in response to salicylic acid (SA), methyl jasmonate (MeJA), and ethylene (Eth) in grape leaves was also investigated. Taken together, these data indicate that VpRBR may contribute to some aspect of powdery mildew resistance in grape.

  6. Neonatal retinoblastoma

    Directory of Open Access Journals (Sweden)

    Tero T Kivelä

    2017-01-01

    Full Text Available From 7% to 10% of all retinoblastomas and from 44% to 71% of familial retinoblastomas in developed countries are diagnosed in the neonatal period, usually through pre- or post-natal screening prompted by a positive family history and sometimes serendipitously during screening for retinopathy of prematurity or other reasons. In developing countries, neonatal diagnosis of retinoblastoma has been less common. Neonatal retinoblastoma generally develops from a germline mutation of RB1, the retinoblastoma gene, even when the family history is negative and is thus usually hereditary. At least one-half of infants with neonatal retinoblastoma have unilateral tumors when the diagnosis is made, typically the International Intraocular Retinoblastoma Classification (Murphree Group B or higher, but most germline mutation carriers will progress to bilateral involvement, typically Group A in the fellow eye. Neonatal leukokoria usually leads to the diagnosis in children without a family history of retinoblastoma, and a Group C tumor or higher is typical in the more advanced involved eye. Almost all infants with neonatal retinoblastoma have at least one eye with a tumor in proximity to the foveola, but the macula of the fellow eye is frequently spared. Consequently, loss of reading vision from both eyes is exceptional. A primary ectopic intracranial neuroblastic tumor known as trilateral retinoblastoma is no more common after neonatal than other retinoblastoma. For many reasons, neonatal retinoblastoma may be a challenge to eradicate, and the early age at diagnosis and relatively small tumors do not guarantee the preservation of both eyes of every involved child. Oncology nurses can be instrumental in contributing to better outcomes by ensuring that hereditary retinoblastoma survivors receive genetic counseling, by referring families of survivors to early screening programs when they are planning for a baby, and by providing psychological and practical support

  7. Retinoblastoma: genetics, diagnosis, treatment and sequelae

    International Nuclear Information System (INIS)

    Halperin, Edward C.

    1995-01-01

    There has been a conceptual breakthrough in our understanding of the molecular and genetic basis of the origins of human neoplasia. Mutations in three broad categories of genes have been shown to contribute to the origins and progression of neoplasia in humans: the oncogenes, the tumor suppressor genes, and the mutator genes. The retinoblastoma gene (RB1) is the best characterized tumor suppressor gene. It was first localized by Knudson and coworkers who observed an association between a deletion on the long arm of chromosome 13 and an inherited predisposition to retinoblastoma. The RB1 gene is composed of 27 exons encompassing more than 200 kilobases of genomic DNA. The product of the RB1 gene is a 105-107 kDa nuclear phosphoprotein which plays a part in regulating cellular DNA synthesis. Tumors arise, as predicted by Knudson's 'two-hit' hypothesis, as a result of bi-allelic mutation of the RB1 gene. Inactivating mutations of the RB1 gene have been identified in various tumors, showing the RB1 gene product has an important role in regulating cell proliferation beyond its effect on retinoblasts. The RB1 gene was cloned and identified in 1986. Returning the RB1 gene to a retinoblastoma cell in culture reduces its tumorgenic potential. Retinoblastoma is the most common malignant intraocular tumor of childhood. The tumor consists of undifferentiated small anaplastic cells which may be round or polygonal. Both Flexner and Wintersteiner described the arrangement of the more differentiated malignant retinoblastoma cells in neuroepithelial rosettes which appear to represent an attempt to differentiate into photoreceptor cells. The tumor commonly presents with a white pupillary light reflex. The diagnosis is generally made based on physical examination, confirmatory photographs and diagnostic imaging studies and, in many cases, a supportive family history. The most widely used grouping system was proposed by Algernon Reese and Robert Ellsworth. The primary goal of

  8. Abnormalities in structure and expression of the retinoblastoma gene in small cell lung cancer cell lines and xenografts in nude mice

    DEFF Research Database (Denmark)

    Rygaard, K; Sorenson, G D; Pettengill, O S

    1990-01-01

    The putative retinoblastoma gene (Rb) is a tumor suppressor gene which is believed to cause retinoblastomas when both alleles are inactivated, leading to lack of the encoded Mr 110,000-116,000 phosphoprotein. Inactivation of the Rb gene has also been found in several other tumor types, including...

  9. Retinoblastoma: Genetics, diagnosis, treatment and sequelae

    International Nuclear Information System (INIS)

    Halperin, Edward C.

    1996-01-01

    There has been a conceptual breakthrough in our understanding of the molecular and genetic basis of the origins of human neoplasia. Mutations in three broad categories of genes have been shown to contribute to the origins and progression of neoplasia in humans: the oncogenes, the tumor suppressor genes, and the mutator genes. The retinoblastoma gene (RB1) is the best characterized tumor suppressor gene. It was first localized by Knudson and coworkers who observed an association between a deletion on the long arm of chromosome 13 and an inherited predisposition to retinoblastoma. The RB1 gene is composed of 27 exons encompassing more than 200 kilobases of genomic DNA. The product of the RB1 gene is a 105-107 kDa nuclear phosphoprotein which plays a part in regulating cellular DNA synthesis. Tumors arise, as predicted by Knudson's 'two-hit' hypothesis, as a result of biallelic mutation of the RB1 gene. Inactivating mutations of the RB1 gene have been identified in various tumors, showing the RB1 gene product has an important role in regulating cell proliferation beyond its effect on retinoblasts. The RB1 gene was cloned and identified in 1986. Returning the RB1 gene to a retinoblastoma cell in culture reduces its tumorgenic potential. Retinoblastoma is the most common malignant intraocular tumor of childhood. The tumor consists of undifferentiated small anaplastic cells which may be round or polygonal. Both Flexner and Wintersteiner described the arrangement of the more differentiated malignant retinoblastoma cells in neuroepithelial rosettes which appear to represent an attempt to differentiate into photoreceptor cells. The tumor commonly presents with a white pupillary light reflex. The diagnosis is generally made based on physical examination, confirmatory photographs and diagnostic imaging studies and, in many cases, a supportive family history. The most widely used grouping system was proposed by Algernon Reese and Robert Ellsworth. The primary goal of

  10. A transgenic mouse model for trilateral retinoblastoma

    NARCIS (Netherlands)

    O'Brien, J.M.; Marcus, D.M.; Bernards, R.A.; Carpenter, J.L.; Windle, J.J.; Mellon, P.; Albert, D.M.

    1990-01-01

    We present a murine model of trilateral retinoblastoma. Ocular retinoblastoma and central nervous system tumors are observed in a line of mice formed by the transgenic expression of SV40 T-antigen. An oncogenic protein known to bind to the retinoblastoma gene product (p105-Rb) is specifically

  11. Transcriptional regulatory program in wild-type and retinoblastoma gene-deficient mouse embryonic fibroblasts during adipocyte differentiation

    DEFF Research Database (Denmark)

    Hakim-Weber, Robab; Krogsdam, Anne-M; Jørgensen, Claus

    2011-01-01

    Although many molecular regulators of adipogenesis have been identified a comprehensive catalogue of components is still missing. Recent studies showed that the retinoblastoma protein (pRb) was expressed in the cell cycle and late cellular differentiation phase during adipogenesis. To investigate...... this dual role of pRb in the early and late stages of adipogenesis we used microarrays to perform a comprehensive systems-level analysis of the common transcriptional program of the classic 3T3-L1 preadipocyte cell line, wild-type mouse embryonic fibroblasts (MEFs), and retinoblastoma gene-deficient MEFs...... of experimental data and computational analyses pinpointed a feedback-loop between Pparg and Foxo1.To analyze the effects of the retinoblastoma protein at the transcriptional level we chose a perturbated system (Rb-/- MEFs) for comparison to the transcriptional program of wild-type MEFs. Gene ontology analysis...

  12. Alteration of plant meristem function by manipulation of the Retinoblastoma-like plant RRB gene

    Science.gov (United States)

    Durfee, Tim [Madison, WI; Feiler, Heidi [Albany, CA; Gruissem, Wilhelm [Forch, CH; Jenkins, Susan [Martinez, CA; Roe, Judith [Manhattan, KS; Zambryski, Patricia [Berkeley, CA

    2007-01-16

    This invention provides methods and compositions for altering the growth, organization, and differentiation of plant tissues. The invention is based on the discovery that, in plants, genetically altering the levels of Retinoblastoma-related gene (RRB) activity produces dramatic effects on the growth, proliferation, organization, and differentiation of plant meristem.

  13. Multifocal osteosarcoma as second tumor after childhood retinoblastoma

    International Nuclear Information System (INIS)

    Potepan, P.; Laffranchi, A.; Danesini, G.M.; Spagnoli, I.; Luksch, R.; Sozzi, G.; Testi, A.; Parafioriti, A.; Giardini, R.

    1999-01-01

    We present a case of multifocal osteosarcoma (MFOS) arising 11.5 years after successful treatment of bilateral retinoblastoma. The clinical, imaging and pathological findings at onset, after therapy, and during follow-up are described. Fluorescent in situ hybridization did not reveal a deletion of the RB-1 retinoblastoma gene, although the presence of an inactivating mutation invisible to this method cannot be ruled out. The MFOS may have been a second multifocal tumor associated with the original retinoblastoma or a post-irradiation sarcoma with extensive metastases. (orig.)

  14. Adenocarcinoma of the ethmoid following radiotherapy for bilateral retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Rowe, L.D.; Lane, R.; Snow, J.B. Jr.

    1980-01-01

    Adenocarcinoma of the ethmoid sinus is rare, representing only 4 to 8% of malignancies of the paranasal sinuses. An extraordinary case of papillary adenocarcinoma of the ethmoid sinus arising 30 years following high-dose radiotherapy for bilateral retinoblastoma is presented. Second fatal mesenchymal and epithelial primaries have been described in 8.5% of patients with bilateral retinoblastomas previously treated with radiotherapy; however, papillary adenocarcinoma arising within the paranasal sinuses has not been reported. Aggressive treatment including partial maxillectomy, radical pansinusectomy, radical neck dissection followed by regional radiotherapy and systemic chemotherapy failed to prevent the development of fatal hepatic metastases. The high incidence of second fatal primary neoplasms in patients with bilateral retinoblastomas receiving radiation suggests an innate susceptibility that may add to the risk of radiotherapy.

  15. Adenocarcinoma of the ethmoid following radiotherapy for bilateral retinoblastoma

    International Nuclear Information System (INIS)

    Rowe, L.D.; Lane, R.; Snow, J.B. Jr.

    1980-01-01

    Adenocarcinoma of the ethmoid sinus is rare, representing only 4 to 8% of malignancies of the paranasal sinuses. An extraordinary case of papillary adenocarcinoma of the ethmoid sinus arising 30 years following high-dose radiotherapy for bilateral retinoblastoma is presented. Second fatal mesenchymal and epithelial primaries have been described in 8.5% of patients with bilateral retinoblastomas previously treated with radiotherapy; however, papillary adenocarcinoma arising within the paranasal sinuses has not been reported. Aggressive treatment including partial maxillectomy, radical pansinusectomy, radical neck dissection followed by regional radiotherapy and systemic chemotherapy failed to prevent the development of fatal hepatic metastases. The high incidence of second fatal primary neoplasms in patients with bilateral retinoblastomas receiving radiation suggests an innate susceptibility that may add to the risk of radiotherapy

  16. A retinoblastoma orthologue is a major regulator of S-phase, mitotic, and developmental gene expression in Dictyostelium.

    Directory of Open Access Journals (Sweden)

    Kimchi Strasser

    Full Text Available The retinoblastoma tumour suppressor, Rb, has two major functions. First, it represses genes whose products are required for S-phase entry and progression thus stabilizing cells in G1. Second, Rb interacts with factors that induce cell-cycle exit and terminal differentiation. Dictyostelium lacks a G1 phase in its cell cycle but it has a retinoblastoma orthologue, rblA.Using microarray analysis and mRNA-Seq transcriptional profiling, we show that RblA strongly represses genes whose products are involved in S phase and mitosis. Both S-phase and mitotic genes are upregulated at a single point in late G2 and again in mid-development, near the time when cell cycling is reactivated. RblA also activates a set of genes unique to slime moulds that function in terminal differentiation.Like its mammalian counterpart Dictyostelium, RblA plays a dual role, regulating cell-cycle progression and transcriptional events leading to terminal differentiation. In the absence of a G1 phase, however, RblA functions in late G2 controlling the expression of both S-phase and mitotic genes.

  17. Transcriptional inhibition by the retinoblastoma protein

    DEFF Research Database (Denmark)

    Fattaey, A; Helin, K; Harlow, E

    1993-01-01

    The retinoblastoma protein, pRB, appears to play a key role in coordinating the regulation of cell cycle position and transcriptional events. pRB undergoes specific cell-cycle-dependent phosphorylation, being underphosphorylated in G1 and heavily phosphorylated in S, G2, and M. The underphosphory......The retinoblastoma protein, pRB, appears to play a key role in coordinating the regulation of cell cycle position and transcriptional events. pRB undergoes specific cell-cycle-dependent phosphorylation, being underphosphorylated in G1 and heavily phosphorylated in S, G2, and M......-mediated transcription would be lost by mutation in the retinoblastoma gene in human tumours, by pRB's interaction with DNA tumour virus oncoproteins, or by phosphorylation during the cell cycle....

  18. Global issues and opportunities for optimized retinoblastoma care.

    Science.gov (United States)

    Gallie, Brenda L; Zhao, Junyang; Vandezande, Kirk; White, Abigail; Chan, Helen S L

    2007-12-01

    The RB1 gene is important in all human cancers. Studies of human retinoblastoma point to a rare retinal cell with extreme dependency on RB1 for initiation but not progression to full malignancy. In developed countries, genetic testing within affected families can predict children at high risk of retinoblastoma before birth; chemotherapy with local therapy often saves eyes and vision; and mortality is 4%. In less developed countries where 92% of children with retinoblastoma are born, mortality reaches 90%. Global collaboration is building for the dramatic change in mortality that awareness, simple expertise and therapies could achieve in less developed countries. Copyright 2007 Wiley-Liss, Inc.

  19. Expression and clinical significance of Pax6 gene in retinoblastoma

    Directory of Open Access Journals (Sweden)

    Hai-Dong Huang

    2013-07-01

    Full Text Available AIM: To discuss the expression and clinical significance of Pax6 gene in retinoblastoma(Rb. METHODS: Totally 15 cases of fresh Rb organizations were selected as observation group and 15 normal retinal organizations as control group. Western-Blot and reverse transcriptase polymerase chain reaction(RT-PCRmethods were used to detect Pax6 protein and Pax6 mRNA expressions of the normal retina organizations and Rb organizations. At the same time, Western Blot method was used to detect the Pax6 gene downstream MATH5 and BRN3b differentiation gene protein level expression. After the comparison between two groups, the expression and clinical significance of Pax6 gene in Rb were discussed. RESULTS: In the observation group, average value of mRNA expression of Pax6 gene was 0.99±0.03; average value of Pax6 gene protein expression was 2.07±0.15; average value of BRN3b protein expression was 0.195±0.016; average value of MATH5 protein expression was 0.190±0.031. They were significantly higher than the control group, and the differences were statistically significant(PCONCLUSION: Abnormal expression of Pax6 gene is likely to accelerate the occurrence of Rb.

  20. Retinoblastoma

    International Nuclear Information System (INIS)

    Schipper, J.

    1980-01-01

    Retinoblastoma is a rare, highly malignant tumour of the retina which predominantly affects young children. The growth originates from single or multiple foci in the retina of one or both eyes. The tumour may occur either sporadically or may be inherited. Retinoblastoma is extra-ordinary in its medical, genetic and therapeutic significance. The irradiation method which has been used for the conservative treatment of retinoblastoma at Utrecht since 1971 is described. Treatment is carried out on a 6 MeV or 8 MeV linear accelerator using a lateral D-shaped field of 26x32 mm 2 . This D-shaped field is especially contoured to irradiate the entire retina with sparing of the radiosensitive lens as much as possible. Between 1971 and 1980, 30 children with retinoblastoma have received irradiation to at least one eye using the accurate irradiation technique. The results of treatment of these patients are presented. In the treatment it is not always possible to entirely exclude the lens from the treatment field. As a consequence, cataract may be induced. (Auth.)

  1. The genetic alteration of retinoblastoma gene in esophageal cancer

    International Nuclear Information System (INIS)

    Cho, Jae Il; Shim, Yung Mok; Kim, Chang Min

    1994-12-01

    Retinoblastoma(RB) gene is the prototype of tumor suppressor gene and it's alteration have been frequently observed in a large number of human tumors. To investigate the role of RB in esophageal cancer, we studied 36 esophageal cancer tissues with Southern blot analysis to detect gross LOH and PCR-SSCP method to find minute LOH and mutation, if any. In the cases with abnormalities, the nucleotide sequence analysis was performed. Allelic loss of chromosome 13q14 occurred in 20 out of 32 informative cases (62.5%) by Southern analysis. Furthermore, PCR-LOH added three positive cases. Mobility shift by PCR-SSCP was observed in one case at exon 22, which showed 1 bp deletion in codon 771 of RB gene resulting in frame shift mutation. Besides, nine PCR-band alteration in tumor tissue compared with normal tissue were observed in exon 14 and 22, but mutation was not found on sequencing analysis suggesting the epigenetic alteration in tumor tissue. Analysis of the clinical data did not show any difference depending upon RB alteration. However, the total incidence of RB gene may play an important role in the development of esophageal cancer. The main genetic alteration of RB gene was deletion detected by Southern blot and one bp deletion leading to frame shift was also observed. 8 figs, 5 tabs. (Author)

  2. The genetic alteration of retinoblastoma gene in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Cho, Jae Il; Shim, Yung Mok; Kim, Chang Min [Korea Cancer Center Hospital of Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

    1994-12-01

    Retinoblastoma(RB) gene is the prototype of tumor suppressor gene and it`s alteration have been frequently observed in a large number of human tumors. To investigate the role of RB in esophageal cancer, we studied 36 esophageal cancer tissues with Southern blot analysis to detect gross LOH and PCR-SSCP method to find minute LOH and mutation, if any. In the cases with abnormalities, the nucleotide sequence analysis was performed. Allelic loss of chromosome 13q14 occurred in 20 out of 32 informative cases (62.5%) by Southern analysis. Furthermore, PCR-LOH added three positive cases. Mobility shift by PCR-SSCP was observed in one case at exon 22, which showed 1 bp deletion in codon 771 of RB gene resulting in frame shift mutation. Besides, nine PCR-band alteration in tumor tissue compared with normal tissue were observed in exon 14 and 22, but mutation was not found on sequencing analysis suggesting the epigenetic alteration in tumor tissue. Analysis of the clinical data did not show any difference depending upon RB alteration. However, the total incidence of RB gene may play an important role in the development of esophageal cancer. The main genetic alteration of RB gene was deletion detected by Southern blot and one bp deletion leading to frame shift was also observed. 8 figs, 5 tabs. (Author).

  3. IVF and retinoblastoma revisited

    NARCIS (Netherlands)

    Dommering, Charlotte J.; van der Hout, Annemarie H.; Meijers-Heijboer, Hanne; Marees, Tamara; Moll, Annette C.

    2012-01-01

    Objective: To evaluate the suggested association between IVF, retinoblastoma, and tumor methylation characteristics. Design: Laboratory analysis. Setting: National Retinoblastoma Center in the Netherlands. Patient(s): Retinoblastoma tumors from seven children conceived by IVF or intracytoplasmic

  4. IVF and retinoblastoma revisited

    NARCIS (Netherlands)

    Dommering, Charlotte J.; van der Hout, Annemarie H.; Meijers-Heijboer, Hanne; Marees, Tamara; Moll, Annette C.

    Objective: To evaluate the suggested association between IVF, retinoblastoma, and tumor methylation characteristics. Design: Laboratory analysis. Setting: National Retinoblastoma Center in the Netherlands. Patient(s): Retinoblastoma tumors from seven children conceived by IVF or intracytoplasmic

  5. Haploinsufficiency of the retinoblastoma protein gene reduces diet-induced obesity, insulin resistance, and hepatosteatosis in mice

    DEFF Research Database (Denmark)

    Mercader, Josep; Ribot, Joan; Murano, Incoronata

    2009-01-01

    Brown adipose tissue activity dissipates energy as heat, and there is evidence that lack of the retinoblastoma protein (pRb) may favor the development of the brown adipocyte phenotype in adipose cells. In this work we assessed the impact of germ-line haploinsufficiency of the pRb gene (Rb) on the...... first evidence that partial deficiency in the Rb gene protects against the development of obesity and associated metabolic disturbances. Key words: brown adipose tissue, white adipose tissue, energy metabolism, genetic animal model....

  6. Retinoblastoma

    International Nuclear Information System (INIS)

    Desjardins, L.; Doz, F.; Schlienger, P.; Validire, P.; Quintana, E.; Zucker, J.M.

    1996-01-01

    Early symptoms of retinoblastoma (leukocoria, strabismus) and the various steps of the diagnosis and differential diagnosis are reviewed. Retrolental fibroplasia, larva migrans, Coats disease, and above all uveitis are the main differential diagnoses. Pathologic features that allow the diagnosis and have a bearing on the prognosis are described. Genetic factors involved in the genesis of retinoblastoma are reviewed, including recent data provides by molecular biology studies of chromosome 13. Currently available treatments include enucleation, external beam radiation, iodine-125 disks, xenon photo-coagulation, cryo-application, chemotherapy, and carbo-platinum combined with diode laser hyperthermia. The indications of each of these methods in intra- and extra-ocular retinoblastomas are discussed, as well as results and complications. Emphasis is put on the high risk of a second cancer. 47 refs., 4 figs

  7. Retinoblastoma – to expand awareness

    African Journals Online (AJOL)

    lead to delay in diagnosis, possibly loss of vision or even loss of life. Both the public and ... These retinoblastomas show altered gene copy number ... and an examination under anaesthesia, in which the number, size and location ... effects than external beam radiotherapy but is not ... attention to arrival at the unit. Advanced.

  8. Conserved retinoblastoma protein-binding motif in human cytomegalovirus UL97 kinase minimally impacts viral replication but affects susceptibility to maribavir

    Directory of Open Access Journals (Sweden)

    Chou Sunwen

    2009-01-01

    Full Text Available Abstract The UL97 kinase has been shown to phosphorylate and inactivate the retinoblastoma protein (Rb and has three consensus Rb-binding motifs that might contribute to this activity. Recombinant viruses containing mutations in the Rb-binding motifs generally replicated well in human foreskin fibroblasts with only a slight delay in replication kinetics. Their susceptibility to the specific UL97 kinase inhibitor, maribavir, was also examined. Mutation of the amino terminal motif, which is involved in the inactivation of Rb, also renders the virus hypersensitive to the drug and suggests that the motif may play a role in its mechanism of action.

  9. Rabbit Model of Retinoblastoma

    Directory of Open Access Journals (Sweden)

    Shin Jeong Kang

    2011-01-01

    Full Text Available We created a rabbit model of retinoblastoma and confirmed the tumor clinically and histopathologically. Seventeen New Zealand rabbits were immunosuppressed with cyclosporin A at doses of 10–15 mg/kg. At day 3, the animals received a 30 μl subretinal injection of 1×106 cultured WERI retinoblastoma cells. Digital fundus images were captured before euthanasia, and the eyes were submitted for histopathology. Retinoblastoma cells grew in all the inoculated eyes and established a tumor under the retina and/or in the vitreous. New blood vessels in the tumor were observed starting at week 5. Cuffs of viable tumor cells surrounded the blood vessels with regions of necrosis present at 70–80 μm from nutrient vessels. Occasional tumor seeds in the vitreous histologically exhibited central necrosis. This rabbit model demonstrated similar fundus appearance and pathologic features to human retinoblastoma and may be used as a model to test various routes of drug delivery for retinoblastoma.

  10. Susceptibility Genes in Thyroid Autoimmunity

    Directory of Open Access Journals (Sweden)

    Yoshiyuki Ban

    2005-01-01

    Full Text Available The autoimmune thyroid diseases (AITD are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD and Hashimoto's thyroiditis (HT and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4 and thyroid specific genes (e.g. TSHR, Tg. Most likely, these loci interact and their interactions may influence disease phenotype and severity.

  11. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-01-01

    From 1971--1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ-rays or JANUS fission-spectrum neutrons. Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice were analyzed for mRb deletions. In all normal mouse tissues studies all six mRb exon fragments were present on Southern blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, 1 of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  12. Analysis of MDM2 and MDM4 single nucleotide polymorphisms, mRNA splicing and protein expression in retinoblastoma.

    Directory of Open Access Journals (Sweden)

    Justina McEvoy

    Full Text Available Retinoblastoma is a childhood cancer of the developing retina that begins in utero and is diagnosed in the first years of life. Biallelic RB1 gene inactivation is the initiating genetic lesion in retinoblastoma. The p53 gene is intact in human retinoblastoma but the pathway is believed to be suppressed by increased expression of MDM4 (MDMX and MDM2. Here we quantify the expression of MDM4 and MDM2 mRNA and protein in human fetal retinae, primary retinoblastomas, retinoblastoma cell lines and several independent orthotopic retinoblastoma xenografts. We found that MDM4 is the major p53 antagonist expressed in retinoblastoma and in the developing human retina. We also discovered that MDM4 protein steady state levels are much higher in retinoblastoma than in human fetal retinae. This increase would not have been predicted based on the mRNA levels. We explored several possible post-transcriptional mechanisms that may contribute to the elevated levels of MDM4 protein. A proportion of MDM4 transcripts are alternatively spliced to produce protein products that are reported to be more stable and oncogenic. We also discovered that a microRNA predicted to target MDM4 (miR191 was downregulated in retinoblastoma relative to human fetal retinae and a subset of samples had somatic mutations that eliminated the miR-191 binding site in the MDM4 mRNA. Taken together, these data suggest that post-transcriptional mechanisms may contribute to stabilization of the MDM4 protein in retinoblastoma.

  13. The retinoblastoma protein as a transcriptional repressor

    DEFF Research Database (Denmark)

    Helin, K; Ed, H

    1993-01-01

    The retinoblastoma protein (pRB) is one of the best-studied tumour suppressor gene products. Its loss during the genesis of many human tumours, its inactivation by several DNA tumour virus oncoproteins, and its ability to inhibit cell growth when introduced into dividing cells all suggest that p...

  14. Experimental Model to Study the Role of Retinoblastoma Gene Product (pRb) for Determination of Adipocyte Differentiation.

    Science.gov (United States)

    Popov, B V; Shilo, P S; Zhidkova, O V; Zaichik, A M; Petrov, N S

    2015-06-01

    Using stable constitutive expression of retinoblastoma gene product (pRb) in polypotent mesenchymal 10T1/2 cells we obtained stable cell lines hyperexpressing functionally active or inactive mutant pRb. The cells producing active exogenous pRb demonstrated high sensitivity to adipocyte differentiation inductors, whereas production of inactive form of the exogenous protein suppressed adipocyte differentiation. The obtained lines can serve as the experimental model for studying the role of pRb in determination of adipocyte differentiation.

  15. Polymerase chain reaction detection of retinoblastoma gene deletions in paraffin-embedded mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1991-01-01

    A Polymerase chain reaction (PCR) technique was used to detect deletions in the mouse retinoblastoma (mRb) gene using microtomed sections from paraffin-embedded radiation-induced and spontaneous tumors as the DNA source. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. Absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mRb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons) were analyzed. Tumors in six neutron-irradiated mice also had no mRb deletions. However, one of six tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice showed a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  16. Current treatment of retinoblastoma

    International Nuclear Information System (INIS)

    Shields, J.A.

    1985-01-01

    Retinoblastoma is a highly malignant intraocular tumor of childhood which requires prompt treatment once the diagnosis has been established. The traditionally accepted methods include enucleation, external irradiation, scleral plaque irradiation, photocoagulation, cryotherapy, chemotherapy. This article will provide an update on the modern methods of treatment which are available for retinoblastoma. It is based largely on personal experience with approximately 200 new patients with retinoblastoma who were evaluated and treated between 1974 and 1984 in the Oncology Service of Wills Eye Hospital with an overall survival of 97%. This article will be an overall review which will not go into statistical detail. (Auth.)

  17. Radiotherapy and genetic susceptibility to cancer in a cohort of retinoblastoma patients

    International Nuclear Information System (INIS)

    Kleinerman, R. A.; Abranson, D. H.; Seddon, J. M.; Stovall, M.; Tucker, M. A.

    2004-01-01

    High-dose radiotherapy for retinoblastoma, a rare childhood cancer of the eye caused by a germline mutation in the RB-1 gene, has been associated with an increased risk of sarcomas, predominantly in the head and neck region, in childhood and adolescence. Many RB patients are cured and survive into adulthood. It is important to quantify their risk of adult-onset cancers, because somatic mutations in the RB-1 gene are common in the pathways of several epithelial cancers that typically occur in adults. We have been studying a large cohort of 1601 RB survivors, who were diagnosed 1914-84 at two medical centers, to identify the risk of second cancers and evaluate the interaction between radiation and genetic factors that may modify these risks. Most of the RB patients were diagnosed at one year of age or younger, 80% of the hereditary patients and 20% of the sporadic patients received radiotherapy for RB. A typical radiation treatment in the 1970s consisted of 45 Gy to the entire retina delivered in 15 fractions over several weeks. At last follow up, 20% of the cohort was 40 years of age and older, an age at which cancer rates begin to rise in the general population. We ascertained the incidence of new cancers through 2001 and compared the observed number of cancers in the cohort to the expected number of cancers estimated from age, sex and calendar year-specific cancer incidence rates from the U. S. We calculated the excess risk (ER) of cancer per 1,000 person years (observed minus expected number of cancers/person years at risk time 1000). The excess risk of second cancers in 963 hereditary patients (ER=9.3) exceeded the risk in the 638 sporadic patients (Excess risk=0.06). Substantially higher risks of second cancers were noted for irradiated (ER=10.1) compared to non-irradiated, hereditary patients (ER=4.5). Increased risks likely related to radiation were observed for cancers of the bone, soft tissue, brain, nasal cavities, and eye and orbit. Newly identified

  18. Computed tomography of retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Lindahl, S.

    Retinoblastoma is the most common primary malignant intraocular tumor in children. The clinical features are leucocoria and/or strabismus. The ophthalmic diagnosis is straight forward in clear eye media with a white gray mass in the fundus. With opaque ocular media, other diagnostic procedures such as CT and ultrasonography are important. In the present study the results of CT examinations of 23 patients with histologically proven retinoblastomas are presented. The mean age of the patients was two years. The characteristic CT finding is a partly calcified intravitreous mass lesion mostly confined within the eyeball. Two cases showed retrobulbar extension and two intracranical tumor extension. No metastasis was found in the brain, liver, spleen, long bones, chest or skull. The radiologic screening procedures for retinoblastoma metastasis are discussed. In patients suspected to have a retinoblastoma, it is recommended to perform CT of the orbits and brain in order to detect the tumor and its possible retrobulbar and intracranial extension.

  19. Computed tomography of retinoblastoma

    International Nuclear Information System (INIS)

    Lindahl, S.

    1986-01-01

    Retinoblastoma is the most common primary malignant intraocular tumor in children. The clinical features are leucocoria and/or strabismus. The ophthalmic diagnosis is straight forward in clear eye media with a white gray mass in the fundus. With opaque ocular media, other diagnostic procedures such as CT and ultrasonography are important. In the present study the results of CT examinations of 23 patients with histologically proven retinoblastomas are presented. The mean age of the patients was two years. The characteristic CT finding is a partly calcified intravitreous mass lesion mostly confined within the eyeball. Two cases showed retrobulbar extension and two intracranical tumor extension. No metastasis was found in the brain, liver, spleen, long bones, chest or skull. The radiologic screening procedures for retinoblastoma metastasis are discussed. In patients suspected to have a retinoblastoma, it is recommended to perform CT of the orbits and brain in order to detect the tumor and its possible retrobulbar and intracranial extension. (orig.)

  20. BTG interacts with retinoblastoma to control cell fate in Dictyostelium.

    Directory of Open Access Journals (Sweden)

    Daniele Conte

    Full Text Available BACKGROUND: In the genesis of many tissues, a phase of cell proliferation is followed by cell cycle exit and terminal differentiation. The latter two processes overlap: genes involved in the cessation of growth may also be important in triggering differentiation. Though conceptually distinct, they are often causally related and functional interactions between the cell cycle machinery and cell fate control networks are fundamental to coordinate growth and differentiation. A switch from proliferation to differentiation may also be important in the life cycle of single-celled organisms, and genes which arose as regulators of microbial differentiation may be conserved in higher organisms. Studies in microorganisms may thus contribute to understanding the molecular links between cell cycle machinery and the determination of cell fate choice networks. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that in the amoebozoan D. discoideum, an ortholog of the metazoan antiproliferative gene btg controls cell fate, and that this function is dependent on the presence of a second tumor suppressor ortholog, the retinoblastoma-like gene product. Specifically, we find that btg-overexpressing cells preferentially adopt a stalk cell (and, more particularly, an Anterior-Like Cell fate. No btg-dependent preference for ALC fate is observed in cells in which the retinoblastoma-like gene has been genetically inactivated. Dictyostelium btg is the only example of non-metazoan member of the BTG family characterized so far, suggesting that a genetic interaction between btg and Rb predated the divergence between dictyostelids and metazoa. CONCLUSIONS/SIGNIFICANCE: While the requirement for retinoblastoma function for BTG antiproliferative activity in metazoans is known, an interaction of these genes in the control of cell fate has not been previously documented. Involvement of a single pathway in the control of mutually exclusive processes may have relevant implication in the

  1. Characterization of the retinoblastoma binding proteins RBP1 and RBP2

    DEFF Research Database (Denmark)

    Fattaey, A R; Helin, K; Dembski, M S

    1993-01-01

    The retinoblastoma gene product, pRB, regulates cell proliferation by binding to and inhibiting the activity of key growth promoting proteins. Several cellular proteins have been shown to bind directly to pRB and the genes encoding a number of them have been isolated. The protein product of one...

  2. modes of presentation, management and outcome of retinoblastoma

    African Journals Online (AJOL)

    SITWALA COMPUTERS

    and short-term outcomes of retinoblastoma treatment at ... incidence of retinoblastoma during the HIV period. Apart .... differentiated retinoblastoma. .... The Zambian health delivery ... the guardian from home and the extra cost of hospital stay.

  3. Repression of germline RNAi pathways in somatic cells by retinoblastoma pathway chromatin complexes.

    Directory of Open Access Journals (Sweden)

    Xiaoyun Wu

    Full Text Available The retinoblastoma (Rb tumor suppressor acts with a number of chromatin cofactors in a wide range of species to suppress cell proliferation. The Caenorhabditis elegans retinoblastoma gene and many of these cofactors, called synMuv B genes, were identified in genetic screens for cell lineage defects caused by growth factor misexpression. Mutations in many synMuv B genes, including lin-35/Rb, also cause somatic misexpression of the germline RNA processing P granules and enhanced RNAi. We show here that multiple small RNA components, including a set of germline-specific Argonaute genes, are misexpressed in the soma of many synMuv B mutant animals, revealing one node for enhanced RNAi. Distinct classes of synMuv B mutants differ in the subcellular architecture of their misexpressed P granules, their profile of misexpressed small RNA and P granule genes, as well as their enhancement of RNAi and the related silencing of transgenes. These differences define three classes of synMuv B genes, representing three chromatin complexes: a LIN-35/Rb-containing DRM core complex, a SUMO-recruited Mec complex, and a synMuv B heterochromatin complex, suggesting that intersecting chromatin pathways regulate the repression of small RNA and P granule genes in the soma and the potency of RNAi. Consistent with this, the DRM complex and the synMuv B heterochromatin complex were genetically additive and displayed distinct antagonistic interactions with the MES-4 histone methyltransferase and the MRG-1 chromodomain protein, two germline chromatin regulators required for the synMuv phenotype and the somatic misexpression of P granule components. Thus intersecting synMuv B chromatin pathways conspire with synMuv B suppressor chromatin factors to regulate the expression of small RNA pathway genes, which enables heightened RNAi response. Regulation of small RNA pathway genes by human retinoblastoma may also underlie its role as a tumor suppressor gene.

  4. Retinoblastoma: a most unusual presentation

    African Journals Online (AJOL)

    Dr. C. Pedro-Egbe

    Although leukocoria and strabismus are the most common presenting signs of retinoblastoma, a retrospective study by Abramson et al. identified 32 distinct presenting signs of retinoblastoma.6-8. A few other studies have also noted some distinct characteristics exhibited by children whose conditions were diagnosed in the ...

  5. Diffuse Anterior Retinoblastoma with Sarcoidosis-Like Nodule

    Directory of Open Access Journals (Sweden)

    Koji Kitazawa

    2015-12-01

    Full Text Available Background: Retinoblastomas account for 4% of malignancies in children, 1-2% of which are diffuse infiltrating retinoblastomas. Diffuse anterior retinoblastoma is rare and does not involve the retina. Here, we report on a diffuse anterior retinoblastoma with large sarcoidosis-like nodules on the iris that were responsive to anti-inflammatory therapy. Case: We present a 6-year-old girl who had anterior uveitis with white nodules on the iris and posterior surface of the cornea in her right eye. The nodules initially responded well to anti-inflammatory treatment. However, anterior segment optical coherence tomography (AS-OCT showed that the nodules gradually grew, shrinking the iris. We then collected the aqueous humor for diagnosis. A biopsy revealed clusters of small cells with a high nuclear-to-cytoplasm ratio with partial rosette formation. Therefore, we diagnosed diffuse anterior retinoblastoma without retinal involvement and performed enucleation of the right eye. The histopathology demonstrated undifferentiated cells similar to those seen on the biopsy, and tumor cells invaded the iris stroma, posterior surface of the cornea, ciliary body, and sclera. After the enucleation, she underwent chemotherapy and remains alive. Conclusion: A differential diagnosis of retinoblastoma should be considered when white nodules refractory to anti-inflammatory therapy occur in the eye, even in the absence of obvious retinal masses. AS-OCT findings are useful in assessing retinoblastoma.

  6. New research progress of microRNAs in retinoblastoma

    Directory of Open Access Journals (Sweden)

    Jing Zeng

    2014-11-01

    Full Text Available Retinoblastoma(RBis the most common intraocular malignancy of children with extremely poor prognosis. MicroRNAs are small non-coding single-stranded RNAs in eukaryotic cells, which regulate the expression of gene by mRNA degradation or translation inhibition. MicroRNAs, acting as oncogenes or tumor suppressor genes, are associated with the occurrence and development of RB directly, which is vital for the early diagnosis and clinical targeted therapy of RB. This review summarized the expression of microRNAs in RB and the related mechanism.

  7. Irradiation sequels of retinoblastomas

    International Nuclear Information System (INIS)

    Benk, V.; Habrand, J.L.; Bloch Michel, E.; Soussaline, M.; Sarrazin, D.

    1993-01-01

    From 1975 to 1985, 34 children with a non-metastatic retinoblastoma were irradiated at the Institut Gustave-Roussy. After enucleation, 19 bilateral tumors were irradiated by two lateral opposed fields and 15 unilateral tumors by one lateral and anterior field, in the case of optic nerve being histologically positive. Dose was 45 Gy, 1.8 Gy per fraction. The 10-year-survival rate for unilateral and bilateral retinoblastomas was 79%. Long term sequels were available for 25 patients: 88% retained one functional eye. Three children with bilateral retinoblastomas developed a cataract in the residual eye between 2 and 5 years after irradiation, none with unilateral tumor. Nine patients (36%), seven with unilateral and two with bilateral tumor developed a cosmetical problem that required multiple surgical rehabilitation between 3 and 14 years after irradiation. Nine children (36%), five with unilateral and four with bilateral tumors developed growth hormone deficit between 2 and 8 years after irradiation that required hormone replacement. Their pituitary gland received 22 to 40 Gy. No osteosarcoma occurred in this population. Among long-term sequels, following irradiation for retinoblastoma, cosmetical deformities represent disabling sequels that could justify new approaches in radiotherapy, as protontherapy combined with 3-D-treatment planning

  8. A TaqI RFLP identified at the retinoblastoma locus on chromosome 13

    Energy Technology Data Exchange (ETDEWEB)

    Shiang, R; Murray, J C [Univ. of Iowa, Iowa City (USA); Wiggs, J; Dryja, T [Massachusetts Eye and Ear Infirmary, Boston (USA)

    1988-09-26

    Probe D95HS0.5 is a 0.6 kb fragment subcloned into Bluescribe a pUC19 derivative from a bacterio phage library isolated by a cDNA probe of the retinoblastoma gene. The fragment is released with the enzymes HindIII and SaII. TaqI identifies a 2 allele polymorphism with a band at 2.1 kb and 1.8 kb with a frequency of 0.97 and 0.03 respectively. There are no constant bands. The probe was assigned to chromosome 13 using a linkage analysis with retinoblastoma. Co-dominant inheritance was shown in 3 CEPH pedigrees.

  9. Retinoblastoma protein functions as a molecular switch determining white versus brown adipocyte differentiation

    DEFF Research Database (Denmark)

    Hansen, Jacob B; Jørgensen, Claus; Petersen, Rasmus K

    2004-01-01

    Adipocyte precursor cells give raise to two major cell populations with different physiological roles: white and brown adipocytes. Here we demonstrate that the retinoblastoma protein (pRB) regulates white vs. brown adipocyte differentiation. Functional inactivation of pRB in wild-type mouse embryo...... fibroblasts (MEFs) and white preadipocytes by expression of simian virus 40 large T antigen results in the expression of the brown fat-specific uncoupling protein 1 (UCP-1) in the adipose state. Retinoblastoma gene-deficient (Rb-/-) MEFs and stem cells, but not the corresponding wild-type cells, differentiate...

  10. PCR detection of retinoblastoma gene deletions in radiation-induced mouse lung adenocarcinomas

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1993-01-01

    From 1971 to 1986, Argonne National Laboratory conducted a series of large-scale studies of tumor incidence in 40,000 BCF 1 mice irradiated with 60 Co γ rays or JANUS fission-spectrum neutrons; normal and tumor tissues from mice in these studies were preserved in paraffin blocks. A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma (mRb) gene in the paraffin-embedded tissues. Microtomed sections were used as the DNA source in PCR reaction mixtures. Six mRb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments (relative to control PCR products) on a Southern blot indicated a deletion of that portion of the mRb gene. The tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death in post-mortem analyses. Spontaneous tumors as well as those from irradiated mice (569 cGy of 60 Co γ rays or 60 cGy of JANUS neutrons, doses that have been found to have approximately equal biological effectiveness in the BCF, mouse) were analyzed for mRb deletions. In all normal mouse tissues studies, all six mRb exon fragments were present on Southem blots. Tumors in six neutron-irradiated mice also had no mRb deletions. However, I of 6 tumors from γ-irradiated mice and 6 of 18 spontaneous tumors from unirradiated mice had a deletion in one or both mRb alleles. All deletions detected were in the 5' region of the mRb gene

  11. RNA-Sequencing of Primary Retinoblastoma Tumors Provides New Insights and Challenges Into Tumor Development

    Directory of Open Access Journals (Sweden)

    Sailaja V. Elchuri

    2018-05-01

    Full Text Available Retinoblastoma is rare tumor of the retina caused by the homozygous loss of the Retinoblastoma 1 tumor suppressor gene (RB1. Loss of the RB1 protein, pRB, results in de-regulated activity of the E2F transcription factors, chromatin changes and developmental defects leading to tumor development. Extensive microarray profiles of these tumors have enabled the identification of genes sensitive to pRB disruption, however, this technology has a number of limitations in the RNA profiles that they generate. The advent of RNA-sequencing has enabled the global profiling of all of the RNA within the cell including both coding and non-coding features and the detection of aberrant RNA processing events. In this perspective, we focus on discussing how RNA-sequencing of rare Retinoblastoma tumors will build on existing data and open up new area’s to improve our understanding of the biology of these tumors. In particular, we discuss how the RB-research field may be to use this data to determine how RB1 loss results in the expression of; non-coding RNAs, causes aberrant RNA processing events and how a deeper analysis of metabolic RNA changes can be utilized to model tumor specific shifts in metabolism. Each section discusses new opportunities and challenges associated with these types of analyses and aims to provide an honest assessment of how understanding these different processes may contribute to the treatment of Retinoblastoma.

  12. Human Papilloma Virus in Retinoblastoma Tissues from Korean Patients

    Science.gov (United States)

    Ryoo, Na-Kyung; Kim, Ji-Eun; Kim, Namju; Lee, Min-Jeong; Khwarg, Sang-In

    2013-01-01

    Purpose Recent reports suggest the association of human papilloma virus (HPV) with retinoblastoma. This study was performed to elucidate whether HPV infection is related to retinoblastoma among Koreans. Methods A total of 54 cases diagnosed with retinoblastoma were enrolled from Seoul National University Children's Hospital and Seoul Metropolitan Government-Seoul National University Boramae Medical Center. Presence of human papilloma viral DNA was detected by in situ hybridization in formalin-fixed paraffin-embedded retinoblastoma tissues using both probes against high- and low risk HPV types. Results The mean age at diagnosis was 22.0 months (range, 1.1 to 98.0 months), and the mean age at enucleation was 27.8 months (range, 1.5 to 112.7 months) among the 54 patients with retinoblastoma. HPV was not detected in any of the retinoblastoma samples using either high risk or low risk HPV probes. Conclusions Our study, being the first study in the Korean population, proposes that HPV infection may have no causal relationship with retinoblastoma in Koreans. PMID:24082775

  13. Retinoblastoma bilateral de aparecimento tardio: relato de caso Late presentation of bilateral retinoblastoma: case report

    Directory of Open Access Journals (Sweden)

    Maria Cecília Santos Cavalcanti Melo

    2008-06-01

    Full Text Available É relatado um caso de retinoblastoma de aparecimento tardio, com características pouco freqüentes, com o objetivo de melhorar o controle da afecção. Em 1993, SJMMF, nove meses, masculino, leucodermo, apresentou tumor na retina esquerda. O paciente tinha história familiar de retinoblastoma. A enucleação foi realizada, comprovando-se retinoblastoma. Os exames para estadiamento sistêmico foram normais. O olho direito evoluiu normal por dez anos. Em exame de rotina, foram constatadas três lesões de retinoblastoma na retina nasal. Foi feita termoterapia transpupilar, com laser de diodo de 810 nm. Após 30 dias, as lesões regrediram. Após 60 dias houve recidiva na borda da lesão, onde foi realizada crioterapia transescleral, com regressão do tumor por seis meses. Durante o controle, observaram-se condensações próximas à lesão tumoral atrófica (sementes vítreas. Foi feito braquiterapia com Iodo125, havendo desaparecimento das mesmas após 30 dias. Novas sementes surgiram três meses pós-braquiterapia, depositadas na superfície retiniana, sendo tratadas com crioterapia transescleral e termoterapia transpupilar, havendo regressão. O paciente evoluiu com nova semente vítrea após seis meses, a qual, após depositar-se na superfície da retina, foi tratada com termoterapia transpupilar. Está em seguimento há 38 meses desde o aparecimento do tumor bilateral, mantendo acuidade visual de 20/20 e exames clínicos normais. Considera-se importante este caso pela pouca freqüência de aparecimento da doença nesta idade. Julga-se necessário o alerta para os casos de retinoblastoma já considerados curados.A case of retinoblastoma with uncommon features is reported, aiming at improving follow-up. In 1993, SJMMF, 9-month-old white boy, presented a squint in the left eye. A retinal tumor was detected. The patient had a family history of retinoblastoma. Enucleation was performed and retinoblastoma was proved. The patient underwent

  14. Modulation and Expression of Tumor Suppressor Genes by Environmental Agents

    National Research Council Canada - National Science Library

    Ostrander, Gary Kent

    1996-01-01

    ... in the retinoblastoma gene in retinoblastoma and hepatocarcinomas following induction with known environmental carcinogens. Studies to date suggest the retinoblastoma gene/protein may play a role in oncogenesis in the medaka.

  15. Clinical Value of CD24 Expression in Retinoblastoma

    Directory of Open Access Journals (Sweden)

    Jia Li

    2012-01-01

    Full Text Available Background. The expression of CD24 has been detected in a wide variety of human malignancies. Downregulation of CD24 inhibits proliferation and induces apoptosis in tumor cells, whereas its upregulation increases tumor growth and metastasis. However, no data on CD24 protein levels in retinoblastoma are available, and the mechanism of CD24 involvement in retinoblastoma progress has not been elucidated. The aim of this study was to explore the expression profile of CD24 in the retinoblastoma tumor samples and to correlate with clinicopathological parameters. Methods. Immunohistochemistry was performed for CD24 on the archival paraffin sections of retinoblastoma and correlated with clinicopathological features. Western blotting was performed to confirm immunoreactivity results. Results. CD24 immunoreactivity was observed in 72.0% (36/50 of the retinoblastoma specimens. Among the 35 low-risk tumors, CD24 was expressed in 62.9% (22/35 tumors and among the 15 high-risk tumors, CD24 was expressed in 93.3% (14/15 tumors. High-risk tumors showed significantly increased expression of CD24 compared to tumors with low-risk (<0.05. Conclusions. This is the first correlation between CD24 expression and histopathology in human retinoblastoma. Our study showed increased expression of CD24 in high risk tumors compared to low risk tumors. Further functional studies are required to explore the role of CD24 in retinoblastoma.

  16. Guidelines for imaging retinoblastoma: imaging principles and MRI standardization

    Energy Technology Data Exchange (ETDEWEB)

    Graaf, Pim de; Rodjan, Firazia; Castelijns, Jonas A. [VU University Medical Center, Department of Radiology, Amsterdam (Netherlands); Goericke, Sophia [University Hospital, Department of Diagnostic and Interventional Radiology and Neuroradiology, Essen (Germany); Galluzzi, Paolo [Azienda Ospedaliera e Universitaria Senese, Policlinico ' ' Le Scotte' ' , Unit of Diagnostic and Therapeutic Neuroradiology, Siena (Italy); Maeder, Philippe [CHUV, Service de Radiodiagnostic et Radiologie Interventionelle, Lausanne (Switzerland); Brisse, Herve J. [Institut Curie, Departement d' Imagerie, Paris (France)

    2012-01-15

    Retinoblastoma is the most common intraocular tumor in children. The diagnosis is usually established by the ophthalmologist on the basis of fundoscopy and US. Together with US, high-resolution MRI has emerged as an important imaging modality for pretreatment assessment, i.e. for diagnostic confirmation, detection of local tumor extent, detection of associated developmental malformation of the brain and detection of associated intracranial primitive neuroectodermal tumor (trilateral retinoblastoma). Minimum requirements for pretreatment diagnostic evaluation of retinoblastoma or mimicking lesions are presented, based on consensus among members of the European Retinoblastoma Imaging Collaboration (ERIC). The most appropriate techniques for imaging in a child with leukocoria are reviewed. CT is no longer recommended. Implementation of a standardized MRI protocol for retinoblastoma in clinical practice may benefit children worldwide, especially those with hereditary retinoblastoma, since a decreased use of CT reduces the exposure to ionizing radiation. (orig.)

  17. The murine retinoblastoma homolog maps to chromosome 14 near Es-10

    NARCIS (Netherlands)

    Stone, J.C.; Crosby, J.J.; Kozak, C.A.; Schievella, A.R.; Bernards, R.A.; Nadeau, J.H.

    1989-01-01

    Restriction fragment length variants have been exploited to map genetically Rb-1, the murine homolog of the human retinoblastoma gene. Rb-1 localized to mouse chromosome 14 on the basis of results from analysis of somatic cell hybrids. In an interspecific backcross involving Mus spretus, Rb-1 and

  18. Retinoblastoma atípico: a propósito de un caso Atypic retinoblastoma: apropos of a case

    Directory of Open Access Journals (Sweden)

    Beatriz N. Rodríguez Rodríguez

    2003-06-01

    Full Text Available En una niña de 11 años de edad se presentó un caso atípico de retinoblastoma unilateral y se consultó inicialmente por una hemorragia vítrea. El ultrasonido no orientó diagnóstico. Posteriormente apareció un hifema total espontáneo con hipertensión ocular incontrolable que decidió la enucleación. El estudio anátomo-patológico concluyó un retinoblastoma poco diferenciado con extensa área de necrosis y hemorragia intratumoral.An atypic case of unilateral retinoblastoma was reported in an 11-year-old girl that was seen due to a vitreal hemorrhage at first. The ultrasound did not help to make a diagnosis. Later on, a total spontaneous hyphema with uncontrollable ocular hypertension appeared that led surgeons to perform enucleation. By the anatomopathological study, it was concluded that it was a little differentiated retinoblastoma with an extensive area of necrosis and intratumoral hemorrhage.

  19. Decreased expression of MEG3 contributes to retinoblastoma progression and affects retinoblastoma cell growth by regulating the activity of Wnt/β-catenin pathway.

    Science.gov (United States)

    Gao, Yali; Lu, Xiaohe

    2016-02-01

    The aberrant expression of MEG3 has been found in some types of cancers; however, little is known concerning the function of MEG3 in retinoblastoma. To elucidate the roles of MEG3 in retinoblastoma, MEG3 expression was quantified in 63 retinoblastoma samples and corresponding nontumor tissues in this work. Moreover, retinoblastoma cell lines were transfected with pcDNA3.1-MEG3 or si-MEG3, after which proliferation, apoptosis, and expression of β-catenin were assayed. TOP-Flash reporter assay was also used to investigate the activity of the Wnt/β-catenin pathway. The results showed that MEG3 was downregulated in retinoblastoma tissues, and the level of MEG3 was negatively associated with IIRC stages and nodal or distant metastasis. More importantly, Kaplan-Meier survival analysis demonstrated that patients with low MEG3 expression had poorer survival and multivariate Cox regression analysis revealed that MEG3 was an independent prognostic factor in retinoblastoma patients. We also observed that MEG3 expression can be modulated by DNA methylation by using 5-aza-CdR treatment. In addition, overexpression of MEG3 suppressed proliferation, promoted apoptosis, and influences the activity of the Wnt/β-catenin pathway in retinoblastoma cell lines. Furthermore, we found that Wnt/β-catenin pathway activator rescued the anticancer effect of MEG3 in retinoblastoma. In conclusion, our study for the first time demonstrated that MEG3 was a tumor suppressor by negatively regulating the activity of the Wnt/β-catenin pathway in the progression of retinoblastoma and might serve as a prognostic biomarker and molecular therapeutic target.

  20. Late onset retinoblastoma presenting with vitreous haemorrhage

    DEFF Research Database (Denmark)

    Bagger, Mette; Prause, Jan Ulrik; Heegard, Steffen

    2012-01-01

    in the retina. A vascularized gelatinous mass was revealed after vitrectomy. Later the patient developed white cysts in the anterior chamber and histological findings were indicative of a retinoblastoma. The patient was enucleated and the diagnosis of retinoblastoma was confirmed. Intraocular surgery in young...... people with unknown retinoblastoma enhances the risk of metastasis development, orbital recurrence and death. Unexplained vitreous haemorrhage can obscure the view of a tumour but ultrasonic findings of a retinal mass calls for further imaging e.g. through MRI. The case illustrates the importance...

  1. [Familial retinoblastoma: cytogenetic study of the tumor].

    Science.gov (United States)

    Robledo Batanero, M; Manzanal Martínez, A; Ayuso García, C; Benítez Ortiz, J

    1990-05-01

    We report a case of familiar retinoblastoma, in which both mother and daughter show bilateral retinoblastoma. The cytogenetic study, in both peripheral blood lymphocytes and tumoral tissue did not show alterations on the 13 chromosome, although we found a complex kariotype in tumoral tissue defined by three celular lines. In all of them appears a marker in which the 6 chromosome is involved (der 6). The derivated of 6 chromosome are markers highly characteristic of the retinoblastoma cases, and can be related with the aggressivity of tumor and the appearance of the second tumors.

  2. Distant metastatic retinoblastoma without central nervous system involvement

    Directory of Open Access Journals (Sweden)

    Mohammad Javed Ali

    2013-01-01

    Full Text Available Retinoblastoma is the most common intraocular malignancy in children, with a reported incidence ranging from 1 in 15,000 to 1 in 18,000 live births. Metastatic retinoblastoma is rare in developed countries, with a reported range from 4.8% in the United States to 5.8% in the United Kingdom. However, the frequency reported from developing countries varies from 9 to 11% at presentation. The mortality is very high owing to late presentations, delayed diagnosis compounded by socio-economic factors. The management of metastatic retinoblastoma is evolving, but it is still a challenge in pediatric oncology. We present a case of an extensive skeletal metastasis that initially presented as a massive orbital retinoblastoma.

  3. Insights on ornithine decarboxylase silencing as a potential strategy for targeting retinoblastoma.

    Science.gov (United States)

    Muthukumaran, Sivashanmugam; Bhuvanasundar, Renganathan; Umashankar, Vetrivel; Sulochana, K N

    2018-02-01

    Ornithine Decarboxylase (ODC) is a key enzyme involved in polyamine synthesis and is reported to be up regulated in several cancers. However, the effect of ODC gene silencing in retinoblastoma is to be understood for utilization in therapeutic applications. Hence, in this study, a novel siRNA (small interference RNA) targeting ODC was designed and validated in Human Y79 retinoblastoma cells for its effects on intracellular polyamine levels, Matrix Metalloproteinase 2 & 9 activity and Cell cycle. The designed siRNA showed efficient silencing of ODC mRNA expression and protein levels in Y79 cells. It also showed significant reduction of intracellular polyamine levels and altered levels of oncogenic LIN28b expression. By this study, a regulatory loop is proposed, wherein, ODC silencing in Y79 cells to result in decreased polyamine levels, thereby, leading to altered protein levels of Lin28b, MMP-2 and MMP-9, which falls in line with earlier studies in neuroblastoma. Thus, by this study, we propose ODC silencing as a prospective strategy for targeting retinoblastoma. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Long non-coding RNA H19 suppresses retinoblastoma progression via counteracting miR-17-92 cluster.

    Science.gov (United States)

    Zhang, Aihui; Shang, Weiwei; Nie, Qiaoli; Li, Ting; Li, Suhui

    2018-04-01

    Long non-coding RNAs (lncRNAs) are frequently dysregulated and play important roles in many cancers. lncRNA H19 is one of the earliest discovered lncRNAs which has diverse roles in different cancers. However, the expression, roles, and action mechanisms of H19 in retinoblastoma are still largely unknown. In this study, we found that H19 is downregulated in retinoblastoma tissues and cell lines. Gain-of-function and loss-of-function assays showed that H19 inhibits retinoblastoma cell proliferation, induces retinoblastoma cell cycle arrest and cell apoptosis. Mechanistically, we identified seven miR-17-92 cluster binding sites on H19, and found that H19 directly bound to miR-17-92 cluster via these seven binding sites. Through binding to miR-17-92 cluster, H19 relieves the suppressing roles of miR-17-92 cluster on p21. Furthermore, H19 represses STAT3 activation induced by miR-17-92 cluster. Hence, our results revealed that H19 upregulates p21 expression, inhibits STAT3 phosphorylation, and downregulates the expression of STAT3 target genes BCL2, BCL2L1, and BIRC5. In addition, functional assays demonstrated that the mutation of miR-17-92 cluster binding sites on H19 abolished the proliferation inhibiting, cell cycle arrest and cell apoptosis inducing roles of H19 in retinoblastoma. In conclusion, our data suggested that H19 inhibits retinoblastoma progression via counteracting the roles of miR-17-92 cluster, and implied that enhancing the action of H19 may be a promising therapeutic strategy for retinoblastoma. © 2017 Wiley Periodicals, Inc.

  5. RNA interference and retinoblastoma-related genes are required for repression of endogenous siRNA targets in Caenorhabditis elegans.

    Science.gov (United States)

    Grishok, Alla; Hoersch, Sebastian; Sharp, Phillip A

    2008-12-23

    In Caenorhabditis elegans, a vast number of endogenous short RNAs corresponding to thousands of genes have been discovered recently. This finding suggests that these short interfering RNAs (siRNAs) may contribute to regulation of many developmental and other signaling pathways in addition to silencing viruses and transposons. Here, we present a microarray analysis of gene expression in RNA interference (RNAi)-related mutants rde-4, zfp-1, and alg-1 and the retinoblastoma (Rb) mutant lin-35. We found that a component of Dicer complex RDE-4 and a chromatin-related zinc finger protein ZFP-1, not implicated in endogenous RNAi, regulate overlapping sets of genes. Notably, genes a) up-regulated in the rde-4 and zfp-1 mutants and b) up-regulated in the lin-35(Rb) mutant, but not the down-regulated genes are highly represented in the set of genes with corresponding endogenous siRNAs (endo-siRNAs). Our study suggests that endogenous siRNAs cooperate with chromatin factors, either C. elegans ortholog of acute lymphoblastic leukemia-1 (ALL-1)-fused gene from chromosome 10 (AF10), ZFP-1, or tumor suppressor Rb, to regulate overlapping sets of genes and predicts a large role for RNAi-based chromatin silencing in control of gene expression in C. elegans.

  6. Gene-wide analysis detects two new susceptibility genes for Alzheimer's Disease

    OpenAIRE

    Escott-Price, Valentina; Bellenguez, Céline; Wang, Li-San; Choi, Seung-Hoan; Harold, Denise; Jones, Lesley; Holmans, Peter Alan; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L.; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A.; Naj, Adam C.; Sims, Rebecca

    2014-01-01

    PUBLISHED BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over...

  7. The effects of BSO on GSH contents and radiosensitivity of retinoblastoma cells

    International Nuclear Information System (INIS)

    Yi Xanjin; Ding Li; Jin Yizun; Ni Chuo; Wang Wenji; Yi Yuzhen

    1995-01-01

    The radiobiological effects of thiol modifier BSO on retinoblastoma were studied using cultured retinoblastoma cell lines Y-79 and So-Rb 50 and retinoblastoma bearing nude mouse. The preliminary results showed that BSO can deplete intracellular GSH contents of retinoblastoma cells in vitro and vivo. In vitro data demonstrated that low and nontoxic concentration BSO increased the retinoblastoma cells radiosensitivity especially under the hypoxic condition

  8. Neoadjuvant/adjuvant treatment of high-risk retinoblastoma: a report from the German Retinoblastoma Referral Centre.

    Science.gov (United States)

    Künkele, Annette; Wilm, Josephine; Holdt, Markus; Lohmann, Dietmar; Bornfeld, Norbert; Eggert, Angelika; Temming, Petra; Schulte, Johannes H

    2015-07-01

    Retinoblastoma can extend beyond the structures of the eye, where cells can enter the bloodstream and cause metastases. Various types of protocols for adjuvant treatment risk-adapted according to histopathological risk factors are used worldwide. Between 1997 and 2009, 420 children were diagnosed with retinoblastoma at the German Retinoblastoma Referral Centre and risk factors were assessed. Patients with post-laminar optic nerve infiltration or choroid or minor scleral invasion received six courses of adjuvant chemotherapy using vincristine, etoposide, carboplatin and cyclophosphamide (group 1). Patients with microscopic extension beyond the sclera to the resection margin of the optic nerve or potential spread due to vitrectomy received chemotherapy plus orbital radiotherapy (group 2). Neoadjuvant chemotherapy was performed in patients with local extraocular invasion detected on MRI. Following this protocol, 42 of the 420 patients and 21 referred from other centres showed high-risk histopathological factors qualifying for adjuvant therapy (57 in group 1 and 6 in group 2). Seven of the 63 patients received neoadjuvant and adjuvant treatment. During a mean follow-up of 5.8 (range 0.4-15.4) years, one of six patients in group 2 developed metastases and died. No patients died from toxicity. The 5-year overall survival was 100% for group 1 and 80% for group 2. This retrospective single-site study reveals a 10% incidence of high-risk features in children with retinoblastoma diagnosed at the German Retinoblastoma Referral Centre. Overall survival rates of 98.3% underline the safety of this adjuvant chemotherapy protocol and its efficiency in preventing metastasis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  9. Detection of retinoblastoma gene deletions in spontaneous and radiation-induced mouse lung adenocarcinomas by polymerase chain reaction

    International Nuclear Information System (INIS)

    Churchill, M.E.; Gemmell, M.A.; Woloschak, G.E.

    1994-01-01

    A polymerase chain reaction (PCR) technique has been developed to detect deletions in the mouse retinoblastoma gene using histological sections from radiation-induced and spontaneous tumors as the DNA source. Six mouse Rb gene exon fragments were amplified in a 40-cycle, 3-temperature PCR protocol. The absence of any of these fragments relative to control PCR products on a Southern blot indicated a deletion of that portion of the mouse Rb gene. Tumors chosen for analysis were lung adenocarcinomas that were judged to be the cause of death. Spontaneous tumors as well as those from irradiated mice (5.69 Gy 60 Co γ rays or 0.6 Gy JANUS neutrons, which have been found to have approximately equal radiobiological effectiveness) were analyzed for mouse Rb deletions. Tumors in 6 neutron-irradiated mice had no mouse Rb deletions. However, 1 of 6 tumors from γ-irradiated mice (17%) and 6 of 18 spontaneous tumors from unirradiated mice (33%) showed a deletion in one or both mouse Rb alleles. All deletions detected were in the 5' region of the mouse Rb gene. 36 refs., 2 figs., 2 tabs

  10. Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice

    NARCIS (Netherlands)

    Boesten, L.S.M.; Zadelaar, A.S.M.; Nieuwkoop, A. van; Hu, L.; Jonkers, J.; Water, B. van de; Gijbels, M.J.J.; Made, I. van der; Winther, M.P.J. de; Havekes, L.M.; Vlijmen, B.J.M. van

    2006-01-01

    The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the

  11. RB1 mutation spectrum in a comprehensive nationwide cohort of retinoblastoma patients

    NARCIS (Netherlands)

    Dommering, Charlotte J.; Mol, Berber M.; Moll, Annette C.; Burton, Margaret; Cloos, Jacqueline; Dorsman, Josephine C.; Meijers-Heijboer, Hanne; van der Hout, Annemarie H.

    Background Retinoblastoma (Rb) is a childhood cancer of the retina, commonly initiated by biallelic inactivation of the RB1 gene. Knowledge of the presence of a heritable RB1 mutation can help in risk management and reproductive decision making. We report here on RB1 mutation scanning in a unique

  12. The retinoblastoma gene is frequently altered leading to loss of expression in primary breast tumours.

    Science.gov (United States)

    Varley, J M; Armour, J; Swallow, J E; Jeffreys, A J; Ponder, B A; T'Ang, A; Fung, Y K; Brammar, W J; Walker, R A

    1989-06-01

    We have analysed the organisation of the retinoblastoma (RB1) gene in 77 primary breast carcinomas, in metastatic tissue derived from 16 of those primary tumours, and in a variety of benign breast lesions. Expression of RB1 was also assessed in most samples by immunohistochemical detection of the RB1 protein in tissue sections. Structural abnormalities to RB1 were detected in DNA from 15/77 (19%) of primary breast carcinomas examined. Where DNA was available from metastatic tissue derived from such primary tumours, the same aberration could be detected. No alterations were seen in benign breast lesions. 16/56 (29%) of tumours examined for expression by immunohistochemical methods showed a proportion of tumour cells to be completely negative for the RB1 protein. All tumours in which a structural alteration to RB1 was detected had a proportion of negative cells, except for one case where all cells were positive. Several primary tumour samples were identified where there was no detectable structural change to the gene, but there was loss of expression in some tumour cells. The data presented here demonstrate that changes to the RB1 gene leading to loss of expression of both alleles are frequent in primary human breast tumours.

  13. Progress in Small Molecule Therapeutics for the Treatment of Retinoblastoma.

    Science.gov (United States)

    Pritchard, Eleanor M; Dyer, Michael A; Guy, R Kiplin

    2016-01-01

    While mortality is low for intraocular retinoblastoma patients in the developed world who receive aggressive multimodal therapy, partial or full loss of vision occurs in approximately 50% of patients with advanced bilateral retinoblastoma. Therapies that preserve vision and reduce late effects are needed. Because clinical trials for retinoblastoma are difficult due to the young age of the patient population and relative rarity of the disease, robust preclinical testing of new therapies is critical. The last decade has seen advances towards identifying new therapies including the development of animal models of retinoblastoma for preclinical testing, progress in local drug delivery to reach intraocular targets, and improved understanding of the underlying biological mechanisms that give rise to retinoblastoma. This review discusses advances in these areas, with a focus on discovery and development of small molecules for the treatment of retinoblastoma, including novel targeted therapeutics such as inhibitors of the MDMX-p53 interaction (nutlin-3a), histone deacetylase (HDAC) inhibitors, and spleen tyrosine kinase (SYK) inhibitors.

  14. Sister chromatid exchange induced by X-irradiation of retinoblastoma lymphocytes

    International Nuclear Information System (INIS)

    Abramovsky-Kaplan, I.; Jones, I.S.

    1984-01-01

    Lymphocyte cultures were employed to assess the degree of spontaneous and induced chromosomal fragility in retinoblastoma. Sister chromatid exchange (SCEs) were scored in metaphases. Three unilateral, three bilateral, eleven family members and controls were studied. Retinoblastoma (RB) lymphocytes did not exhibit increased spontaneous fragility. X-irradiation (25-200 rad) did not significantly increase SCE in unilateral retinoblastoma lymphocytes when compared with controls (P greater than 0.50). However, bilaterally affected subjects and three unaffected relatives demonstrated a statistically significant increase in SCE (P less than 0.01). In conclusion, hereditary retinoblastoma lymphocytes appear more radiosensitive than sporadic retinoblastoma, perhaps, reflecting the increased second malignancies in germinal mutation retinoblastoma. In addition, the analysis of radiation-induced SCE in peripheral blood lymphocytes of RB patients and family members may provide a valuable tool increasing the accuracy of genetic counseling for this disorder. Additional studies of RB patients and families are needed to assess the relevance of this approach to genetic counseling

  15. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

    Science.gov (United States)

    Escott-Price, Valentina; Bellenguez, Céline; Wang, Li-San; Choi, Seung-Hoan; Harold, Denise; Jones, Lesley; Holmans, Peter; Gerrish, Amy; Vedernikov, Alexey; Richards, Alexander; DeStefano, Anita L; Lambert, Jean-Charles; Ibrahim-Verbaas, Carla A; Naj, Adam C; Sims, Rebecca; Jun, Gyungah; Bis, Joshua C; Beecham, Gary W; Grenier-Boley, Benjamin; Russo, Giancarlo; Thornton-Wells, Tricia A; Denning, Nicola; Smith, Albert V; Chouraki, Vincent; Thomas, Charlene; Ikram, M Arfan; Zelenika, Diana; Vardarajan, Badri N; Kamatani, Yoichiro; Lin, Chiao-Feng; Schmidt, Helena; Kunkle, Brian; Dunstan, Melanie L; Vronskaya, Maria; Johnson, Andrew D; Ruiz, Agustin; Bihoreau, Marie-Thérèse; Reitz, Christiane; Pasquier, Florence; Hollingworth, Paul; Hanon, Olivier; Fitzpatrick, Annette L; Buxbaum, Joseph D; Campion, Dominique; Crane, Paul K; Baldwin, Clinton; Becker, Tim; Gudnason, Vilmundur; Cruchaga, Carlos; Craig, David; Amin, Najaf; Berr, Claudine; Lopez, Oscar L; De Jager, Philip L; Deramecourt, Vincent; Johnston, Janet A; Evans, Denis; Lovestone, Simon; Letenneur, Luc; Hernández, Isabel; Rubinsztein, David C; Eiriksdottir, Gudny; Sleegers, Kristel; Goate, Alison M; Fiévet, Nathalie; Huentelman, Matthew J; Gill, Michael; Brown, Kristelle; Kamboh, M Ilyas; Keller, Lina; Barberger-Gateau, Pascale; McGuinness, Bernadette; Larson, Eric B; Myers, Amanda J; Dufouil, Carole; Todd, Stephen; Wallon, David; Love, Seth; Rogaeva, Ekaterina; Gallacher, John; George-Hyslop, Peter St; Clarimon, Jordi; Lleo, Alberto; Bayer, Anthony; Tsuang, Debby W; Yu, Lei; Tsolaki, Magda; Bossù, Paola; Spalletta, Gianfranco; Proitsi, Petra; Collinge, John; Sorbi, Sandro; Garcia, Florentino Sanchez; Fox, Nick C; Hardy, John; Naranjo, Maria Candida Deniz; Bosco, Paolo; Clarke, Robert; Brayne, Carol; Galimberti, Daniela; Scarpini, Elio; Bonuccelli, Ubaldo; Mancuso, Michelangelo; Siciliano, Gabriele; Moebus, Susanne; Mecocci, Patrizia; Zompo, Maria Del; Maier, Wolfgang; Hampel, Harald; Pilotto, Alberto; Frank-García, Ana; Panza, Francesco; Solfrizzi, Vincenzo; Caffarra, Paolo; Nacmias, Benedetta; Perry, William; Mayhaus, Manuel; Lannfelt, Lars; Hakonarson, Hakon; Pichler, Sabrina; Carrasquillo, Minerva M; Ingelsson, Martin; Beekly, Duane; Alvarez, Victoria; Zou, Fanggeng; Valladares, Otto; Younkin, Steven G; Coto, Eliecer; Hamilton-Nelson, Kara L; Gu, Wei; Razquin, Cristina; Pastor, Pau; Mateo, Ignacio; Owen, Michael J; Faber, Kelley M; Jonsson, Palmi V; Combarros, Onofre; O'Donovan, Michael C; Cantwell, Laura B; Soininen, Hilkka; Blacker, Deborah; Mead, Simon; Mosley, Thomas H; Bennett, David A; Harris, Tamara B; Fratiglioni, Laura; Holmes, Clive; de Bruijn, Renee F A G; Passmore, Peter; Montine, Thomas J; Bettens, Karolien; Rotter, Jerome I; Brice, Alexis; Morgan, Kevin; Foroud, Tatiana M; Kukull, Walter A; Hannequin, Didier; Powell, John F; Nalls, Michael A; Ritchie, Karen; Lunetta, Kathryn L; Kauwe, John S K; Boerwinkle, Eric; Riemenschneider, Matthias; Boada, Mercè; Hiltunen, Mikko; Martin, Eden R; Schmidt, Reinhold; Rujescu, Dan; Dartigues, Jean-François; Mayeux, Richard; Tzourio, Christophe; Hofman, Albert; Nöthen, Markus M; Graff, Caroline; Psaty, Bruce M; Haines, Jonathan L; Lathrop, Mark; Pericak-Vance, Margaret A; Launer, Lenore J; Van Broeckhoven, Christine; Farrer, Lindsay A; van Duijn, Cornelia M; Ramirez, Alfredo; Seshadri, Sudha; Schellenberg, Gerard D; Amouyel, Philippe; Williams, Julie

    2014-01-01

    Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

  16. Gene-wide analysis detects two new susceptibility genes for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Valentina Escott-Price

    Full Text Available Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls.In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6 and 14 (IGHV1-67 p = 7.9×10-8 which indexed novel susceptibility loci.The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.

  17. Regulation of the retinoblastoma protein-related p107 by G1 cyclin complexes

    NARCIS (Netherlands)

    Beijersbergen, R.L.; Carlée, L.; Kerkhoven, R.M.; Bernards, R.A.

    1995-01-01

    The orderly progression through the cell cycle is mediated by the sequential activation of several cyclin/cyclin-dependent kinase (cdk) complexes. These kinases phosphorylate a number of cellular substrates, among which is the product of the retinoblastoma gene, pRb. Phosphorylation of pRb in late

  18. Inverse gene-for-gene interactions contribute additively to tan spot susceptibility in wheat.

    Science.gov (United States)

    Liu, Zhaohui; Zurn, Jason D; Kariyawasam, Gayan; Faris, Justin D; Shi, Gongjun; Hansen, Jana; Rasmussen, Jack B; Acevedo, Maricelis

    2017-06-01

    Tan spot susceptibility is conferred by multiple interactions of necrotrophic effector and host sensitivity genes. Tan spot of wheat, caused by Pyrenophora tritici-repentis, is an important disease in almost all wheat-growing areas of the world. The disease system is known to involve at least three fungal-produced necrotrophic effectors (NEs) that interact with the corresponding host sensitivity (S) genes in an inverse gene-for-gene manner to induce disease. However, it is unknown if the effects of these NE-S gene interactions contribute additively to the development of tan spot. In this work, we conducted disease evaluations using different races and quantitative trait loci (QTL) analysis in a wheat recombinant inbred line (RIL) population derived from a cross between two susceptible genotypes, LMPG-6 and PI 626573. The two parental lines each harbored a single known NE sensitivity gene with LMPG-6 having the Ptr ToxC sensitivity gene Tsc1 and PI 626573 having the Ptr ToxA sensitivity gene Tsn1. Transgressive segregation was observed in the population for all races. QTL mapping revealed that both loci (Tsn1 and Tsc1) were significantly associated with susceptibility to race 1 isolates, which produce both Ptr ToxA and Ptr ToxC, and the two genes contributed additively to tan spot susceptibility. For isolates of races 2 and 3, which produce only Ptr ToxA and Ptr ToxC, only Tsn1 and Tsc1 were associated with tan spot susceptibility, respectively. This work clearly demonstrates that tan spot susceptibility in this population is due primarily to two NE-S interactions. Breeders should remove both sensitivity genes from wheat lines to obtain high levels of tan spot resistance.

  19. MicroRNAs-449a and -449b exhibit tumor suppressive effects in retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Martin, Alissa [Division of Hematology, Oncology, and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611 (United States); Jones, Aunica [Cancer Biology and Epigenomics Program, Ann and Robert H. Lurie Children’s Hospital of Chicago Research Center, Chicago, IL 60611 (United States); Bryar, Paul J. [Departments of Ophthalmology and Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 (United States); Mets, Marilyn [Division of Ophthalmology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611 (United States); Department of Ophthalmology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611 (United States); Weinstein, Joanna [Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611 (United States); Division of Hematology, Oncology, and Stem Cell Transplantation, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL 60611 (United States); Zhang, Gang [Biostatistics Research Core, Ann and Robert H. Lurie Children’s Hospital of Chicago Research Center, Chicago, IL 60611 (United States); Laurie, Nikia A., E-mail: n-laurie@northwestern.edu [Cancer Biology and Epigenomics Program, Ann and Robert H. Lurie Children’s Hospital of Chicago Research Center, Chicago, IL 60611 (United States); Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611 (United States)

    2013-11-01

    Highlights: •We validate miR-449a/b expression in primary human retinoblastomas and cell lines. •Exogenous miRs-449a/b inhibited proliferation in retinoblastoma cell lines. •Exogenous miRs-449a/b increased apoptosis in retinoblastoma cell lines. •miRs-449a/b could serve as viable therapeutic targets for retinoblastoma treatment. -- Abstract: Retinoblastoma is the most common pediatric cancer of the eye. Currently, the chemotherapeutic treatments for retinoblastoma are broad-based drugs such as vincristine, carboplatin, or etoposide. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. The purpose of our study is to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. We are the first to confirm an inhibitory effect of miR-449a and -449b in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when these miRNAs are overexpressed. This study suggests that these miRNAs could serve as viable therapeutic targets for retinoblastoma treatment.

  20. In vitro Rb-1 gene transfer to retinoblastoma cell lines

    International Nuclear Information System (INIS)

    Choi, Sang Wook; Ham, Yong Hoh; Kim, Mee Heui

    1994-04-01

    After transfection of Rb-vector to packaging cell line (CRIP) by Ca-P precipitation method, we could select nineteen colonies of G-418 resistant clone by ring cloning. Each colony was transduced to NIH3T3 cells to select the one which produces high titer virus. After NIH3T3 cells transduction, we could get 28 colony counts for the high, 127 for the middle, and 6 for the low viral titer. With the supernatant of the high viral titer colony (CRIPRb 2-5). We transduct retinoblastoma cell lines. 5 figs, 11 refs. (Author)

  1. MicroRNAs horizon in retinoblastoma.

    Directory of Open Access Journals (Sweden)

    Mojgan Mirakholi

    2013-12-01

    Full Text Available In the retinoblastoma research, it is of great interest to identify molecular markers associated with the genetics of tumorigenesis. microRNAs (miRNAs are small non-coding RNA molecules that play a regulatory role in many crucial cellular pathways such as differentiation, cell cycle progression, and apoptosis. A body of evidences showed dysregulation of miRNAs in tumor biology and many diseases. They potentially play a significant role in tumorigenesis processes and have been the subject of research in many types of cancers including retinal tumorigenesis. miRNA expression profiling was found to be associated with tumor development, progression and treatment. These associations demonstrate the putative applications of miRNAs in monitoring of different aspect of tumors consisting diagnostic, prognostic and therapeutic. Herein, we review the current literature concerning to the study of miRNA target recognition, function to tumorigenesis and treatment in retinoblastoma. Identification the specific miRNA biomarkers associated with retinoblastoma cancer may help to establish new therapeutic approaches for salvage affected eyes in patients.

  2. The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma

    International Nuclear Information System (INIS)

    Yi Xianjin; Ni Chuo; Wang Wengi; Li Ding; Jin Yizun

    1993-01-01

    Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by the specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity of BSO on retinoblastoma were reported. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is (2.7 +- 1.3) x 10 -12 mmol/cell, (1.4 +- 0.2) x 10 -12 mmol/cell, and 2.8 +- 1.2 μmol/g respectively. The ID50 of BSO on Y-79 and So-Rb50 in air for 3h exposure is 2.5 mM and 0.2 mM respectively. GSH depletion by 0.1 mM BSO for 24h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma bearing nude mice after BSO administration is differential. BSH depletion after BSO exposure in Y-79 cells in vitro decrease the D 0 value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under the hypoxic condition is 1.21 and 1.36 respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of cell line and BSO can increase hypoxic retinoblastoma cells radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenograft is needed

  3. Design and Implementation of the Retinoblastoma Collaborative Laboratory.

    Science.gov (United States)

    Qaiser, Seemi; Limo, Alice; Gichana, Josiah; Kimani, Kahaki; Githanga, Jessie; Waweru, Wairimu; Dimba, Elizabeth A O; Dimaras, Helen

    2017-01-01

    The purpose of this work was to describe the design and implementation of a digital pathology laboratory, the Retinoblastoma Collaborative Laboratory (RbCoLab) in Kenya. The RbCoLab is a central lab in Nairobi that receives retinoblastoma specimens from all over Kenya. Specimens were processed using evidence-based standard operating procedures. Images were produced by a digital scanner, and pathology reports were disseminated online. The lab implemented standard operating procedures aimed at improving the accuracy, completeness, and timeliness of pathology reports, enhancing the care of Kenyan retinoblastoma patients. Integration of digital technology to support pathology services supported knowledge transfer and skills transfer. A bidirectional educational network of local pathologists and other clinicians in the circle of care of the patients emerged and served to emphasize the clinical importance of cancer pathology at multiple levels of care. A 'Robin Hood' business model of health care service delivery was developed to support sustainability and scale-up of cancer pathology services. The application of evidence-based protocols, comprehensive training, and collaboration were essential to bring improvements to the care of retinoblastoma patients in Kenya. When embraced as an integrated component of retinoblastoma care, digital pathology offers the opportunity for frequent connection and consultation for development of expertise over time.

  4. Intensity modulated radiotherapy (IMRT) in bilateral retinoblastoma

    International Nuclear Information System (INIS)

    Atalar, Banu; Ozyar, Enis; Gunduz, Kaan; Gungor, Gorkem

    2010-01-01

    External beam radiotherapy (EBRT) for retinoblastoma has traditionally been done with conventional radiotherapy techniques which resulted high doses to the surrounding normal tissues. A 20 month-old girl with group D bilateral retinoblastoma underwent intensity modulated radiotherapy (IMRT) to both eyes after failing chemoreduction and focal therapies including cryotherapy and transpupillary thermotherapy. In this report, we discuss the use of IMRT as a method for reducing doses to adjacent normal tissues while delivering therapeutic doses to the tumour tissues compared with 3-dimensional conformal radiotherapy (3DCRT). At one year follow-up, the patient remained free of any obvious radiation complications. Image guided IMRT provides better dose distribution than 3DCRT in retinoblastoma eyes, delivering the therapeutic dose to the tumours and minimizing adjacent tissue damage

  5. The toxic effects, GSH depletion and radiosensitivity by BSO on retinoblastoma

    International Nuclear Information System (INIS)

    Xianjin Yi; Li Ding; Yizun Jin; Chuo Ni; Wenji Wang

    1994-01-01

    Retinoblastoma is the most common intraocular malignant tumor in children. Previous investigations have reported that buthionine sulfoximine (BSO) can deplete intracellular glutathione (GSH) by specific inhibition and increase cellular radiosensitivity. The toxic effects, GSH depletion and radiosensitivity effects of BSO on retinoblastoma cells are reported in this paper. GSH content of retinoblastoma cell lines Y-79, So-Rb50 and retinoblastoma xenograft is 2.7 ± 1.3 X 1.0 -12 mmol/cell, 1.4 ± 0.2 X 1.0 -12 mmol/cell, and 2.8 ± 1.2 μmol/g, respectively. The ID 50 of BSO on Y-79 and So-Rb50 in air for 3 h exposure is 2.5 mM and 0.2 mM, respectively. GSH depletion by 0.1 mM BSO for 24 h on Y-79 cells and 0.01 mM BSO for 24 h on So-Rb50 cells is 16.35%, and 4.7% of control. GSH depletion in tumor and other organ tissues in retinoblastoma-bearing nude mice after BSO administration is differential. GSH depletion after BSO exposure in Y-79 cells in vitro decreases the Do value of retinoblastoma cells. The SER of 0.01 mM and 0.05 mM BSO for 24 h under hypoxic conditions is 1.21 and 1.36, respectively. Based on these observations, the authors conclude that BSO toxicity on retinoblastoma cells depends on the characteristics of the cell line and that BSO can increase hypoxic retinoblastoma cells' radiosensitivity in vitro. Further study of BSO radiosensitization on retinoblastoma in vivo using nude mouse xenografts is needed. 25 refs., 3 figs., 3 tabs

  6. Retinoblastoma: concerning its initiation and treatment

    Directory of Open Access Journals (Sweden)

    Ying-Ping Deng

    2013-06-01

    Full Text Available Retinoblastoma (RB is the most common intraocular cancer of infancy and childhood. This cancer is initiated by mutation on RB1, the tumor suppressor gene that is responsible for the regulation of both cell cycle and gnome stability in retinal cells. Patients with a constitutional mutation on RB1 can be inherited. RB occurs approximately 1 in every 15 000-20 000 live births. The worldwide mortality for this cancer is about 5%-11%. However, this rate rises to about 40%-70% in developing countries due to a delay in diagnosis. A wide variety of options are available for the treatment, but often a combination of therapies is adopted to optimize individualized care.

  7. Drugs Approved for Retinoblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for retinoblastoma. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  8. Radiation management of retinoblastoma

    International Nuclear Information System (INIS)

    Takemasa, Kazuhiko; Ito, Hisao; Nishiguchi, Iku; Hashimoto, Shozo; Tanaka, Yasuhiko; Oguchi, Yoshihisa

    1992-01-01

    Forty-five patients with retinoblastoma were treated at Keio University Hospital from 1970 to 1990. Thirty-two patients had unilateral lesions and 13 had bilateral lesions. Twenty-nine patients with unilateral and 12 with bilateral lesions underwent enucleation for advanced tumor. As a result, 3 patients with unilateral retinoblastoma and all patients with bilateral disease were treated with radiotherapy (40-50 Gy) combined with or without cryotherapy and/or photocoagulation. One patient with unilateral lesion treated with radiotherapy and chemotherapy had metastases at the first visit to our clinic and was excluded from this analysis. Among 16 eyes (15 patients) treated with radiotherapy, 6 eyes had recurrence and needed retreatment. Cataract occurred in 6 of 12 eyes and good vision was preserved in 5 of 10 eyes in which function could be evaluated. (author)

  9. Radiation management of retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Takemasa, Kazuhiko; Ito, Hisao; Nishiguchi, Iku; Hashimoto, Shozo; Tanaka, Yasuhiko; Oguchi, Yoshihisa (Keio Univ., Tokyo (Japan). School of Medicine)

    1992-06-01

    Forty-five patients with retinoblastoma were treated at Keio University Hospital from 1970 to 1990. Thirty-two patients had unilateral lesions and 13 had bilateral lesions. Twenty-nine patients with unilateral and 12 with bilateral lesions underwent enucleation for advanced tumor. As a result, 3 patients with unilateral retinoblastoma and all patients with bilateral disease were treated with radiotherapy (40-50 Gy) combined with or without cryotherapy and/or photocoagulation. One patient with unilateral lesion treated with radiotherapy and chemotherapy had metastases at the first visit to our clinic and was excluded from this analysis. Among 16 eyes (15 patients) treated with radiotherapy, 6 eyes had recurrence and needed retreatment. Cataract occurred in 6 of 12 eyes and good vision was preserved in 5 of 10 eyes in which function could be evaluated. (author).

  10. Alteration in Methylation Pattern of Retinoblastoma 1 Gene Promotor Region in Intestinal Metaplasia with or without Helicobacter pylori and Gastric Cancer Patients.

    Science.gov (United States)

    Boyacioglu, Seda Orenay; Kasap, Elmas; Yuceyar, Hakan; Korkmaz, Mehmet

    2016-01-01

    Helicobacter pylori, intestinal metaplasia (IM), and gene methylation play important roles in gastric carcinogenesis. However, the association among H. pylori infection, IM, gastric cancer (GC), and gene methylation is not fully understood. Cell cycle control involving retinoblastoma 1 (RB1) gene is one of the main regulatory pathways reported to be altered in gastric carcinogenesis. The purpose of this research is to assess the methylation status of RB1 gene in GC and IM with or without H. pylori infection, and to discuss the possible role of H. pylori-induced RB1 gene methylation in the mechanism of gastric carcinogenesis. The methylation profile of RB1 gene was analyzed by sodium bisulfite modification and methylation-specific PCR in GC (n = 24), IM patients with H. pylori positive (n = 20) and negative (n = 20), and control subjects (n = 20). According to methylation levels in RB1 gene; the high correlation values were detected between H. pylori positive-IM group and GC group, and between H. pylori positive-IM and H. pylori negative-IM groups (p gene. High methylation levels in RB1 gene in H. pylori positive individuals may suggest an elevated risk of gastric cancer occurrence.

  11. Cancer incidence after retinoblastoma - Radiation dose and sarcoma risk

    NARCIS (Netherlands)

    Wong, FL; Boice, JD; Abramson, DH; Tarone, RE; Kleinerman, RA; Stovall, M; Goldman, MB; Seddon, JM; Tarbell, N; Fraumeni, JF; Li, FP

    1997-01-01

    Context.-There is a substantial risk of a second cancer for persons with hereditary retinoblastoma, which is enhanced by radiotherapy. Objective.-To examine long-term risk of new primary cancers in survivors of childhood retinoblastoma and quantify the role of radiotherapy in sarcoma development.

  12. Naturally death-resistant precursor cells revealed as the origin of retinoblastoma

    DEFF Research Database (Denmark)

    Trinh, Emmanuelle; Lazzerini Denchi, Eros; Helin, Kristian

    2004-01-01

    The molecular mechanisms and the cell-of-origin leading to retinoblastoma are not well defined. In this issue of Cancer Cell, Bremner and colleagues describe the first inheritable model of retinoblastoma, revealing that loss of the pocket proteins pRb and p107 deregulates cell cycle exit in retinal...... precursors. The authors show that a subset of these precursors contain an inherent resistance to apoptosis, and that while most terminally differentiate, some are likely to acquire additional mutations, leading to tumor formation. Thus, this work defines the cell-of-origin of retinoblastoma and suggests...... that mutations giving increased proliferative capacity are required for retinoblastoma development....

  13. Inhibition of E2F-1 transactivation by direct binding of the retinoblastoma protein

    DEFF Research Database (Denmark)

    Helin, K; Harlow, E; Fattaey, A

    1993-01-01

    Loss of a functional retinoblastoma tumor suppressor gene product, pRB, is a key step in the development of many human tumors. pRB is a negative regulator of cell proliferation and appears to participate in control of entry into the S phase of the cell cycle. The recent demonstration that pRB binds...

  14. Immunohistochemical demonstration of glial markers in retinoblastomas

    DEFF Research Database (Denmark)

    Schrøder, H D

    1987-01-01

    Twenty retinoblastomas were studied immunohistochemically in order to visualize glial cells. In the retina, the glial cells in the ganglion cell layer and the Müller cells were GFAP positive, while only the glial cells of the ganglion cell layer expressed S-100 reactivity. In the tumours S-100/GFAP...... cells reactive for both S-100 and GFAP were demonstrated. The latter findings may represent differentiation in a glial direction in the more mature parts of retinoblastoma....

  15. A fast, simple method for screening radiation susceptibility genes by RNA interference

    International Nuclear Information System (INIS)

    Tsuji, Atsushi B.; Sudo, Hitomi; Sugyo, Aya; Otsuki, Marika; Miyagishi, Makoto; Taira, Kazunari; Imai, Takashi; Harada, Yoshi-nobu

    2005-01-01

    Radiotherapy can cause unacceptable levels of damage to normal tissues in some cancer patients. To understand the molecular mechanisms underlying radiation-induced physiological responses, and to be able to predict the radiation susceptibility of normal tissues in individual patients, it is important to identify a comprehensive set of genes responsible for radiation susceptibility. We have developed a simple and rapid 96-well screening protocol using cell proliferation assays and RNA interference to identify genes associated with radiation susceptibility. We evaluated the performance of alamarBlue-, BrdU-, and sulforhodamine B-based cell proliferation assays using the 96-well format. Each proliferation assay detected the known radiation susceptibility gene, PRKDC. In a trial screen using 28 shRNA vectors, another known gene, CDKN1A, and one new radiation susceptibility gene, ATP5G3, were identified. Our results indicate that this method may be useful for large-scale screens designed to identify novel radiation susceptibility genes

  16. Inhibition of cell proliferation by p107, a relative of the retinoblastoma protein

    DEFF Research Database (Denmark)

    Zhu, L; van den Heuvel, S; Helin, K

    1993-01-01

    The cellular protein p107 shares many structural and biochemical features with the retinoblastoma gene product, pRB. We have isolated a full-length cDNA for human p107 and have used this clone to study the function of p107. We show that, like pRB, p107 is a potent inhibitor of E2F-mediated trans...

  17. Atraso diagnóstico do retinoblastoma Delayed diagnosis in retinoblastoma

    Directory of Open Access Journals (Sweden)

    Karla E. S. Rodrigues

    2004-12-01

    Full Text Available OBJETIVOS: Identificar os principais sinais e sintomas do retinoblastoma e determinar o tempo médio entre o início dos sintomas e o diagnóstico. MÉTODOS: Estudo retrospectivo, com revisão dos prontuários das crianças diagnosticadas com retinoblastoma entre janeiro de 1991 e junho de 2000 no Departamento de Pediatria do Hospital do Câncer de São Paulo. Análise estatística: teste t de Student, análise e variância, teste de Tukey-HSD (honest significant differences, teste de Levene, análise de regressão linear, curva ROC, regressão logística e análise de sobrevida pelo método de Kaplan-Meier. RESULTADOS: Foram revisados 327 prontuários, sendo 171 pacientes do sexo masculino. A idade média foi de 25 meses. Doença localizada foi verificada em 269 pacientes. Os sintomas mais freqüentes foram leucocoria (79%, estrabismo (10,7% e tumoração (3,4%. O tempo médio de queixa foi de 5,8 meses. Pacientes maiores de 2 anos de idade apresentaram maior tempo de queixa em relação aos lactentes (7,2 meses versus 4,7 meses; p = 0,001. Pacientes com estrabismo tiveram maior tempo de queixa (8,8 meses em comparação com pacientes com tumoração (2,3 meses ou leucocoria (5,6 meses (p = 0,014. Pacientes com doença metastática apresentaram maior tempo de queixa (10,6 meses; p OBJECTIVES: To identify the main symptoms of retinoblastoma and to determine the mean time between symptom onset and diagnosis (lag time. PATIENTS AND METHODS: We carried out a retrospective analysis of the patients diagnosed with retinoblastoma between January 1991 and June 2000, at the Pediatric Department of the Hospital do Câncer, São Paulo, Brazil. Statistical analyses performed were: Student's t test, ANOVA, Tukey-HSD test (honest significant differences, Levene's test, multiple regression, ROC curve, logistic regression, Kaplan-Meier, and log rank. RESULTS: 327 medical records (171 males were reviewed. The mean age was 25 months. Localized disease was

  18. Retinoblastoma incidence patterns in the US Surveillance, Epidemiology, and End Results program.

    Science.gov (United States)

    Wong, Jeannette R; Tucker, Margaret A; Kleinerman, Ruth A; Devesa, Susan S

    2014-04-01

    IMPORTANCE Several studies have found no temporal or demographic differences in the incidence of retinoblastoma except for age at diagnosis, whereas other studies have reported variations in incidence by sex and race/ethnicity. OBJECTIVE To examine updated US retinoblastoma incidence patterns by sex, age at diagnosis, laterality, race/ethnicity, and year of diagnosis. DESIGN, SETTING, AND PARTICIPANTS The Surveillance, Epidemiology, and End Results (SEER) databases were examined for retinoblastoma incidence patterns by demographic and tumor characteristics. We studied 721 children in SEER 18 registries, 659 in SEER 13 registries, and 675 in SEER 9 registries. MAIN OUTCOMES AND MEASURES Incidence rates, incidence rate ratios (IRRs), and annual percent changes in rates. RESULTS During 2000-2009 in SEER 18, there was a significant excess of total retinoblastoma among boys compared with girls (IRR, 1.18; 95% CI, 1.02 to 1.36), in contrast to earlier reports of a female predominance. Bilateral retinoblastoma among white Hispanic boys was significantly elevated relative to white non-Hispanic boys (IRR, 1.81; 95% CI, 1.22 to 2.79) and white Hispanic girls (IRR, 1.75; 95% CI, 1.11 to 2.91) because of less rapid decreases in bilateral rates since the 1990s among white Hispanic boys than among the other groups. Retinoblastoma rates among white non-Hispanics decreased significantly since 1992 among those younger than 1 year and since 1998 among those with bilateral disease. CONCLUSIONS AND RELEVANCE Although changes in the availability of prenatal screening practices for retinoblastoma may have contributed to these incidence patterns, further research is necessary to determine their actual effect on the changing incidence of retinoblastoma in the US population. In addition, consistent with other cancers, an excess of retinoblastoma diagnosed in boys suggests a potential effect of sex on cancer origin.

  19. Apoptosis, proliferation and p53, cyclin D1, and retinoblastoma gene expression in relation to radiation response in transitional cell carcinoma of the bladder

    International Nuclear Information System (INIS)

    Moonen, Luc; Ong, Francisca; Gallee, Maarten; Verheij, Marcel; Horenblas, Simon; Hart, Augustinus A.M.; Bartelink, Harry

    2001-01-01

    Purpose: To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with local control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation. Methods and Materials: Paraffin-embedded pretreatment biopsies from 83 patients with invasive transitional cell carcinoma of the bladder were scored morphologically for apoptosis and immunohistochemically for Ki67, p53, cyclin D1, and retinoblastoma gene expression. Survival analysis methods were used to assess overall survival, local control, and freedom from distant metastases. A multiple proportional hazard (PH) regression analysis was performed to study the prognostic value of the above mentioned biologic parameters (all divided into two categories, except Ki67) in addition to classical prognostic factors such as T stage, histologic grade, multifocality of the tumor, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years. Results: Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a median of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a median of 12%. P53 protein was detectable in 61% of the tumors. Overexpression of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantly associated with p53 expression (p=0.04) and cyclin D1 overexpression (p=0.023). Cyclin D1 overexpression was found more often in Rb-positive tumors than in Rb-negative tumors (p=0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage or grade. In the PH analysis local control was found to be significantly better for tumors with wild-type p53 (p=0.028). Also, tumors with an apoptotic index above the median value (0

  20. Retinoblastoma: genetic considerations and report of a new animal model

    NARCIS (Netherlands)

    Albert, D.M.; O'Brien, J.M.; Marcus, D.M.; Bernards, R.A.

    1990-01-01

    Retinoblastoma is the most common primary, intraocular neoplasm of childhood. Histologically, retinoblastoma resembles, in many respects, other pediatric malignancies such as medulloblastoma and neuroblastoma. These tumors are composed of small, basophilic cells with scanty cytoplasm and often

  1. Atraso diagnóstico do retinoblastoma

    OpenAIRE

    Rodrigues,Karla E. S.; Latorre,Maria do Rosário D. O.; Camargo,Beatriz de

    2004-01-01

    OBJETIVOS: Identificar os principais sinais e sintomas do retinoblastoma e determinar o tempo médio entre o início dos sintomas e o diagnóstico. MÉTODOS: Estudo retrospectivo, com revisão dos prontuários das crianças diagnosticadas com retinoblastoma entre janeiro de 1991 e junho de 2000 no Departamento de Pediatria do Hospital do Câncer de São Paulo. Análise estatística: teste t de Student, análise e variância, teste de Tukey-HSD (honest significant differences), teste de Levene, análise de ...

  2. Herramienta para la Deteccion de Retinoblastoma

    OpenAIRE

    Vargas-Cuentas , Natalia Indira; Roman-Gonzalez , Avid

    2015-01-01

    International audience; El retinoblastoma, es un tumor que se presenta en la retina de las personas, especialmente en los niños. Una detección temprana del mismo, podría ser muy útil y salvar la vida del niño. Es en ese sentido, que el presente trabajo propone una herramienta sencilla para la detección de retinoblastoma analizando fotografías tomadas con flash en las cuales, en el ojo del niño se puede detectar la presencia de leucoria. Esta detección se realiza utilizando las funciones de de...

  3. Craniospinal Irradiation for Trilateral Retinoblastoma Following Ocular Irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Marks, Lawrence B.; Bentel, Gunilla; Sherouse, George W.; Spencer, David P.; Light, Kim

    2015-01-15

    A case study is presented. Craniospinal radiotherapy and a three-field pineal boost for trilateral retinoblastoma were delivered to a patient previously irradiated for ocular retinoblastoma. The availability of CT-based three-dimensional treatment planning provided the capability of identifying the previously irradiated volume as a three-dimensional anatomic structure and of designing a highly customized set of treatment beams that minimized reirradiation of that volume.

  4. Genetics Home Reference: retinoblastoma

    Science.gov (United States)

    ... Some studies suggest that additional genetic changes can influence the development of retinoblastoma ; these changes may help explain variations ... usually occurs in childhood, typically leading to the development of ... and there is no family history of the disease. Affected individuals are born ...

  5. Induction of growth stimulation in skin fibroblasts from retinoblastoma donors after ionizing radiation

    International Nuclear Information System (INIS)

    Diatloff-Zito, C.; Macieira-Coelho, A.; Turleau, C.; Cabanis, M.O.; Grouchy, J. de

    1983-01-01

    Skin fibroblasts from normal children and two children with a 13q14 deletion retinoblastoma (Rb) were submitted to fractionated doses of γ radiations. Irradiation reduced the population doublings in normal fibroblasts and the decline was inversely related to the dose. An increase in population doublings was obtained with one of the Rb cell lines. Foci appeared in the irradiated culture of the other Rb donor. It is suggested that fibroblasts from patients with Rb are able to express some phenotypical properties of transformed cells, perhaps related to factors rendering them more susceptible to carcinogens [fr

  6. Inhibitory effect of puerarin on proliferation of retinoblastoma cells ...

    African Journals Online (AJOL)

    ... 71.4 ± 4.5 % for control and Bmi-1 siRNA-treated groups, respectively. Conclusions: The results show that puerarin exert suppressive effects on human retinoblastoma Y79 cells and therefore may find application in the treatment of intraocular tumor. Keywords: Cancer, Puerarin, Retinoblastoma Y79 cells, mTOR inhibition, ...

  7. Ultrasonographic findings of retinoblastoma

    International Nuclear Information System (INIS)

    Chung, Sung Hoo; Kang, Ik Won; Park, Yang Hee; Kim, Chu Wan; Chi, Je Geun

    1982-01-01

    Retinoblastoma is the most common intraocular tumor in infants and young children which has relatively favorable prognosis with early diagnosis and adequate treatment, however, it can be lethal if the treatment is delayed or inadequate. Clinically, early diagnosis is often difficult because of minimal subjective and objective signs and symptoms, and the patients are usually too young to complain visual disturbance. When ophthalmoscopicexamination is impossible due to presence of opaue media in front of tumor mass as associated inflammatory reaction, hemorrhage, corneal opacity, retinal detachment, etc, ultrasonography is necessary for diagnosis of retinoblastoma. Authors analyzed ultrasonographic al findings with pathological correlation on 10 cases of confirmed retinoblastoma during the period of March 1981 to September1982 at the Seoul National University Hospital. In all cases, ultrasonography demonstrates intraocular masses and all of which are cystic type.Reflectivity of masses are higher than retroorbital fat tissue in 8 cases, and 7 cases show irregular internal echogenic texture. There is no correlation between reflexivity and internal echogenic texture with microscopic findings as rosette, pseudo rosette and micro cysts. Calcifications are demonstrated by ultrasonography as strong reflectiveness with posterior sonic shadowing in 9 cases and 9 of 10 cases are well correlated with calcifications in pathologic specimens. Anechoic cystic areas are shown in 9 cases, and 6 of 10 cases are well correlated with necrosis in pathologic specimen. In all cases, there is no attenuation of sound within tumor masses, and no demonstrable choroidal excavation. Associated retinal detachment is hardly identifiable in irregular contour and internal texture of cystic tumor masses

  8. Genetic Susceptibility to Vitiligo: GWAS Approaches for Identifying Vitiligo Susceptibility Genes and Loci

    Science.gov (United States)

    Shen, Changbing; Gao, Jing; Sheng, Yujun; Dou, Jinfa; Zhou, Fusheng; Zheng, Xiaodong; Ko, Randy; Tang, Xianfa; Zhu, Caihong; Yin, Xianyong; Sun, Liangdan; Cui, Yong; Zhang, Xuejun

    2016-01-01

    Vitiligo is an autoimmune disease with a strong genetic component, characterized by areas of depigmented skin resulting from loss of epidermal melanocytes. Genetic factors are known to play key roles in vitiligo through discoveries in association studies and family studies. Previously, vitiligo susceptibility genes were mainly revealed through linkage analysis and candidate gene studies. Recently, our understanding of the genetic basis of vitiligo has been rapidly advancing through genome-wide association study (GWAS). More than 40 robust susceptible loci have been identified and confirmed to be associated with vitiligo by using GWAS. Most of these associated genes participate in important pathways involved in the pathogenesis of vitiligo. Many susceptible loci with unknown functions in the pathogenesis of vitiligo have also been identified, indicating that additional molecular mechanisms may contribute to the risk of developing vitiligo. In this review, we summarize the key loci that are of genome-wide significance, which have been shown to influence vitiligo risk. These genetic loci may help build the foundation for genetic diagnosis and personalize treatment for patients with vitiligo in the future. However, substantial additional studies, including gene-targeted and functional studies, are required to confirm the causality of the genetic variants and their biological relevance in the development of vitiligo. PMID:26870082

  9. Expression of multidrug resistance proteins in retinoblastoma

    Directory of Open Access Journals (Sweden)

    Swati Shukla

    2017-11-01

    Full Text Available AIM: To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. METHODS: Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. RESULTS: Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1 expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp was observed in the drug resistant Y79 cells as well as in PCNC. CONCLUSION: Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy.

  10. Expression of multidrug resistance proteins in retinoblastoma.

    Science.gov (United States)

    Shukla, Swati; Srivastava, Arpna; Kumar, Sunil; Singh, Usha; Goswami, Sandeep; Chawla, Bhavna; Bajaj, Mandeep Singh; Kashyap, Seema; Kaur, Jasbir

    2017-01-01

    To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC) were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin) were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp) was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1) expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp) was observed in the drug resistant Y79 cells as well as in PCNC. Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy.

  11. Expression of multidrug resistance proteins in retinoblastoma

    Science.gov (United States)

    Shukla, Swati; Srivastava, Arpna; Kumar, Sunil; Singh, Usha; Goswami, Sandeep; Chawla, Bhavna; Bajaj, Mandeep Singh; Kashyap, Seema; Kaur, Jasbir

    2017-01-01

    AIM To elucidate the mechanism of multidrug resistance in retinoblastoma, and to acquire more insights into in vivo drug resistance. METHODS Three anticancer drug resistant Y79 human RB cells were generated against vincristine, etoposide or carboplatin, which are used for conventional chemotherapy in RB. Primary cultures from enucleated eyes after chemotherapy (PCNC) were also prepared. Their chemosensitivity to chemotherapeutic agents (vincristine, etoposide and carboplatin) were measured using MTT assay. Western blot analysis was performed to evaluate the expression of p53, Bcl-2 and various multidrug resistant proteins in retinoblastoma cells. RESULTS Following exposure to chemotherapeutic drugs, PCNC showed less sensitivity to drugs. No significant changes observed in the p53 expression, whereas Bcl-2 expression was found to be increased in the drug resistant cells as well as in PCNC. Increased expression of P-glycoprotein (P-gp) was observed in drug resistant Y79 cells; however there was no significant change in the expression of P-gp found between primary cultures of primarily enucleated eyes and PCNC. Multidrug resistance protein 1 (Mrp-1) expression was found to be elevated in the drug resistant Y79 cells as well as in PCNC. No significant change in the expression of lung resistance associated protein (Lrp) was observed in the drug resistant Y79 cells as well as in PCNC. CONCLUSION Our results suggest that multidrug resistant proteins are intrinsically present in retinoblastoma which causes treatment failure in managing retinoblastoma with chemotherapy. PMID:29181307

  12. Clinical presentation of retinoblastoma in Alexandria: A step toward earlier diagnosis.

    Science.gov (United States)

    Soliman, Sameh E; Eldomiaty, Wesam; Goweida, Mohamed B; Dowidar, Amgad

    2017-01-01

    To evaluate the clinical presentation of retinoblastoma in Alexandria, Egypt, correlate the timing of accurate diagnosis with the presence of advanced disease and identify causes of delayed presentation. Retrospective noncomparative single institution study reviews demographic and clinical data of all new children with retinoblastoma presenting to Alexandria Main University ocular oncology clinic (OOC) from January 2012 to June 2014. Diagnosis time was from initial parental complaint to retinoblastoma diagnosis and referral time was from retinoblastoma diagnosis to presentation to the Alexandria OCC. Delayed Diagnosis and referral were counted if >2 weeks. Advanced presentation is defined as clinical TNMH (8th edition) staging of cT2 or cT3 (international intraocular retinoblastoma classification group D or E) in at least one eye or the presence of extra-ocular disease (cT4). Seventy eyes of 47 children were eligible: 52% unilateral, 7% with family history and 96% presented with leukocorea. Sixty-four percent of children had advanced intraocular disease and none had extra-ocular disease. Delayed presentation occurred in 58% of children and was significantly associated with advanced disease in both unilaterally and bilaterally affected children (p = 0.003, 0.002 respectively). The delay in diagnosis was more in unilateral cases while the delay in referral was more in bilateral cases. The main cause of delayed presentation in unilateral retinoblastoma was misdiagnosis (30%) while parental shopping for second medical opinion (30%) was the main cause in bilateral children. Delayed diagnosis is a problem affecting retinoblastoma management. Better medical education and training, health education and earlier screening are recommended to achieve earlier diagnosis.

  13. Radiation management of retinoblastoma

    International Nuclear Information System (INIS)

    Takemasa, Kazuhiko; Ito, Hisao; Hashimoto, Shozo; Tanaka, Yasuhiko; Oguchi, Yoshihisa

    1991-01-01

    An analysis has been conducted of 45 patients treated for retinoblastoma at Keio University Hospital between 1970 and 1990. Of these patients, 32 had unilateral lesion and 13 had bilateral lesion. Further, since their disease was far advanced, 29 patients with unilateral lesion and 12 patients with bilateral lesion underwent enucleation. As a result, 3 patients with unilateral retinoblastoma and all patients with bilateral manifestation of the disease were treated with radiotherapy (45-50 Gy) with or without cryotherapy and photocoagulation. One patient with unilateral lesion, who had received both radiotherapy and chemotherapy, showed metastases at the first presentation at our clinic and thus was excluded from this analysis. Among 16 eyes of 15 patients who were given radiotherapy, 6 eyes developed recurrence and needed to have further treatment. In 6 eyes out of 12, cataract developed, and out of 10 eyes in which eye function was evaluable, good vision was able to be preserved in 5 eyes. (author)

  14. Whole Gene Capture Analysis of 15 CRC Susceptibility Genes in Suspected Lynch Syndrome Patients.

    Science.gov (United States)

    Jansen, Anne M L; Geilenkirchen, Marije A; van Wezel, Tom; Jagmohan-Changur, Shantie C; Ruano, Dina; van der Klift, Heleen M; van den Akker, Brendy E W M; Laros, Jeroen F J; van Galen, Michiel; Wagner, Anja; Letteboer, Tom G W; Gómez-García, Encarna B; Tops, Carli M J; Vasen, Hans F; Devilee, Peter; Hes, Frederik J; Morreau, Hans; Wijnen, Juul T

    2016-01-01

    Lynch Syndrome (LS) is caused by pathogenic germline variants in one of the mismatch repair (MMR) genes. However, up to 60% of MMR-deficient colorectal cancer cases are categorized as suspected Lynch Syndrome (sLS) because no pathogenic MMR germline variant can be identified, which leads to difficulties in clinical management. We therefore analyzed the genomic regions of 15 CRC susceptibility genes in leukocyte DNA of 34 unrelated sLS patients and 11 patients with MLH1 hypermethylated tumors with a clear family history. Using targeted next-generation sequencing, we analyzed the entire non-repetitive genomic sequence, including intronic and regulatory sequences, of 15 CRC susceptibility genes. In addition, tumor DNA from 28 sLS patients was analyzed for somatic MMR variants. Of 1979 germline variants found in the leukocyte DNA of 34 sLS patients, one was a pathogenic variant (MLH1 c.1667+1delG). Leukocyte DNA of 11 patients with MLH1 hypermethylated tumors was negative for pathogenic germline variants in the tested CRC susceptibility genes and for germline MLH1 hypermethylation. Somatic DNA analysis of 28 sLS tumors identified eight (29%) cases with two pathogenic somatic variants, one with a VUS predicted to pathogenic and LOH, and nine cases (32%) with one pathogenic somatic variant (n = 8) or one VUS predicted to be pathogenic (n = 1). This is the first study in sLS patients to include the entire genomic sequence of CRC susceptibility genes. An underlying somatic or germline MMR gene defect was identified in ten of 34 sLS patients (29%). In the remaining sLS patients, the underlying genetic defect explaining the MMRdeficiency in their tumors might be found outside the genomic regions harboring the MMR and other known CRC susceptibility genes.

  15. Retinoblastoma: Assessing the Level of Knowledge of Tumour By ...

    African Journals Online (AJOL)

    For 60% leucocoria was the only sign suspect of retinoblastoma, for 80% strabismus was the only sign of retinoblastoma, only 10% had associated leucocoria and strabismus as two early signs of this cancer. Twelve percent had a score equal to 3/3, eight (8%) had a score equal to 2/3, and 80% had a score of less than or ...

  16. Diffuse infiltrating retinoblastoma invading subarachnoid space

    Directory of Open Access Journals (Sweden)

    Kase S

    2011-06-01

    Full Text Available Satoru Kase1, Kazuhiko Yoshida1, Shigenobu Suzuki2, Koh-ichi Ohshima3, Shigeaki Ohno4, Susumu Ishida11Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Sapporo; 2Department of Ophthalmic Oncology, National Cancer Center Hospital, Tokyo; 3Section of Ophthalmology, Okayama Medical Center, Okayama; 4Department of Ocular Inflammation and Immunology, Hokkaido University Graduate School of Medicine, Sapporo, JapanAbstract: We report herein an unusual case of diffuse infiltrating retinoblastoma involving the brain, which caused a patient’s death 27 months after enucleation. An eight-year-old boy complained of blurred vision in his right eye (OD in October 2006. Funduscopic examination showed optic disc swelling, dense whitish vitreous opacity, and an orange-colored subretinal elevated lesion adjacent to the optic disc. Fluorescein angiography revealed hyperfluorescence in the peripapillary region at an early-phase OD. Because the size of the subretinal lesion and vitreous opacity gradually increased, he was referred to us. His visual acuity was 20/1000 OD on June 20, 2007. Slit-lamp biomicroscopy showed a dense anterior vitreous opacity. Ophthalmoscopically, the subretinal orange-colored area spread out until reaching the mid peripheral region. A B-mode sonogram and computed tomography showed a thick homogeneous lesion without calcification. Gadolinium-enhanced magnetic resonance imaging showed a markedly enhanced appearance of the underlying posterior retina. Enucleation of the right eye was performed nine months after the initial presentation. Histopathology demonstrated retinal detachment and a huge choroidal mass invading the optic nerve head. The tumor was consistent with diffuse infiltrating retinoblastoma. The patient died due to brain involvement 27 months after enucleation. Ophthalmologists should be aware that diffuse infiltrating retinoblastoma may show an unfavorable course if its diagnosis is delayed

  17. Proton Radiation Therapy for the Treatment of Retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Mouw, Kent W. [Harvard Radiation Oncology Program, Boston, Massachusetts (United States); Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Sethi, Roshan V.; Yeap, Beow Y.; MacDonald, Shannon M.; Chen, Yen-Lin E.; Tarbell, Nancy J.; Yock, Torunn I.; Munzenrider, John E.; Adams, Judith [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States); Grabowski, Eric [Department of Pediatrics, Massachusetts General Hospital, Boston, Massachusetts (United States); Mukai, Shizuo [Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts (United States); Shih, Helen A., E-mail: hshih@partners.org [Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts (United States)

    2014-11-15

    Purpose: To investigate long-term disease and toxicity outcomes for pediatric retinoblastoma patients treated with proton radiation therapy (PRT). Methods and Materials: This is a retrospective analysis of 49 retinoblastoma patients (60 eyes) treated with PRT between 1986 and 2012. Results: The majority (84%) of patients had bilateral disease, and nearly half (45%) had received prior chemotherapy. At a median follow-up of 8 years (range, 1-24 years), no patients died of retinoblastoma or developed metastatic disease. The post-PRT enucleation rate was low (18%), especially in patients with early-stage disease (11% for patients with International Classification for Intraocular Retinoblastoma [ICIR] stage A-B disease vs 23% for patients with ICIR stage C-D disease). Post-PRT ophthalmologic follow-up was available for 61% of the preserved eyes (30 of 49): 14 of 30 eyes (47%) had 20/40 visual acuity or better, 7 of 30 (23%) had moderate visual acuity (20/40-20/600), and 9 of 30 (30%) had little or no useful vision (worse than 20/600). Twelve of 60 treated eyes (20%) experienced a post-PRT event requiring intervention, with cataracts the most common (4 eyes). No patients developed an in-field second malignancy. Conclusions: Long-term follow-up of retinoblastoma patients treated with PRT demonstrates that PRT can achieve high local control rates, even in advanced cases, and many patients retain useful vision in the treated eye. Treatment-related ocular side effects were uncommon, and no radiation-associated malignancies were observed.

  18. Información sobre las secuelas y futuros riesgos para los sobrevivientes de retinoblastoma Information on late effects and future risks for retinoblastoma survivors

    Directory of Open Access Journals (Sweden)

    Laura Schwartz

    2005-04-01

    Full Text Available Los índices de sobrevida de los pacientes con cáncer en la infancia han aumentado en las últimas décadas. Se observan secuelas como consecuencia de esta enfermedad y su tratamiento. Los sobrevivientes de retinoblastoma presentan efectos adversos como consecuencia de la cirugía, la radioterapia y la quimioterapia. Las formas bilaterales irradiadas presentan un riesgo aumentado de desarrollar un segundo cáncer. Tanto los casos que presentaron retinoblastoma unilateral o bilateral pueden transmitir esta enfermedad a su descendencia. El diagnóstico de este tumor es excepcional después de los 4 años de edad y no se sabe claramente qué conocimiento tienen estos sobrevivientes del diagnóstico, del tratamiento y de los futuros riesgos. El consentimiento informado y el posterior resumen de historia clínica no aclaran demasiado a los padres. Los pacientes curados de retinoblastoma se verían beneficiados con un seguimiento prolongado en las instituciones en que fueron tratados, ya que les permitiría recibir información acerca de lo padecido, del tratamiento, de los riesgos y se podrían identificar las consecuencias posteriores de la enfermedad y su tratamiento.The survival rates of childhood cancer have increased in the past few decades. Late consequences related to the cancer and the treatment are observed. The late effects in retinoblastoma survivors are related to the surgery, the radiotherapy and the chemotherapy. Patients with irradiated bilateral retinoblastoma are at high risk to develop a second cancer. Survivors of bilateral or unilateral forms could transmit this disease to their offspring. The diagnosis of retinoblastoma is exceptional after 4 years of age, and it is not clear whether these survivors have knowledge of their diagnosis, treatment and future risks. The informed consent and the summary of the clinical histories do not help to clarify the situation. It will be of great benefit for the patients cured of retinoblastoma

  19. X-ray sensitivity of fibroblasts from patients with hereditary retinoblastoma and their families

    International Nuclear Information System (INIS)

    Pledger, J.V.; Craft, A.W.; Bartlett, K.; Long, D.R.

    1987-01-01

    The in vitro response to X-irradiation of cultured human fibroblasts was studied using a colony forming assay. A comprehensive reference range was established, giving a median Dsub(0) value of 98.5 cGy with an interquartile range of 86.5-110.5 cGy. Cells from 3 retinoblastoma family pedigrees were studied and the cell survival after exposure to X-rays was compared between affected (11 samples) and unaffected (26 samples) family members. No significant differences in response to ionising radiation were found between the controls, the affected and the unaffected members of the 3 families. The affected members had a median Dsub(0) of 97.5 cGy (interquartile range 87.5-107.5 cGy) and the unaffected members had a median Dsub(0) of 102 cGy (interquartile range 93-111 cGy). Thus radiosensitivity is not a useful marker for the detection of the retinoblastoma gene. (author)

  20. Breaking down barriers to communicating complex retinoblastoma information: can graphics be the solution?

    Science.gov (United States)

    Chiu, Hannah H; Dimaras, Helen; Downie, Rob; Gallie, Brenda

    2015-06-01

    To investigate the impact of a graphical timeline summarizing bilateral retinoblastoma disease and treatment outcomes on parents' understanding of complex medical information. Cross-sectional survey. Parents of children with retinoblastoma who were being actively managed at The Hospital for Sick Children were recruited. Forty-five parents from 42 families participated. After a standardized presentation on retinoblastoma and visual tool named Disease-Specific electronic Patient Illustrated Clinical Timeline (DePICT), parents completed a 19-item questionnaire designed to assess their understanding of treatment choices for 2 eyes in bilateral retinoblastoma as communicated using DePICT. SPSS was used to perform statistical analysis. Forty-five parents from 42 families participated (65% female). Median age of participants was 34 years. Median level of participant education was completion of college/trade school. The median level of annual income was $40,000 to $70,000 CDN. Median time since diagnosis of retinoblastoma in their child was 13.5 months. Twenty-three (51%) participants were parents of children with unilateral retinoblastoma, and 22 (49%) were parents of children with bilateral retinoblastoma. Median number of correct answers was 15 of 19, and mean score was 77%. Normal distribution of scores was noted. English as a first language was significantly associated with score (p = 0.01). No significant association was observed between other variables and score in all analyses. This study builds on the validation of DePICT by demonstrating that parents can achieve good comprehension even when considering choices for treatment for 2 eyes with bilateral retinoblastoma. Clinical application of this tool can enhance the consent process. Copyright © 2015 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

  1. World disparities in risk definition and management of retinoblastoma: a report from the International Retinoblastoma Staging Working Group.

    Science.gov (United States)

    Chantada, Guillermo L; Doz, François; Orjuela, Manuela; Qaddoumi, Ibrahim; Sitorus, Rita S; Kepak, Tomas; Furmanchuk, Anna; Castellanos, Mauricio; Sharma, Tarun; Chevez-Barrios, Patricia; Rodriguez-Galindo, Carlos

    2008-03-01

    Following from the publication of the International Retinoblastoma Staging System, an open internet discussion group was created at the www.cure4kids.org resource. The results of a survey distributed among participants are discussed. Although most patients with retinoblastoma were treated under prospective protocols, there was a wide variation in the definition of risk criteria and in the criteria for giving adjuvant chemotherapy following enucleation. Definition of high-risk histological features and the criteria for use of adjuvant therapy will be standardized in future studies. Internet meetings are a valuable mechanism for enabling participation from under-resourced countries in the development of cooperative studies. (c) 2007 Wiley-Liss, Inc.

  2. Knockdown of hypoxia-inducible factor-1 alpha reduces proliferation, induces apoptosis and attenuates the aggressive phenotype of retinoblastoma WERI-Rb-1 cells under hypoxic conditions.

    Science.gov (United States)

    Xia, Tian; Cheng, Hao; Zhu, Yu

    2014-01-01

    Hypoxia-inducible factor-1 alpha (HIF-1α) plays a critical role in tumor cell adaption to hypoxia by inducing the transcription of numerous genes. The role of HIF-1α in malignant retinoblastoma remains unclear. We analyzed the role of HIF-1α in WERI-Rb-1 retinoblastoma cells under hypoxic conditions. CoCl2 (125 mmol/L) was added to the culture media to mimic hypoxia. HIF-1α was silenced using siRNA. Gene and protein expression were measured by semi-quantitative RT-PCR and Western blotting. Cell cycle and apoptosis were analyzed by flow cytometry. Cell proliferation, adhesion and invasion were assayed using MTT, Transwell invasion, and cell adhesion assays respectively. Hypoxia significantly upregulated HIF-1α protein expression and the HIF-1α target genes VEGF, GLUT1, and Survivin mRNA. HIF-1α mRNA expression was not affected by hypoxia. Transfection of the siRNA expression plasmid pRNAT-CMV3.2/Neo-HIF-1α silenced HIF-1α by approximately 80% in hypoxic WERI-Rb-1 cells. The knockdown of HIF-1α under hypoxic conditions downregulated VEGF, GLUT1, and Survivin mRNA. It also inhibited proliferation, promoted apoptosis, induced the G0/G1 phase cell cycle arrest, and reduced the adhesion and invasion of WERI-Rb-1 cells. HIF-1α plays a major role in the survival and aggressive phenotype of retinoblastoma cells under hypoxic conditions. Targeting HIF-1α may be a promising therapeutic strategy for human malignant retinoblastoma.

  3. Postradiation leiomyosarcoma of the orbit complicating bilateral retinoblastoma

    International Nuclear Information System (INIS)

    Font, R.L.; Jurco, S.; Brechner, R.J.

    1983-01-01

    A 31-year-old woman had bilateral retinoblastoma diagnosed in early childhood. The right eye was enucleated at the age of 1 year, and the left eye was treated with radiation therapy (a total dose of 16,000 rad). Twenty-three years later, in 1975, a subcutaneous mass was noted in the left periorbital region. A biopsy specimen of the mass was taken and a diagnosis of pleomorphic postradiation sarcoma was made. Electron microscopic studies of the periorbital mass confirmed the diagnosis of leiomyosarcoma. After additional radiation therapy, the residual mass was surgically excised. Five years later, a right renal mass, which histologically proved to be a renal cell carcinoma, was discovered. She was treated with nephrectomy, radiation, and chemotherapy. A recent follow-up examination disclosed that the patient is alive and apparently without any evidence of metastatic disease, 30 years after the diagnosis of bilateral retinoblastoma was made. The literature is reviewed regarding postradiation sarcomas and the occurrence of second malignant neoplasms in patients with retinoblastoma

  4. Postradiation leiomyosarcoma of the orbit complicating bilateral retinoblastoma.

    Science.gov (United States)

    Font, R L; Jurco, S; Brechner, R J

    1983-10-01

    A 31-year-old woman had bilateral retinoblastoma diagnosed in early childhood. The right eye was enucleated at the age of 1 year, and the left eye was treated with radiation therapy (a total dose of 16,000 rad). Twenty-three years later, in 1975, a subcutaneous mass was noted in the left periorbital region. A biopsy specimen of the mass was taken and a diagnosis of pleomorphic postradiation sarcoma was made. Electron microscopic studies of the periorbital mass confirmed the diagnosis of leiomyosarcoma. After additional radiation therapy, the residual mass was surgically excised. Five years later, a right renal mass, which histologically proved to be a renal cell carcinoma, was discovered. She was treated with nephrectomy, radiation, and chemotherapy. A recent follow-up examination disclosed that the patient is alive and apparently without any evidence of metastatic disease, 30 years after the diagnosis of bilateral retinoblastoma was made. The literature is reviewed regarding postradiation sarcomas and the occurrence of second malignant neoplasms in patients with retinoblastoma.

  5. Gain of DNA methylation is enhanced in the absence of CTCF at the human retinoblastoma gene promoter

    International Nuclear Information System (INIS)

    Dávalos-Salas, Mercedes; Furlan-Magaril, Mayra; González-Buendía, Edgar; Valdes-Quezada, Christian; Ayala-Ortega, Erandi; Recillas-Targa, Félix

    2011-01-01

    Long-term gene silencing throughout cell division is generally achieved by DNA methylation and other epigenetic processes. Aberrant DNA methylation is now widely recognized to be associated with cancer and other human diseases. Here we addressed the contribution of the multifunctional nuclear factor CTCF to the epigenetic regulation of the human retinoblastoma (Rb) gene promoter in different tumoral cell lines. To assess the DNA methylation status of the Rb promoter, genomic DNA from stably transfected human erythroleukemic K562 cells expressing a GFP reporter transgene was transformed with sodium bisulfite, and then PCR-amplified with modified primers and sequenced. Single- and multi-copy integrants with the CTCF binding site mutated were isolated and characterized by Southern blotting. Silenced transgenes were reactivated using 5-aza-2'-deoxycytidine and Trichostatin-A, and their expression was monitored by fluorescent cytometry. Rb gene expression and protein abundance were assessed by RT-PCR and Western blotting in three different glioma cell lines, and DNA methylation of the promoter region was determined by sodium bisulfite sequencing, together with CTCF dissociation and methyl-CpG-binding protein incorporation by chromatin immunoprecipitation assays. We found that the inability of CTCF to bind to the Rb promoter causes a dramatic loss of gene expression and a progressive gain of DNA methylation. This study indicates that CTCF plays an important role in maintaining the Rb promoter in an optimal chromatin configuration. The absence of CTCF induces a rapid epigenetic silencing through a progressive gain of DNA methylation. Consequently, CTCF can now be seen as one of the epigenetic components that allows the proper configuration of tumor suppressor gene promoters. Its aberrant dissociation can then predispose key genes in cancer cells to acquire DNA methylation and epigenetic silencing

  6. Scleral buckling for retinal detachment in patients with retinoblastoma

    International Nuclear Information System (INIS)

    Buzney, S.M.; Pruett, R.C.; Regan, C.D.; Walton, D.S.; Smith, T.R.

    1984-01-01

    Three children (two girls and one boy) with bilateral retinoblastoma each developed a presumed rhegmatogenous retinal detachment in one eye. All three eyes had previously received radiation and cryotherapy. In each case the retinal detachment responded promptly to conventional surgical methods via scleral buckling in the area of treated retinoblastoma and presumed retinal break. All three eyes have retained useful vision for follow-up periods of 3.5 to 12 years

  7. Scleral buckling for retinal detachment in patients with retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Buzney, S.M.; Pruett, R.C.; Regan, C.D.; Walton, D.S.; Smith, T.R.

    1984-10-15

    Three children (two girls and one boy) with bilateral retinoblastoma each developed a presumed rhegmatogenous retinal detachment in one eye. All three eyes had previously received radiation and cryotherapy. In each case the retinal detachment responded promptly to conventional surgical methods via scleral buckling in the area of treated retinoblastoma and presumed retinal break. All three eyes have retained useful vision for follow-up periods of 3.5 to 12 years.

  8. Retinoblastoma: experience of a referral center in the North Region of Portugal

    Directory of Open Access Journals (Sweden)

    Rocha-Bastos R

    2014-05-01

    Full Text Available RA da Rocha-Bastos,1 JR Araújo,1 RS Silva,2 MJ Gil-da-Costa,2 E Brandão,1 NJ Farinha,2,3 F Falcão-Reis,1,4 T Dinah-Bragança1 1Department of Ophthalmology, Hospital São João, 2Hematology and Oncology Unit, Pediatric Hospital, Hospital São João, 3Pediatrics Department, Faculty of Medicine, University of Porto, 4Department of Sense Organs, Faculty of Medicine, University of Porto, Porto, Portugal Purpose: To describe the experience of the Ophthalmology Department of Hospital São João (HSJ, a tertiary health care center in North Region, Portugal, in terms of the diagnosis, treatment, and follow-up of retinoblastoma. Methods: This was a retrospective study of patients diagnosed with retinoblastoma in Hospital São João, between 1978 and 2012. Results: Fifty patients with retinoblastoma were evaluated in our institution between 1978 and 2012. Four patients were excluded due to loss of follow-up. Among the 46 retinoblastoma cases, 33 (71.7% were unilateral and 13 (28.3% bilateral, with a mean age at diagnosis of 22.19 months and 6.92 months, respectively (P<0.001. Leukocoria was the most common presenting sign (36.9%, followed by strabismus (19.6%, a combination of leukocoria and strabismus (8.7%, and buphthalmia (2.2%. Between 1978 and 1992, nine retinoblastoma cases were referred to our hospital, all of them unilateral, and, in each case, enucleation was performed, with or without salvage therapy. Between 1993 and 2012, 18 eyes with retinoblastoma were successfully managed with conservative treatment. Conclusion: Demographic results were generally coincident with previous reports. It is crucial to screen leukocoria in pediatric practice, even in asymptomatic children. The outcome of retinoblastoma treatment in our hospital is similar to other series in developed countries. Keywords: retinoblastoma, leukocoria, strabismus, enucleation, pediatric cancer

  9. Imaging in the trilateral retinoblastoma syndrome

    International Nuclear Information System (INIS)

    Bagley, L.J.; Hurst, R.W.; Zimmerman, R.A.; Shields, J.A.; Shields, C.L.; De Potter, P.

    1996-01-01

    The medical records, CT, and MRI of ten children with trilateral retinoblastoma were reviewed. The intracranial pathology consisted of eight pineal neoplasms and two parasellar lesions, at least seven of the which were calcified. Two lesions demonstrated calcification only (no soft tissue mass) at initial presentation. Hydrocephalus was seen in eight cases, and concurrent or subsequent subarachnoid dissemination was documented in seven. Only one patient is known to be alive at the present time. The imaging features of the midline intracranial tumors mirror those of the ocular neoplasm. As calcification may be the only clue to the presence of the intracranial malignancy, close surveillance of high-risk patients with retinoblastoma with initial CT and follow-up MRI is suggested. (orig.). With 3 figs., 1 tab

  10. Imaging in the trilateral retinoblastoma syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Bagley, L.J. [Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104 (United States); Hurst, R.W. [Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104 (United States); Zimmerman, R.A. [Department of Radiology, Children`s Hospital of Philadelphia, 34 th St. and Civic Center Blvd., Philadelphia, PA 19104 (United States); Shields, J.A. [Ocular Oncology Service, Wills Eye Hospital, 900 Walnut St., Philadelphia, PA 19107 (United States); Shields, C.L. [Ocular Oncology Service, Wills Eye Hospital, 900 Walnut St., Philadelphia, PA 19107 (United States); De Potter, P. [Ocular Oncology Service, Wills Eye Hospital, 900 Walnut St., Philadelphia, PA 19107 (United States)

    1996-02-01

    The medical records, CT, and MRI of ten children with trilateral retinoblastoma were reviewed. The intracranial pathology consisted of eight pineal neoplasms and two parasellar lesions, at least seven of the which were calcified. Two lesions demonstrated calcification only (no soft tissue mass) at initial presentation. Hydrocephalus was seen in eight cases, and concurrent or subsequent subarachnoid dissemination was documented in seven. Only one patient is known to be alive at the present time. The imaging features of the midline intracranial tumors mirror those of the ocular neoplasm. As calcification may be the only clue to the presence of the intracranial malignancy, close surveillance of high-risk patients with retinoblastoma with initial CT and follow-up MRI is suggested. (orig.). With 3 figs., 1 tab.

  11. Sonic Hedgehog Initiates Cochlear Hair Cell Regeneration through Downregulation of Retinoblastoma Protein

    Science.gov (United States)

    Lu, Na; Chen, Yan; Wang, Zhengmin; Chen, Guoling; Lin, Qin; Chen, Zheng-Yi; Li, Huawei

    2013-01-01

    Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration. PMID:23211596

  12. Socioeconomic and psychological impact of treatment for unilateral intraocular retinoblastoma.

    Science.gov (United States)

    Soliman, S E; Dimaras, H; Souka, A A; Ashry, M H; Gallie, B L

    2015-06-01

    To identify the socioeconomic and psychosocial impacts of clinical treatment decisions for advanced unilateral intraocular retinoblastoma. Retrospective observational case series. institutional study at Alexandria Main University Hospital. records of 66 unilateral retinoblastoma cases treated from May 2005 to May 2013 were retrospectively reviewed. Sixty cases were eligible (International Intraocular Retinoblastoma Classification [IIRC] group C, D or E). two treatment groups were compared: enucleation vs. salvage treatment. Salvage treatment eyes were further subdivided based on IIRC group. Six socioeconomic parameters (financial burden, financial impact, psychological, social, medical and tumor impacts) were scored. Parameter scores ranged from 0 to 3, for overall score range 0 (no adverse impact) to 18 (severe adverse impact). derived Socioeconomic scores were correlated with treatment and outcomes. The enucleation group (28 eyes) had a median overall Socioeconomic score of 4/18, significantly lower than the salvage treatment group (32 eyes), median score 11/18 (PSocioeconomic score varied with IIRC group. Attempted eye salvage failed in 25 children, due to uncontrolled tumor (44%) and socioeconomic impact of cumulative therapies (56%). Treatment duration and Socioeconomic score were higher for the 5 children in the salvage treatment group who developed metastatic disease compared to those without metastasis (Psocioeconomic and psychosocial impacts of attempted ocular salvage for unilateral intraocular retinoblastoma are severe, in comparison to primary enucleation. Primary enucleation is a good treatment for unilateral retinoblastoma. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  13. Epidemiologic Study of Retinoblastoma in Recife, Pernambuco - Brazil: January 1985 - July 1997 Estudo Epidemiológico do Retinoblastoma no Recife - Pernambuco - Brasil: janeiro 1985 - julho 1997

    Directory of Open Access Journals (Sweden)

    Armando Anderson Abreu

    1999-10-01

    Full Text Available Background: Retinoblastoma is by far the most frequent malignant intraocular tumor of childhood. This study was performed to characterize the clinical, diagnostic, treatment and prognostic aspects in patients with retinoblastoma in three reference centers for this pathology in the city of Recife, Pernambuco - Brazil. Methods: A consecutive series of 85 patients with retinoblastoma was reviewed. The authors selected 66 patients (77.6% that fulfilled the inclusion criteria for these study. Results: Of a total of 66 patients with retinoblastoma, 4.5% had a previous history of the disease in the family. Males were more affected than females at a ratio (male/female of 1.12. The mean age of appearance of the first symptoms was 23.8 months, with leukocoria and ocular hyperemia being the most frequent. The mean age at time of diagnosis was 31.7 months and for surgical treatment 32.8 months. The right eye was affected in 42.4% of the cases and the left was involved in 37.9% of cases. The tumor was unilateral in 80.3% and bilateral in 19.7% of the cases. There was extraocular involvement in 62.1%, and it was intraocular in 37.9% of the patients. Treatment was surgery combined with chemotherapy in 47.0% of the patients. 27.3% of the patients died and 19.7% abandoned the treatment. Conclusions: The data on the epidemiology of retinoblastoma found in our city resembles that of other developing countries, concerning the epidemioloy of retinoblastoma.Objetivo: O retinoblastoma é o tumor maligno intraocular mais freqüente da infância. O objetivo deste estudo foi avaliar aspectos clínicos, de diagnóstico, tratamento e prognóstico em pacientes portadores de retinoblastoma atendidos em três centros de referência para esta patologia na cidade do Recife - PE. Métodos: Revisamos 85 prontuários de portadores de retinoblastoma e apresentamos o resultado da análise de 66 destes pacientes, atendidos durante o período de janeiro de 1985 a julho de 1997

  14. A study on the toxicity of three radiosensitizers on retinoblastoma cells by MTT assay

    International Nuclear Information System (INIS)

    Yi Xianjin; Jin Yizun; Ding Li; Ni Zhou; Wang Wenji

    1994-01-01

    The toxicity of three radiosensitizers BSO, CM and RSU-1069 on retinoblastoma cells was determined and the efficiency of in vitro MTT assay on drug-screening for retinoblastoma was also evaluated. The results showed that the MTT assay is very useful. The toxicity of radiosensitizers on retinoblastoma cells is dependent on cell line characteristics, drug concentration and time of exposure to it

  15. {sup 106}Ruthenium Plaque Therapy (RPT) for Retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Murakami, Naoya, E-mail: namuraka@ncc.go.jp [Department of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Suzuki, Shigenobu [Department of Ophthalmic Oncology, National Cancer Center Hospital, Tokyo (Japan); Ito, Yoshinori [Department of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Yoshimura, Ryoichi [Department of Diagnostic Radiology and Oncology, Head and Neck Reconstruction Division, Graduate School, Tokyo Medical and Dental University, Tokyo (Japan); Inaba, Koji; Kuroda, Yuki; Morota, Madoka; Mayahara, Hiroshi; Sakudo, Mototake; Wakita, Akihisa; Okamoto, Hiroyuki; Sumi, Minako; Kagami, Yoshikazu [Department of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Nakagawa, Keiichi; Ohtomo, Kuni [Department of Radiology, University of Tokyo Hospital, Tokyo (Japan); Itami, Jun [Department of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan)

    2012-09-01

    Purpose: To evaluate the effectiveness of episcleral {sup 106}ruthenium plaque therapy (RPT) in the management of retinoblastoma. Methods and Materials: One hundred one RPTs were retrospectively analyzed that were performed in 90 eyes of 85 patients with retinoblastoma at National Cancer Center Hospital between 1998 and 2008. Each RPT had a corresponding tumor and 101 tumors were considered in the analysis of local control. Median follow-up length was 72.8 months. Median patient age at the RPT was 28 months. Median prescribed doses at reference depth and outer surface of the sclera were 47.4 Gy and 162.3 Gy, respectively. Results: Local control rate (LCR) and ocular retention rate (ORR) at 2 years were 33.7% and 58.7%, respectively. Unilateral disease, International Classification of Retinoblastoma group C or more advanced at the first presentation or at the time of RPT, vitreous and/or subretinal seeding, tumor size greater than 5 disc diameter (DD), reference depth greater than 5 mm, dose rate at reference depth lower than 0.7 Gy/hour, dose at the reference depth lower than 35 Gy, and (biologically effective dose with an {alpha}/{beta} ratio of 10 Gy) at the reference depth lower than 40 Gy{sub 10} were associated with unfavorable LCR. Two patients died of metastatic disease. Radiation complications included retinal detachment in 12 eyes (13.3%), proliferative retinopathy in 6 (6.7%), rubeosis iris in 2 (2.2%), and posterior subcapsular cataract in 23 (25.6%). Conclusion: RPT is an effective eye-preserving treatment for retinoblastoma.

  16. Colorimetric and longitudinal analysis of leukocoria in recreational photographs of children with retinoblastoma.

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    Alireza Abdolvahabi

    Full Text Available Retinoblastoma is the most common primary intraocular tumor in children. The first sign that is often reported by parents is the appearance of recurrent leukocoria (i.e., "white eye" in recreational photographs. A quantitative definition or scale of leukocoria--as it appears during recreational photography--has not been established, and the amount of clinical information contained in a leukocoric image (collected by a parent remains unknown. Moreover, the hypothesis that photographic leukocoria can be a sign of early stage retinoblastoma has not been tested for even a single patient. This study used commercially available software (Adobe Photoshop® and standard color space conversion algorithms (operable in Microsoft Excel® to quantify leukocoria in actual "baby pictures" of 9 children with retinoblastoma (that were collected by parents during recreational activities i.e., in nonclinical settings. One particular patient with bilateral retinoblastoma ("Patient Zero" was photographed >7, 000 times by his parents (who are authors of this study over three years: from birth, through diagnosis, treatment, and remission. This large set of photographs allowed us to determine the longitudinal and lateral frequency of leukocoria throughout the patient's life. This study establishes: (i that leukocoria can emerge at a low frequency in early-stage retinoblastoma and increase in frequency during disease progression, but decrease upon disease regression, (ii that Hue, Saturation and Value (i.e., HSV color space are suitable metrics for quantifying the intensity of retinoblastoma-linked leukocoria; (iii that different sets of intraocular retinoblastoma tumors can produce distinct leukocoric reflections; and (iv the Saturation-Value plane of HSV color space represents a convenient scale for quantifying and classifying pupillary reflections as they appear during recreational photography.

  17. The modality and results of complex treatment of extended retinoblastoma in children

    International Nuclear Information System (INIS)

    Belkina, B.M.; Durnov, L.A.; Polyakov, V.G.; Goldobenko, G.V.; Glekov, I.V.; Ushakova, T.L.

    1997-01-01

    Analysis of the results of combined treatment of retinoblastoma in children according to the program developed in the Scientific and Research Institute of Pediatric Oncology and Hematology is performed. The treatment program permits to avoid in many cases the unjustified removal of eye. Combination of treatment methods (surgery, radiotherapy and chemotherapy) and their sequence depends on the classification by stages of retinoblastoma development according to the TNM system. Five year survival in case of monoretinoblastoma with surgical operation at the first stage and without is 92% and 82% corresponding while in case of double retinoblastoma - 83% and 84%

  18. Tratamiento conservador en pacientes con retinoblastoma bilateral

    Directory of Open Access Journals (Sweden)

    Juan C. Suárez

    2008-11-01

    Full Text Available OBJETIVO: comparar el tratamiento convencional del retinoblastoma bilateral, usado hasta hace algunos años, consistente en radioterapia o enucleación bilateral, con el tratamiento conservador actual que incluye termoterapia transpupilar (TTT o TTT/quimioterapia al menos en un ojo, en niños con diagnóstico de retinoblastoma bilateral. DISEÑO: estudio retrospectivo descriptivo. MUESTRA: 20 pacientes con diagnóstico de retinoblastoma bilateral que consultaron al Hospital Universitario San Vicente de Paúl, de Medellín, Colombia, entre 1997 y 2007. MÉTODO: se hizo enucleación del ojo con el tumor de mayor tamaño. En el otro ojo se hizo tratamiento con TTT, con el láser diodo (810 nm, spot amplio, solo o combinado con otras terapias. RESULTADOS: se dividió a los pacientes en dos grupos: 16 pacientes (32 ojos en el grupo 1 tratados conservadoramente y 4 pacientes (8 ojos en el grupo 2 con tratamiento convencional. El rango de edad fue de 1-72 meses en el grupo 1 y de 1-12 meses en el grupo 2. El tiempo de seguimiento fue de 7-67 meses para el grupo 1 y de 13-73 meses para el grupo 2. En el grupo 1 se hizo enucleación de 16 ojos (50%, radioterapia externa de uno (3,1%, quimioterapia más termoterapia de 5 (15,6% y quimioterapia más termoterapia más crioterapia de 10 (31,3%. En todos los pacientes se logró preservar al menos un ojo. En el grupo 2, se enuclearon 7 ojos (87,5% y se hizo radioterapia externa más enucleación en un paciente (12.5%. Además, todos los pacientes recibieron quimioterapia. CONCLUSIÓN: la terapia conservadora actual consistente en tratamiento local (termoterapia, crioterapia o braquiterapia y quimiorreducción permite preservar al menos un ojo y en algunos casos de los dos, muchas veces con buena agudeza visual, en niños con retinoblastoma bilateral; se evitan así la enucleación bilateral y la radioterapia externa usada en el tratamiento convencional con todos sus efectos secundarios. La enucleación contin

  19. Network Analysis of Human Genes Influencing Susceptibility to Mycobacterial Infections

    Science.gov (United States)

    Lipner, Ettie M.; Garcia, Benjamin J.; Strong, Michael

    2016-01-01

    Tuberculosis and nontuberculous mycobacterial infections constitute a high burden of pulmonary disease in humans, resulting in over 1.5 million deaths per year. Building on the premise that genetic factors influence the instance, progression, and defense of infectious disease, we undertook a systems biology approach to investigate relationships among genetic factors that may play a role in increased susceptibility or control of mycobacterial infections. We combined literature and database mining with network analysis and pathway enrichment analysis to examine genes, pathways, and networks, involved in the human response to Mycobacterium tuberculosis and nontuberculous mycobacterial infections. This approach allowed us to examine functional relationships among reported genes, and to identify novel genes and enriched pathways that may play a role in mycobacterial susceptibility or control. Our findings suggest that the primary pathways and genes influencing mycobacterial infection control involve an interplay between innate and adaptive immune proteins and pathways. Signaling pathways involved in autoimmune disease were significantly enriched as revealed in our networks. Mycobacterial disease susceptibility networks were also examined within the context of gene-chemical relationships, in order to identify putative drugs and nutrients with potential beneficial immunomodulatory or anti-mycobacterial effects. PMID:26751573

  20. Undefined familial colorectal cancer and the role of pleiotropism in cancer susceptibility genes.

    Science.gov (United States)

    Dobbins, Sara E; Broderick, Peter; Chubb, Daniel; Kinnersley, Ben; Sherborne, Amy L; Houlston, Richard S

    2016-10-01

    Although family history is a major risk factor for colorectal cancer (CRC) a genetic diagnosis cannot be obtained in over 50 % of familial cases when screened for known CRC cancer susceptibility genes. The genetics of undefined-familial CRC is complex and recent studies have implied additional clinically actionable mutations for CRC in susceptibility genes for other cancers. To clarify the contribution of non-CRC susceptibility genes to undefined-familial CRC we conducted a mutational screen of 114 cancer susceptibility genes in 847 patients with early-onset undefined-familial CRC and 1609 controls by analysing high-coverage exome sequencing data. We implemented American College of Medical Genetics and Genomics standards and guidelines for assigning pathogenicity to variants. Globally across all 114 cancer susceptibility genes no statistically significant enrichment of likely pathogenic variants was shown (6.7 % cases 57/847, 5.3 % controls 85/1609; P = 0.15). Moreover there was no significant enrichment of mutations in genes such as TP53 or BRCA2 which have been proposed for clinical testing in CRC. In conclusion, while we identified genes that may be considered interesting candidates as determinants of CRC risk warranting further research, there is currently scant evidence to support a role for genes other than those responsible for established CRC syndromes in the clinical management of familial CRC.

  1. Role of T cell receptor delta gene in susceptibility to celiac disease.

    Science.gov (United States)

    Roschmann, E; Wienker, T F; Volk, B A

    1996-02-01

    There is a strong genetic influence on the susceptibility to celiac disease. Although in the vast majority of patients with celiac disease, the HLA-DQ(alpha1*0501, beta1*0201) heterodimer encoded by the alleles HLA-DQA1*0501 and HLA-DQB1*0201 seems to confer the primary disease susceptibility, it cannot be excluded that other genes contribute to disease susceptibility, as indicated by the difference in concordance rates between monozygotic twins and HLA identical siblings (70% vs. 30%). Obviously other genes involved in the genetic control of T cell mediated immune response could potentially influence susceptibility to celiac disease. The density of T cells using the gammadelta T cell receptor (TCR) is considerably increased in the jejunal epithelium of patients with celiac disease, an abnormality considered to be specific for celiac disease. This suggests an involvement of gammadelta T cells in the pathogenesis of the disease. To ascertain whether the TCR delta (TCRD) gene contributes to celiac disease susceptibility we carried out an association study and genetic linkage analysis using a highly polymorphic microsatellite marker at the TCRD locus on chromosome 14q11.2. The association study demonstrated no significant difference in allele frequencies of the TCRD gene marker between celiac disease patients and controls; accordingly, the relative risk estimates did not reach the level of statistical significance. In the linkage analysis, performed in 23 families, the logarithm of the odds (LOD) scores calculated for celiac disease versus the TCRD gene marker excluded linkage, suggesting that there is no determinant contributing to celiac disease status at or 5 cM distant to the analyzed TCRD gene marker. In conclusion, the results of the present study provide no evidence that the analyzed TCRD gene contributes substantially to celiac disease susceptibility.

  2. Clinicopathological pattern and management of retinoblastoma in ...

    African Journals Online (AJOL)

    shobha

    leucocoria, proptosis, hyphaema without history of trauma, unexplained ... Conclusion: Retinoblastoma, a treatable tumor is characterized by late presentation as illustrated in our ..... Great Britain 1969-80: Incidence, treatment and survival.

  3. Cdh11 Acts as a Tumor Suppressor in a Murine Retinoblastoma Model by Facilitating Tumor Cell Death

    Science.gov (United States)

    Marchong, Mellone N.; Yurkowski, Christine; Ma, Clement; Spencer, Clarellen; Pajovic, Sanja; Gallie, Brenda L.

    2010-01-01

    CDH11 gene copy number and expression are frequently lost in human retinoblastomas and in retinoblastomas arising in TAg-RB mice. To determine the effect of Cdh11 loss in tumorigenesis, we crossed Cdh11 null mice with TAg-RB mice. Loss of Cdh11 had no gross morphological effect on the developing retina of Cdh11 knockout mice, but led to larger retinal volumes in mice crossed with TAg-RB mice (p = 0.01). Mice null for Cdh11 presented with fewer TAg-positive cells at postnatal day 8 (PND8) (p = 0.01) and had fewer multifocal tumors at PND28 (p = 0.016), compared to mice with normal Cdh11 alleles. However, tumor growth was faster in Cdh11-null mice between PND8 and PND84 (p = 0.003). In tumors of Cdh11-null mice, cell death was decreased 5- to 10-fold (p<0.03 for all markers), while proliferation in vivo remained unaffected (p = 0.121). Activated caspase-3 was significantly decreased and β-catenin expression increased in Cdh11 knockdown experiments in vitro. These data suggest that Cdh11 displays tumor suppressor properties in vivo and in vitro in murine retinoblastoma through promotion of cell death. PMID:20421947

  4. Cdh11 acts as a tumor suppressor in a murine retinoblastoma model by facilitating tumor cell death.

    Directory of Open Access Journals (Sweden)

    Mellone N Marchong

    2010-04-01

    Full Text Available CDH11 gene copy number and expression are frequently lost in human retinoblastomas and in retinoblastomas arising in TAg-RB mice. To determine the effect of Cdh11 loss in tumorigenesis, we crossed Cdh11 null mice with TAg-RB mice. Loss of Cdh11 had no gross morphological effect on the developing retina of Cdh11 knockout mice, but led to larger retinal volumes in mice crossed with TAg-RB mice (p = 0.01. Mice null for Cdh11 presented with fewer TAg-positive cells at postnatal day 8 (PND8 (p = 0.01 and had fewer multifocal tumors at PND28 (p = 0.016, compared to mice with normal Cdh11 alleles. However, tumor growth was faster in Cdh11-null mice between PND8 and PND84 (p = 0.003. In tumors of Cdh11-null mice, cell death was decreased 5- to 10-fold (p<0.03 for all markers, while proliferation in vivo remained unaffected (p = 0.121. Activated caspase-3 was significantly decreased and beta-catenin expression increased in Cdh11 knockdown experiments in vitro. These data suggest that Cdh11 displays tumor suppressor properties in vivo and in vitro in murine retinoblastoma through promotion of cell death.

  5. Optical Coherence Tomography-Guided Decisions in Retinoblastoma Management.

    Science.gov (United States)

    Soliman, Sameh E; VandenHoven, Cynthia; MacKeen, Leslie D; Héon, Elise; Gallie, Brenda L

    2017-06-01

    Assess the role of handheld optical coherence tomography (OCT) in guiding management decisions during diagnosis, treatment, and follow-up of eyes affected by retinoblastoma. Retrospective, noncomparative, single-institution case series. All children newly diagnosed with retinoblastoma from January 2011 to December 2015 who had an OCT session during their active treatment at The Hospital for Sick Children (SickKids) in Toronto, Canada. The OCT sessions for fellow eyes of unilateral retinoblastoma without any suspicious lesion and those performed more than 6 months after the last treatment were excluded. Data collected included age at presentation, sex, family history, RB1 mutation status, 8th edition TNMH cancer staging and International Intraocular Retinoblastoma Classification (IIRC), and number of OCT sessions per eye. Details of each session were scored for indication-related details (informative or not) and assessed for guidance (directive or not), diagnosis (staging changed, new tumors found or excluded), treatment (modified, stopped, or modality shifted), or follow-up modified. Frequency of OCT-guided management decisions, stratified by indication and type of guidance (confirmatory vs. influential). Sixty-three eyes of 44 children had 339 OCT sessions over the course of clinical management (median number of OCT scans per eye, 5; range, 1-15). The age at presentation and presence of a heritable RB1 mutation significantly correlated with an increased number of OCT sessions. Indications included evaluation of post-treatment scar (55%) or fovea (16%), and posterior pole scanning for new tumors (11%). Of all sessions, 92% (312/339) were informative; 19 of 27 noninformative sessions had large, elevated lesions; of these, 14 of 19 were T2a or T2b (IIRC group C or D) eyes. In 94% (293/312) of the informative sessions, OCT directed treatment decisions (58%), diagnosis (16%), and follow-up (26%). Optical coherence tomography influenced and changed management from pre

  6. Retinoblastoma in the Democratic Republic of Congo: 20-Year Review from a Tertiary Hospital in Kinshasa

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    Aimé Kazadi Lukusa

    2012-01-01

    Full Text Available Background. To determine clinical profile and management of retinoblastoma among children at Kinshasa in Democratic Republic of Congo. Patients and methods. The medical records of patients with a diagnosis of retinoblastoma seen at the University Hospital of Kinshasa from January 1985 till December 2005 were retrospectively reviewed. Demographic profile, clinical data, modes of treatment and outcome were analysed. Results. A total of 49 children, of whom 40 had adequate data on record were identified as retinoblastoma (28 males and 12 females. Nine cases had bilateral disease. The median age at the first symptoms was 9 months (range, 1 month to 6 years for unilateral retinoblastoma and 18 months (range, 1 month to 3.5 years for bilateral retinoblastoma. The median age at the first oncology consultation was 2.4 years (range, 6 months to 6 years for unilateral retinoblastoma and 2.4years (range, 9 months to 4 years for bilateral disease. Leukokoria was present in 67.5% of subjects. Seventy-five percent abandoned the treatment. The mortality was 92.5%. Conclusion. In Democratic Republic of Congo, retinoblastoma remains a life threatening disease characterized by late referral to a specialized unit and affordability of chemotherapy; all leading to an extension of the disease and high mortality.

  7. Identification of candidate new cancer susceptibility genes using yeast genomics

    International Nuclear Information System (INIS)

    Brown, M.; Brown, J.A.; Game, J.C.

    2003-01-01

    A large proportion of cancer susceptibility syndromes are the result of mutations in genes in DNA repair or in cell-cycle checkpoints in response to DNA damage, such as ataxia telangiectasia (AT), Fanconi's anemia (FA), Bloom's syndrome (BS), Nijmegen breakage syndrome (NBS), and xeroderma pigmentosum (XP). Mutations in these genes often cause gross chromosomal instability leading to an increased mutation rate of all genes including those directly responsible for cancer. We have proposed that because the orthologs of these genes in budding yeast, S. cerevisiae, confer protection against killing by DNA damaging agents it should be possible to identify new cancer susceptibility genes by identifying yeast genes whose deletion causes sensitivity to DNA damage. We therefore screened the recently completed collection of individual gene deletion mutants to identify genes that affect sensitivity to DNA-damaging agents. Screening for sensitivity in this obtained up to now with the F98 glioma model othe fact that each deleted gene is replaced by a cassette containing two molecular 'barcodes', or 20-mers, that uniquely identify the strain when DNA from a pool of strains is hybridized to an oligonucleotide array containing the complementary sequences of the barcodes. We performed the screen with UV, IR, H 2 0 2 and other DNA damaging agents. In addition to identifying genes already known to confer resistance to DNA damaging agents we have identified, and individually confirmed, several genes not previously associated with resistance. Several of these are of unknown function. We have also examined the chromosomal stability of selected strains and found that IR sensitive strains often but not always exhibit genomic instability. We are presently constructing a yeast artificial chromosome to globally interrogate all the genes in the deletion pool for their involvement in genomic stability. This work shows that budding yeast is a valuable eukaryotic model organism to identify

  8. Identification of candidate genes for dyslexia susceptibility on chromosome 18.

    Directory of Open Access Journals (Sweden)

    Thomas S Scerri

    2010-10-01

    Full Text Available Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s conferring susceptibility by a two stage strategy of linkage and association analysis.Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R, dymeclin (DYM and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L.Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.

  9. Histopathologic grading of anaplasia in retinoblastoma.

    Science.gov (United States)

    Mendoza, Pia R; Specht, Charles S; Hubbard, G Baker; Wells, Jill R; Lynn, Michael J; Zhang, Qing; Kong, Jun; Grossniklaus, Hans E

    2015-04-01

    To determine whether the degree of tumor anaplasia has prognostic value by evaluating its correlation with high-risk histopathologic features and clinical outcomes in a series of retinoblastoma patients. Retrospective clinicopathologic study. The clinical and pathologic findings in 266 patients who underwent primary enucleation for retinoblastoma were reviewed. The histologic degree of anaplasia was graded as retinocytoma, mild, moderate, or severe as defined by increasing cellular pleomorphism, number of mitoses, nuclear size, and nuclear hyperchromatism. Nuclear morphometric characteristics were measured. The clinical and pathologic data of 125 patients were compared using Kaplan-Meier estimates of survival. Fisher exact test and multivariate regression were used to analyze the association between anaplasia grade and high-risk histologic features. Increasing grade of anaplasia was associated with decreased overall survival (P = .003) and increased risk of metastasis (P = .0007). Histopathologic features that were associated with anaplasia included optic nerve invasion (P anaplasia grading as predictors of distant metastasis and death showed that high-risk histopathology was statistically significant as an independent predictor (P = .01 for metastasis, P = .03 for death) but anaplasia was not (P = .63 for metastasis, P = .30 for death). In the absence of high-risk features, however, severe anaplasia identified an additional risk for metastasis (P = .0004) and death (P = .01). Grading of anaplasia may be a useful adjunct to standard histopathologic criteria in identifying retinoblastoma patients who do not have high-risk histologic features but still have an increased risk of metastasis and may need adjuvant therapy. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Can preoperative MR imaging predict optic nerve invasion of retinoblastoma?

    International Nuclear Information System (INIS)

    Song, Kyoung Doo; Eo, Hong; Kim, Ji Hye; Yoo, So-Young; Jeon, Tae Yeon

    2012-01-01

    Purpose: To evaluate the accuracy of pre-operative MRI for the detection of optic nerve invasion in retinoblastoma. Materials and methods: Institutional review board approval and informed consent were waived for this retrospective study. A total of 41 patients were included. Inclusion criteria were histologically proven retinoblastoma, availability of diagnostic-quality preoperative MR images acquired during the 4 weeks before surgery, unilateral retinoblastoma, and normal-sized optic nerve. Two radiologists retrospectively reviewed the MR images independently. Five imaging findings (diffuse mild optic nerve enhancement, focal strong optic nerve enhancement, optic sheath enhancement, tumor location, and tumor size) were evaluated against optic nerve invasion of retinoblastoma. The predictive performance of all MR imaging findings for optic nerve invasion was also evaluated by the receiver operating characteristic curve analysis. Results: Optic nerve invasion was histopathologically confirmed in 24% of study population (10/41). The differences in diffuse mild enhancement, focal strong enhancement, optic sheath enhancement, and tumor location between patients with optic nerve invasion and patients without optic nerve invasion were not significant. Tumor sizes were 16.1 mm (SD: 2.2 mm) and 14.9 mm (SD: 3.6 mm) in patients with and without optic nerve involvement, respectively (P = 0.444). P-Values from binary logistic regression indicated that all five imaging findings were not significant predictors of tumor invasion of optic nerve. The AUC values of all MR imaging findings for the prediction of optic nerve invasion were 0.689 (95% confidence interval: 0.499–0.879) and 0.653 (95% confidence interval: 0.445–0.861) for observer 1 and observer 2, respectively. Conclusion: Findings of MRI in patients with normal-sized optic nerves have limited usefulness in preoperatively predicting the presence of optic nerve invasion in retinoblastoma.

  11. Can preoperative MR imaging predict optic nerve invasion of retinoblastoma?

    Energy Technology Data Exchange (ETDEWEB)

    Song, Kyoung Doo, E-mail: kdsong0308@gmail.com [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of); Eo, Hong, E-mail: rtombow@gmail.com [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of); Kim, Ji Hye, E-mail: jhkate.kim@samsung.com [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of); Yoo, So-Young, E-mail: sy1131.yoo@samsung.com [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of); Jeon, Tae Yeon, E-mail: hathor97.jeon@samsung.com [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710 (Korea, Republic of)

    2012-12-15

    Purpose: To evaluate the accuracy of pre-operative MRI for the detection of optic nerve invasion in retinoblastoma. Materials and methods: Institutional review board approval and informed consent were waived for this retrospective study. A total of 41 patients were included. Inclusion criteria were histologically proven retinoblastoma, availability of diagnostic-quality preoperative MR images acquired during the 4 weeks before surgery, unilateral retinoblastoma, and normal-sized optic nerve. Two radiologists retrospectively reviewed the MR images independently. Five imaging findings (diffuse mild optic nerve enhancement, focal strong optic nerve enhancement, optic sheath enhancement, tumor location, and tumor size) were evaluated against optic nerve invasion of retinoblastoma. The predictive performance of all MR imaging findings for optic nerve invasion was also evaluated by the receiver operating characteristic curve analysis. Results: Optic nerve invasion was histopathologically confirmed in 24% of study population (10/41). The differences in diffuse mild enhancement, focal strong enhancement, optic sheath enhancement, and tumor location between patients with optic nerve invasion and patients without optic nerve invasion were not significant. Tumor sizes were 16.1 mm (SD: 2.2 mm) and 14.9 mm (SD: 3.6 mm) in patients with and without optic nerve involvement, respectively (P = 0.444). P-Values from binary logistic regression indicated that all five imaging findings were not significant predictors of tumor invasion of optic nerve. The AUC values of all MR imaging findings for the prediction of optic nerve invasion were 0.689 (95% confidence interval: 0.499–0.879) and 0.653 (95% confidence interval: 0.445–0.861) for observer 1 and observer 2, respectively. Conclusion: Findings of MRI in patients with normal-sized optic nerves have limited usefulness in preoperatively predicting the presence of optic nerve invasion in retinoblastoma.

  12. Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Ursula Winter

    Full Text Available Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure or metronomic (7-day continuous exposure treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50 was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks and metronomic (5 days a week for 2 weeks topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3-23 was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p0.05. In mice, continuous topotecan lead to significantly lower tumor volumes compared to conventional treatment after 14 days of treatment (p<0.05. Continuous exposure to melphalan or topotecan increased the chemosensitivity of retinoblastoma and endothelial cells to both chemotherapy agents with lower IC50 values compared to short-term treatment. These findings were validated in an in vivo model. None of the dosing modalities induced

  13. The N Terminus of the Retinoblastoma Protein Inhibits DNA Replication via a Bipartite Mechanism Disrupted in Partially Penetrant Retinoblastomas

    Science.gov (United States)

    Borysov, Sergiy I.; Nepon-Sixt, Brook S.

    2015-01-01

    The N-terminal domain of the retinoblastoma (Rb) tumor suppressor protein (RbN) harbors in-frame exon deletions in partially penetrant hereditary retinoblastomas and is known to impair cell growth and tumorigenesis. However, how such RbN deletions contribute to Rb tumor- and growth-suppressive functions is unknown. Here we establish that RbN directly inhibits DNA replication initiation and elongation using a bipartite mechanism involving N-terminal exons lost in cancer. Specifically, Rb exon 7 is necessary and sufficient to target and inhibit the replicative CMG helicase, resulting in the accumulation of inactive CMGs on chromatin. An independent N-terminal loop domain, which forms a projection, specifically blocks DNA polymerase α (Pol-α) and Ctf4 recruitment without affecting DNA polymerases ε and δ or the CMG helicase. Individual disruption of exon 7 or the projection in RbN or Rb, as occurs in inherited cancers, partially impairs the ability of Rb/RbN to inhibit DNA replication and block G1-to-S cell cycle transit. However, their combined loss abolishes these functions of Rb. Thus, Rb growth-suppressive functions include its ability to block replicative complexes via bipartite, independent, and additive N-terminal domains. The partial loss of replication, CMG, or Pol-α control provides a potential molecular explanation for how N-terminal Rb loss-of-function deletions contribute to the etiology of partially penetrant retinoblastomas. PMID:26711265

  14. Analysis of the RB1 gene in children with retinoblastoma having residential connections to West Cumbria, England

    Energy Technology Data Exchange (ETDEWEB)

    Cowell, J K [Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263 (United States); Morris, J A [Department of Pathology, Royal Lancaster Infirmary, Lancaster LA1 4RP (United Kingdom); Tawn, E J [Westlakes Research Institute, Moor Row, Cumbria CA24 3JY (United Kingdom)

    2005-03-01

    Six of eight cases of retinoblastoma previously identified as having a residential association with West Cumbria, England, in which the Sellafield nuclear installation is situated, were examined for the presence of a constitutional RB1 mutation. No mutations were detected, thus providing strong evidence against an environmental or occupational genotoxic effect causing germline mutations in the parents of these children. (note)

  15. Radiation management of retinoblastoma; An analysis

    Energy Technology Data Exchange (ETDEWEB)

    Takemasa, Kazuhiko; Ito, Hisao; Hashimoto, Shozo; Tanaka, Yasuhiko; Oguchi, Yoshihisa (Keio Univ., Tokyo (Japan). School of Medicine)

    1991-12-01

    An analysis has been conducted of 45 patients treated for retinoblastoma at Keio University Hospital between 1970 and 1990. Of these patients, 32 had unilateral lesion and 13 had bilateral lesion. Further, since their disease was far advanced, 29 patients with unilateral lesion and 12 patients with bilateral lesion underwent enucleation. As a result, 3 patients with unilateral retinoblastoma and all patients with bilateral manifestation of the disease were treated with radiotherapy (45-50 Gy) with or without cryotherapy and photocoagulation. One patient with unilateral lesion, who had received both radiotherapy and chemotherapy, showed metastases at the first presentation at our clinic and thus was excluded from this analysis. Among 16 eyes of 15 patients who were given radiotherapy, 6 eyes developed recurrence and needed to have further treatment. In 6 eyes out of 12, cataract developed, and out of 10 eyes in which eye function was evaluable, good vision was able to be preserved in 5 eyes. (author).

  16. Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease.

    Science.gov (United States)

    Chiba, Hirofumi; Kakuta, Yoichi; Kinouchi, Yoshitaka; Kawai, Yosuke; Watanabe, Kazuhiro; Nagao, Munenori; Naito, Takeo; Onodera, Motoyuki; Moroi, Rintaro; Kuroha, Masatake; Kanazawa, Yoshitake; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Negoro, Kenichi; Nagasaki, Masao; Unno, Michiaki; Shimosegawa, Tooru

    2018-01-01

    Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score ([Formula: see text]) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing [Formula: see text] >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of [Formula: see text] (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 ([Formula: see text] = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). We confirmed the existence of cis-regulated ASM around

  17. Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease

    Science.gov (United States)

    Chiba, Hirofumi; Kakuta, Yoichi; Kinouchi, Yoshitaka; Kawai, Yosuke; Watanabe, Kazuhiro; Nagao, Munenori; Naito, Takeo; Onodera, Motoyuki; Moroi, Rintaro; Kuroha, Masatake; Kanazawa, Yoshitake; Kimura, Tomoya; Shiga, Hisashi; Endo, Katsuya; Negoro, Kenichi; Nagasaki, Masao; Unno, Michiaki; Shimosegawa, Tooru

    2018-01-01

    Background Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. Methods CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score (ΔRAS¯) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing ΔRAS¯ >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. Results We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of ΔRAS¯ (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 (ΔRAS¯ = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). Conclusions We confirmed the existence of cis-regulated ASM around IBD

  18. Characterization, treatment and prognosis of retinoblastoma with central nervous system metastasis.

    Science.gov (United States)

    Hu, Huimin; Zhang, Weiling; Wang, Yizhuo; Huang, Dongsheng; Shi, Jitong; Li, Bin; Zhang, Yi; Zhou, Yan

    2018-04-23

    Retinoblastoma is the most common primary intraocular tumor and more and more attention has been paid to the developing countries. This study was aimed to evaluate the clinical features, treatment, and prognosis of retinoblastoma patients with central nervous system (CNS) metastasis in Beijing Tongren Hospital, one of the largest tertiary eye centers in China. Clinical data of 31 consecutive retinoblastoma patients with CNS metastases, who were diagnosed at the Department of Pediatrics in Beijing Tongren Hospital between September 2005 and December 2015, were retrospective analyzed. The median age at presentation was 29 months (range from 5 to 108 months). Magnetic resonance imaging (MRI) results indicated that 16 patients (56.6%, 16/31) presented with meningeal involvement, 12 (38.7%, 12/31) presented with intracranial mass, 11 (35.5%, 11/31) presented with thickened optic nerve, and 5 (16.1%, 5/31) presented with concurrent meningeal and spinal cord membrane involvement. Retinoblastoma cells were detected in the cerebrospinal fluid (CSF) of 12 patients (44.4%, 12/27). Laboratory examinations on the blood and CSF were performed for 11 patients who had received six cycles of systemic chemotherapy, indicated that the serum level of neurone-specific enolase (NSE) after chemotherapy was significantly lower than that before chemotherapy (P < 0.05). At the end of the follow-up, 25 patients were dead with a median survival time of 6 months (1 d - 21 months), and 6 cases were alive and continued to receive treatment. Our results were basically consistent with previous reports in the developing countries, and it could be guidance for clinical treatment, prognosis and prevention of CNS metastases in retinoblastoma.

  19. Irradiation sequels of retinoblastomas. Sequelles de l'irradiation externe des retinoblastomes

    Energy Technology Data Exchange (ETDEWEB)

    Benk, V; Habrand, J L; Bloch Michel, E; Soussaline, M; Sarrazin, D [Centre de Lutte Contre le Cancer Gustave-Roussy, 94 - Villejuif (France)

    1993-01-01

    From 1975 to 1985, 34 children with a non-metastatic retinoblastoma were irradiated at the Institut Gustave-Roussy. After enucleation, 19 bilateral tumors were irradiated by two lateral opposed fields and 15 unilateral tumors by one lateral and anterior field, in the case of optic nerve being histologically positive. Dose was 45 Gy, 1.8 Gy per fraction. The 10-year-survival rate for unilateral and bilateral retinoblastomas was 79%. Long term sequels were available for 25 patients: 88% retained one functional eye. Three children with bilateral retinoblastomas developed a cataract in the residual eye between 2 and 5 years after irradiation, none with unilateral tumor. Nine patients (36%), seven with unilateral and two with bilateral tumor developed a cosmetical problem that required multiple surgical rehabilitation between 3 and 14 years after irradiation. Nine children (36%), five with unilateral and four with bilateral tumors developed growth hormone deficit between 2 and 8 years after irradiation that required hormone replacement. Their pituitary gland received 22 to 40 Gy. No osteosarcoma occurred in this population. Among long-term sequels, following irradiation for retinoblastoma, cosmetical deformities represent disabling sequels that could justify new approaches in radiotherapy, as protontherapy combined with 3-D-treatment planning.

  20. Circuit-wide Transcriptional Profiling Reveals Brain Region-Specific Gene Networks Regulating Depression Susceptibility.

    Science.gov (United States)

    Bagot, Rosemary C; Cates, Hannah M; Purushothaman, Immanuel; Lorsch, Zachary S; Walker, Deena M; Wang, Junshi; Huang, Xiaojie; Schlüter, Oliver M; Maze, Ian; Peña, Catherine J; Heller, Elizabeth A; Issler, Orna; Wang, Minghui; Song, Won-Min; Stein, Jason L; Liu, Xiaochuan; Doyle, Marie A; Scobie, Kimberly N; Sun, Hao Sheng; Neve, Rachael L; Geschwind, Daniel; Dong, Yan; Shen, Li; Zhang, Bin; Nestler, Eric J

    2016-06-01

    Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Identification of Genetic Susceptibility to Childhood Cancer through Analysis of Genes in Parallel

    Science.gov (United States)

    Plon, Sharon E.; Wheeler, David A.; Strong, Louise C.; Tomlinson, Gail E.; Pirics, Michael; Meng, Qingchang; Cheung, Hannah C.; Begin, Phyllis R.; Muzny, Donna M.; Lewis, Lora; Biegel, Jaclyn A.; Gibbs, Richard A.

    2011-01-01

    Clinical cancer genetic susceptibility analysis typically proceeds sequentially beginning with the most likely causative gene. The process is time consuming and the yield is low particularly for families with unusual patterns of cancer. We determined the results of in parallel mutation analysis of a large cancer-associated gene panel. We performed deletion analysis and sequenced the coding regions of 45 genes (8 oncogenes and 37 tumor suppressor or DNA repair genes) in 48 childhood cancer patients who also (1) were diagnosed with a second malignancy under age 30, (2) have a sibling diagnosed with cancer under age 30 and/or (3) have a major congenital anomaly or developmental delay. Deleterious mutations were identified in 6 of 48 (13%) families, 4 of which met the sibling criteria. Mutations were identified in genes previously implicated in both dominant and recessive childhood syndromes including SMARCB1, PMS2, and TP53. No pathogenic deletions were identified. This approach has provided efficient identification of childhood cancer susceptibility mutations and will have greater utility as additional cancer susceptibility genes are identified. Integrating parallel analysis of large gene panels into clinical testing will speed results and increase diagnostic yield. The failure to detect mutations in 87% of families highlights that a number of childhood cancer susceptibility genes remain to be discovered. PMID:21356188

  2. The BTNL2 G16071A gene polymorphism increases granulomatous disease susceptibility

    Science.gov (United States)

    Tong, Xiang; Ma, Yao; Niu, Xundong; Yan, Zhipeng; Liu, Sitong; Peng, Bo; Peng, Shifeng; Fan, Hong

    2016-01-01

    Abstract Objective: The butyrophilin-like 2 (BTNL2) G16071A gene polymorphism has been implicated in the susceptibility to granulomatous diseases, but the results were inconclusive. The objective of the current study was to precisely explore the relationship between BTNL2 G16071A gene polymorphism and granulomatous disease susceptibility by the meta-analysis including false-positive report probability (FPRP) test. Methods: A systematic literature search in the PubMed, Embase, and Wanfang databases, China National Knowledge Internet, and commercial Internet search engines was conducted to identify studies published up to April 1, 2016. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the effect size. Statistical analysis was conducted using the STATA 12.0 software and FPRP test sheet. Results: In total, all 4324 cases and 4386 controls from 14 eligible studies were included in the current meta-analysis. By the overall meta-analysis, we found a significant association between BTNL2 G16071A gene polymorphism and granulomatous disease susceptibility (A vs G: OR = 1.25, 95% CI = 1.07–1.45, P = 0.005). The meta-regression analyses showed that a large proportion of the between-study heterogeneity was significantly attributed to the ethnicity (A vs G, P = 0.013) and the types of granulomatous diseases (A vs G, P = 0.002). By the subgroup meta-analysis, the BTNL2 G16071A gene polymorphism was associated with granulomatous disease susceptibility in Caucasians (A vs G: OR = 1.37, 95% CI = 1.18–1.58, P susceptibility (A vs G: OR = 1.52, 95% CI = 1.39–1.66, P susceptibility (A vs G, FPRP susceptibility among Caucasians (A vs G, FPRP susceptibility, especially increasing the sarcoidosis susceptibility. In addition, the polymorphism may be greatly associated with likelihood of granulomatous diseases among Caucasians. PMID:27472712

  3. Radiotherapy for retinoblastoma

    International Nuclear Information System (INIS)

    Murayama, Shigeyuki; Kagami, Yoshikazu; Tokuue, Koichi; Sumi, Minako; Ikeda, Hiroshi; Kaneko; Akihiro

    1999-01-01

    A retrospective chart review was made of the patients with retinoblastoma received eye conservative therapy between 1980 and 1992. Of 112, 77 had bilateral disease and 35 had unilateral disease. A definitive external radiation therapy (ERT) was used in 106 eyes and ERT combined with concurrent or adjuvant therapy in 29 eyes. Five-year cumulative eye-ball conservation rate for Reese-Ellsworth classification group I to V were 95%, 95.5%, 93.3%, 100% and 58.5%, respectively. Useful vision (>0.01) was maintained in 90.2% of 61 eyes which were treated by definitive ERT initially and experienced no local recurrence. (author)

  4. Retinoblastoma - MR appearance using a surface coil in comparison with histopathological results

    Energy Technology Data Exchange (ETDEWEB)

    Lemke, Arne-Joern; Kazi, Iris; Mergner, Ulrike; Senfft von Pilsach, Marie-Isabell; Felix, Roland [Campus Virchow-Klinikum, Charite, Universitaetsmedizin Berlin, Berlin (Germany); Foerster, Paul I. [Universitaetsaugenklinik, Klinikum der Universitaet Muenchen-Innenstadt, Muenchen (Germany); Heimann, Heinrich; Bechrakis, Nikolaos; Foerster, Michael [Campus Benjamin-Franklin, Charite, Universitaetsmedizin Berlin, Berlin (Germany); Schueler, Andreas [Universitaetsaugenklinik Essen, Essen (Germany); Hosten, Norbert [Institut fuer Diagnostische Radiologie und Neuroradiologie, Klinikum der Ernst-Moritz-Arndt-Universitaets Greifswald, Greifswald (Germany)

    2007-01-15

    The purpose of this work was to evaluate the characteristic appearance of untreated retinoblastoma on a large sample in comparison to the histological findings after therapeutical enucleation. In a prospective clinical trial 46 children with retinoblastoma in 63 affected untreated eyes were examined under general anesthesia on MRI using a 1.5-T system. The examinations were performed with a special surface coil applying an examination protocol including fast T2- and T1-weighted spin echo sequences and additional fast T1-WI after intravenous injection of Gd-DTPA in different planes. The imaging results were compared to the histopathological findings in 29 patients with 30 affected eyes. Comparing MRI findings and histopathological results, optic nerve infiltration was detected with a sensitivity of 53.8% and a specificity of 82.3% on MRI, infiltration of the choroid with a sensitivity of 75.0% and a specificity of 100.0%, and the degree of tumor calcification with a sensitivity of 91.7% and a specificity of 88.9%. In this study the characteristic MR appearance of untreated retinoblastoma was evaluated. MRI was helpful in relevant aspects of pretherapeutical retinoblastoma staging, deficits remain regarding optic nerve infiltration. (orig.)

  5. Peso y talla en niños con retinoblastoma

    Directory of Open Access Journals (Sweden)

    Cecilia Ridaura-Sanz

    2015-03-01

    Full Text Available Introducción: la talla baja se ha descrito como característica clínica de niños con retinoblastoma. Esta particularidad puede estar relacionada directamente con la enfermedad de base o con factores externos.  Objetivo: el propósito de esta investigación fue conocer la frecuencia de talla y peso bajos en niños mexicanos con retinoblastoma y correlacionar los valores antropométricos con variables de la enfermedad y ambientales. Materiales y métodos: se analizaron expedientes clínicos de 346 pacientes con retinoblastoma. Se obtuvieron los datos de peso y talla referidos al ingreso; antes del tratamiento. Se comparó el valor de Z con las referencias de la distribución normal de la población mexicana. La asociación de las medidas antropométricas con las variables clínicas, sociales y genéticas se estableció con la prueba de c2. Resultados: la talla y el peso promedio de los niños con retinoblastoma fueron significativamente más bajos que los de la población general (p < 0.001 y p = 0.013, respectivamente. La talla y peso bajos fueron más frecuentes en niños con enfermedad avanzada, provenientes de medio rural y de bajo nivel socioeconómico. Conclusiones: los déficits en peso y talla en niños con retinoblastoma se deben a factores relacionados con enfermedad avanzada al momento del diagnóstico, lo cual a su vez es consecuencia de la situación de marginación de la población rural mexicana. Dado que la mayoría de las variables sociales y ambientales están muy relacionadas y que no podemos descartar posibles factores genéticos, las conclusiones de este estudio deben verificarse analizando las medidas de los padres y hermanos y establecer grupos comparativos para controlar las variables confusas.

  6. A pp32-retinoblastoma protein complex modulates androgen receptor-mediated transcription and associates with components of the splicing machinery

    International Nuclear Information System (INIS)

    Adegbola, Onikepe; Pasternack, Gary R.

    2005-01-01

    We have previously shown pp32 and the retinoblastoma protein interact. pp32 and the retinoblastoma protein are nuclear receptor transcriptional coregulators: the retinoblastoma protein is a coactivator for androgen receptor, the major regulator of prostate cancer growth, while pp32, which is highly expressed in prostate cancer, is a corepressor of the estrogen receptor. We now show pp32 increases androgen receptor-mediated transcription and the retinoblastoma protein modulates this activity. Using affinity purification and mass spectrometry, we identify members of the pp32-retinoblastoma protein complex as PSF and nonO/p54nrb, proteins implicated in coordinate regulation of nuclear receptor-mediated transcription and splicing. We show that the pp32-retinoblastoma protein complex is modulated during TPA-induced K562 differentiation. Present evidence suggests that nuclear receptors assemble multiprotein complexes to coordinately regulate transcription and mRNA processing. Our results suggest that pp32 and the retinoblastoma protein may be part of a multiprotein complex that coordinately regulates nuclear receptor-mediated transcription and mRNA processing

  7. Molecular-genetic analysis of two cases with retinoblastoma ...

    Indian Academy of Sciences (India)

    Unknown

    Effective counselling and management of retinoblastoma families using genetic information is presently practised in many parts of ... to chromosomal deletion, single-nucleotide alteration, microdeletion, loss ... informed consent of the parent.

  8. Novel function of the retinoblastoma protein in fat: regulation of white versus brown adipocyte differentiation

    DEFF Research Database (Denmark)

    Hansen, Jacob B; te Riele, Hein; Kristiansen, Karsten

    2004-01-01

    the major energy store and brown adipocytes being potent energy-dissipaters through thermogenesis. Yet, little is known about factors differentially regulating the formation of white and brown fat cells. Members of the retinoblastoma protein family (pRB, p107, p130) have been implicated in the regulation...... of adipocyte differentiation, and expression and phosphorylation of the three retinoblastoma family proteins oscillate in a characteristic manner during differentiation of the white preadipocyte cell line 3T3-L1. We have recently demonstrated a surprising function of the retinoblastoma protein...... in the regulation of white versus brown adipocyte differentiation in vitro and possibly in vivo. Here we summarize the current knowledge on the retinoblastoma protein in fat cells, with particular emphasis on its potential role in adipocyte lineage commitment and differentiation....

  9. Downregulation of HDAC9 inhibits cell proliferation and tumor formation by inducing cell cycle arrest in retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Yiting; Wu, Dan; Xia, Fengjie; Xian, Hongyu; Zhu, Xinyue [Medical School of Nanjing University, Department of Ophthalmology, Jinling Hospital, Nanjing, 210002 (China); Cui, Hongjuan, E-mail: hcui@swu.edu.cn [State Key Laboratory of Silkworm Genome Biology, Institute of Sericulture and Systems Biology, Southwest University, Chongqing, 400716 (China); Huang, Zhenping, E-mail: huangzhenping19633@163.com [Medical School of Nanjing University, Department of Ophthalmology, Jinling Hospital, Nanjing, 210002 (China)

    2016-04-29

    Histone deacetylase 9 (HDAC9) is a member of class II HDACs, which regulates a wide variety of normal and abnormal physiological functions. Recently, HDAC9 has been found to be overexpressed in some types of human cancers. However, the role of HDAC9 in retinoblastoma remains unclear. In this study, we found that HDAC9 was commonly expressed in retinoblastoma tissues and HDAC9 was overexpressed in prognostically poor retinoblastoma patients. Through knocking down HDAC9 in Y79 and WERI-Rb-1 cells, the expression level of HDAC9 was found to be positively related to cell proliferation in vitro. Further investigation indicated that knockdown HDAC9 could significantly induce cell cycle arrest at G1 phase in retinoblastoma cells. Western blot assay showed downregulation of HDAC9 could significantly decrease cyclin E2 and CDK2 expression. Lastly, xenograft study in nude mice showed that downregulation of HDAC9 inhibited tumor growth and development in vivo. Therefore, our results suggest that HDAC9 could serve as a novel potential therapeutic target in the treatment of retinoblastoma. - Highlights: • High expression of HDAC9 correlates with poor patient prognosis. • Downregulation of HDAC9 inhibits cell proliferation in retinoblastoma cells. • Downregulation of HDAC9 induces cell cycle arrest at G1 phase in retinoblastoma cells. • Downregulation of HDAC9 suppresses tumor growth in nude mice.

  10. A 10-year experience of outcome in chemotherapy-treated hereditary retinoblastoma.

    Science.gov (United States)

    Bartuma, Katarina; Pal, Niklas; Kosek, Sonja; Holm, Stefan; All-Ericsson, Charlotta

    2014-08-01

    The aim is to report the 10-year retrospective experience of systemic chemotherapy for a population-based group of patients with hereditary retinoblastoma at a national referral centre. The outcomes include control rates, treatment side-effects, adjuvant therapy, failure rate, survival, secondary cancers and visual acuity. All patients (n = 24, 46 eyes) diagnosed with retinoblastoma and treated with systemic chemotherapy at a national referral centre during 2001-2011 were included. Data were extracted from medical records. The patients were followed for a mean of 60 months (range 13-144). Four-six cycles of VEC was administered to all newly diagnosed group B/C/D/E eyes with bilateral disease and 83% (38 of 46) responded to the treatment. None of the patients discontinued chemotherapy because of adverse reactions. Altogether 26% (12 of 46) of the eyes received second-line therapy (other than thermotherapy, cryotherapy and chemotherapy). The failure rate was 35% (16 of 46) and mortality rate 0%. None of the patients developed CNS manifestations (metastases or trilateral retinoblastoma). One of the patients developed a second primary tumour (osteosarcoma) 4 years following retinoblastoma diagnosis. Altogether 17% (4 of 24) patients received radiation therapy, 28% (13 of 46) of the eyes had to be enucleated, and one patient underwent bilateral enucleation. The age-correlated visual acuity was mean of 73% of expected visual acuity. Group A/B retinoblastomas have a distinct chemotherapy response, while group C/D/E tumours do not respond as well. The success rate was 65%; while patients have a good prognosis for life, approximately one-third of all hereditary cases received radiation therapy or underwent enucleation. © 2013 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  11. Intra-arterial chemotherapy for the management of retinoblastoma: four-year experience.

    Science.gov (United States)

    Gobin, Y Pierre; Dunkel, Ira J; Marr, Brian P; Brodie, Scott E; Abramson, David H

    2011-06-01

    To determine whether intra-arterial chemotherapy is safe and effective in advanced intraocular retinoblastoma. Retinoblastoma often presents with advanced intraocular disease and, despite conventional treatment with intravenous chemotherapy and external beam radiation therapy, may still require enucleation. Single-arm, prospective registry from May 30, 2006, to May 30, 2010, at an ophthalmic oncology referral center with ambulatory care. A total of 95 eyes of 78 patients with unilateral or bilateral retinoblastoma were treated. The intervention was selective catheterization of the ophthalmic artery and injection of chemotherapy, usually melphalan with or without topotecan. Drug dosage was determined by age and angioanatomy. The main outcome measures were procedural success, event-free (enucleation or radiotherapy) ocular survival, and ocular and extraocular complications. Catheterization succeeded in 98.5% of procedures. There were 289 chemotherapy injections (median, 3 per eye). The Kaplan-Meier estimates of ocular event-free survival rates at 2 years were 70.0% (95% confidence interval, 57.9%-82.2%) for all eyes, 81.7% (95% confidence interval, 66.8%-96.6%) for eyes that received intra-arterial chemotherapy as primary treatment, and 58.4% (95% confidence interval, 39.5%-77.2%) for eyes that had previous treatment failure with intravenous chemotherapy and/or external beam radiation therapy. There were no permanent extraocular complications. Our experience suggests that intra-arterial chemotherapy is safe and effective in the treatment of advanced intraocular retinoblastoma.

  12. Postirradiation sarcoma in retinoblastoma. Induction or predisposition

    International Nuclear Information System (INIS)

    Schwarz, M.B.; Burgess, L.P.; Fee, W.E. Jr.; Donaldson, S.S.

    1988-01-01

    An alarmingly high rate of postirradiation sarcomas following treatment for retinoblastoma has been described in the literature. We present four new cases and report 57 others from the English literature. Osteogenic sarcoma was the predominant histologic type (58%), followed by fibrosarcoma (21%) and various other sarcomas (21%). The average latency period between irradiation and development of the second primary (sarcoma) was 12.4 years. Irrespective of irradiation, a genetic linkage between retinoblastoma and osteogenic sarcoma on the 13q14 chromosome is recognized. Through a pleiotropic effect of this same chromosome, a predisposition for other sarcomas may exist as well. Finally, a strong role for radiation induction is proposed for all of these postirradiation sarcomas. This is based on the increased number of sarcomas arising in the field of prior irradiation (sites uncharacteristic of spontaneously occurring primary sarcomas) and the prolonged latency periods.13 references

  13. Causes, outcome and prevention of abandonment in retinoblastoma in India.

    Science.gov (United States)

    Kumar, Archana; Moulik, Nirmalya Roy; Mishra, Ravi Krishna; Kumar, Dipak

    2013-05-01

    The high-cure rates of 90% in retinoblastoma are not replicated in developing countries due to late presentation and poor compliance to treatment. The present study takes a closer look at causes of abandonment of therapy and effectiveness of counselling in reducing abandonment. A retrospective study of children with retinoblastoma registered at our centre from March 2008 through August 2011. Fifty (49.50%) of 101 children registered for treatment abandoned therapy. Abandonment rates were significantly higher in rural as compared to urban children (P = 0.02). There was no significant difference in rate of abandonment between stages or laterality of disease and other socio-demographic factors. Telephone calls were more effective than letters in tracing patients (31.2% vs. 2.4%). Major reasons cited behind abandonment were financial problems (30%) and unwillingness to enucleate (20%). Of the 12 children who returned and were retreated 6 (50%) died of progressive disease. Nineteen (73%) of those who did not return died at home. Abandonment rates steadily declined from 71.42% in 2008 to 16.66% in 2011 (P = 0.01) due to effective pre-abandonment counselling by a support team under the National Retinoblastoma Registry of India from 2009. Abandonment rates for children with retinoblastoma continue to be unacceptably high. Rural background, financial constraints and hesitancy to enucleate were important causes behind abandonment. Outcome of patients who abandoned treatment was uniformly dismal. Inclusion of support team and intensified initial counselling helped in improving compliance. Copyright © 2013 Wiley Periodicals, Inc.

  14. Quantification of lacrimal function after D-shaped field irradiation for retinoblastoma

    International Nuclear Information System (INIS)

    Imhof, S.M.; Tan, K.E.W.P.; Hofman, P.

    1993-01-01

    To study the quantitative effects of mega-voltage external beam irradiation in a D-shaped field in patients with retinoblastoma, biomicroscopy was performed in 61 patients and tear function tests (Schirmer-lactoferrin and lysozyme tests) on 45 eyes in 34 irradiated patients. The results were compared with those obtained in 25 non-irradiated control eyes. The Schirmer test was significantly diminished in irradiated eyes, as were the lactoferrin and lysozyme values. A mild to severe keratitis was found in 17 of the 61 patients (28%). A significant correlation (p<0.005) was found between the severe keratitis and the mean Schirmer values; the mean lactoferrin and lysozyme values were diminished in all patients but did not correlate significantly with the corneal abnormalities. These quantitative data, obtained in patients treated for retinoblastoma, affirm the qualitative data found in patients irradiated for other reasons such as orbital or sinus tumours. Irradiation for retinoblastoma is not a harmless treatment and serious late side effects have to be considered. (Author)

  15. Roles of Breast Cancer Susceptibility Genes BRCA’s in Mammary Epithelial Cell Differentiation

    Science.gov (United States)

    2006-03-01

    FANCA . Hum. Mol. Genet. 11, 2591-2597 (2002). 13. Tessari, M.A. et al. Transcriptional activation of the cyclin A gene by the architectural...caretakercancer susceptibility gene FANCA (24), as well several IFN- or caspase- associated proteins, were down-regulated. Concomitantly, in these cells...a mammary differentiation factor STAT5B and a caretaker cancer susceptibility gene FANCA were down-regulated. Nev- ertheless, it has yet to be

  16. Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein

    International Nuclear Information System (INIS)

    Lu, Na; Chen, Yan; Wang, Zhengmin; Chen, Guoling; Lin, Qin; Chen, Zheng-Yi; Li, Huawei

    2013-01-01

    Highlights: ► Shh activation in neonatal cochleae enhances sensory cell proliferation. ► Proliferating supporting cells can transdifferentiate into hair cells. ► Shh promotes proliferation by transiently modulating pRb activity. ► Shh inhibits pRb by inhibiting transcription and increasing phosphorylation of pRb. -- Abstract: Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration.

  17. Folate Decorated Nanomicelles Loaded with a Potent Curcumin Analogue for Targeting Retinoblastoma

    Directory of Open Access Journals (Sweden)

    Hashem Alsaab

    2017-04-01

    Full Text Available The aim of this study was to develop a novel folate receptor-targeted drug delivery system for retinoblastoma cells using a promising anticancer agent, curcumin-difluorinated (CDF, loaded in polymeric micelles. Folic acid was used as a targeting moiety to enhance the targeting and bioavailability of CDF. For this purpose, amphiphilic poly(styrene-co-maleic acid-conjugated-folic acid (SMA-FA was synthesized and utilized to improve the aqueous solubility of a highly hydrophobic, but very potent anticancer compound, CDF, and its targeted delivery to folate overexpressing cancers. The SMA-FA conjugate was first synthesized and characterized by 1H NMR, FTIR and DSC. Furthermore, the chromatographic condition (HPLC for estimating CDF was determined and validated. The formulation was optimized to achieve maximum entrapment of CDF. The particle size of the micelles was measured and confirmed by dynamic light scattering (DLS and transmission electron microscopy (TEM. Cytotoxicity studies were conducted on (Y-79 and WERI-RB retinoblastoma cells. Results showed that the solubility of CDF could be increased with the newly-synthesized polymer, and the entrapment efficiency was >85%. The drug-loaded nanomicelles exhibited an appropriate size of <200 nm and a narrow size distribution. The formulation did not show any adverse cytotoxicity on a human retinal pigment epithelial cell (ARPE-19, indicating its safety. However, it showed significant cell killing activity in both Y-79 and WERI-RB retinoblastoma cell lines, indicating its potency in killing cancer cells. In conclusion, the folic acid-conjugated SMA loaded with CDF showed promising potential with high safety and pronounced anticancer activity on the tested retinoblastoma cell lines. The newly-formulated targeted nanomicelles thus could be a viable option as an alternative approach to current retinoblastoma therapies.

  18. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Multiple-tissue cDNA panel PCR revealed that the gene is expressed widely in human tissues: liver, kidney, pancreas, spleen, thymus and prostate. The protein appears to be localized to the nucleus. pp 33-37. Ethnic variations of a retinoblastoma susceptibility gene (RB1) polymorphism in eight Asian populations.

  19. Multiple malignancies in a patient with bilateral retinoblastoma

    NARCIS (Netherlands)

    Ceha, H. M.; Balm, A. J.; de Jong, D.; van 't Veer, L. J.

    1998-01-01

    A case is presented of a patient with bilateral retinoblastoma, treated at infancy with surgery, chemotherapy and radiotherapy, who subsequently developed at least four additional histologically distinct malignancies: a Ewing sarcoma of the left fibula, two extraskeletal osteosarcomas of the left

  20. Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes

    Science.gov (United States)

    2013-03-14

    behavioral teaching strategies and best practice for teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals...AFRL-SA-WP-TR-2013-0013 Comprehensive Clinical Phenotyping and Genetic Mapping for the Discovery of Autism Susceptibility Genes...Genetic Mapping for the Discovery of Autism Susceptibility Genes 5a. CONTRACT NUMBER N/A 5b. GRANT NUMBER N/A 5c. PROGRAM ELEMENT NUMBER N/A 6

  1. Repair and replication of DNA in hereditary (bilateral) retinoblastoma cells after X-irradiation

    International Nuclear Information System (INIS)

    Cleaver, J.E.; Char, D.; Charles, W.C.; Rand, N.

    1982-01-01

    Fibroblasts from patients with hereditary retinoblastoma reportedly exhibit increased sensitivity to killing by X-rays. Although some human syndromes with similar or greater hypersensitivity to DNA-damaging agents (e.g., X-rays, ultraviolet light, and chemical carcinogens), such as xeroderma pigmentosum, are deficient in DNA repair, most do not have such clearly demonstrable defects in repair. Retinoblastoma cells appear to be normal in repairing single-strand breaks and performing repair replication after X-irradiation and also in synthesizing poly(adenosine diphosphoribose). Semiconservative DNA replication in these cells, however, is slightly more resistant than normal after X-irradiation, suggesting that continued replication of damaged parental DNA could contribute to the pathogenesis of the disease. This effect is small, however, and may be a consequence rather than a cause of the fundamental enzymatic abnormality in retinoblastoma that causes the tumorigenesis

  2. Aspiration of radiation cataract in children of retinoblastoma

    International Nuclear Information System (INIS)

    Kawashima, Hidetoshi; Minoda, Kensei.

    1985-01-01

    We operated on the radiation cataracts of 12 retinoblastoma patients who had been treated by conservative therapeutic means including radiation, cryoapplication, photocoagulation, and cytostatic agents. Before the surgery, we checked that the tumor had disappeared or scarred by means of CT-scan, Ultrasonography, X-ray, and so on. Visual acuity of 1.0 or more was retained in two eyes (17 %). Four eyes (33 %) retained visual acuity of 0.6-0.4, one eye (8 %) retained 0.1 and the remaining five eyes (42 %) had visual acuity of less than 0.1. We experienced no serious complications during or after the surgeries. The reason for poorer visual acuity was either macular involvement of the tumor or radiation retinopathy due to larger dosis of radiation. Therefore, we conclude that aspiration of radiation cataract is an effective treatment of retinoblastoma patients after the tumor has disappeared or scarred. (author)

  3. Profiling safety of intravitreal injections for retinoblastoma using an anti-reflux procedure and sterilisation of the needle track.

    Science.gov (United States)

    Munier, Francis L; Soliman, Sameh; Moulin, Alexandre P; Gaillard, Marie-Claire; Balmer, Aubin; Beck-Popovic, Maja

    2012-08-01

    The preservation of globe integrity has always been a major concern during the treatment of retinoblastoma for fear of extraocular or metastatic spread. Intravitreal chemotherapy has been attempted as a desperate salvage therapy only for eyes with refractory retinoblastoma. Published data on the safety and efficacy of this route are, however, limited. A modified technique of intravitreal injection in eyes with retinoblastoma is described. All children with retinoblastoma who received one or more intravitreal injections using this technique were retrospectively reviewed concerning ocular complications of the injection procedure as well as clinical or histopathological evidence of tumour spread. 30 eyes of 30 children with retinoblastoma received a total of 135 intravitreal injections, with a median follw-up duration of 13.5 months. No extraocular spread was seen on clinical follow-up in any patients and there was no tumour contamination of the retrieved entry sites histopathologically analysed among the five enucleated eyes. No significant ocular side effects were observed except transient localised vitreous haemorrhage (3/135). This technique is potentially safe and effective at a low cost and may play a promising role, especially in the treatment of recurrent and/or resistant vitreous disease in retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy. However, this treatment should not replace the primary standard of care of retinoblastoma and should not be considered in group E eyes. Its application should be approved by an ophthalmological-oncological team and it should be performed by an experienced eye surgeon in a tertiary referral centre after careful selection of a tumour-free injection site.

  4. Ethnic variations of a retinoblastoma susceptibility gene (RB1 ...

    Indian Academy of Sciences (India)

    Unknown

    1Department of Paediatrics, National University of Singapore, Lower Kent Ridge Road, Singapore 119074. 2National Neuroscience Institute, Singapore 308433. 3Department of Paediatrics, University Diponegoro, Indonesia 50241. 4Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15261, USA.

  5. Psychosocial factors influencing parental decision to allow or refuse potentially lifesaving enucleation in children with retinoblastoma

    Directory of Open Access Journals (Sweden)

    Rolando Enrique D. Domingo

    2017-01-01

    Full Text Available Objective: Retinoblastoma is the most common malignancy of the eye and ocular adnexa in the Philippines. It is curable when treated early, but delay in enucleation is common due to the parental refusal of surgery for varied reasons. The aim of this study is to identify the psychosocial barriers and facilitating factors for accepting versus refusing enucleation as treatment for retinoblastoma. Methods: This is a cross-sectional descriptive study utilizing structured interviews and a questionnaire. It was conducted at the Retinoblastoma Clinic of the Philippine General Hospital. A questionnaire using the Likert scale was constructed after performing key informant interviews and focus group discussions. It was pretested and revised before parents of patients with retinoblastoma were invited to participate in the study. Descriptive statistics, quantitative item analyses using inter-item correlations and item-total correlations was performed. Results: Factors that correlate with refusal to enucleate are the beliefs that cancer is a fatal illness, the fear of unacceptable esthetic outcome of the surgery, and the cost of treatment. Favorable factors include value of life, high regard for the opinion of medical practitioners, and appreciation of the efficacy of treatment. Conclusions: There are several favorable factors and barriers that health practitioners must consider in facilitating parental decision-making toward enucleation for retinoblastoma.

  6. Inhibition of Retinoblastoma Protein Inactivation

    Science.gov (United States)

    2017-11-01

    CONTRACT NUMBER Inhibition of Retinoblastoma Protein Inactivation 5b. GRANT NUMBER W81XWH-14-1-0329 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Seth M...confirmed 108 compounds as giving a dose-response curve with at least 30% inhibition at 10 µM. The flowchart of hit progression is shown on the...Cancer Research Program under Award No. W81XWH-14-1-0329 to S.M.R. Opinions, interpretations, conclusions, and recommendations are those of the author

  7. Liver tumor formation by a mutant retinoblastoma protein in the transgenic mice is caused by an upregulation of c-Myc target genes

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Bo; Hikosaka, Keisuke; Sultana, Nishat; Sharkar, Mohammad Tofael Kabir [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Noritake, Hidenao [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Kimura, Wataru; Wu, Yi-Xin [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Kobayashi, Yoshimasa [Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Uezato, Tadayoshi [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan); Miura, Naoyuki, E-mail: nmiura@hama-med.ac.jp [Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handa-yama, Higashi-ku, Hamamatsu 431-3192 (Japan)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Fifty percent of the mutant Rb transgenic mice produced liver tumors. Black-Right-Pointing-Pointer In the tumor, Foxm1, Skp2, Bmi1 and AP-1 mRNAs were up-regulated. Black-Right-Pointing-Pointer No increase in expression of the Myc-target genes was observed in the non-tumorous liver. Black-Right-Pointing-Pointer Tumor formation depends on up-regulation of the Myc-target genes. -- Abstract: The retinoblastoma (Rb) tumor suppressor encodes a nuclear phosphoprotein that regulates cellular proliferation, apoptosis and differentiation. In order to adapt itself to these biological functions, Rb is subjected to modification cycle, phosphorylation and dephosphorylation. To directly determine the effect of phosphorylation-resistant Rb on liver development and function, we generated transgenic mice expressing phosphorylation-resistant human mutant Rb (mt-Rb) under the control of the rat hepatocyte nuclear factor-1 gene promoter/enhancer. Expression of mt-Rb in the liver resulted in macroscopic neoplastic nodules (adenomas) with {approx}50% incidence within 15 months old. Interestingly, quantitative reverse transcriptase-PCR analysis showed that c-Myc was up-regulated in the liver of mt-Rb transgenic mice irrespective of having tumor tissues or no tumor. In tumor tissues, several c-Myc target genes, Foxm1, c-Jun, c-Fos, Bmi1 and Skp2, were also up-regulated dramatically. We determined whether mt-Rb activated the Myc promoter in the HTP9 cells and demonstrated that mt-Rb acted as an inhibitor of wild-type Rb-induced repression on the Myc promoter. Our results suggest that continued upregulation of c-Myc target genes promotes the liver tumor formation after about 1 year of age.

  8. Discharge and infection in retinoblastoma post-enucleation sockets

    NARCIS (Netherlands)

    Mourits, Daphne L.; Hartong, Dyonne T.; Budding, Andries E.; Bosscha, Machteld I.; Tan, H. Stevie; Moll, Annette C.

    2017-01-01

    To investigate the causes and treatment options for socket discharge and infection in patients enucleated for retinoblastoma (Rb). A questionnaire was filled out by (parents of) ocular prosthesis-wearing patients with a history of enucleation as treatment for Rb. We collected data on patients'

  9. CT and MR findings in retinoblastoma : correlation with histopathologic examination

    International Nuclear Information System (INIS)

    Park, Son Won; Han, Moon Hee; Chi, Je G.; Yu, Young Suk; Kim, Yeon Mee; Chung, Jin Haeng; Yu, In Kyu; Chang, Kee Hyun; Yeon, Kyung Mo

    1997-01-01

    To evaluate histopathologic correlation of the component of the lesion on CT and MR of retinoblastomas. Gross pathologic findings of 24 enucleated eyeballs in 24 patients with retinoblastomas were compared with preoperative CT (n=19) and MR (n=5) findings. In eight eyeballs, in which there were findings other than mass, histopathologic findings were reviewed and correlated with image findings. Retinal detachment and subretinal hemorrhage which were not detected on CT were demonstrated in two of eight eyeballs on histopathologic examination. In one eyeball, retinal detachment and subretinal effusion were detected on both CT and in a pathologic specimen. In two eyeballs with peripheral heterogeneous MR enhancement of the masses, tumor necrosis and calcification were demonstrated in the central non-emhancing portion of the mass, In two eveballs, linear soft tissue along the retina apart from the main mass were revealed as tumor spread along the retinal surface. In one patient, retinal thickening on MR was presumed to be an MR artifact and no lesion was found in the gross specimen. On CT, retinal detachment and subretinal hemorrhage associated with retinoblastoma can mimic mass, and tumor spread along the retinal surface can be seen as a linear retinal lesion. On MR, tumor necrosis and calcification can be a cause of heterogeneous enhancement

  10. A longitudinal investigation of parenting stress in caregivers of children with retinoblastoma.

    Science.gov (United States)

    Willard, Victoria W; Qaddoumi, Ibrahim; Zhang, Hui; Huang, Lu; Russell, Kathryn M; Brennan, Rachel; Wilson, Matthew W; Rodriguez-Galindo, Carlos; Phipps, Sean

    2017-04-01

    Retinoblastoma is typically diagnosed in young children and may present unique parenting challenges. Qualitative research suggests that parents experience distress related to the initial diagnosis and treatment that subsequently resolves. The objectives were to systematically assess parenting stress over time in parents of young children with retinoblastoma and to examine associations between parenting stress and child outcomes. Parents of children with retinoblastoma completed the Parenting Stress Index (PSI) during serial psychological assessments scheduled based on the child's age (6 months to 5 years). Caregivers of 92 patients (85.9% mothers) completed the assessments. Child outcomes included developmental functioning and parent-reported adaptive functioning. At baseline and age 5, all subscales on the PSI were within normal limits, and most were significantly below normative means (i.e., demonstrating low levels of stress). All domains remained relatively stable over time. Associations between parenting stress and child outcomes were much stronger at age 5 than at baseline. Child-directed parenting stress was a small but significant contributor to declines in child functioning over time. Parents of children with retinoblastoma report normal levels of parenting stress while their children are young. However, baseline parenting stress appears to contribute to changes in child functioning over time. Future studies should assess illness-related aspects of adjustment to further understand the parenting experience of young children with cancer and/or having a visually impaired child. © 2016 Wiley Periodicals, Inc.

  11. [Relationship between interleukin-17A gene polymorphisms and the susceptibility to childhood asthma].

    Science.gov (United States)

    Zhong, Fang-Fang; Zou, Yan; Liu, Chun-Yan; Liu, Wen-Jun

    2016-12-01

    To explore the relationship between polymorphisms of interleukin-17A (IL-17A) gene promoter (-197G/A and -692C/T) and the susceptibility to childhood asthma, to further identify the candidate genes for asthma, and to provide a basis for early prevention of asthma in high-risk children. Sixty-five outpatients or inpatients with childhood asthma between August 2013 and August 2015 were assigned to asthma group. Seventy healthy children within the same period were assigned to control group. Using peripheral venous blood from the two groups, PCR with sequence-specific primers was carried out to determine single nucleotide polymorphisms at positions -197G/A and -692C/T in IL-17A gene promoter. A statistical analysis was used to evaluate differences in genotype and allele frequencies between the two groups. Compared with the control group, the asthma group had significantly higher frequencies of TT genotype (29% vs 16%; P=0.012) and T allele (52% vs 42%; P=0.039) at position -692C/T of IL-17A gene. Children with T allele had 1.413-fold higher risk of childhood asthma than those with C allele (OR=1.413, 95%CI: 1.015-1.917). There were no significant differences in genotype and allele frequencies at position -197G/A in IL-17A gene between the two groups (p>0.05). Polymorphisms at position -692C/T in IL-17A gene promoter is associated with the susceptibility to childhood asthma. Children with -692T allele are more susceptible to childhood asthma. There is no significant relationship between polymorphisms at position -197G/A in IL-17A gene promoter and the susceptibility to childhood asthma.

  12. Outcome of Retinoblastoma Following Limited Sessions of Intra-Arterial Chemotherapy in Iran

    International Nuclear Information System (INIS)

    Ghassemi, Fariba; Ghanaati, Hossein; Karkhaneh, Reza; Boujabadi, Leila; Tabatabaie, Seied Zia; Rajabi, Mohammad Taher

    2014-01-01

    The management of retinoblastoma remains a challenge to the multidisciplinary team, particularly as treatment affects not only visual outcomes, but also ocular retention and morbidity. Management of retinoblastoma has evolved over the past two decades. To report the result of intra-ophthalmic artery chemotherapy (IAC) for the treatment of refractory and advanced retinoblastoma tumors. All patients who had failed to respond adequately to previous treatments and six naive patients with advanced retinoblastoma, receiving IAC between 2009 and 2012, were included in this institutional interventional case series. The patients received 1-2 treatments of IAC given 4-8 weeks apart. Complete response was defined as regressed tumor and complete disappearance of seeding clinically and partial response was defined as partial regression of the tumor with live parts of the tumor and/or lessening of seeds, but not complete disappearance of them clinically. A total of 24 eyes of 24 patients were treated with IAC during the study period. The mean age at the time of IAC was 38.9 months (14-120 months), and the mean follow-up was 16.8 months (3-36 months) after IAC. Tumor control was achieved in 14 eyes (58.3%). Type 3 (combined fleshy and calcified remnants) was the most common type of regression (37.5%). Complications included vitreous hemorrhage in nine eyes (37.5%), arterial occlusion in two (8.3%), cyclitic membrane possibly secondary to ischemia and tractional retinal detachment in one patient (4.2%), chorioretinal atrophy in three (12.5%) patients, and neovascular glaucoma in one eye (4.2%). In eight (33.3%) patients, no complication happened. Globe salvage was achieved in 62.5% of the cases. The success rate for naive patients was 84%. Sixty-seven percent of the cases received transpupillary thermotherapy and cryotherapy before IAC. Intra-ophthalmic artery melphalan is an effective treatment for advanced cases of retinoblastoma, with a reasonable level of success. In the short

  13. Sonic hedgehog initiates cochlear hair cell regeneration through downregulation of retinoblastoma protein

    Energy Technology Data Exchange (ETDEWEB)

    Lu, Na [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114 (United States); Chen, Yan [Central Laboratory, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Wang, Zhengmin [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Institute of Biomedical Sciences, Fudan University, Shanghai 200032 (China); Chen, Guoling [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Lin, Qin [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Department of Otolaryngology, First Affiliated Hospital of Fujian Medical University, Otolaryngology Institute of Fujian Province, Fuzhou (China); Chen, Zheng-Yi, E-mail: Zheng-yi_chen@meei.harvard.edu [Department of Otolaryngology and Program in Neuroscience, Harvard Medical School and Eaton Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, MA 02114 (United States); Li, Huawei, E-mail: hwli@shmu.edu.cn [Otology Skull Base Surgery Department, Hearing Research Institute, Eye and ENT Hospital of Shanghai Medical School, Fudan University, Shanghai 200031 (China); Institute of Biomedical Sciences, Fudan University, Shanghai 200032 (China)

    2013-01-11

    Highlights: Black-Right-Pointing-Pointer Shh activation in neonatal cochleae enhances sensory cell proliferation. Black-Right-Pointing-Pointer Proliferating supporting cells can transdifferentiate into hair cells. Black-Right-Pointing-Pointer Shh promotes proliferation by transiently modulating pRb activity. Black-Right-Pointing-Pointer Shh inhibits pRb by inhibiting transcription and increasing phosphorylation of pRb. -- Abstract: Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration.

  14. Identification of Variants in Breast Cancer Susceptibility Genes and Determination of Functional and Clinical Significance of Novel Mutations

    Science.gov (United States)

    2014-10-01

    to cause other cancer susceptibility (CDKN2A, MLH1, MSH2, MSH6, PMS2 ); 3) genes known or postulated to be moderate penetrance cancer susceptibility...susceptibility (CDKN2A, MLH1, MSH2, MSH6, PMS2 ); 3) genes known or postulated to be moderate penetrance cancer susceptibility genes (ATM, BARD1, BRIP1...three patients in TP53 and 12 patients in MLH1, MSH2, MSH6, or PMS2 ; no VUSs were found in CDH1, CDKN2A, STK11 or PTEN. Three additional patients each

  15. Radiation management of bilateral retinoblastoma: the need to preserve vision

    International Nuclear Information System (INIS)

    Gagnon, J.D.; Ware, C.M.; Moss, W.T.; Stevens, K.R.

    1980-01-01

    Thirty-four patients with retinoblastoma were treated in the Radiation Therapy Department of the University of Oregon Health Sciences Center from 1944 to 1978. Twenty-five of these patients had bilateral disease. Most patients were treated with megavoltage equipment and received doses of 5000 rad in 5 weeks. According to the lifetable method, five year survival was 67.6%; it increased to 85.7% if patients who were treated with orthovoltage equipment were excluded. Seventy-one percent of evaluable patients had useful vision at 5 years; an additional two patients had useful vision for two years after radiation therapy. The value of even limited vision during this critical time of sensorimotor and psychological development is discussed. Orthovoltage equipment should not be used to irradiate patients with retinoblastoma

  16. Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma

    DEFF Research Database (Denmark)

    Helin, K; Holm, K; Niebuhr, A

    1997-01-01

    107, or p130 leads to growth arrest in the G1 phase of the cell cycle, and this arrest is abolished by complex formation with the adenovirus E1A, human papilloma virus E7, or simian virus 40 T oncoproteins. Inactivation of pRB by gross structural alterations or point mutations in the RB-1 gene has...... been described in a variety of human tumors, including retinoblastomas, osteosarcomas, and small cell lung carcinomas. Despite the structural and functional similarity between pRB, p107, and p130, alterations in the latter two proteins have not been identified in human tumors. We have screened a panel...

  17. Gene susceptibility in Iranian asthmatic patients: a narrative review ...

    African Journals Online (AJOL)

    As environmental factors are important in the development of asthma, genetic factors could have a critical role in the expression of the disease. Hence, we carried out a systematic review to assess the susceptible genes for asthma in Iranian population. We conducted a literature search by using the electronic database ...

  18. Gene-environment interaction involving recently identified colorectal cancer susceptibility loci

    Science.gov (United States)

    Kantor, Elizabeth D.; Hutter, Carolyn M.; Minnier, Jessica; Berndt, Sonja I.; Brenner, Hermann; Caan, Bette J.; Campbell, Peter T.; Carlson, Christopher S.; Casey, Graham; Chan, Andrew T.; Chang-Claude, Jenny; Chanock, Stephen J.; Cotterchio, Michelle; Du, Mengmeng; Duggan, David; Fuchs, Charles S.; Giovannucci, Edward L.; Gong, Jian; Harrison, Tabitha A.; Hayes, Richard B.; Henderson, Brian E.; Hoffmeister, Michael; Hopper, John L.; Jenkins, Mark A.; Jiao, Shuo; Kolonel, Laurence N.; Le Marchand, Loic; Lemire, Mathieu; Ma, Jing; Newcomb, Polly A.; Ochs-Balcom, Heather M.; Pflugeisen, Bethann M.; Potter, John D.; Rudolph, Anja; Schoen, Robert E.; Seminara, Daniela; Slattery, Martha L.; Stelling, Deanna L.; Thomas, Fridtjof; Thornquist, Mark; Ulrich, Cornelia M.; Warnick, Greg S.; Zanke, Brent W.; Peters, Ulrike; Hsu, Li; White, Emily

    2014-01-01

    BACKGROUND Genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) that are associated with risk of colorectal cancer (CRC). Prior research has evaluated the presence of gene-environment interaction involving the first 10 identified susceptibility loci, but little work has been conducted on interaction involving SNPs at recently identified susceptibility loci, including: rs10911251, rs6691170, rs6687758, rs11903757, rs10936599, rs647161, rs1321311, rs719725, rs1665650, rs3824999, rs7136702, rs11169552, rs59336, rs3217810, rs4925386, and rs2423279. METHODS Data on 9160 cases and 9280 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and Colon Cancer Family Registry (CCFR) were used to evaluate the presence of interaction involving the above-listed SNPs and sex, body mass index (BMI), alcohol consumption, smoking, aspirin use, post-menopausal hormone (PMH) use, as well as intake of dietary calcium, dietary fiber, dietary folate, red meat, processed meat, fruit, and vegetables. Interaction was evaluated using a fixed-effects meta-analysis of an efficient Empirical Bayes estimator, and permutation was used to account for multiple comparisons. RESULTS None of the permutation-adjusted p-values reached statistical significance. CONCLUSIONS The associations between recently identified genetic susceptibility loci and CRC are not strongly modified by sex, BMI, alcohol, smoking, aspirin, PMH use, and various dietary factors. IMPACT Results suggest no evidence of strong gene-environment interactions involving the recently identified 16 susceptibility loci for CRC taken one at a time. PMID:24994789

  19. Sporadic Retinoblastoma and Parental Smoking and Alcohol Consumption before and after Conception: A Report from the Children's Oncology Group.

    Directory of Open Access Journals (Sweden)

    Saeedeh Azary

    Full Text Available Retinoblastoma is the most frequent tumor of the eye in children and very little is known about the etiology of non-familial (sporadic retinoblastoma. In this study we examined whether parental tobacco smoking or alcohol consumption (pre- or post-conception contribute to the two phenotypes (bilateral or unilateral of sporadic retinoblastoma.Two large multicenter case-control studies identified 488 cases through eye referral centers in the United States and Canada or through the Children's Oncology Group. Controls (n = 424 were selected from among friends and relatives of cases and matched by age. Risk factor information was obtained via telephone interview. We employed multivariable logistic regression to estimate the effects of parental tobacco smoking and alcohol consumption on retinoblastoma.Maternal smoking before and during pregnancy contributed to unilateral retinoblastoma risk in the child: year before pregnancy conditional Odds Ratio (OR, 8.9; 95% confidence interval (CI 1.5-51, and unconditional OR, 2.4; 95% CI, 1.3-4.7; month before or during pregnancy, conditional OR, 3.3; 95% CI, 0.5-20.8, and unconditional OR, 2.8; 95% CI, 1.1-7.0. No association was found for maternal or paternal alcohol consumption.The results of this study indicate that maternal active smoking during pregnancy may be a risk factor for sporadic retinoblastoma. Our study supports a role for tobacco exposures in embryonal tumors.

  20. Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala

    Science.gov (United States)

    Bendfeldt, Giovana; Lou, Hong; Giron, Veronica; Garrido, Claudia; Valverde, Patricia; Barnoya, Margarita; Castellanos, Mauricio

    2014-01-01

    Analysis of 327 consecutive cases at a pediatric referral hospital of Guatemala reveals that retinoblastoma accounts for 9.4% of all cancers and the estimated incidence is 7.0 cases/million children, higher than the United States or Europe. The number of familial cases is low, and there is a striking disparity in indigenous children due to late diagnosis, advanced disease, rapid progression and elevated mortality. Nine germline mutations in 18 patients were found; two known and five new mutations. Hypermethylation of RB1 was identified in 13% of the tumors. An early diagnosis program could identify cases at an earlier age and improve outcome of retinoblastoma in this diverse population. PMID:24814393

  1. Retinoblastoma and the Genetic Theory of Cancer: An Old Paradigm Trying to Survive to the Evidence

    International Nuclear Information System (INIS)

    Mastrangelo, D.; Lore, C.; Hadjistilianou, T.; De Francesco, S.

    2009-01-01

    Retinoblastoma (Rb) is considered to represent the prototype of cancer linked to the sequential loss or inactivation of both alleles of a so-called “tumor suppressor gene”, the Rb1 gene. The pathogenetic mechanism behind this tumor was first hypothesized by Knudson in 1971 and further confirmed by others who identified the Rb1 gene whose loss or inactivation was claimed to be responsible for the disease. However, after about four decades of continuous research in the field of molecular biology, the evidence behind the role of the Rb1 gene in Rb appears to be seriously flawed in the light of epidemiological, biological, and clinical evidences. This editorial summarizes the inconsistencies on this subject. Nevertheless, the molecular biology establishment still adheres to the biased view of the genetic origin of Rb and other cancers, and hardly any alternative explanations are taken into account.

  2. Disease susceptibility genes shared by primary biliary cirrhosis and Crohn's disease in the Japanese population.

    Science.gov (United States)

    Aiba, Yoshihiro; Yamazaki, Keiko; Nishida, Nao; Kawashima, Minae; Hitomi, Yuki; Nakamura, Hitomi; Komori, Atsumasa; Fuyuno, Yuta; Takahashi, Atsushi; Kawaguchi, Takaaki; Takazoe, Masakazu; Suzuki, Yasuo; Motoya, Satoshi; Matsui, Toshiyuki; Esaki, Motohiro; Matsumoto, Takayuki; Kubo, Michiaki; Tokunaga, Katsushi; Nakamura, Minoru

    2015-09-01

    We previously identified TNFSF15 as the most significant susceptibility gene at non-HLA loci for both primary biliary cirrhosis (PBC) and Crohn's diseases (CD) in the Japanese population. The aim of this study is to identify further disease susceptibility genes shared by PBC and CD. We selected 15 and 33 genetic variants that were significantly associated with PBC and CD, respectively, based on previously reported genome-wide association studies of the Japanese population. Next, an association study was independently performed for these genetic variants in CD (1312 CD patients and 3331 healthy controls) and PBC (1279 PBC patients and 1015 healthy controls) cohorts. Two CD susceptibility genes, ICOSLG rs2838519 and IL12B rs6556412, were also nominally associated with susceptibility to PBC (P=3.85 × 10(-2) and P=8.40 × 10(-3), respectively). Three PBC susceptibility genes, CXCR5 rs6421571, STAT4 rs7574865 and NFKB1 rs230534, were nominally associated with susceptibility to CD (P=2.82 × 10(-2), P=3.88 × 10(-2) and P=2.04 × 10(-2), respectively). The effect of ICOSLG and CXCR5 variants were concordant but the effect of STAT4, NFKB1 and IL12B variants were discordant for PBC and CD. TNFSF15 and ICOSLG-CXCR5 might constitute a shared pathogenic pathway in the development of PBC and CD in the Japanese population, whereas IL12B-STAT4-NFKB1 might constitute an opposite pathogenic pathway, reflecting the different balance between Th1 and Th17 in the two diseases.

  3. Virulence properties of methicillin-susceptible Staphylococcus aureus food isolates encoding Panton-Valentine Leukocidin gene.

    Science.gov (United States)

    Sudagidan, Mert; Aydin, Ali

    2010-04-15

    In this study, three Panton-Valentine Leukocidin gene carrying methicillin-susceptible Staphylococcus aureus (MSSA) strains (M1-AAG42B, PY30C-b and YF1B-b) were isolated from different food samples in Kesan-Edirne, Turkey. These strains were characterized on the basis of MLST type, spa type, virulence factor gene contents, antibiotic susceptibilities against 21 antibiotics and biofilm formation. The genetic relatedness of the strains was determined by PFGE. In addition, the complete gene sequences of lukS-PV and lukF-PV were also investigated. All strains were found to be susceptible to tested antibiotics and they were mecA negative. Three strains showed the same PFGE band pattern, ST152 clonal type and t355 spa type. In the detection of virulence factor genes, sea, seb, sec, sed, see, seg, seh, sei, sej, sek, sel, sem, sen, seo, sep, seq, seu, eta, etb, set1, geh and tst genes were not detected. All strains showed the positive results for alpha- and beta-haemolysin genes (hla and hlb), protease encoding genes (sspA, sspB and aur), lukE and lukD leukocidin genes (lukED). The strains were found to be non-biofilm formers. By this study, the virulence properties of the strains were described and this is one of the first reports regarding PVL-positive MSSA strains from food. (c) 2010 Elsevier B.V. All rights reserved.

  4. Clinical presentation of intraocular retinoblastoma; 5-year hospital-based registry in Egypt

    International Nuclear Information System (INIS)

    El Zomor, H.; Nour, R.; Alieldin, A.; Taha, H.; Montasr, M.M.; Moussa, E.; El Nadi, E.; Alfaar, A.S.; Alfaar, A.S.; El Zomor, H.; Taha, H.; Alieldin, A.; Montasr, M.M.; Moussa, E.; El Nadi, E.; Ezzat, S.

    2015-01-01

    Purpose: To study the presenting signs of Retinoblastoma in Egypt at Egypt’s main pediatric oncology referral center. Methods: This is a prospective descriptive study (hospital-based registry) conducted at Children’s Cancer Hospital Egypt between July 2007 and December 2012. Results: Out of 262 patients diagnosed with retinoblastoma, 244 were suffering from intra-ocular disease at presentation. One hundred thirty-nine (57%) patients presented with unilateral disease, while 105 (43%) suffered bilateral disease. The mean age at presentation was 20.6 ± 17 months, averaging 18.87 ± 11.76 months for bilateral and 25.72 ± 18.78 months for unilateral disease. The most common clinical presentation was leukocoria in 180 (73.8%) patients, strabismus in 32 (13.1%) patients and decreased visual acuity in 12 (4.9%) patients. Group D and E disease represented 62% of all affected eyes. Patients with advanced disease (Group C–E) had longer duration of symptoms.Conclusion: In Egypt, retinoblastoma patients present more frequently with advanced disease. There is an ever-increasing need to develop a national team dedicated to studying disease significance and formulating a national awareness program.

  5. Impact of Maspin Polymorphism rs2289520 G/C and Its Interaction with Gene to Gene, Alcohol Consumption Increase Susceptibility to Oral Cancer Occurrence.

    Science.gov (United States)

    Yang, Po-Yu; Miao, Nae-Fang; Lin, Chiao-Wen; Chou, Ying-Erh; Yang, Shun-Fa; Huang, Hui-Chuan; Chang, Hsiu-Ju; Tsai, Hsiu-Ting

    2016-01-01

    The purpose of this study was to identify gene polymorphisms of mammary serine protease inhibitor (Maspin) specific to patients with oral cancer susceptibility and clinicopathological status. Three single-nucleotide polymorphisms (SNPs) of the Maspin gene from 741 patients with oral cancer and 601 non-cancer controls were analyzed by real-time PCR. The participants with G/G homozygotes or with G/C heterozygotes of Maspin rs2289520 polymorphism had a 2.07-fold (p = 0.01) and a 2.01-fold (p = 0.02) risk of developing oral cancer compared to those with C/C homozygotes. Moreover, gene-gene interaction increased the risk of oral cancer susceptibility among subjects expose to oral cancer related risk factors, including areca, alcohol, and tobacco consumption. G allele of Maspin rs2289520 polymorphism may be a factor that increases the susceptibility to oral cancer. The interactions of gene to oral cancer-related environmental risk factors have a synergetic effect that can further enhance oral cancer development.

  6. [Treatment modalities and results of comprehensive therapy for extended retinoblastoma in children].

    Science.gov (United States)

    Belkina, B M; Durnov, L A; Poliakov, V G; Goldobenko, G V; Glekov, I V; Ushakova, T L

    1997-01-01

    New procedures of laser therapy and chemotherapy have extended the scope of application of organ-saving treatment at advanced stages of retinoblastoma in childhood, thus making it possible to preserve the eye fully functional or cosmetic. Not having to perform such mutilating procedures as ophthalmectomy or eye socket exenteration contributes to psychological and physical rehabilitation. At the same time, as a comparison of the results of surgery carried out at initial stages and surgery-free treatment showed that palliative therapy is characterized by impressive rates of 5-year survival. New vistas have opened of in the management of pediatric retinoblastoma, particularly in cases of stage III tumor and bilateral involvement.

  7. Optimized lens-sparing treatment of retinoblastoma with electron beams

    NARCIS (Netherlands)

    Steenbakkers, RJHM; Altschuler, MD; DAngio, GJ; Goldwein, JW; Kassaee, A

    1997-01-01

    Purpose: The ideal lens-sparing radiotherapy technique for retinoblastoma calls for 100% dose to the entire retina including the ora serrata and zero dose to the lens, Published techniques, most of which use photons, have not accomplished this ideal treatment. We describe here a technique that

  8. Retinoblastoma in Adolescence: Report of an Unusual Presentation

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Khalili

    2010-04-01

    Full Text Available Herein, we report the clinical, pathologic and photographic findings of a 16year-old girl who presented with gradual enlargement of a vascularized, hemorrhagicperipapillary mass that eventually led to vitreous hemorrhage and rubeosis iridis.Histopathological findings after enucleation were positive for retinoblastoma. Thepatient did not have any metastasis during her 20 months of follow up.

  9. Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.

    Science.gov (United States)

    Guo, Xingyi; Shi, Jiajun; Cai, Qiuyin; Shu, Xiao-Ou; He, Jing; Wen, Wanqing; Allen, Jamie; Pharoah, Paul; Dunning, Alison; Hunter, David J; Kraft, Peter; Easton, Douglas F; Zheng, Wei; Long, Jirong

    2018-03-01

    Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.

  10. Influence of doxorubicin on fluconazole susceptibility and efflux pump gene expression of Candida dubliniensis.

    LENUS (Irish Health Repository)

    Schulz, Bettina

    2012-05-01

    The effect of doxorubicin (DOX) on the fluconazole (FLU) susceptibility of C. dubliniensis was investigated. Isolates were exposed to DOX and FLU in a chequerboard assay and resistance gene expressions were analysed after DOX exposure. The susceptibility of the yeast to FLU was decreased in the presence of DOX in the chequerboard assay with FIC indices suggesting an antagonistic effect. Gene expression analyses showed an overexpression of CdCDR2. Hence, DOX was found to have an impact on resistance mechanisms in C. dubliniensis isolates.

  11. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility

    Directory of Open Access Journals (Sweden)

    Pradhan V

    2010-01-01

    Full Text Available Systemic lupus erythematosus (SLE is a prototype autoimmune disease. SLE is a result of one or more immune mechanisms, like autoantibody production, complement activation, multiple inflammation and immune complex deposition leading to organ tissue damage. SLE affected patients are susceptible to common and opportunistic infections. There are several reports suggesting that Mycobacterium tuberculosis infection precipitates SLE in patients from endemic areas. Genetic factors and environmental factors also play an important role in the overall susceptibility to SLE pathophysiology. Recently, protein tyrosine phosphatase, non-receptor type 22 (PTPN22 gene, has been found to be associated with several autoimmune diseases like SLE, Grave′s disease and Hashimoto thyroiditis. The missense R620W polymorphism, rs 2476601, in PTPN22 gene at the nucleotide 1858 in codon 620 (620Arg > Trp has been associated with autoimmune diseases. The PTPN22 locus is also found to be responsible for development of pulmonary tuberculosis in certain populations. The PTPN22 1858C/T gene locus will be ideal to look for SLE susceptibility to tuberculosis in the Indian population. In this review, we focus on human PTPN22 gene structure and function as well as the association of PTPN22 gene polymorphisms with SLE susceptibility

  12. Profiling gene expression of antimony response genes in Leishmania (Viannia) panamensis and infected macrophages and its relationship with drug susceptibility.

    Science.gov (United States)

    Barrera, Maria Claudia; Rojas, Laura Jimena; Weiss, Austin; Fernandez, Olga; McMahon-Pratt, Diane; Saravia, Nancy G; Gomez, Maria Adelaida

    2017-12-01

    The mechanisms of Leishmania resistance to antimonials have been primarily determined in experimentally derived Leishmania strains. However, their participation in the susceptibility phenotype in field isolates has not been conclusively established. Being an intracellular parasite, the activity of antileishmanials is dependent on internalization of drugs into host cells and effective delivery to the intracellular compartments inhabited by the parasite. In this study we quantified and comparatively analyzed the gene expression of nine molecules involved in mechanisms of xenobiotic detoxification and Leishmania resistance to antimonial drugs in resistant and susceptible laboratory derived and clinical L.(Viannia) panamensis strains(n=19). In addition, we explored the impact of Leishmania susceptibility to antimonials on the expression of macrophage gene products having putative functions in transport, accumulation and metabolism of antimonials. As previously shown for other Leishmania species, a trend of increased abcc3 and lower aqp-1 expression was observed in the laboratory derived Sb-resistant L.(V.) panamensis line. However, this was not found in clinical strains, in which the expression of abca2 was significantly higher in resistant strains as both, promastigotes and intracellular amastigotes. The effect of drug susceptibility on host cell gene expression was evaluated on primary human macrophages from patients with cutaneous leishmaniasis (n=17) infected ex-vivo with the matched L.(V.) panamensis strains isolated at diagnosis, and in THP-1 cells infected with clinical strains (n=6) and laboratory adapted L.(V.) panamensis lines. Four molecules, abcb1 (p-gp), abcb6, aqp-9 and mt2a were differentially modulated by drug resistant and susceptible parasites, and among these, a consistent and significantly increased expression of the xenobiotic scavenging molecule mt2a was observed in macrophages infected with Sb-susceptible L. (V.) panamensis. Our results

  13. Toxoplasmosis and Polygenic Disease Susceptibility Genes: Extensive Toxoplasma gondii Host/Pathogen Interactome Enrichment in Nine Psychiatric or Neurological Disorders

    Directory of Open Access Journals (Sweden)

    C. J. Carter

    2013-01-01

    Full Text Available Toxoplasma gondii is not only implicated in schizophrenia and related disorders, but also in Alzheimer's or Parkinson's disease, cancer, cardiac myopathies, and autoimmune disorders. During its life cycle, the pathogen interacts with ~3000 host genes or proteins. Susceptibility genes for multiple sclerosis, Alzheimer's disease, schizophrenia, bipolar disorder, depression, childhood obesity, Parkinson's disease, attention deficit hyperactivity disorder (multiple sclerosis, and autism (, but not anorexia or chronic fatigue are highly enriched in the human arm of this interactome and 18 (ADHD to 33% (MS of the susceptibility genes relate to it. The signalling pathways involved in the susceptibility gene/interactome overlaps are relatively specific and relevant to each disease suggesting a means whereby susceptibility genes could orient the attentions of a single pathogen towards disruption of the specific pathways that together contribute (positively or negatively to the endophenotypes of different diseases. Conditional protein knockdown, orchestrated by T. gondii proteins or antibodies binding to those of the host (pathogen derived autoimmunity and metabolite exchange, may contribute to this disruption. Susceptibility genes may thus be related to the causes and influencers of disease, rather than (and as well as to the disease itself.

  14. Skin fibroblasts from a D-deletion type retinoblastoma patient are abnormally X-ray sensitive

    International Nuclear Information System (INIS)

    Weichselbaum, R.R.; Nove, J.; Little, J.B.

    1977-01-01

    Retinoblastoma is a rare malignant eye tumour that appears either spontaneously or in genetically predisposed persons. The latter group is composed of persons who inherit the tumour with a dominant mode of transmission (the familial type) and those who have a deletion in the long arm of chromosome 13 referred to as the D-deletion type. When this deletion is present it is observed in many somatic cells and is often associated with structural defects. Survivors of the genetic forms of retinoblastoma have an increased risk of the development of cancers at other sites. A single genetic locus is unlikely to predispose many somatic cells to tumour formation unless a fundamental molecular defect, possibly related to DNA repair, is present. In order to investigate this hypothesis a study was made of the in vitro X-ray sensitivity of skin fibroblasts derived from three retinoblastoma patients, comprising a pair of twins with the familial type accompanied by no gross chromosome abnormalities, and a patient with the D-deletion type. It was found that fibroblasts derived from the D-deletion patient were significantly more radiosensitive than those from the other two patients. X-ray survival curves are shown. It is concluded that skin fibroblasts derived from a patient with the D-deletion variant of retinoblastoma are abnormally radiosensitive. Future investigations may indicate a specific defect in molecular repair of DNA that will explain the predisposition of these patients to the development of other tumours. (U.K.)

  15. Total retinal detachments due to retinoblastoma: Outcomes following intra-arterial chemotherapy/ophthalmic artery chemosurgery.

    Directory of Open Access Journals (Sweden)

    Megan A Rowlands

    Full Text Available To report on the rate and timing of retinal reattachment and outcomes for retinoblastoma children who have total retinal detachments at presentation to our center and were treated with intra-arterial chemotherapy (ophthalmic artery chemosurgery, OAC.Single-center retrospective review of retinoblastoma patients who presented with total retinal detachments and were subsequently treated with OAC at MSKCC between May 2006 and July 2016. Endpoints were retinal detachment resolution, visual function, ERG amplitude, ocular survival, and patient survival from metastases.87 eyes of 84 retinoblastoma patients were included. Using a survival multistate model, by 36 months of follow-up, there was a 54% cumulative probability of complete retinal reattachment and a 76% probability of partial reattachment. 24% of eyes that completely reattached received only OAC without any prior or adjuvant treatments. Eyes that completely reattached were significantly more likely to have been diagnosed at a younger age (p<0.0001 and to have greater initial ERG values (p = 0.006. At final follow-up, 14% of eyes had gained at least 25 μV of ERG activity, and 8.0% had achieved hand motion vision or better, including one to 20/60. 13% of eyes were enucleated. No patient died from metastatic disease, and only one developed metastases.OAC can successfully treat previously considered "non-salvageable" retinoblastoma eyes with total retinal detachments, promote retinal reattachment in the majority of eyes, and preserve ocular and patient survival.

  16. Presenting signs of retinoblastoma at a tertiary level teaching ...

    African Journals Online (AJOL)

    The commonest presenting sign was proptosis 22(53.7%) followed by leucocorea nine (22%),ocular inflammation four (9.0 %), strabismus three (7.3%), glaucoma one (2.4%), loss of vision one (2.4%)and hyphemaone (2.4%). Conclusion: The commonest presenting signs of retinoblastoma in our set up were Proptosis ...

  17. A palliative approach for rehabilitation of a pediatric patient with retinoblastoma

    Directory of Open Access Journals (Sweden)

    Himanshi Aggarwal

    2013-01-01

    Full Text Available Retinoblastoma is a highly malignant neoplasm. Most of the cases are usually far advanced at the time of detection, requiring enucleation to salvage the child′s life. However, the cosmetic rehabilitation of these patients should always be an integral part of their treatment, which helps in their re-integration in the society. This paper presents a case of 5-year-old patient who had undergone enucleation of her left eye due to retinoblastoma. A multidisciplinary approach, including ophthalmologist, psychotherapist, and a prosthodontist, was adopted to meet her physical, psychological, functional, emotional, social, and cosmetic demands. The patient was rehabilitated cosmetically with precisely fabricated ocular prosthesis. An ocular prosthesis is a highly positive and non-invasive approach to improve the cosmetic appearance and psychological well-being of patient.

  18. Gene Variants Are Associated with PCOS Susceptibility and Hyperandrogenemia in Young Korean Women

    Directory of Open Access Journals (Sweden)

    Do Kyeong Song

    2014-08-01

    Full Text Available BackgroundThe fat mass and obesity-associated (FTO gene is associated with obesity and type 2 diabetes mellitus. Obesity and insulin resistance are also common features of polycystic ovary syndrome (PCOS. Therefore, the FTO gene might be a candidate gene for PCOS susceptibility. The aim of the present study was to evaluate the effects of FTO gene variants on PCOS susceptibility and metabolic and reproductive hormonal parameters.MethodsWe recruited 432 women with PCOS (24±5 years and 927 healthy women with regular menstrual cycles (27±5 years and performed a case-control association study. We genotyped the single nucleotide polymorphisms rs1421085, rs17817449, and rs8050136 in the FTO gene and collected metabolic and hormonal measurements.ResultsLogistic regression revealed that the G/G genotype (rs1421085, 1.6%, the C/C genotype (rs17817449, 1.6%, and the A/A genotype (rs8050136, 1.6% were strongly associated with an increased risk of PCOS (odds ratio, 2.551 to 2.559; all P<0.05. The strengths of these associations were attenuated after adjusting for age and BMI. The women with these genotypes were more obese and exhibited higher free androgen indices (P<0.05 and higher free testosterone levels (P=0.053 to 0.063 compared to the other genotypes. However the significant differences disappeared after adjusting for body mass index (BMI. When we analyzed the women with PCOS and the control groups separately, there were no significant differences in the metabolic and reproductive hormonal parameters according to the FTO gene variants.ConclusionThe rs1421085, rs17817449, and rs8050136 variants of the FTO gene were associated with PCOS susceptibility and hyperandrogenemia in young Korean women. These associations may be mediated through an effect of BMI.

  19. Trilateral retinoblastoma with unilateral eye involvement

    Directory of Open Access Journals (Sweden)

    Gabriel Costa de Andrade

    2015-08-01

    Full Text Available SummaryRetinoblastomas (RB are the main forms of intraocular tumor in childhood, with a worldwide incidence of 1 case per 15,000 to 20,000 live births. Trilateral RB (RBT is a rare combination of unilateral or bilateral RB with a midline intracranial neoplasm of neuroblastic origin, usually found in the pineal region or the suprasellar region, presenting variable incidence of 0.5% up to 6% among patients with RB. The article reports a case of unilateral RBT in a patient treated at Hospital A.C.Camargo.

  20. Association between TNF-α-238G/A gene polymorphism and OCD susceptibility: A meta-analysis.

    Science.gov (United States)

    Jiang, Caixiao; Ma, Xinyan; Qi, Shunxiang; Han, Guangyue; Li, Yan; Liu, Yanfang; Liu, Lanfen

    2018-02-01

    Tumor necrosis factor-alpha (TNF-α) is an important cytokine and has been reported to be associated with the pathogenesis of many autoimmune and inflammatory diseases. TNF-α gene is located on a region that has been found to be associated with obsessive-compulsive disorder (OCD). We performed this meta-analysis to assess the relationship between susceptibility to OCD and the TNF-α-238G/A gene polymorphism. An extensive search of the available literature on the association between the susceptibility to OCD and the TNF gene polymorphism was conducted by searching PubMed, Web of Knowledge, Embase, Chinese Web of Knowledge, Wanfang, and Chongqing VIP database. The database was searched up to December 2016 and includes language of English and/or Chinese with the keywords of "obsessive-compulsive disorder" or "OCD," polymorphism or variant or mutation, "tumor necrosis factor" or "TNF" or "cytokine." The association between TNF-α-238G/A gene polymorphism and the susceptibility of OCD was anticipated by odds ratio (OR) with the corresponding 95% confidence interval (95% CI). Four studies including 435 cases and 1073 controls were incorporated in our meta-analysis. In general, TNF-α-238G/A gene polymorphism might lead to a decreased risk of OCD susceptibility (G vs A genotype model: OR = 1.01, 95% CI = 0.37-2.77, P = .981; GG vs AA+AG model: OR = 0.93, 95% CI = 0.37-2.36, P = .879; GG+AG vs AA model: OR = 0.22, 95% CI = 0.06-0.73, P = .014; GG vs AA model: OR = 0.21, 95% CI = 0.06-0.71, P = .012; AG vs AA model: OR = 0.29, 95% CI = 0.07-1.16, P = .081; GG+AA vs AG model: OR = 1.17, 95% CI = 0.55-2.51, P = .683). TNF-α-238G/A gene polymorphism might lead to a decreased risk of OCD susceptibility.

  1. A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility

    DEFF Research Database (Denmark)

    Damotte, V; Guillot-Noel, L; Patsopoulos, N A

    2014-01-01

    adhesion molecule (CAMs) biological pathway using Cytoscape software. This network is a strong candidate, as it is involved in the crossing of the blood-brain barrier by the T cells, an early event in MS pathophysiology, and is used as an efficient therapeutic target. We drew up a list of 76 genes...... in interaction with other genes as a group. Pathway analysis is an alternative way to highlight such group of genes. Using SNP association P-values from eight multiple sclerosis (MS) GWAS data sets, we performed a candidate pathway analysis for MS susceptibility by considering genes interacting in the cell...... belonging to the CAM network. We highlighted 64 networks enriched with CAM genes with low P-values. Filtering by a percentage of CAM genes up to 50% and rejecting enriched signals mainly driven by transcription factors, we highlighted five networks associated with MS susceptibility. One of them, constituted...

  2. RB1 mutations and second primary malignancies after hereditary retinoblastoma

    NARCIS (Netherlands)

    Dommering, Charlotte J.; Marees, Tamara; van der Hout, Annemarie H.; Imhof, Saskia M.; Meijers-Heijboer, Hanne; Ringens, Peter J.; van Leeuwen, Flora E.; Moll, Annette C.

    2012-01-01

    Survivors of hereditary retinoblastoma have a high risk of second primary malignancies, but it has not been investigated whether specific RB1 germline mutations are associated with greater risk of second primary malignancies in a large cohort. We conducted a retrospective cohort study of 199

  3. RB1 mutations and second primary malignancies after hereditary retinoblastoma

    NARCIS (Netherlands)

    Dommering, Charlotte J.; Marees, Tamara; van der Hout, Annemarie H.; Imhof, Saskia M.; Meijers-Heijboer, Hanne; Ringens, Peter J.; van Leeuwen, Flora E.; Moll, Annette C.

    Survivors of hereditary retinoblastoma have a high risk of second primary malignancies, but it has not been investigated whether specific RB1 germline mutations are associated with greater risk of second primary malignancies in a large cohort. We conducted a retrospective cohort study of 199

  4. Presentation of retinoblastoma at a paediatric eye clinic in Ghana ...

    African Journals Online (AJOL)

    Background: Retinobalstoma, the commonest childhood malignant intraocular tumour, is usually diagnosed early with over 90% survival rate in developed countries. In developing countries, the diagnosis is late resulting in less than 50% survival. Objective: To determine retinoblastoma stages at presentation and patients¡¦ ...

  5. Intravitreal chemotherapy in retinoblastoma: expanded use beyond intravitreal seeds.

    Science.gov (United States)

    Abramson, David H; Ji, Xunda; Francis, Jasmine H; Catalanotti, Federica; Brodie, Scott E; Habib, Larissa

    2018-06-06

    Ophthalmic artery chemosurgery (OAC) has changed the face of retinoblastoma treatment and led to a higher rate of globe salvage. The introduction of intravitreal chemotherapy (IVitC) has further enhanced globe salvage with increased success in treatment of intravitreal seeds. Our group has seen success at treating non-vitreous disease that is refractory to OAC using IVitC. This study was undertaken to quantify and report on this success. A retrospective review was used to identify patients treated with IVitC for indications other than vitreous seeds from two centres. The indication, prior and concurrent treatment, response time and duration of treatment were documented. Kaplan-Meier estimates were used to evaluate ocular and recurrence-free survival. Ocular toxicity was evaluated using the 30 Hz flicker electroretinogram (ERG). Continuous and categorical variables were compared with Student's t-test and χ 2 test, respectively. Fifty-six eyes from 52 retinoblastoma patients were identified. There were no disease-related or treatment-related deaths. One patient developed a second primary malignancy (pinealoblastoma) and subsequent leptomeningeal spread. Ninety-eight per cent of the eyes showed clinical regression. Recurrence was seen in 14.3%. Of the recurrences, five occurred in retinal tumours and three in subretinal seeds. The Kaplan-Meier estimated risk of recurrence in all patients treated was 83.5% (95% CI 7.9 to 14.1) at 10 months. The mean change in ERG over treatment course was -17.7 μV. Intravitreal chemotherapy is successful for the treatment of subretinal seeds and recurrent retinal tumours and could be considered as adjunctive therapy in globe-sparing treatment of retinoblastoma. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  6. Investigation of Gamma-aminobutyric acid (GABA A receptors genes and migraine susceptibility

    Directory of Open Access Journals (Sweden)

    Ciccodicola Alfredo

    2008-12-01

    Full Text Available Abstract Background Migraine is a neurological disorder characterized by recurrent attacks of severe headache, affecting around 12% of Caucasian populations. It is well known that migraine has a strong genetic component, although the number and type of genes involved is still unclear. Prior linkage studies have reported mapping of a migraine gene to chromosome Xq 24–28, a region containing a cluster of genes for GABA A receptors (GABRE, GABRA3, GABRQ, which are potential candidate genes for migraine. The GABA neurotransmitter has been implicated in migraine pathophysiology previously; however its exact role has not yet been established, although GABA receptors agonists have been the target of therapeutic developments. The aim of the present research is to investigate the role of the potential candidate genes reported on chromosome Xq 24–28 region in migraine susceptibility. In this study, we have focused on the subunit GABA A receptors type ε (GABRE and type θ (GABRQ genes and their involvement in migraine. Methods We have performed an association analysis in a large population of case-controls (275 unrelated Caucasian migraineurs versus 275 controls examining a set of 3 single nucleotide polymorphisms (SNPs in the coding region (exons 3, 5 and 9 of the GABRE gene and also the I478F coding variant of the GABRQ gene. Results Our study did not show any association between the examined SNPs in our test population (P > 0.05. Conclusion Although these particular GABA receptor genes did not show positive association, further studies are necessary to consider the role of other GABA receptor genes in migraine susceptibility.

  7. Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour.

    Science.gov (United States)

    Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

    2015-02-01

    The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N = 366, M = 17.11 years, 74.9% male). Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour.

  8. Gene Expression Analysis of Plum pox virus (Sharka) Susceptibility/Resistance in Apricot (Prunus armeniaca L.).

    Science.gov (United States)

    Rubio, Manuel; Ballester, Ana Rosa; Olivares, Pedro Manuel; Castro de Moura, Manuel; Dicenta, Federico; Martínez-Gómez, Pedro

    2015-01-01

    RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease)/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925), which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene) or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein) PPVres region could also be involved in the resistance.

  9. Association of vitamin D receptor BsmI (rs1544410) gene polymorphism with the chronic kidney disease susceptibility.

    Science.gov (United States)

    Zhou, Tian-Biao; Jiang, Zong-Pei; Huang, Miao-Fang

    2015-02-01

    Association of vitamin D receptor (VDR) BsmI (rs1544410) gene polymorphism with the chronic kidney disease (CKD) susceptibility from the published reports are still conflicting. This meta-analysis was performed to evaluate the relationship between VDR BsmI (rs1544410) gene polymorphism and the risk of CKD. The association studies were identified from PubMed, Cochrane Library and China Biological Medicine Database on 1 March 2014, and eligible investigations were included and synthesized using meta-analysis method. Nine reports were recruited into this meta-analysis for the association of VDR BsmI gene polymorphism with CKD susceptibility. In this meta-analysis for overall populations, the BsmI B allele BB genotype and bb genotype were not associated with the risk of CKD (B allele: OR = 1.12, 95% CI: 0.88-1.44, p = 0.36; BB genotype: OR = 1.15, 95% CI: 0.81-1.62, p = 0.43; bb genotype: OR = 0.86, 95% CI: 0.61-1.20, p = 0.36). Furthermore, VDR BsmI gene polymorphism was not associated with CKD susceptibility in Asians and in Caucasians. In conclusion, the BsmI gene polymorphism was not associated with CKD susceptibility in overall populations, in Asians and in Caucasians. However, more studies should be conducted to confirm it.

  10. Screening for susceptibility genes in hereditary non-polyposis colorectal cancer.

    Science.gov (United States)

    Yu, Li; Yin, Bo; Qu, Kaiying; Li, Jingjing; Jin, Qiao; Liu, Ling; Liu, Chunlan; Zhu, Yuxing; Wang, Qi; Peng, Xiaowei; Zhou, Jianda; Cao, Peiguo; Cao, Ke

    2018-06-01

    In the present study, hereditary non-polyposis colorectal cancer (HNPCC) susceptibility genes were screened for using whole exome sequencing in 3 HNPCC patients from 1 family and using single nucleotide polymorphism (SNP) genotyping assays in 96 other colorectal cancer and control samples. Peripheral blood was obtained from 3 HNPCC patients from 1 family; the proband and the proband's brother and cousin. High-throughput sequencing was performed using whole exome capture technology. Sequences were aligned against the HAPMAP, dbSNP130 and 1,000 Genome Project databases. Reported common variations and synonymous mutations were filtered out. Non-synonymous single nucleotide variants in the 3 HNPCC patients were integrated and the candidate genes were identified. Finally, SNP genotyping was performed for the genes in 96 peripheral blood samples. In total, 60.4 Gb of data was retrieved from the 3 HNPCC patients using whole exome capture technology. Subsequently, according to certain screening criteria, 15 candidate genes were identified. Among the 96 samples that had been SNP genotyped, 92 were successfully genotyped for 15 gene loci, while genotyping for HTRA1 failed in 4 sporadic colorectal cancer patient samples. In 12 control subjects and 81 sporadic colorectal cancer patients, genotypes at 13 loci were wild-type, namely DDX20, ZFYVE26, PIK3R3, SLC26A8, ZEB2, TP53INP1, SLC11A1, LRBA, CEBPZ, ETAA1, SEMA3G, IFRD2 and FAT1 . The CEP290 genotype was mutant in 1 sporadic colorectal cancer patient and was wild-type in all other subjects. A total of 5 of the 12 control subjects and 30 of the 81 sporadic colorectal cancer patients had a mutant HTRA1 genotype. In all 3 HNPCC patients, the same mutant genotypes were identified at all 15 gene loci. Overall, 13 potential susceptibility genes for HNPCC were identified, namely DDX20, ZFYVE26, PIK3R3, SLC26A8, ZEB2, TP53INP1, SLC11A1, LRBA, CEBPZ, ETAA1, SEMA3G, IFRD2 and FAT1 .

  11. Microarray analysis of gene expression profiles of Schistosoma japonicum derived from less-susceptible host water buffalo and susceptible host goat.

    Directory of Open Access Journals (Sweden)

    Jianmei Yang

    Full Text Available BACKGROUND: Water buffalo and goats are natural hosts for S. japonicum in endemic areas of China. The susceptibility of these two hosts to schistosome infection is different, as water buffalo are less conducive to S. japonicum growth and development. To identify genes that may affect schistosome development and survival, we compared gene expression profiles of schistosomes derived from these two natural hosts using high-throughput microarray technology. RESULTS: The worm recovery rate was lower and the length and width of worms from water buffalo were smaller compared to those from goats following S. japonicum infection for 7 weeks. Besides obvious morphological difference between the schistosomes derived from the two hosts, differences were also observed by scanning and transmission electron microscopy. Microarray analysis showed differentially expressed gene patterns for parasites from the two hosts, which revealed that genes related to lipid and nucleotide metabolism, as well as protein folding, sorting, and degradation were upregulated, while others associated with signal transduction, endocrine function, development, immune function, endocytosis, and amino acid/carbohydrate/glycan metabolism were downregulated in schistosomes from water buffalo. KEGG pathway analysis deduced that the differentially expressed genes mainly involved lipid metabolism, the MAPK and ErbB signaling pathways, progesterone-mediated oocyte maturation, dorso-ventral axis formation, reproduction, and endocytosis, etc. CONCLUSION: The microarray gene analysis in schistosomes derived from water buffalo and goats provide a useful platform to disclose differences determining S. japonicum host compatibility to better understand the interplay between natural hosts and parasites, and identify schistosome target genes associated with susceptibility to screen vaccine candidates.

  12. Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

    NARCIS (Netherlands)

    Cenit, M.C.; Simeon, C.P.; Vonk, M.C.; Callejas-Rubio, J.L.; Espinosa, G.; Carreira, P.; Blanco, F.J.; Narvaez, J.; Tolosa, C.; Roman-Ivorra, J.A.; Gomez-Garcia, I.; Garcia-Hernandez, F.J.; Gallego, M.; Garcia-Portales, R.; Egurbide, M.V.; Fonollosa, V.; Garcia de la Pena, P.; Lopez-Longo, F.J.; Gonzalez-Gay, M.A.; The Spanish Scleroderma, G.; Hesselstrand, R.; Riemekasten, G.; Witte, T.J.M. de; Voskuyl, A.E.; Schuerwegh, A.J.; Madhok, R.; Fonseca, C.; Denton, C.; Nordin, A.; Palm, O.; Laar, J.M. van; Hunzelmann, N.; Distler, J.H.; Kreuter, A.; Herrick, A.; Worthington, J.; Koeleman, B.P.; Radstake, T.R.D.J.; Martin, J.

    2012-01-01

    OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and

  13. Evaluation of Fanconi anaemia genes FANCA, FANCC and FANCL in cervical cancer susceptibility.

    Science.gov (United States)

    Juko-Pecirep, Ivana; Ivansson, Emma L; Gyllensten, Ulf B

    2011-08-01

    Disrupting the function of any of the 13 Fanconi anaemia (FA) genes causes a DNA repair deficiency disorder, with patients being susceptible to a number of cancer types. Variation in the family of FA genes has been suggested to affect risk of cervical cancer. The current study evaluates the influence of three genes in the FA pathway on cervical cancer risk in Swedish women. TagSNPs in FANCA, FANCC and FANCL were selected using the Tagger algorithm in Haploview. A total of 81 tagSNPs were genotyped in 782 cases (CIN3 or ICC) and 775 controls using the Illumina GoldenGate Assay and statistically analyzed for association with cervical cancer. 72 SNPs were successfully genotyped in >98% of the samples. Nominal associations were detected for FANCA rs11649196 (p=0.05) and rs4128763 in FANCC (p=0.02). The associations did not withstand correction for multiple testing. The current study does not support that genetic variation in FANCA, FANCC or FANCL genes affects susceptibility to cervical cancer in the Swedish population. Copyright © 2011 Elsevier Inc. All rights reserved.

  14. Genetic variations of MMP9 gene and intracerebral hemorrhage susceptibility: a case-control study in Chinese Han population.

    Science.gov (United States)

    Yang, Jie; Wu, Bo; Lin, Sen; Zhou, Junshan; Li, Yingbin; Dong, Wei; Arima, Hisatomi; Zhang, Chanfei; Liu, Yukai; Liu, Ming

    2014-06-15

    To investigate the association between genetic variations of matrix metalloproteinase 9 (MMP9) gene and intracerebral hemorrhage (ICH) susceptibility in Chinese Han population. The clinical data and peripheral blood samples from the patients with ICH and hypertension, and controlled subjects with hypertension only, were collected. MassARRAY Analyzer was used to genotype the tagger single nucleotide polymorphism (SNP) of MMP9 gene. Haploview4.2 and Unphased3.1.7 were employed to construct haplotypes and to analyze the association between genetic variations (alleles, genotypes and haplotypes) of MMP9 gene and ICH susceptibility. 181 patients with ICH and hypertension, and 197 patients with hypertension only, were recruited between Sep 2009 and Oct 2010. Patients in the ICH group were younger (61.80 ± 13.27 vs. 72.44 ± 12.71 years, ppopulation. Our logistical regression analysis showed that there were no significant associations between genetic variations of the MPP9 gene and ICH susceptibility (all p>0.05). The genetic variations of MMP9 gene were not significantly associated with ICH susceptibility in the Chinese Han population. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Rice Yellow Mottle Virus stress responsive genes from susceptible and tolerant rice genotypes

    Directory of Open Access Journals (Sweden)

    Siré Christelle

    2008-03-01

    Full Text Available Abstract Background The effects of viral infection involve concomitant plant gene variations and cellular changes. A simple system is required to assess the complexity of host responses to viral infection. The genome of the Rice yellow mottle virus (RYMV is a single-stranded RNA with a simple organisation. It is the most well-known monocotyledon virus model. Several studies on its biology, structure and phylogeography have provided a suitable background for further genetic studies. 12 rice chromosome sequences are now available and provide strong support for genomic studies, particularly physical mapping and gene identification. Results The present data, obtained through the cDNA-AFLP technique, demonstrate differential responses to RYMV of two different rice cultivars, i.e. susceptible IR64 (Oryza sativa indica, and partially resistant Azucena (O. s. japonica. This RNA profiling provides a new original dataset that will enable us to gain greater insight into the RYMV/rice interaction and the specificity of the host response. Using the SIM4 subroutine, we took the intron/exon structure of the gene into account and mapped 281 RYMV stress responsive (RSR transcripts on 12 rice chromosomes corresponding to 234 RSR genes. We also mapped previously identified deregulated proteins and genes involved in partial resistance and thus constructed the first global physical map of the RYMV/rice interaction. RSR transcripts on rice chromosomes 4 and 10 were found to be not randomly distributed. Seven genes were identified in the susceptible and partially resistant cultivars, and transcripts were colocalized for these seven genes in both cultivars. During virus infection, many concomitant plant gene expression changes may be associated with host changes caused by the infection process, general stress or defence responses. We noted that some genes (e.g. ABC transporters were regulated throughout the kinetics of infection and differentiated susceptible and

  16. Thermography in the diagnosis of retinoblastoma in children

    International Nuclear Information System (INIS)

    Bogdasarov, Yu.B.; Lenskaya, O.P.; Belkina, B.M.

    1985-01-01

    The authors presented the results of thermographic examination in combination with echography and computerized tomography were presented in children with suspected retinoblastoma (30 primary examined patients and 30 patients examined to assess therapeutic efficacy). The results of the examination showed the relationship of the hyperthermia zone with tumor stage. All the patients recieved remote gamma-therapy and polychemotherapy. The usefulness of the thermographic method for efficacy assessment was shown

  17. The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation

    DEFF Research Database (Denmark)

    Fajas, Lluis; Egler, Viviane; Reiter, Raphael

    2002-01-01

    The retinoblastoma protein (RB) has previously been shown to facilitate adipocyte differentiation by inducing cell cycle arrest and enhancing the transactivation by the adipogenic CCAAT/enhancer binding proteins (C/EBP). We show here that the peroxisome proliferator-activated receptor gamma...

  18. Rhegmatogenous retinal detachment in an eye of retinoblastoma treated by radiation and cryocoagulation

    International Nuclear Information System (INIS)

    Inoue, Makoto; Tanaka, Yasuhiko; Kawai, Masataka; Nii, Seiji; Katsura, Hiroshi; Kaneko, Akihiro

    1999-01-01

    A 4-month-old female infant was diagnosed as bilateral retinoblastoma. The left eye was treated by enucleation and the right by radiation. The right eye received repeated thermochemotherapy, cryocoagulation and photocoagulation for recurrence. Total retinal detachment was detected after surgery for complicated cataract at the age of 2 years 9 months. Vitreous surgery led to the detection of posterior vitreous detachment and retinal breaks in the coagulated scar areas with vitreoretinal adhesion around the calcified tumor. During the following one year, the retina has been attached with no reoccurrence of the tumor. This case illustrates that rhegmatogenous retinal detachment is a possibility in retinoblastoma treated by radiation or retinal coagulations. (author)

  19. The LXCXE Retinoblastoma Protein-Binding Motif of FOG-2 Regulates Adipogenesis.

    Science.gov (United States)

    Goupille, Olivier; Penglong, Tipparat; Kadri, Zahra; Granger-Locatelli, Marine; Denis, Raphaël; Luquet, Serge; Badoual, Cécile; Fucharoen, Suthat; Maouche-Chrétien, Leila; Leboulch, Philippe; Chrétien, Stany

    2017-12-19

    GATA transcription factors and their FOG cofactors play a key role in tissue-specific development and differentiation, from worms to humans. Mammals have six GATA and two FOG factors. We recently demonstrated that interactions between retinoblastoma protein (pRb) and GATA-1 are crucial for erythroid proliferation and differentiation. We show here that the LXCXE pRb-binding site of FOG-2 is involved in adipogenesis. Unlike GATA-1, which inhibits cell division, FOG-2 promotes proliferation. Mice with a knockin of a Fog2 gene bearing a mutated LXCXE pRb-binding site are resistant to obesity and display higher rates of white-to-brown fat conversion. Thus, each component of the GATA/FOG complex (GATA-1 and FOG-2) is involved in pRb/E2F regulation, but these molecules have markedly different roles in the control of tissue homeostasis. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion

    Directory of Open Access Journals (Sweden)

    Fatou K. Ndiaye

    2017-06-01

    Full Text Available Objectives: Genome-wide association studies (GWAS have identified >100 loci independently contributing to type 2 diabetes (T2D risk. However, translational implications for precision medicine and for the development of novel treatments have been disappointing, due to poor knowledge of how these loci impact T2D pathophysiology. Here, we aimed to measure the expression of genes located nearby T2D associated signals and to assess their effect on insulin secretion from pancreatic beta cells. Methods: The expression of 104 candidate T2D susceptibility genes was measured in a human multi-tissue panel, through PCR-free expression assay. The effects of the knockdown of beta-cell enriched genes were next investigated on insulin secretion from the human EndoC-βH1 beta-cell line. Finally, we performed RNA-sequencing (RNA-seq so as to assess the pathways affected by the knockdown of the new genes impacting insulin secretion from EndoC-βH1, and we analyzed the expression of the new genes in mouse models with altered pancreatic beta-cell function. Results: We found that the candidate T2D susceptibility genes' expression is significantly enriched in pancreatic beta cells obtained by laser capture microdissection or sorted by flow cytometry and in EndoC-βH1 cells, but not in insulin sensitive tissues. Furthermore, the knockdown of seven T2D-susceptibility genes (CDKN2A, GCK, HNF4A, KCNK16, SLC30A8, TBC1D4, and TCF19 with already known expression and/or function in beta cells changed insulin secretion, supporting our functional approach. We showed first evidence for a role in insulin secretion of four candidate T2D-susceptibility genes (PRC1, SRR, ZFAND3, and ZFAND6 with no previous knowledge of presence and function in beta cells. RNA-seq in EndoC-βH1 cells with decreased expression of PRC1, SRR, ZFAND6, or ZFAND3 identified specific gene networks related to T2D pathophysiology. Finally, a positive correlation between the expression of Ins2 and the

  1. Gene Expression Analysis of Plum pox virus (Sharka Susceptibility/Resistance in Apricot (Prunus armeniaca L..

    Directory of Open Access Journals (Sweden)

    Manuel Rubio

    Full Text Available RNA-Seq has proven to be a very powerful tool in the analysis of the Plum pox virus (PPV, sharka disease/Prunus interaction. This technique is an important complementary tool to other means of studying genomics. In this work an analysis of gene expression of resistance/susceptibility to PPV in apricot is performed. RNA-Seq has been applied to analyse the gene expression changes induced by PPV infection in leaves from two full-sib apricot genotypes, "Rojo Pasión" and "Z506-7", resistant and susceptible to PPV, respectively. Transcriptomic analyses revealed the existence of more than 2,000 genes related to the pathogen response and resistance to PPV in apricot. These results showed that the response to infection by the virus in the susceptible genotype is associated with an induction of genes involved in pathogen resistance such as the allene oxide synthase, S-adenosylmethionine synthetase 2 and the major MLP-like protein 423. Over-expression of the Dicer protein 2a may indicate the suppression of a gene silencing mechanism of the plant by PPV HCPro and P1 PPV proteins. On the other hand, there were 164 genes involved in resistance mechanisms that have been identified in apricot, 49 of which are located in the PPVres region (scaffold 1 positions from 8,050,804 to 8,244,925, which is responsible for PPV resistance in apricot. Among these genes in apricot there are several MATH domain-containing genes, although other genes inside (Pleiotropic drug resistance 9 gene or outside (CAP, Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis-related 1 protein; and LEA, Late embryogenesis abundant protein PPVres region could also be involved in the resistance.

  2. Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour

    NARCIS (Netherlands)

    Richards, Jennifer S; Hartman, Catharina A; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Arias Vásquez, Alejandro; Buitelaar, Jan K

    The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive

  3. The SH2D2A gene and susceptibility to multiple sclerosis

    DEFF Research Database (Denmark)

    Lorentzen, A.R.; Smestad, C.; Lie, B.A.

    2008-01-01

    We previously reported an association between the SH2D2A gene encoding TSAd and multiple sclerosis (MS). Here a total of 2128 Nordic MS patients and 2004 controls were genotyped for the SH2D2A promoter GA repeat polymorphism and rs926103 encoding a serine to asparagine substitution at amino acid...... that the SH2D2A gene may contribute to susceptibility to MS Udgivelsesdato: 2008/7/15...

  4. Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans.

    Directory of Open Access Journals (Sweden)

    Heather E Wheeler

    Full Text Available Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4. Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3. Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05, including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.

  5. More epigenetic hits than meets the eye: microRNAs and genes associated with the tumorigenesis of retinoblastoma

    Directory of Open Access Journals (Sweden)

    Adriana H.O. Reis

    2012-12-01

    Full Text Available Retinoblastoma (RB, a childhood neoplasia of the retinoblasts, can occur unilaterally or bilaterally, with one or multiple foci per eye. RB is associated with somatic loss-of-function of both alleles of the tumor suppressor gene RB1. Hereditary forms emerge due to germline loss-of-function mutations in RB1 alleles. RB has long been the prototypic ‘‘model’’ cancer ever since Knudson’s ‘‘two-hit’’ hypothesis. However, a simple two-hit model for RB is challenged by an increasing number of studies documenting additional hits that contribute to RB development. Here we review the genetics and epigenetics of RB with a focus on the role of small noncoding RNAs (microRNAs and on novel findings indicating the relevance of DNA methylation in the development and prognosis of this neoplasia. Studies point to an elaborated landscape of genetic and epigenetic complexity, in which a number of events and pahtways play crucial roles in the origin and prognosis of RB. These include roles for microRNAs, inprinted loci, and parent-of-origin contributions to RB1 regulation and RB progression. This complexity is also manifested in the structure of the RB1 locus itself: it includes numerous repetitive DNA segments and retrotransposon insertion elements, some of which are actively transcribed from the RB1 locus. Altogether, we conclude that RB1 loss of function represents the tip of an iceberg of events that determine RB development, progression, severity, and disease risk. Comprehensive assessment of personalized RB risk will require genetic and epigenetic evaluations beyond RB1 protein coding sequences.

  6. Leiomyosarcoma of the bladder in a 16-year-old girl with a history of cyclophosphamide therapy for bilateral retinoblastoma during infancy

    International Nuclear Information System (INIS)

    Al-Zahrani, Ali A.; Kamal, Baher A.; Eldarawani, Hamed M.; Hashim, Tariq M.

    2006-01-01

    A 16-year-old female with bladder leiomyosarcoma had a history of bilateral retinoblastoma at 6 months of life. She received cyclophosphamide chemotherapy after surgical enucleation. In this report, we discussed the possible role of retinoblastoma or cyclophosphamide as a target for development of bladder leiomyosarcoma. (author)

  7. Hereditary cancer genes are highly susceptible to splicing mutations

    Science.gov (United States)

    Soemedi, Rachel; Maguire, Samantha; Murray, Michael F.; Monaghan, Sean F.

    2018-01-01

    Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5′ and 3′ splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing. PMID:29505604

  8. Hereditary cancer genes are highly susceptible to splicing mutations.

    Directory of Open Access Journals (Sweden)

    Christy L Rhine

    2018-03-01

    Full Text Available Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77% of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36% of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we found that three main causal genes of Lynch Syndrome, MLH1, MSH2, and PMS2, belonged to a class of 86 disease genes which are enriched for splicing mutations. Other cancer genes were also enriched in the 86 susceptible genes. The enrichment of splicing mutations in hereditary cancers strongly argues for additional priority in interpreting clinical sequencing data in relation to cancer and splicing.

  9. T-cell receptor variable genes and genetic susceptibility to celiac disease: an association and linkage study.

    Science.gov (United States)

    Roschmann, E; Wienker, T F; Gerok, W; Volk, B A

    1993-12-01

    Genetic susceptibility of celiac disease is primarily associated with a particular combination of and HLA-DQA1/DQB1 gene; however, this does not fully account for the genetic predisposition. Therefore, the aim of this study was to examine whether T-cell receptor (TCR) genes may be susceptibility genes in celiac disease. HLA class II typing was performed by polymerase chain reaction amplification in combination with sequence-specific oligonucleotide hybridization. TCR alpha (TCRA), TCR gamma (TCRG), and TCR beta (TCRB) loci were investigated by restriction fragment length polymorphism analysis. Allelic frequencies of TCRA, TCRG, and TCRB variable genes were compared between patients with celiac disease (n = 53) and control patients (n = 67), and relative risk (RR) estimates were calculated. The RR was 1.67 for allele C1 at TCRA1, 3.35 for allele D2 at TCRA2, 1.66 for allele B2 at TCRG, and 1.35 for allele B at TCRB, showing no significant association. Additionally, linkage analysis was performed in 23 families. The logarithm of odd scores for celiac disease vs. the TCR variable genes at TCRA, TCRG, and TCRB showed no significant linkage. These data suggest that the analyzed TCR variable gene segments V alpha 1.2, V gamma 11, and V beta 8 do not play a major role in susceptibility to celiac disease.

  10. Multilocus analysis reveals three candidate genes for Chinese migraine susceptibility.

    Science.gov (United States)

    An, X-K; Fang, J; Yu, Z-Z; Lin, Q; Lu, C-X; Qu, H-L; Ma, Q-L

    2017-08-01

    Several genome-wide association studies (GWASs) in Caucasian populations have identified 12 loci that are significantly associated with migraine. More evidence suggests that serotonin receptors are also involved in migraine pathophysiology. In the present study, a case-control study was conducted in a cohort of 581 migraine cases and 533 ethnically matched controls among a Chinese population. Eighteen polymorphisms from serotonin receptors and GWASs were selected, and genotyping was performed using a Sequenom MALDI-TOF mass spectrometry iPLEX platform. The genotypic and allelic distributions of MEF2D rs2274316 and ASTN2 rs6478241 were significantly different between migraine patients and controls. Univariate and multivariate analysis revealed significant associations of polymorphisms in the MEF2D and ASTN2 genes with migraine susceptibility. MEF2D, PRDM16 and ASTN2 were also found to be associated with migraine without aura (MO) and migraine with family history. And, MEF2D and ASTN2 also served as genetic risk factors for the migraine without family history. The generalized multifactor dimensionality reduction analysis identified that MEF2D and HTR2E constituted the two-factor interaction model. Our study suggests that the MEF2D, PRDM16 and ASTN2 genes from GWAS are associated with migraine susceptibility, especially MO, among Chinese patients. It appears that there is no association with serotonin receptor related genes. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. High Frequency of Interactions between Lung Cancer Susceptibility Genes in the Mouse : Mapping of Sluc5 to Sluc14

    NARCIS (Netherlands)

    Fijneman, Remond J.A.; Jansen, Ritsert C.; Valk, Martin A. van der; Demant, Peter

    1998-01-01

    Although several genes that cause monogenic familial cancer syndromes have been identified, susceptibility to sporadic cancer remains unresolved. Animal experiments have demonstrated multigenic control of tumor susceptibility. Recently, we described four mouse lung cancer susceptibility (Sluc) loci,

  12. Effects of disruption of heat shock genes on susceptibility of Escherichia coli to fluoroquinolones

    Directory of Open Access Journals (Sweden)

    Morioka Mizue

    2003-08-01

    Full Text Available Abstract Background It is well known that expression of certain bacterial genes responds rapidly to such stimuli as exposure to toxic chemicals and physical agents. It is generally believed that the proteins encoded in these genes are important for successful survival of the organism under the hostile conditions. Analogously, the proteins induced in bacterial cells exposed to antibiotics are believed to affect the organisms' susceptibility to these agents. Results We demonstrated that Escherichia coli cells exposed to levofloxacin (LVFX, a fluoroquinolone (FQ, induce the syntheses of heat shock proteins and RecA. To examine whether the heat shock proteins affect the bactericidal action of FQs, we constructed E. coli strains with mutations in various heat shock genes and tested their susceptibility to FQs. Mutations in dnaK, groEL, and lon increased this susceptibility; the lon mutant exhibited the greatest effects. The increased susceptibility of the lon mutant was corroborated by experiments in which the gene encoding the cell division inhibitor, SulA, was subsequently disrupted. SulA is induced by the SOS response and degraded by the Lon protease. The findings suggest that the hypersusceptibility of the lon mutant to FQs could be due to abnormally high levels of SulA protein resulting from the depletion of Lon and the continuous induction of the SOS response in the presence of FQs. Conclusion The present results show that the bactericidal action of FQs is moderately affected by the DnaK and GroEL chaperones and strongly affected by the Lon protease. FQs have contributed successfully to the treatment of various bacterial infections, but their widespread use and often misuse, coupled with emerging resistance, have gradually compromised their utility. Our results suggest that agents capable of inhibiting the Lon protease have potential for combination therapy with FQs.

  13. Cobalt60 plaques in recurrent retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Fass, D.; McCormick, B.; Abramson, D.; Ellsworth, R. (Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, NY, NY (USA))

    1991-08-01

    Cobalt60 plaque irradiation is one treatment option for patients with recurrent retinoblastoma following conventional external beam irradiation (ERT). Tumorocidal doses can be delivered without excessive risk of normal tissue injury. In patients not considered candidates for xenon arc or cryotherapy, 60Co is an alternative to enucleation. Between 1968 and 1987, 85 patients were treated with 60Co plaques, 72 of whom had failed prior ERT. Age at diagnosis ranged from 1 week to 4 years. There are 37 males and 35 females. Seventy-one patients had bilateral disease and one had unilateral. Three patients had both eyes plaqued. Prior ERT ranged from 30 to 70 Gy (mean 4200 Gy). Time from initial therapy to failure ranged from 13 to 60 months. Cobalt plaques of 10 mm, 15 mm, or 10 {times} 15 mm were used depending on tumor size and location. Dose prescribed to the apex of the tumor ranged from 30 to 50 Gy (median 40 Gy) given over 3 to 8 days. Twelve patients had two plaque applications; three patients had three plaque applications. All patients were followed with routine ophthalmoscopic examinations. Follow-up ranged from 2 to 22 years (mean 8.7). Seven patients died of metastatic disease; 10 patients developed non-ocular second tumors. Thirty patients required enucleation. Twenty-two patients had clear tumor progression, two patients had radiation complications, and six patients had a combination of tumor growth and complications. Cobalt60 can salvage eyes in retinoblastoma patients failing ERT. Currently, the authors are using I125 in an attempt to spare normal ocular tissue and reduce subsequent complications.

  14. Cobalt60 plaques in recurrent retinoblastoma

    International Nuclear Information System (INIS)

    Fass, D.; McCormick, B.; Abramson, D.; Ellsworth, R.

    1991-01-01

    Cobalt60 plaque irradiation is one treatment option for patients with recurrent retinoblastoma following conventional external beam irradiation (ERT). Tumorocidal doses can be delivered without excessive risk of normal tissue injury. In patients not considered candidates for xenon arc or cryotherapy, 60Co is an alternative to enucleation. Between 1968 and 1987, 85 patients were treated with 60Co plaques, 72 of whom had failed prior ERT. Age at diagnosis ranged from 1 week to 4 years. There are 37 males and 35 females. Seventy-one patients had bilateral disease and one had unilateral. Three patients had both eyes plaqued. Prior ERT ranged from 30 to 70 Gy (mean 4200 Gy). Time from initial therapy to failure ranged from 13 to 60 months. Cobalt plaques of 10 mm, 15 mm, or 10 x 15 mm were used depending on tumor size and location. Dose prescribed to the apex of the tumor ranged from 30 to 50 Gy (median 40 Gy) given over 3 to 8 days. Twelve patients had two plaque applications; three patients had three plaque applications. All patients were followed with routine ophthalmoscopic examinations. Follow-up ranged from 2 to 22 years (mean 8.7). Seven patients died of metastatic disease; 10 patients developed non-ocular second tumors. Thirty patients required enucleation. Twenty-two patients had clear tumor progression, two patients had radiation complications, and six patients had a combination of tumor growth and complications. Cobalt60 can salvage eyes in retinoblastoma patients failing ERT. Currently, the authors are using I125 in an attempt to spare normal ocular tissue and reduce subsequent complications

  15. Chemotherapy as an adjuvant to Radiotherapy in treatment of Retinoblastoma

    International Nuclear Information System (INIS)

    Ahmed, A.H.M.

    2015-01-01

    Retinoblastoma is the most common primary intraocular malignancy of childhood. A potentially curable cancer, its treatment has improved significantly over the last few decades. Various studies show that while enucleation remains the standard of care for advanced intraocular tumours, conservative modalities that can result in globe salvage and preservation of useful vision are being increasingly employed. Such modalities include systemic chemotherapy, focal consolidation with transpupillary thermo therapy, laser photocoagulation and cryotherapy, plaque brachytherapy, and delivery of local chemotherapy using subconjunctival, sub-tenon, or intra-arterial routes. When used alone or in combination, these treatment modalities can help in avoidance of external beam radiotherapy or enucleation, thus reducing the potential for long-term side effects, while salvaging useful vision. Radioactive plaque brachytherapy has an established role in selected patients with intraocular retinoblastoma. Local injections of chemotherapeutic agents via the sub-tenon or sub-conjunctival route have been used with varying degrees of success, usually as an adjunct to systemic chemotherapy. Intra-arterial ophthalmic artery delivery of melphalan has shown promising results.

  16. Tumours following retinoblastoma radiotherapy

    International Nuclear Information System (INIS)

    Mollot, J.-P.

    1978-01-01

    Radioinduced tumours in young patients irradiated in childhood for retinoblastoma take on a particularly deadly aspect. The onset of this true clinical entity characterized by a long post-irradiation latency period induced by a dose above 6000 rads is a real tragedy. The vast majority of patients then enter into a long martyrdom ending in death. The only cure is surgical, but seldom possible. Treatment is limited to palliative radiotherapy, effective for a while, and chemiotherapy as a last resort but often difficult to prescribe. Prevention alone is the answer. The quality and reliability of the radiotherapeutic treatment depend not only on the personal talent of the radiotherapist but above all on the standard of the equipment. A strong reduction in the doses employed as well as recent technological progress improving the material, its precision and reproducibility appear already to have lowered the frequency curve of these fatal radioinduced tumours [fr

  17. Various ocular MR imaging in a mouse implanted with a new cell line of retinoblastoma and the correlation with the pathology: preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Dong Hun; Kim, Il Joong; Yang, Jae Han; Byun, Joo Nam; Lee, Bong Jae [Chosun University, College of Medicine, Gwangju (Korea, Republic of); Kim, Jeong Hun; Yu, Young Suk [Seoul National University, College of Medicine, Seoul (Korea, Republic of)

    2007-05-15

    We wanted to show various MR and correlated pathologic images of retinoblastoma in nude mouse with a new human retinoblastoma cell line (SNUOT-Rb1), which was inoculated into the intravitreous cavity. The established cell line was inoculated into the intravitreous cavity of 36 eyeballs of 18 mice and the transplanted retinoblastoma was examined for 3 months. The T1-weighted (T1WI), T2-weighted (T2WI), and contrast enhanced (Gd-DTPA) T1-weighted images were obtained with using a small loop coil. After scanning, the mice's eyeballs were extracted and the hematoxylin and eosin stained specimens were examined with a microscope. We compared the MR imagings with pathologic findings and evaluated the character of the tumors. The innoculated cells in the eyeballs of the mice grew into retinoblastoma (23/36, 64%). The eyeballs with retinoblastoma protruded externally and showed focal hemorrhage. Most tumors showed iso-signal intensity on TIWI (13/23, 57%), high signal intensity on T2WI (17/23, 74%), and good enhancement (21/23, 91%) with contrast. Almost all of the tumors (n = 21) were located in the retina and three extraretinal tumors were confirmed by pathology. Involvement of the optic nerve was suspected on MRI and this was confirmed by pathology in 6 cases and 5 cases, respectively. We could demonstrate various MR imagings of transplanted retinoblastoma by using the new tumor cell line in vivo.

  18. Various ocular MR imaging in a mouse implanted with a new cell line of retinoblastoma and the correlation with the pathology: preliminary study

    International Nuclear Information System (INIS)

    Kim, Dong Hun; Kim, Il Joong; Yang, Jae Han; Byun, Joo Nam; Lee, Bong Jae; Kim, Jeong Hun; Yu, Young Suk

    2007-01-01

    We wanted to show various MR and correlated pathologic images of retinoblastoma in nude mouse with a new human retinoblastoma cell line (SNUOT-Rb1), which was inoculated into the intravitreous cavity. The established cell line was inoculated into the intravitreous cavity of 36 eyeballs of 18 mice and the transplanted retinoblastoma was examined for 3 months. The T1-weighted (T1WI), T2-weighted (T2WI), and contrast enhanced (Gd-DTPA) T1-weighted images were obtained with using a small loop coil. After scanning, the mice's eyeballs were extracted and the hematoxylin and eosin stained specimens were examined with a microscope. We compared the MR imagings with pathologic findings and evaluated the character of the tumors. The innoculated cells in the eyeballs of the mice grew into retinoblastoma (23/36, 64%). The eyeballs with retinoblastoma protruded externally and showed focal hemorrhage. Most tumors showed iso-signal intensity on TIWI (13/23, 57%), high signal intensity on T2WI (17/23, 74%), and good enhancement (21/23, 91%) with contrast. Almost all of the tumors (n = 21) were located in the retina and three extraretinal tumors were confirmed by pathology. Involvement of the optic nerve was suspected on MRI and this was confirmed by pathology in 6 cases and 5 cases, respectively. We could demonstrate various MR imagings of transplanted retinoblastoma by using the new tumor cell line in vivo

  19. Is There a Predisposition Gene for Ewing's Sarcoma?

    Directory of Open Access Journals (Sweden)

    R. L. Randall

    2010-01-01

    Full Text Available Ewing's sarcoma is a highly malignant tumor of children and young adults. The molecular mechanisms that underlie Ewing's Sarcoma development are beginning to be understood. For example, most cases of this disease harbor somatic chromosomal translocations that fuse the EWSR1 gene on chromosome 22 with members of the ETS family. While some cooperative genetic events have been identified, such as mutations in TP53 or deletions of the CDKN2A locus, these appear to be absent in the vast majority of cases. It is therefore uncertain whether EWS/ETS translocations are the only consistently present alteration in this tumor, or whether there are other recurrent abnormalities yet to be discovered. One method to discover such mutations is to identify familial cases of Ewing's sarcoma and to then map the susceptibility locus using traditional genetic mapping techniques. Although cases of sibling pairs with Ewing's sarcoma exist, familial cases of Ewing's sarcoma have not been reported. While Ewing's sarcoma has been reported as a 2nd malignancy after retinoblastoma, significant associations of Ewing's sarcoma with classic tumor susceptibility syndromes have not been identified. We will review the current evidence, or lack thereof, regarding the potential of a heritable condition predisposing to Ewing's sarcoma.

  20. Is There a Predisposition Gene for Ewing's Sarcoma?

    Science.gov (United States)

    Randall, R. L.; Lessnick, S. L.; Jones, K. B.; Gouw, L. G.; Cummings, J. E.; Cannon-Albright, L.; Schiffman, J. D.

    2010-01-01

    Ewing's sarcoma is a highly malignant tumor of children and young adults. The molecular mechanisms that underlie Ewing's Sarcoma development are beginning to be understood. For example, most cases of this disease harbor somatic chromosomal translocations that fuse the EWSR1 gene on chromosome 22 with members of the ETS family. While some cooperative genetic events have been identified, such as mutations in TP53 or deletions of the CDKN2A locus, these appear to be absent in the vast majority of cases. It is therefore uncertain whether EWS/ETS translocations are the only consistently present alteration in this tumor, or whether there are other recurrent abnormalities yet to be discovered. One method to discover such mutations is to identify familial cases of Ewing's sarcoma and to then map the susceptibility locus using traditional genetic mapping techniques. Although cases of sibling pairs with Ewing's sarcoma exist, familial cases of Ewing's sarcoma have not been reported. While Ewing's sarcoma has been reported as a 2nd malignancy after retinoblastoma, significant associations of Ewing's sarcoma with classic tumor susceptibility syndromes have not been identified. We will review the current evidence, or lack thereof, regarding the potential of a heritable condition predisposing to Ewing's sarcoma. PMID:20300555

  1. Asthma susceptible genes in Chinese population: A meta-analysis

    Directory of Open Access Journals (Sweden)

    He Chao

    2010-09-01

    Full Text Available Abstract Background Published data regarding the associations between genetic variants and asthma risk in Chinese population were inconclusive. The aim of this study was to investigate asthma susceptible genes in Chinese population. Methods The authors conducted 18 meta-analyzes for 18 polymorphisms in 13 genes from eighty-two publications. Results Seven polymorphisms were found being associated with risk of asthma, namely: A Disintegrin and Metalloprotease 33 (ADAM33 T1-C/T (odds ratio [OR] = 6.07, 95% confidence interval [CI]: 2.69-13.73, Angiotensin-Converting Enzyme (ACE D/I (OR = 3.85, 95%CI: 2.49-5.94, High-affinity IgE receptor β chain (FcεRIβ -6843G/A (OR = 1.49, 95%CI: 1.01-2.22, Interleukin 13(IL-13 -1923C/T (OR = 2.99, 95%CI: 2.12-4.24, IL-13 -2044A/G (OR = 1.49, 95%CI: 1.07-2.08, Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES -28C/G (OR = 1.64, 95%CI: 1.09-2.46, Tumor Necrosis Factor-α (TNF-α -308G/A(OR = 1.42, 95%CI: 1.09, 1.85. After subgroup analysis by age, the ACE D/I, β2-Adrenergic Receptor (β2-AR -79G/C, TNF-α -308G/A, Interleukin 4 receptor(IL-4R -1902G/A and IL-13 -1923C/T polymorphisms were found significantly associated with asthma risk in Chinese children. In addition, the ACE D/I, FcεRIβ -6843G/A, TNF-α -308G/A, IL-13 -1923C/T and IL-13 -2044A/G polymorphisms were associated with asthma risk in Chinese adults. Conclusion ADAM33, FcεRIβ, RANTES, TNF-α, ACE, β2-AR, IL-4R and IL-13 genes could be proposed as asthma susceptible genes in Chinese population. Given the limited number of studies, more data are required to validate these associations.

  2. Analysis of metal and biocides resistance genes in drug resistance and susceptible Salmonella enterica from food animals

    Science.gov (United States)

    Background Generally drug resistant bacteria carry antibiotic resistance genes and heavy metal and biocide resistance genes on large conjugative plasmids. The presence of these metal and biocide resistance genes in susceptible bacteria are not assessed comprehensively. Hence, WGS data of susceptib...

  3. Epstein-Barr virus-induced gene 3 (EBI3) polymorphisms and expression are associated with susceptibility to pulmonary tuberculosis.

    Science.gov (United States)

    Zheng, Ruijuan; Liu, Haipeng; Song, Peng; Feng, Yonghong; Qin, Lianhua; Huang, Xiaochen; Chen, Jianxia; Yang, Hua; Liu, Zhonghua; Cui, Zhenglin; Hu, Zhongyi; Ge, Baoxue

    2015-07-01

    Tuberculosis (TB) remains a major global health problem and host genetic factors play a critical role in susceptibility and resistance to TB. The aim of this study was to identify novel candidate genes associated with TB susceptibility. We performed a population-based case-control study to genotype 13 tag SNPs spanning Epstein-Barr virus-induced gene 3 (EBI3), colony stimulating factor 2 (CSF2), IL-4, interferon beta 1 (IFNB1), chemokine (C-X-C motif) ligand 14 (CXCL14) and myeloid differentiation primary response gene 88 (Myd88) genes in 435 pulmonary TB patients and 375 health donors from China. We observed that EBI3 gene rs4740 polymorphism was associated with susceptibility to pulmonary tuberculosis (PTB) and the allele G was associated with a protective effect against PTB. Furthermore, EBI3 deficiency led to reduced bacterial burden and histopathological impairment in the lung of mice infected with Mycobacterium bovis BCG. Meanwhile, higher abundance of EBI3 was observed in the granuloma of PTB patients and in the lung tissue of BCG-infected mice. Of note, the expression of EBI3 in macrophages was remarkably induced by mycobacteria infection at both mRNA and protein level. In conclusion, EBI3 gene rs4740 polymorphism is closely associated with susceptibility to PTB and the elevation and enrichment of EBI3 in the lung which at least partially derived from macrophages may contribute to the exacerbation of mycobacterial infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

  4. Transcription factor SP4 is a susceptibility gene for bipolar disorder.

    Directory of Open Access Journals (Sweden)

    Xianjin Zhou

    Full Text Available The Sp4 transcription factor plays a critical role for both development and function of mouse hippocampus. Reduced expression of the mouse Sp4 gene results in a variety of behavioral abnormalities relevant to human psychiatric disorders. The human SP4 gene is therefore examined for its association with both bipolar disorder and schizophrenia in European Caucasian and Chinese populations respectively. Out of ten SNPs selected from human SP4 genomic locus, four displayed significant association with bipolar disorder in European Caucasian families (rs12668354, p = 0.022; rs12673091, p = 0.0005; rs3735440, p = 0.019; rs11974306, p = 0.018. To replicate the genetic association, the same set of SNPs was examined in a Chinese bipolar case control sample. Four SNPs displayed significant association (rs40245, p = 0.009; rs12673091, p = 0.002; rs1018954, p = 0.001; rs3735440, p = 0.029, and two of them (rs12673091, rs3735440 were shared with positive SNPs from European Caucasian families. Considering the genetic overlap between bipolar disorder and schizophrenia, we extended our studies in Chinese trios families for schizophrenia. The SNP7 (rs12673091, p = 0.012 also displayed a significant association. The SNP7 (rs12673091 was therefore significantly associated in all three samples, and shared the same susceptibility allele (A across all three samples. On the other hand, we found a gene dosage effect for mouse Sp4 gene in the modulation of sensorimotor gating, a putative endophenotype for both schizophrenia and bipolar disorder. The deficient sensorimotor gating in Sp4 hypomorphic mice was partially reversed by the administration of dopamine D2 antagonist or mood stabilizers. Both human genetic and mouse pharmacogenetic studies support Sp4 gene as a susceptibility gene for bipolar disorder or schizophrenia. The studies on the role of Sp4 gene in hippocampal development may provide novel insights for the contribution of hippocampal abnormalities in these

  5. A gene expression signature of Retinoblastoma loss-of-function predicts resistance to neoadjuvant chemotherapy in ER-positive/HER2-positive breast cancer patients.

    Science.gov (United States)

    Risi, Emanuela; Grilli, Andrea; Migliaccio, Ilenia; Biagioni, Chiara; McCartney, Amelia; Guarducci, Cristina; Bonechi, Martina; Benelli, Matteo; Vitale, Stefania; Biganzoli, Laura; Bicciato, Silvio; Di Leo, Angelo; Malorni, Luca

    2018-07-01

    HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively; Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.

  6. Differential gene expression of two extreme honey bee (Apis mellifera) colonies showing varroa tolerance and susceptibility.

    Science.gov (United States)

    Jiang, S; Robertson, T; Mostajeran, M; Robertson, A J; Qiu, X

    2016-06-01

    Varroa destructor, an ectoparasitic mite of honey bees (Apis mellifera), is the most serious pest threatening the apiculture industry. In our honey bee breeding programme, two honey bee colonies showing extreme phenotypes for varroa tolerance/resistance (S88) and susceptibility (G4) were identified by natural selection from a large gene pool over a 6-year period. To investigate potential defence mechanisms for honey bee tolerance to varroa infestation, we employed DNA microarray and real time quantitative (PCR) analyses to identify differentially expressed genes in the tolerant and susceptible colonies at pupa and adult stages. Our results showed that more differentially expressed genes were identified in the tolerant bees than in bees from the susceptible colony, indicating that the tolerant colony showed an increased genetic capacity to respond to varroa mite infestation. In both colonies, there were more differentially expressed genes identified at the pupa stage than at the adult stage, indicating that pupa bees are more responsive to varroa infestation than adult bees. Genes showing differential expression in the colony phenotypes were categorized into several groups based on their molecular functions, such as olfactory signalling, detoxification processes, exoskeleton formation, protein degradation and long-chain fatty acid metabolism, suggesting that these biological processes play roles in conferring varroa tolerance to naturally selected colonies. Identification of differentially expressed genes between the two colony phenotypes provides potential molecular markers for selecting and breeding varroa-tolerant honey bees. © 2016 The Royal Entomological Society.

  7. A systems genetics approach identifies CXCL14, ITGAX, and LPCAT2 as novel aggressive prostate cancer susceptibility genes.

    Directory of Open Access Journals (Sweden)

    Kendra A Williams

    2014-11-01

    Full Text Available Although prostate cancer typically runs an indolent course, a subset of men develop aggressive, fatal forms of this disease. We hypothesize that germline variation modulates susceptibility to aggressive prostate cancer. The goal of this work is to identify susceptibility genes using the C57BL/6-Tg(TRAMP8247Ng/J (TRAMP mouse model of neuroendocrine prostate cancer. Quantitative trait locus (QTL mapping was performed in transgene-positive (TRAMPxNOD/ShiLtJ F2 intercross males (n = 228, which facilitated identification of 11 loci associated with aggressive disease development. Microarray data derived from 126 (TRAMPxNOD/ShiLtJ F2 primary tumors were used to prioritize candidate genes within QTLs, with candidate genes deemed as being high priority when possessing both high levels of expression-trait correlation and a proximal expression QTL. This process enabled the identification of 35 aggressive prostate tumorigenesis candidate genes. The role of these genes in aggressive forms of human prostate cancer was investigated using two concurrent approaches. First, logistic regression analysis in two human prostate gene expression datasets revealed that expression levels of five genes (CXCL14, ITGAX, LPCAT2, RNASEH2A, and ZNF322 were positively correlated with aggressive prostate cancer and two genes (CCL19 and HIST1H1A were protective for aggressive prostate cancer. Higher than average levels of expression of the five genes that were positively correlated with aggressive disease were consistently associated with patient outcome in both human prostate cancer tumor gene expression datasets. Second, three of these five genes (CXCL14, ITGAX, and LPCAT2 harbored polymorphisms associated with aggressive disease development in a human GWAS cohort consisting of 1,172 prostate cancer patients. This study is the first example of using a systems genetics approach to successfully identify novel susceptibility genes for aggressive prostate cancer. Such

  8. The Canine POMC Gene, Obesity in Labrador Retrievers and Susceptibility to Diabetes Mellitus

    OpenAIRE

    Davison, L.J.; Holder, A.; Catchpole, B.; O'Callaghan, C.A.

    2017-01-01

    Background Diabetes mellitus (DM) in dogs is a common endocrinopathy with a complex genetic architecture. Disease susceptibility in several breeds is associated with polymorphisms in immune response genes, but in the Labrador retriever breed, no genetic associations with DM have been identified. A deletion in the pro-opiomelanocortin (POMC) gene in Labrador retrievers is associated with increased appetite and risk of obesity. Hypothesis/Objectives To characterize the POMC deletion i...

  9. Assessment of PALB2 as a candidate melanoma susceptibility gene.

    Directory of Open Access Journals (Sweden)

    Lauren G Aoude

    Full Text Available Partner and localizer of BRCA2 (PALB2 interacts with BRCA2 to enable double strand break repair through homologous recombination. Similar to BRCA2, germline mutations in PALB2 have been shown to predispose to Fanconi anaemia as well as pancreatic and breast cancer. The PALB2/BRCA2 protein interaction, as well as the increased melanoma risk observed in families harbouring BRCA2 mutations, makes PALB2 a candidate for melanoma susceptibility. In order to assess PALB2 as a melanoma predisposition gene, we sequenced the entire protein-coding sequence of PALB2 in probands from 182 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, and BAP1. In addition, we interrogated whole-genome and exome data from another 19 kindreds with a strong family history of melanoma for deleterious mutations in PALB2. Here we report a rare known deleterious PALB2 mutation (rs118203998 causing a premature truncation of the protein (p.Y1183X in an individual who had developed four different cancer types, including melanoma. Three other family members affected with melanoma did not carry the variant. Overall our data do not support a case for PALB2 being associated with melanoma predisposition.

  10. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    Science.gov (United States)

    Crampton, Steve P.; Morawski, Peter A.; Bolland, Silvia

    2014-01-01

    Systemic lupus erythematosus (SLE) represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS) and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease. PMID:25147296

  11. Linking susceptibility genes and pathogenesis mechanisms using mouse models of systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Steve P. Crampton

    2014-09-01

    Full Text Available Systemic lupus erythematosus (SLE represents a challenging autoimmune disease from a clinical perspective because of its varied forms of presentation. Although broad-spectrum steroids remain the standard treatment for SLE, they have many side effects and only provide temporary relief from the symptoms of the disease. Thus, gaining a deeper understanding of the genetic traits and biological pathways that confer susceptibility to SLE will help in the design of more targeted and effective therapeutics. Both human genome-wide association studies (GWAS and investigations using a variety of mouse models of SLE have been valuable for the identification of the genes and pathways involved in pathogenesis. In this Review, we link human susceptibility genes for SLE with biological pathways characterized in mouse models of lupus, and discuss how the mechanistic insights gained could advance drug discovery for the disease.

  12. E2F target genes: unraveling the biology

    DEFF Research Database (Denmark)

    Bracken, Adrian P; Ciro, Marco; Cocito, Andrea

    2004-01-01

    The E2F transcription factors are downstream effectors of the retinoblastoma protein (pRB) pathway and are required for the timely regulation of numerous genes essential for DNA replication and cell cycle progression. Several laboratories have used genome-wide approaches to discover novel target...

  13. Long-term medical outcomes in survivors of extra-ocular retinoblastoma: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience.

    Science.gov (United States)

    Friedman, Danielle Novetsky; Sklar, Charles A; Oeffinger, Kevin C; Kernan, Nancy A; Khakoo, Yasmin; Marr, Brian P; Wolden, Suzanne L; Abramson, David H; Dunkel, Ira J

    2013-04-01

    Data on long-term outcomes of survivors of extra-ocular retinoblastoma are lacking. The authors sought to provide the first report characterizing long-term outcomes among survivors of extra-ocular retinoblastoma. Retrospective analysis of long-term medical outcomes in 19 survivors of extra-ocular retinoblastoma treated between 1992 and 2009. Severity of outcomes was graded using Common Terminology Criteria for Adverse Events. All patients received intensive multimodality therapy for their extra-ocular disease after management of their primary intra-ocular disease, including conventional chemotherapy (n = 19, 100%), radiotherapy (n = 15, 69%), and/or high-dose chemotherapy with autologous stem cell transplant (n = 17, 89%). The median follow-up was 7.8 years from diagnosis of extra-ocular retinoblastoma (range 2-17.8 years). The most common long-term non-visual outcomes were hearing loss (n = 15, 79%), short stature (n = 7, 37%), and secondary malignancies [SMN] (n = 6, 31%). Sixty-eight percent of survivors exhibited ≥2 non-visual long-term outcomes of any grade. Except short stature, which was not graded for severity, Grade 3-4 outcomes were limited to: ototoxicity (n = 8; n = 4 require hearing aids), SMNs (n = 6), and unequal limb length (n = 1). Five patients who developed SMNs carried a known RB1 mutation. SMNs developed at a median of 11.1 years after initial diagnosis; two patients died of their SMN. Long-term cardiac, pulmonary, hepatobiliary, or renal conditions were not identified in any survivors. Long-term outcomes are commonly seen in extra-ocular retinoblastoma survivors but the majority are mild-moderate in their severity. Longer comprehensive follow-up is needed to fully assess treatment-related outcomes but the information collected to date may affect management decisions for children with extra-ocular disease. Copyright © 2012 Wiley Periodicals, Inc.

  14. Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy

    International Nuclear Information System (INIS)

    Casula, Milena; Sini, MariaCristina; Palomba, Grazia; The Italian Melanoma Intergroup; Palmieri, Giuseppe; Muggiano, Antonio; Cossu, Antonio; Budroni, Mario; Caracò, Corrado; Ascierto, Paolo A; Pagani, Elena; Stanganelli, Ignazio; Canzanella, Sergio

    2009-01-01

    Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease. A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16 CDKN2A , BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16 CDKN2A genes. For melanoma susceptibility, investigations at germline level indicated that p16 CDKN2A was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16 CDKN2A gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16 CDKN2A silencing). Our findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis

  15. Intra-Arterial Chemotherapy as Primary Therapy for Retinoblastoma in Infants Less than 3 Months of Age: A Series of 10 Case-Studies.

    Directory of Open Access Journals (Sweden)

    Miaojuan Chen

    Full Text Available Retinoblastoma is the most common primary malignant intra-ocular tumor in children. Although intra-arterial chemotherapy (IAC by selectively infusing chemotherapy through the ophthalmic artery has become an essential technique in the treatment of advanced intra-ocular retinoblastoma in children, the outcome of IAC as primary therapy for infants less than 3 months of age remains unknown. In this retrospective study, we reviewed the outcome of IAC as primary therapy for retinoblastoma in infants less than 3 months of age.We retrospectively reviewed ten retinoblastoma patients attending our center from January 2009 to September 2015 and beginning primary IAC before the age of 3 months. The patient characteristics, overall outcomes and therapy-related complications were assessed.The mean patient age at the first IAC treatment was 10.4 weeks (range 4.9-12.9 weeks. These eyes were classified according to the International Classification of Retinoblastoma (ICRB as group A (n = 0, B (n = 2, C (n = 0, D (n = 9, or E (n = 2. A total of 28 catheterizations were performed, and the procedure was stopped in one patient because of internal carotid artery spasm. Each eye received a mean of 2.6 cycles of IAC (range 2-4 cycles. After IAC with a mean follow-up of 28.3 months (range 9-65 months, tumor regression was observed in 12 of 13 eyes. One eye was enucleated due to tumor progression. All patients are alive and no patient has developed metastatic disease or other malignancies.Our experience suggests IAC as primary therapy is a feasible and promising treatment for retinoblastoma in infants less than 3 months of age.

  16. Retinoblastoma pathway defects show differential ability to activate the constitutive DNA damage response in human tumorigenesis

    DEFF Research Database (Denmark)

    Tort, F.; Bartkova, J.; Sehested, M.

    2006-01-01

    culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse...... with their hierarchical positions along the retinoblastoma pathway. Our data provide new insights into oncogene-evoked DDR in human tumorigenesis, with potential implications for individualized management of tumors with elevated cyclin D1 versus cyclin E, due to their distinct clinical variables and biological behavior....

  17. Association Analysis Suggests SOD2 as a Newly Identified Candidate Gene Associated With Leprosy Susceptibility.

    Science.gov (United States)

    Ramos, Geovana Brotto; Salomão, Heloisa; Francio, Angela Schneider; Fava, Vinícius Medeiros; Werneck, Renata Iani; Mira, Marcelo Távora

    2016-08-01

    Genetic studies have identified several genes and genomic regions contributing to the control of host susceptibility to leprosy. Here, we test variants of the positional and functional candidate gene SOD2 for association with leprosy in 2 independent population samples. Family-based analysis revealed an association between leprosy and allele G of marker rs295340 (P = .042) and borderline evidence of an association between leprosy and alleles C and A of markers rs4880 (P = .077) and rs5746136 (P = .071), respectively. Findings were validated in an independent case-control sample for markers rs295340 (P = .049) and rs4880 (P = .038). These results suggest SOD2 as a newly identified gene conferring susceptibility to leprosy. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  18. Radiation-sensitive genetically susceptible pediatric sub-populations

    Energy Technology Data Exchange (ETDEWEB)

    Kleinerman, Ruth A. [National Cancer Institute, NIH, DHHS, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, Rockville, MD (United States)

    2009-02-15

    Major advances in pediatric cancer treatment have resulted in substantial improvements in survival. However, concern has emerged about the late effects of cancer therapy, especially radiation-related second cancers. Studies of childhood cancer patients with inherited cancer syndromes can provide insights into the interaction between radiation and genetic susceptibility to multiple cancers. Children with retinoblastoma (Rb), neurofibromatosis type 1 (NF1), Li-Fraumeni syndrome (LFS), and nevoid basal cell carcinoma syndrome (NBCCS) are at substantial risk of developing radiation-related second and third cancers. A radiation dose-response for bone and soft-tissue sarcomas has been observed in hereditary Rb patients, with many of these cancers occurring in the radiation field. Studies of NF1 patients irradiated for optic pathway gliomas have reported increased risks of developing another cancer associated with radiotherapy. High relative risks for second and third cancers were observed for a cohort of 200 LFS family members, especially children, possibly related to radiotherapy. Children with NBCCS are very sensitive to radiation and develop multiple basal cell cancers in irradiated areas. Clinicians following these patients should be aware of their increased genetic susceptibility to multiple primary malignancies enhanced by sensitivity to ionizing radiation. (orig.)

  19. Mapping of gene expression reveals CYP27A1 as a susceptibility gene for sporadic ALS.

    Directory of Open Access Journals (Sweden)

    Frank P Diekstra

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls. These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls. Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 × 10(-51 withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible

  20. Absence of linkage between MHC and a gene involved in susceptibility to human schistosomiasis

    Directory of Open Access Journals (Sweden)

    Chiarella J.M.

    1998-01-01

    Full Text Available Six hundred million people are at risk of infection by Schistosoma mansoni. MHC haplotypes have been reported to segregate with susceptibility to schistosomiasis in murine models. In humans, a major gene related to susceptibility/resistance to infection by S. mansoni (SM1 and displaying the mean fecal egg count as phenotype was detected by segregation analysis. This gene displayed a codominant mode of inheritance with an estimated frequency of 0.20-0.25 for the deleterious allele and accounted for more than 50% of the variance of infection levels. To determine if the SM1 gene segregates with the human MHC chromosomal region, we performed a linkage study by the lod score method. We typed for HLA-A, B, C, DR and DQ antigens in 11 informative families from an endemic area for schistosomiasis in Bahia, Brazil, by the microlymphocytotoxicity technique. HLA-DR typing by the polymerase chain reaction with sequence-specific primers (PCR-SSP and HLA-DQ were confirmed by PCR-sequence-specific oligonucleotide probes (PCR-SSOP. The lod scores for the different q values obtained clearly indicate that there is no physical linkage between HLA and SM1 genes. Thus, susceptibility or resistance to schistosomiasis, as defined by mean fecal egg count, is not primarily dependent on the host's HLA profile. However, if the HLA molecule plays an important role in specific immune responses to S. mansoni, this may involve the development of the different clinical aspects of the disease such as granuloma formation and development of hepatosplenomegaly.

  1. Update on Intra-Arterial Chemotherapy for Retinoblastoma

    Directory of Open Access Journals (Sweden)

    Mario Zanaty

    2014-01-01

    Full Text Available The tools for managing retinoblastoma have been increasing in the past decade. While globe-salvage still relies heavily on intravenous chemotherapy, tumors in advanced stage that failed chemotherapy are now referred for intra-arterial chemotherapy (IAC to avoid enucleation. However, IAC still has many obstacles to overcome. We present an update on the indications, complications, limitations, success, and technical aspects of IAC. Given its safety and high efficacy, it is expected that IAC will replace conventional strategies and will become a first-line option even for tumors that are amenable for other strategies.

  2. Deregulated MAPK activity prevents adipocyte differentiation of fibroblasts lacking the retinoblastoma protein

    DEFF Research Database (Denmark)

    Hansen, Jacob B; Petersen, Rasmus K; Jørgensen, Claus

    2002-01-01

    A functional retinoblastoma protein (pRB) is required for adipose conversion of preadipocyte cell lines and primary mouse embryo fibroblasts (MEFs) in response to treatment with standard adipogenic inducers. Interestingly, lack of functional pRB in MEFs was recently linked to elevated Ras activity...

  3. Genome-wide association studies of adolescent idiopathic scoliosis suggest candidate susceptibility genes

    Science.gov (United States)

    Sharma, Swarkar; Gao, Xiaochong; Londono, Douglas; Devroy, Shonn E.; Mauldin, Kristen N.; Frankel, Jessica T.; Brandon, January M.; Zhang, Dongping; Li, Quan-Zhen; Dobbs, Matthew B.; Gurnett, Christina A.; Grant, Struan F.A.; Hakonarson, Hakon; Dormans, John P.; Herring, John A.; Gordon, Derek; Wise, Carol A.

    2011-01-01

    Adolescent idiopathic scoliosis (AIS) is an unexplained and common spinal deformity seen in otherwise healthy children. Its pathophysiology is poorly understood despite intensive investigation. Although genetic underpinnings are clear, replicated susceptibility loci that could provide insight into etiology have not been forthcoming. To address these issues, we performed genome-wide association studies (GWAS) of ∼327 000 single nucleotide polymorphisms (SNPs) in 419 AIS families. We found strongest evidence of association with chromosome 3p26.3 SNPs in the proximity of the CHL1 gene (P protein related to Robo3. Mutations in the Robo3 protein cause horizontal gaze palsy with progressive scoliosis (HGPPS), a rare disease marked by severe scoliosis. Other top associations in our GWAS were with SNPs in the DSCAM gene encoding an axon guidance protein in the same structural class with Chl1 and Robo3. We additionally found AIS associations with loci in CNTNAP2, supporting a previous study linking this gene with AIS. Cntnap2 is also of functional interest, as it interacts directly with L1 and Robo class proteins and participates in axon pathfinding. Our results suggest the relevance of axon guidance pathways in AIS susceptibility, although these findings require further study, particularly given the apparent genetic heterogeneity in this disease. PMID:21216876

  4. Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue

    Directory of Open Access Journals (Sweden)

    Colin J. Palmer

    2017-10-01

    Conclusions: Cdkal1 is necessary for normal mitochondrial morphology and function in adipose tissue. These results suggest that the type 2 diabetes susceptibility gene CDKAL1 has novel functions in regulating mitochondrial activity.

  5. Mutations in BRCA1, BRCA2 and other breast and ovarian cancer susceptibility genes in Central and South American populations.

    Science.gov (United States)

    Jara, Lilian; Morales, Sebastian; de Mayo, Tomas; Gonzalez-Hormazabal, Patricio; Carrasco, Valentina; Godoy, Raul

    2017-10-06

    Breast cancer (BC) is the most common malignancy among women worldwide. A major advance in the understanding of the genetic etiology of BC was the discovery of BRCA1 and BRCA2 (BRCA1/2) genes, which are considered high-penetrance BC genes. In non-carriers of BRCA1/2 mutations, disease susceptibility may be explained of a small number of mutations in BRCA1/2 and a much higher proportion of mutations in ethnicity-specific moderate- and/or low-penetrance genes. In Central and South American populations, studied have focused on analyzing the distribution and prevalence of BRCA1/2 mutations and other susceptibility genes that are scarce in Latin America as compared to North America, Europe, Australia, and Israel. Thus, the aim of this review is to present the current state of knowledge regarding pathogenic BRCA variants and other BC susceptibility genes. We conducted a comprehensive review of 47 studies from 12 countries in Central and South America published between 2002 and 2017 reporting the prevalence and/or spectrum of mutations and pathogenic variants in BRCA1/2 and other BC susceptibility genes. The studies on BRCA1/2 mutations screened a total of 5956 individuals, and studies on susceptibility genes analyzed a combined sample size of 11,578 individuals. To date, a total of 190 different BRCA1/2 pathogenic mutations in Central and South American populations have been reported in the literature. Pathogenic mutations or variants that increase BC risk have been reported in the following genes or genomic regions: ATM, BARD1, CHECK2, FGFR2, GSTM1, MAP3K1, MTHFR, PALB2, RAD51, TOX3, TP53, XRCC1, and 2q35.

  6. The success of primary chemotherapy for group D heritable retinoblastoma.

    Science.gov (United States)

    Cohen, V M L; Kingston, J; Hungerford, J L

    2009-07-01

    To report the ocular survival and event-free survival following primary multiagent chemotherapy for group D, heritable bilateral retinoblastoma (RB). The RB database was used to identify children with heritable, bilateral RB treated with primary chemotherapy (six cycles of vincristine, etoposide and carboplatin). Only Group D eyes with more than 12 months' follow-up were analysed. The timing, number and type of salvage treatments were recorded. Kaplan-Meier estimates for the ocular survival and event-free survival (percentage of eyes that avoided external beam radiotherapy and/or enucleation) were performed as a function of time. Of 18 group D eyes, two (11%) were treated successfully with chemotherapy alone, nine (50%) underwent successful salvage treatment, and seven (39%) were enucleated. The median time from completing chemotherapy to enucleation was 9 months (range 4 to 25 months). Ocular survival was 67% at 2 years. External beam radiotherapy proved successful salvage treatment in five of nine eyes, so the event-free survival was 34% at 2 years. Multiagent chemotherapy alone is rarely sufficient for the preservation of group D eyes. External beam radiotherapy and plaque radiotherapy remain important salvage treatments for advanced, heritable retinoblastoma.

  7. Mapping the genes for susceptibility and response to Leishmania tropica in mouse

    Czech Academy of Sciences Publication Activity Database

    Sohrabi, Yahya; Havelková, Helena; Kobets, Tetyana; Šíma, Matyáš; Volkova, Valeriya; Grekov, Igor; Jarošíková, T.; Kurey, Irina; Vojtíšková, Jarmila; Svobodová, M.; Demant, P.; Lipoldová, Marie

    2013-01-01

    Roč. 7, č. 7 (2013), s. 1-17 ISSN 1935-2735 R&D Projects: GA ČR GA310/08/1697; GA MŠk LH12049 Institutional support: RVO:68378050 Keywords : Leishmania tropica * gene controlling susceptibility * host-parasite interactions * leishmaniasis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.489, year: 2013

  8. Post-radiation retinal infiltrates simulating recurrent retinoblastoma: a clinical and pathologic case report

    International Nuclear Information System (INIS)

    Judisch, G.F.; Folberg, R.

    1987-01-01

    An 8-month-old boy was found to have a sporadic unilateral stage IIa retinoblastoma, extending inferiorly and temporally from the right fovea. Within 5 weeks of diagnosis the tumor was treated with 4500 rads fractionated over 20 treatments. Examination under anesthesia (EUA) 1 month later revealed unequivocal clinical and echographic evidence of tumor regression. EUA 3 months after completion of radiation therapy revealed continued tumor regression with no evidence of new tumor formation. The third EUA, performed 6 months after radiation treatment, showed that multiple discreet gray-white retinal infiltrates had developed, predominantly in the area immediately below the regressed tumor. Because of concern that these lesions represented viable retinoblastoma, the eye was enucleated. Pathologic examination of these lesions revealed them to be collections of foamy cells containing melanin granules suggestive of pigment epithelial origin

  9. Restrictions in daily life after retinoblastoma from the perspective of the survivors

    NARCIS (Netherlands)

    van Dijk, J.; Oostrom, K.J.; Huisman, J.; Moll, A.C.; Cohen-Kettenis, P.T.; Ringens, P.J.; Imhof, S.M.

    2010-01-01

    Background. Little is known about the impact of retinoblastoma (RB) on the health status of survivors in terms of disabilities and worries, both of which may restrict participation in activities of daily life. Methods. In this population-based cross-sectional study, content analysis was used to

  10. HLA non-class II genes may confer type I diabetes susceptibility in a Mapuche (Amerindian) affected family.

    Science.gov (United States)

    Pérez-Bravo, Francisco; Martinez-Laso, Jorge; Martin-Villa, Jose M; Moscoso, Juan; Moreno, Almudena; Serrano-Vela, Juan I; Zamora, Jorge; Asenjo, Silvia; Gleisner, Andrea; Arnaiz-Villena, Antonio

    2006-01-01

    A rare case of type I diabetes is studied in an Amerindian (Mapuche) family from Chile, analyzing glutamic acid decarboxylase, islet-cell autoantibodies and human leukocyte antigen (HLA) genes. The affected sib is the only one that has one specific HLA haplotype combination that differs from the other sibs only in the HLA class I genes. It is concluded that HLA diabetes susceptibility factors may be placed outside the class II region or even that susceptibility factors do not exist in the HLA region in this Amerindian family.

  11. Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making.

    Science.gov (United States)

    Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha; Zhou, Xiaolin

    2017-09-01

    The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. © The Author (2017). Published by Oxford University Press.

  12. Identifying new susceptibility genes on dopaminergic and serotonergic pathways for the framing effect in decision-making

    Science.gov (United States)

    Gao, Xiaoxue; Liu, Jinting; Gong, Pingyuan; Wang, Junhui; Fang, Wan; Yan, Hongming; Zhu, Lusha

    2017-01-01

    Abstract The framing effect refers the tendency to be risk-averse when options are presented positively but be risk-seeking when the same options are presented negatively during decision-making. This effect has been found to be modulated by the serotonin transporter gene (SLC6A4) and the catechol-o-methyltransferase gene (COMT) polymorphisms, which are on the dopaminergic and serotonergic pathways and which are associated with affective processing. The current study aimed to identify new genetic variations of genes on dopaminergic and serotonergic pathways that may contribute to individual differences in the susceptibility to framing. Using genome-wide association data and the gene-based principal components regression method, we examined genetic variations of 26 genes on the pathways in 1317 Chinese Han participants. Consistent with previous studies, we found that the genetic variations of the SLC6A4 gene and the COMT gene were associated with the framing effect. More importantly, we demonstrated that the genetic variations of the aromatic-L-amino-acid decarboxylase (DDC) gene, which is involved in the synthesis of both dopamine and serotonin, contributed to individual differences in the susceptibility to framing. Our findings shed light on the understanding of the genetic basis of affective decision-making. PMID:28431168

  13. Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETATAG retinoblastoma tumors

    Directory of Open Access Journals (Sweden)

    Samuel K Houston

    2011-01-01

    Full Text Available Samuel K Houston1, Yolanda Piña1, Timothy G Murray1, Hinda Boutrid1, Colleen Cebulla2, Amy C Schefler1, Wei Shi1, Magda Celdran1, William Feuer1, Jaime Merchan3, Ted J Lampidis41Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Ophthalmology, The Ohio State University, Columbus, OH, USA; 3Division of Hematology/Oncology, Department of Medicine, 4Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USAPurpose: The purpose of this study was to evaluate the effect of optimally timed combination treatment with angiogenic and glycolytic inhibitors on tumor burden, hypoxia, and angiogenesis in advanced retinoblastoma tumors.Methods: LHBETATAG mice (n = 30 were evaluated. Mice were divided into 5 groups (n = 6 and received injections at 16 weeks of age (advanced tumors with a saline, b anecortave acetate (AA, c 2-deoxyglucose (2-DG, d AA + 2-DG (1 day post-AA treatment, or e AA + 2-DG (1 week post-AA treatment. Eyes were enucleated at 21 weeks and tumor sections were analyzed for hypoxia, angiogenesis, and tumor burden.Results: Eyes treated with 2-DG 1 day post-AA injection showed a 23% (P = 0.03 reduction in tumor burden compared with 2-DG alone and a 61% (P < 0.001 reduction compared with saline-treated eyes. Eyes treated with 2-DG 1 week post-AA injection showed no significant decrease in tumor burden compared with 2-DG alone (P = 0.21 and a 56% (P < 0.001 decrease in comparison with saline-treated eyes. 2-DG significantly reduced the total density of new blood vessels in tumors by 44% compared to saline controls (P < 0.001, but did not affect the density of mature vasculature.Conclusions: Combination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control. Synergistic effects were shown to be dependent on the temporal course of treatment

  14. Radiation-induced fibrosarcoma of the mandible following treatment for bilateral retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Ferlito, A; Recher, G [Padua Univ. (Italy); Tomazzoli, L

    1979-10-01

    A case of fibrosarcoma of the mandible following radiotherapy for bilateral retinoblastoma and occurring in an 11-year-old female child is described. After a clinical description of the case, reported with histological documentation, problems connected with the pathogenesis of the malignancies are dealt with. Besides irradiation, genetic mutation as a carcinogenetic co-factor is taken into consideration. (author).

  15. Susceptibilities to carbapenems and presence of cphA gene on food-borne Aeromonas

    Directory of Open Access Journals (Sweden)

    Bibiana María Martín Talavera

    2006-07-01

    Full Text Available The purpose of this study was to determine the susceptibilities of food-borne Aeromonas to carbapenems, as well as to investigate the presence of a metallo carbapenemase-encoding gene, named cphA. Minimum Inhibitory Concentration (MIC was determined following NCCLS standards. All the tested microorganisms were susceptible to imipenem, meropenem and biapenem. However, a strong inoculum size effect on carbapenem MICs was observed for most of the strains. Six strains, out of seven, showed the presence of metallo--beta-lactamases but cphA gene was detected in only two strains of A. veronii bv. sobria.O objetivo deste estudo foi determinar a suscetibilidade de aeromonas de origem alimentar a carbapenems bem como investigar a presença de um gene codificante de metalocarbapenemase, denominado "cph A". A suscetibilidade in vitro foi determinada pelo metodo de diluição em agar. Todas as cepas foram suscetíveis a Imipenem, Meropenem e Biapenem. Porém foi observado um forte efeito de tamanho do inóculo sobre as CIM das carbapenems na maioria das cepas. A detecção de metalo-beta-lactamase foi realizada pelo metodo lodometrico. Seis cepas das sete testadas demostraron a presença da enzima. A presença do gene cphA foi determinada por PCR e foi detectada em duas cepas de A veronii bv. sobria.

  16. Recent decreasing frequency of enucleation for intraocular retinoblastoma in Upper Egypt

    International Nuclear Information System (INIS)

    Abdallh, A.M.

    2006-01-01

    To evaluate the efficacy of combined systematic chemotherapy (chemoreduction) and local ophthalmic therapy (LT) is preventing or delaying external beam radiotherapy (EBRT) and enucleation in patients with intraocular retinoblastoma. This was a prospective, nonrandomized, single-institution, clinical study. Twenty-eight patients (37 eyes) with newly diagnosed intraocular retinoblastoma were included in this study. Primary enucleation was performed for 7 eyes with advanced intraocular retinoblastoma at presentation before starting chemoreduction. Using Reese-Ellsworth (RE) staging for RB, the remaining 30 eyes were as follows: Two in group I, 3 in group II, 8 in group III, 7 in group IV, and 9 in group V. All the 30 eyes were initially treated with 6 cycles of chemoredution using vincristine, etoposide and carboplatin, repeated every three weeks. After total of 6 cycles, each tumor was re-evaluated decide on the next mode of therapy. In cases where the tumor was reduced enough, LT (Thermotherapy, or cryotherapy, but plaque radiotherapy was unavailable) was applied. In cases where the tumor was reduced but insufficient for LT, we added another 3 cycles of same regimen in some patients; or we performed chemotherapy (CTT) for others, according to size of the residual tumor. Eyes failed to respond to tochemorduction and LT, received EBRT or were enucleated. Following 6 cycles of chemoreduction, all tumors showed an initial regression, and all vitreous and subretinal seeds showed calcification or disappearance of most of them. Among the 30 eyes, 12 eyes achieved complete response (CR), and 18 eyes achieved partial response (PR). Only 7 eyes (stage I to III) showed sufficient reduction of tumor size for the LT to be applied for, for which, TTT (4 eyes), and cryotherapy (3 eyes) were performed. Chemotherapy (CTT) was performed for 9 patients (13 eyes, 15 tumors). At the end of follow-up period, 14 of the total 30 eyes (46.7%) could not be salvaged with chemoreduction and LT

  17. Candidate chromosome 1 disease susceptibility genes for Sjogren’s syndrome xerostomia are narrowed by novel NOD.B10 congenic mice

    Science.gov (United States)

    Mongini, Patricia K. A.; Kramer, Jill M.; Ishikawa, Tomo-o; Herschman, Harvey; Esposito, Donna

    2014-01-01

    Sjogren’s syndrome (SS) is characterized by salivary gland leukocytic infiltrates and impaired salivation (xerostomia). Cox-2 (Ptgs2) is located on chromosome 1 within the span of the Aec2 region. In an attempt to demonstrate that COX-2 drives antibody-dependent hyposalivation, NOD.B10 congenic mice bearing a Cox-2flox gene were generated. A congenic line with non-NOD alleles in Cox-2-flanking genes failed manifest xerostomia. Further backcrossing yielded disease-susceptible NOD.B10 Cox-2flox lines; fine genetic mapping determined that critical Aec2 genes lie within a 1.56 to 2.17 Mb span of DNA downstream of Cox-2. Bioinformatics analysis revealed that susceptible and non-susceptible lines exhibit non-synonymous coding SNPs in 8 protein-encoding genes of this region, thereby better delineating candidate Aec2 alleles needed for SS xerostomia. PMID:24685748

  18. Differential in vivo gene expression of major Leptospira proteins in resistant or susceptible animal models.

    Science.gov (United States)

    Matsui, Mariko; Soupé, Marie-Estelle; Becam, Jérôme; Goarant, Cyrille

    2012-09-01

    Transcripts of Leptospira 16S rRNA, FlaB, LigB, LipL21, LipL32, LipL36, LipL41, and OmpL37 were quantified in the blood of susceptible (hamsters) and resistant (mice) animal models of leptospirosis. We first validated adequate reference genes and then evaluated expression patterns in vivo compared to in vitro cultures. LipL32 expression was downregulated in vivo and differentially regulated in resistant and susceptible animals. FlaB expression was also repressed in mice but not in hamsters. In contrast, LigB and OmpL37 were upregulated in vivo. Thus, we demonstrated that a virulent strain of Leptospira differentially adapts its gene expression in the blood of infected animals.

  19. Lentivirus-Mediated Knockdown of Astrocyte Elevated Gene-1 Inhibits Growth and Induces Apoptosis through MAPK Pathways in Human Retinoblastoma Cells.

    Directory of Open Access Journals (Sweden)

    Ying Chang

    Full Text Available To explore expression and function of astrocyte elevated gene-1 (AEG-1 in human retinoblastoma (RB.The expression of AEG-1 in histological sections of human RBs and in RB cell lines was examined using immunohistochemical staining and RT-PCR and Western blotting respectively. We knocked down AEG-1 gene levels by AEG-1-siRNA lentivirus transfection of human RB cell lines SO-RB50 and Y79, and using an MTT assay, we assessed the role of AEG-1 on RB cell proliferation. The biological significance of lentivirus transfection induced AEG-1 down-regulation was examined by assessing the apoptosis rate in the transfected RB cells by Annexin V-APC staining and flow cytometry. We additionally measured the expression of Bcl-2, Bax, cleaved-caspase-3 and caspase-3, and the phosphorylation and non-phosphorylation alternation of MAPKs.AEG-1 expression was detected to be strongly positive in the histological slides of 35 out of 54 (65% patients with RB. AEG-1 expression increased significantly (P<0.05 with tumor stage. In the RB cell lines SO-RB50, Y79 and WERI-RB1 as compared with retinal pigment epithelium cells, expression of AEG-1 mRNA and AEG-1 protein was significantly higher. In AEG-1-siRNA lentivirus transfected cell cultures as compared with negative control lentivirus transfected cell cultures, levels of AEG-1 mRNA and of AEG-1 protein (P<0.05 and cell growth rates (P<0.01 were significantly lower, and apoptosis rate (P<0.001, Bax/Bcl-2 ratio and cleaved-caspase-3 protein level were significantly increased. The P-ERK/ERK ratio was significantly decreased in the AEG-1-siRNA lentivirus transfected cell lines.Expression of AEG-1 was associated with RB, in histological slides of patients and in cell culture experiments. Lentivirus transfection induced knockdown of AEG-1 had a tumor suppressive effect, potentially by tumor cell apoptosis induction through inhibition of ERK.

  20. A meta-analysis of xeroderma pigmentosum gene D Ls751Gln polymorphism and susceptibility to hepatocellular carcinoma.

    Science.gov (United States)

    Wang, Yu; Zhao, Yingren; Zhang, Aiyun; Ma, Juan; Wang, Zhenzhen; Zhang, Xu

    2015-01-01

    Hepatocellular carcinoma (HCC) is one of most common malignant tumors worldwide, but with unclear mechanisms. Xeroderma pigmentosum gene D (XPD) is one important DNA damage repair gene and can be involved in protein mutation. Currently little has been known about XPD polymorphism and HCC susceptibility in Chinese people. This study used a meta-analysis approach to comprehensively investigate the correlation between XPD polymorphism and HCC susceptibility in Chinese population, based on previously published literatures. A computer retrieval system was used to collect all case-control studies about XPD Lys751Gln polymorphism and HCC susceptibility. Data in literatures were extracted for meta-analysis. After the primary screening, four independent studies, which were published in 3 English articles and one Chinese article, were recruited in this study. There were 1,717 samples included in all studies. Using Gln/Gln + Lys/Gln, Lys/Lys + Lys/Gln and Lys allels as the reference, HCC disease alleles including Lys/Lys, Gln/Gln and Gln had OR values (95% CI, I(2)) of 1.007 (0.657~4.672, 91%), 3.516 (0.220~20.661, 48%) and 3.225 (0.278~12.326, 84%), respectively. The polymorphism of XPD751 loci is closely correlated with primary HCC. Lys751Gln polymorphism of XPD gene can be used as one susceptibility factor for HCC.

  1. Association Study between Polycystic Ovarian Syndrome and the Susceptibility Genes Polymorphisms in Hui Chinese Women.

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    Lingxia Ha

    Full Text Available Polycystic ovary syndrome (PCOS is one of the most common endocrine-metabolic disorders. Evidence of familial aggregation analysis and different clinical traits among different regions and ethnicities indicated that the pathogenesis of PCOS is associated with multiple genetic and environmental factors. Our previous research had identified three susceptibility loci (rs2479106, DENND1A; rs13405728, LHCGR; rs13429458, THADA for PCOS in Han Chinese women. The overall aim of this study was to investigate the relationship between three susceptibility gene polymorphisms and PCOS in Hui ethnic women.151 patients with PCOS (case group and 99 healthy women (control group were recruited from the Reproductive Medicine Center of the General Hospital of Ningxia Medical University. Clinical data and serum hormone characteristics of case and control groups were collected and analyzed. The three susceptibility single-nucleotide polymorphisms have been replicated in both case and control groups. Gene polymorphisms were detected by direct sequencing after polymerase chain reaction.The Body Mass Index, LH, LH/FSH ratio and total testosterone were significantly elevated in PCOS patients compared to control group (P0.05.The present study suggested that the SNP rs13405728 in the LHCGR gene was associated with PCOS in Hui ethnic women, and its TT genotype characterized with higher level of TT, TG and LDL.

  2. Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes

    Science.gov (United States)

    2012-12-05

    teaching students with autism spectrum disorders 4.52 Learn strategies for incorporating IEP goals and district standard into daily teaching...W403 Columbus, OH 43205 Final Report Comprehensive Clinical Phenotyping & Genetic Mapping for the Discovery of Autism Susceptibility Genes...QFOXGHDUHDFRGH 1.0 Summary In 2006, the Central Ohio Registry for Autism (CORA) was initiated as a collaboration between Wright-Patterson Air

  3. Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE.

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    Anna Hellquist

    2009-12-01

    Full Text Available Systemic lupus erythematosus (SLE is a complex autoimmune disorder with multiple susceptibility genes. We have previously reported suggestive linkage to the chromosomal region 14q21-q23 in Finnish SLE families.Genetic fine mapping of this region in the same family material, together with a large collection of parent affected trios from UK and two independent case-control cohorts from Finland and Sweden, indicated that a novel uncharacterized gene, MAMDC1 (MAM domain containing glycosylphosphatidylinositol anchor 2, also known as MDGA2, MIM 611128, represents a putative susceptibility gene for SLE. In a combined analysis of the whole dataset, significant evidence of association was detected for the MAMDC1 intronic single nucleotide polymorphisms (SNP rs961616 (P -value = 0.001, Odds Ratio (OR = 1.292, 95% CI 1.103-1.513 and rs2297926 (P -value = 0.003, OR = 1.349, 95% CI 1.109-1.640. By Northern blot, real-time PCR (qRT-PCR and immunohistochemical (IHC analyses, we show that MAMDC1 is expressed in several tissues and cell types, and that the corresponding mRNA is up-regulated by the pro-inflammatory cytokines tumour necrosis factor alpha (TNF-alpha and interferon gamma (IFN-gamma in THP-1 monocytes. Based on its homology to known proteins with similar structure, MAMDC1 appears to be a novel member of the adhesion molecules of the immunoglobulin superfamily (IgCAM, which is involved in cell adhesion, migration, and recruitment to inflammatory sites. Remarkably, some IgCAMs have been shown to interact with ITGAM, the product of another SLE susceptibility gene recently discovered in two independent genome wide association (GWA scans.Further studies focused on MAMDC1 and other molecules involved in these pathways might thus provide new insight into the pathogenesis of SLE.

  4. Research advances in susceptibility genes and their role in the pathogenesis of nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    XUAN Shiying

    2016-03-01

    Full Text Available Currently the incidence of nonalcoholic fatty liver disease (NAFLD is increasing, and the age of onset is getting younger worldwide, resulting in a heavy economic burden for both individuals and the society. Since NAFLD is closely related to heredity, metabolism, and the environment, genetic factors play an important role in the development and progression of NAFLD. With the development and wide application of the techniques from the genome-wide association studies, new research advances have been achieved in the susceptibility genes of NAFLD. This review summarizes the related research findings at home and abroad, and investigates the pathogenic factors for NAFLD and related mechanisms with a focus on the polymorphisms of susceptibility genes.

  5. Differential gene expression in response to Fusarium oxysporum infection in resistant and susceptible genotypes of flax (Linum usitatissimum L.).

    Science.gov (United States)

    Dmitriev, Alexey A; Krasnov, George S; Rozhmina, Tatiana A; Novakovskiy, Roman O; Snezhkina, Anastasiya V; Fedorova, Maria S; Yurkevich, Olga Yu; Muravenko, Olga V; Bolsheva, Nadezhda L; Kudryavtseva, Anna V; Melnikova, Nataliya V

    2017-12-28

    Flax (Linum usitatissimum L.) is a crop plant used for fiber and oil production. Although potentially high-yielding flax varieties have been developed, environmental stresses markedly decrease flax production. Among biotic stresses, Fusarium oxysporum f. sp. lini is recognized as one of the most devastating flax pathogens. It causes wilt disease that is one of the major limiting factors for flax production worldwide. Breeding and cultivation of flax varieties resistant to F. oxysporum is the most effective method for controlling wilt disease. Although the mechanisms of flax response to Fusarium have been actively studied, data on the plant response to infection and resistance gene candidates are currently very limited. The transcriptomes of two resistant and two susceptible flax cultivars with respect to Fusarium wilt, as well as two resistant BC 2 F 5 populations, which were grown under control conditions or inoculated with F. oxysporum, were sequenced using the Illumina platform. Genes showing changes in expression under F. oxysporum infection were identified in both resistant and susceptible flax genotypes. We observed the predominant overexpression of numerous genes that are involved in defense response. This was more pronounced in resistant cultivars. In susceptible cultivars, significant downregulation of genes involved in cell wall organization or biogenesis was observed in response to F. oxysporum. In the resistant genotypes, upregulation of genes related to NAD(P)H oxidase activity was detected. Upregulation of a number of genes, including that encoding beta-1,3-glucanase, was significantly greater in the cultivars and BC 2 F 5 populations resistant to Fusarium wilt than in susceptible cultivars in response to F. oxysporum infection. Using high-throughput sequencing, we identified genes involved in the early defense response of L. usitatissimum against the fungus F. oxysporum. In response to F. oxysporum infection, we detected changes in the

  6. Worldwide enucleation techniques and materials for treatment of retinoblastoma: an international survey.

    Directory of Open Access Journals (Sweden)

    Daphne L Mourits

    Full Text Available To investigate the current practice of enucleation with or without orbital implant for retinoblastoma in countries across the world.A digital survey identifying operation techniques and material used for orbital implants after enucleation in patients with retinoblastoma.We received a response of 58 surgeons in 32 different countries. A primary artificial implant is routinely inserted by 42 (72.4% surgeons. Ten (17.2% surgeons leave the socket empty, three (5.2% decide per case. Other surgeons insert a dermis fat graft as a standard primary implant (n=1, or fill the socket in a standard secondary procedure (n=2; one uses dermis fat grafts and one artificial implants. The choice for porous implants was more frequent than for non-porous implants: 27 (58.7% and 15 (32.6%, respectively. Both porous and non-porous implant types are used by 4 (8.7% surgeons. Twenty-five surgeons (54.3% insert bare implants, 11 (23.9% use separate wrappings, eight (17.4% use implants with prefab wrapping and two insert implants with and without wrapping depending on type of implant. Attachment of the muscles to the wrapping or implant (at various locations is done by 31 (53.4% surgeons. Eleven (19.0% use a myoconjunctival technique, nine (15.5% suture the muscles to each other and seven (12.1% do not reattach the muscles. Measures to improve volume are implant exchange at an older age (n=4, the use of Restylane SQ (n=1 and osmotic expanders (n=1. Pegging is done by two surgeons.No (worldwide consensus exists about the use of material and techniques for enucleation for the treatment of retinoblastoma. Considerations for the use of different techniques are discussed.

  7. Impact of MCP-1 and CCR-2 gene polymorphisms on coronary artery disease susceptibility.

    Science.gov (United States)

    Lin, Hsiu-Ling; Ueng, Kwo-Chang; Hsieh, Yih-Shou; Chiang, Whei-Ling; Yang, Shun-Fa; Chu, Shu-Chen

    2012-09-01

    Coronary artery disease (CAD) was the second leading cause of death during the last 3 years in Taiwan. Smooth muscle cells, monocytes/macrophages, and endothelial cells produce monocyte chemoattractant protein-1 (MCP-1) within atherosclerotic plaques following binding to the chemokine receptor-2 (CCR-2). Previous studies have well-documented the association between MCP-1 expression and susceptibility to, or clinicopathological features, of CAD. This study investigated the relationships between MCP-1-2518A/G and CCR-2-V64I genetic polymorphisms and CAD in the Taiwanese population. A total of 608 subjects, including 392 non-CAD controls and 216 patients with CAD, were recruited and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to evaluate the effects of these two polymorphic variants on CAD. Results indicated a significant association between MCP-1 -2548 gene polymorphism and susceptibility to CAD. GG genotypes (OR = 1.629; 95 % CI = 1.003-2.644), or individuals with at least one G allele (OR = 1.511; 95 % CI = 1.006-2.270), had a higher risk of CAD as compared with AA genotypes. Results also revealed that subjects with at least one A allele of the V64I CCR2 gene polymorphism had significantly increased risk of CAD. G allele in MCP-1-2518 might contribute to higher prevalence of atrial fibrillation in CAD patients (OR = 4.254; p CCR-2 64I gene polymorphisms represent important factors in determining susceptibility to CAD, and the contribution of MCP-1-2518G could be through effects on atrial fibrillation in CAD patients.

  8. MDM2 SNP309, gene-gene interaction, and tumor susceptibility: an updated meta-analysis

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    Wu Wei

    2011-05-01

    Full Text Available Abstract Background The tumor suppressor gene p53 is involved in multiple cellular pathways including apoptosis, transcriptional control, and cell cycle regulation. In the last decade it has been demonstrated that the single nucleotide polymorphism (SNP at codon 72 of the p53 gene is associated with the risk for development of various neoplasms. MDM2 SNP309 is a single nucleotide T to G polymorphism located in the MDM2 gene promoter. From the time that this well-characterized functional polymorphism was identified, a variety of case-control studies have been published that investigate the possible association between MDM2 SNP309 and cancer risk. However, the results of the published studies, as well as the subsequent meta-analyses, remain contradictory. Methods To investigate whether currently published epidemiological studies can clarify the potential interaction between MDM2 SNP309 and the functional genetic variant in p53 codon72 (Arg72Pro and p53 mutation status, we performed a meta-analysis of the risk estimate on 27,813 cases with various tumor types and 30,295 controls. Results The data we reviewed indicated that variant homozygote 309GG and heterozygote 309TG were associated with a significant increased risk of all tumor types (homozygote comparison: odds ratio (OR = 1.25, 95% confidence interval (CI = 1.13-1.37; heterozygote comparison: OR = 1.10, 95% CI = 1.03-1.17. We also found that the combination of GG and Pro/Pro, TG and Pro/Pro, GG and Arg/Arg significantly increased the risk of cancer (OR = 3.38, 95% CI = 1.77-6.47; OR = 1.88, 95% CI = 1.26-2.81; OR = 1.96, 95% CI = 1.01-3.78, respectively. In a stratified analysis by tumor location, we also found a significant increased risk in brain, liver, stomach and uterus cancer (OR = 1.47, 95% CI = 1.06-2.03; OR = 2.24, 95%CI = 1.57-3.18; OR = 1.54, 95%CI = 1.04-2.29; OR = 1.34, 95%CI = 1.07-1.29, respectively. However, no association was seen between MDM2 SNP309 and tumor susceptibility

  9. FGF receptor genes and breast cancer susceptibility

    DEFF Research Database (Denmark)

    Agarwal, D; Pineda, S; Michailidou, K

    2014-01-01

    Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying...... genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium.Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry......, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression.Results:Little evidence of association with breast cancer risk...

  10. Genome Wide Association Study of SNP-, Gene-, and Pathway-based Approaches to Identify Genes Influencing Susceptibility to Staphylococcus aureus Infections

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    Zhan eYe

    2014-05-01

    Full Text Available Background: We conducted a genome-wide association study (GWAS to identify specific genetic variants that underlie susceptibility to disease caused by Staphylococcus aureus in humans. Methods: Cases (n=309 and controls (n=2,925 were genotyped at 508,921 single nucleotide polymorphisms (SNPs. Cases had at least one laboratory and clinician confirmed disease caused by S. aureus whereas controls did not. R-package (for SNP association, EIGENSOFT (to estimate and adjust for population stratification and gene- (VEGAS and pathway-based (DAVID, PANTHER, and Ingenuity Pathway Analysis analyses were performed.Results: No SNP reached genome-wide significance. Four SNPs exceeded the pConclusion: We identified potential susceptibility genes for S. aureus diseases in this preliminary study but confirmation by other studies is needed. The observed associations could be relevant given the complexity of S. aureus as a pathogen and its ability to exploit multiple biological pathways to cause infections in humans.

  11. Antimicrobial susceptibility and occurrence of resistance genes among Salmonella enterica serovar Weltevreden from different countries

    DEFF Research Database (Denmark)

    Aarestrup, Frank Møller; Lertworapreecha, M.; Evans, M.C.

    2003-01-01

    and gentamicin. All nine ampicillin-resistant isolates contained a sequence similar to the bla(TEM-1b) gene, one of the eight chloramphenicol-resistant isolates a sequence similar to the catA1 gene, all three neomycin-resistant isolates a sequence similar to the aphA-2 gene, 16 (73%) of the 22 streptomycin...... isolates were examined for susceptibility to antimicrobial agents, and resistant isolates were examined for the presence of selected resistance genes by PCR. Results: Only 48 (9.5%) of the isolates were resistant to one or more of the antimicrobial agents tested. A low frequency of resistance was found...

  12. Growth patterns of survivors of retinoblastoma treated with ophthalmic artery chemosurgery.

    Directory of Open Access Journals (Sweden)

    Sruti S Akella

    Full Text Available Although studies from pediatric cancers (largely acute lymphoblastic leukemia have shown that patients undergoing systemic chemotherapy may experience decreased growth velocity during the treatment phase, no such data exist for retinoblastoma patients treated with systemic chemotherapy or ophthalmic artery chemosurgery (OAC. The purpose of this study is to report growth patterns of our retinoblastoma (Rb population who were treated with OAC in a retrospective, single center (Memorial Sloan Kettering Cancer Center review of 341 patients treated between 2006 and 2016. Children who only received OAC were classified as naive; those who were treated initially with systemic chemotherapy and subsequently presented to our center for OAC were termed secondary; and a small group of patients who received single-agent systemic chemotherapy prior to OAC were labeled bridge. For all patients, height and weight were recorded at monthly intervals during OAC (short-term and then annually during a follow-up period (long-term up to 3 years after treatment. Excluded from this study were children who received external radiation therapy and those with genetic syndromes, which are independently associated with growth derangements. During OAC, there was no significant difference in growth velocity between the naïve and secondary groups. In either group, number of treatments also did not affect growth rate. Three years after the end of OAC, naïve patients were in the 68th percentile by height (95% CI 61.30, 74.63 compared to secondary patients in the 61st percentile (95% CI 51.1, 71.47. Both groups were in the same weight percentiles during the first two years of follow-up but at the three-year follow-up period, naïve patients were in the 63rd percentile (95% CI 57.4, 69.4 and secondary patients were in the 60th percentile (95% CI 50.4, 69.7. OAC for retinoblastoma does not appear to impact short-term growth velocity, weight gain during the treatment period or after

  13. The calcitonin receptor gene is a candidate for regulation of susceptibility to herpes simplex type 1 neuronal infection leading to encephalitis in rat.

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    Nada Abdelmagid

    Full Text Available Herpes simplex encephalitis (HSE is a fatal infection of the central nervous system (CNS predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL, Hse1, on rat chromosome 4 (confidence interval 24.3-31 Mb; LOD score 29.5 governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.

  14. A retrospective review of visual outcome and complications in the treatment of retinoblastoma.

    LENUS (Irish Health Repository)

    O'Doherty, M

    2005-01-01

    The aim of this study was to look at the visual outcome and treatment complications of children diagnosed with Retinoblastoma during the years 1985-2003 inclusive. A retrospective review of all patients records was performed. Patient characteristics, treatment methods and complications were recorded. Twenty eight children presented to Temple street Hospital between 1985-2003. Six of these infants had bilateral tumours. The mean age at presentation was 23.7 months. Sixty-nine percent presented with Leucocoria, of these 33% also had a squint. The mean duration of symptoms was only known in 58% and this figure was approximately 19.8 months. Enucleation was performed in 24 eyes of 24 patients. Three patients required adjuvant chemotherapy post enucleation. Two eyes was treated with external beam radiation and one eye with plaque radiotherapy. One eye (second eye) was treated with systemic chemotherapy and radiation. Five eyes of three patients were treated with systemic chemotherapy followed by adjuvant Argon laser, cryotherapy and diode laser to each eye.The complications of each treatment group was recorded. The visual outcome in the salvaged eyes was favourable. There were no deaths recorded. Though chemotherapy with adjuvant local treatments provide adequate treatment for early tumours, enucleation still plays a major role in the treatment of Retinoblastoma. The total eye salvage rate in this study was 29% with an enucleation rate of 90% in unilateral cases and 33% in bilateral cases. Sixty-six percent of bilateral eyes affected were salvaged. Seventy-one percent of tumours were diagnosed after a parent noticed a gross abnormality of the eye. This highlights the possible need for screening for retinoblastoma in the infant population.

  15. Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

    Directory of Open Access Journals (Sweden)

    Dong Yoon Kim

    2016-11-01

    Full Text Available Abstract Background To evaluate the inhibitory effects of aflibercept on the growth and subretinal invasion of retinoblastoma. Methods Xenotransplantation and orthotopic mouse models were created by injecting Y-79 cells subcutaneously and intravitreally, respectively. After induction of retinoblastoma, animals were intraperitoneally injected with aflibercept (25 mg/kg body weight or saline twice a week for 3 weeks. Tumor size was measured weekly and compared between the two groups. At 4 weeks, animals were sacrificed and an immunohistochemical examination was conducted to compare the microvascular density and degree of apoptosis between groups. In addition, the degree of choroidal invasion was also analyzed in the orthotopic xenotransplantation model. A co-culture system of Y-79 or WERI-Rb-1 cells and human umbilical vein endothelial cells (HUVECs was used for in vitro experiments, and the anti-angiogenic effect of aflibercept was evaluated by analyzing cell numbers. Results In the Y-79 xenotransplantation model, aflibercept treatment significantly inhibited tumor growth at 4 weeks versus baseline compared with saline-injected mice (188.53 ± 118.53 mm3 vs. 747.87 ± 118.83 mm3, respectively, P < 0.001. Tumors isolated from aflibercept-treated mice contained fewer blood vessels (8.59 % ± 7.60 % vs. 14.91 % ± 4.53 %, respectively, P < 0.05 and an increased number of apoptotic cells (15.10 ± 9.13 vs. 4.44 ± 2.24, respectively, P < 0.05. In the orthotopic model, the degree of subretinal invasion of tumor cells was significantly reduced after aflibercept treatment (0.07 ± 0.06 vs. 0.15 ± 0.10, P < 0.05. And addition of aflibercept to co-cultures of HUVECs and Y-79, WERI-Rb-1 cells significantly reduced HUVEC proliferation. Conclusions Aflibercept reduced retinoblastoma angiogenesis in association with a significant reduction in tumor growth and invasion. These findings suggest that

  16. 3D diagnostic imaging of retinoblastoma with a novel optical coherence tomography clinical system

    NARCIS (Netherlands)

    Nadyarnykh, O.; Moll, Annette C; De Boer, Johannes F.

    Purpose : Reliable in-vivo differentiation between the vital tumor / benign masses, and side effects is the main challenge for retinoblastoma, a retinal malignancy occurring in infancy. We have started an observational clinical study using our novel swept source OCT imaging system operating at

  17. Comparison of esterase gene amplification, gene expression and esterase activity in insecticide susceptible and resistant strains of the brown planthopper, Nilaparvata lugens (Stål).

    Science.gov (United States)

    Vontas, J G; Small, G J; Hemingway, J

    2000-12-01

    Organophosphorus and carbamate insecticide resistance in Nilaparvata lugens is based on amplification of a carboxylesterase gene, Nl-EST1. An identical gene occurs in susceptible insects. Quantitative real-time PCR was used to demonstrate that Nl-EST1 is amplified 3-7-fold in the genome of resistant compared to susceptible planthoppers. Expression levels were similar to amplification levels, with 1-15-fold more Nl-EST1 mRNA in individual insects and 5-11-fold more Nl-EST1 mRNA in mass whole body homogenates of resistant females compared to susceptibles. These values corresponded to an 8-10-fold increase in esterase activity in the head and thorax of individual resistant insects. Although amplification, expression and activity levels of Nl-EST1 in resistant N. lugens were similar, the correlation between esterase activity and Nl-EST1 mRNA levels in resistant individuals was not linear.

  18. Amplification of the E2F1 transcription factor gene in the HEL erythroleukemia cell line

    DEFF Research Database (Denmark)

    Saito, M; Helin, K; Valentine, M B

    1995-01-01

    , we isolated genomic clones encompassing the human E2F1 gene. We then used fluorescence in situ hybridization to localize E2F1 to human chromosome 20q11, telomeric to the p107 locus, a gene whose product is related to the retinoblastoma gene product (pRb). This finding contrasts with the 1p36 and 6q22...

  19. The detection and differentiation of methicillin-resistant and methicillin-susceptible Staphylococcus aureus endocarditis by using the BD GeneOhm StaphSR Assay.

    Science.gov (United States)

    Frey, Amy B; Wilson, Deborah A; LaSalvia, Margaret M; Tan, Carmela D; Rodriguez, E Rene; Shrestha, Nabin K; Hall, Gerri S; Procop, Gary W

    2011-11-01

    We use the BD GeneOhm StaphSR Assay (BD Diagnostics, Oakville, Canada) to screen for Staphylococcus aureus nasal colonization and sought to evaluate this assay for the assessment of valve specimens from patients with endocarditis. We examined 23 paired fresh and formalin-fixed, paraffin-embedded cardiac valve tissue samples, 12 of which had S aureus endocarditis, using the BD GeneOhm StaphSR Assay for the detection and differentiation of methicillin-susceptible and methicillin-resistant S aureus. This assay appropriately characterized all specimens with respect to the presence or absence of S aureus. There was an 87.5% correlation between the presence or absence of the mecA gene and the oxacillin susceptibility results for the S aureus isolates studied. The GeneOhm StaphSR assay accurately detected S aureus in cardiac valve tissue samples. Rare discordances were observed between oxacillin susceptibility status and mecA gene detection by this assay.

  20. HSD3B and gene-gene interactions in a pathway-based analysis of genetic susceptibility to bladder cancer.

    Directory of Open Access Journals (Sweden)

    Angeline S Andrew

    Full Text Available Bladder cancer is the 4(th most common cancer among men in the U.S. We analyzed variant genotypes hypothesized to modify major biological processes involved in bladder carcinogenesis, including hormone regulation, apoptosis, DNA repair, immune surveillance, metabolism, proliferation, and telomere maintenance. Logistic regression was used to assess the relationship between genetic variation affecting these processes and susceptibility in 563 genotyped urothelial cell carcinoma cases and 863 controls enrolled in a case-control study of incident bladder cancer conducted in New Hampshire, U.S. We evaluated gene-gene interactions using Multifactor Dimensionality Reduction (MDR and Statistical Epistasis Network analysis. The 3'UTR flanking variant form of the hormone regulation gene HSD3B2 was associated with increased bladder cancer risk in the New Hampshire population (adjusted OR 1.85 95%CI 1.31-2.62. This finding was successfully replicated in the Texas Bladder Cancer Study with 957 controls, 497 cases (adjusted OR 3.66 95%CI 1.06-12.63. The effect of this prevalent SNP was stronger among males (OR 2.13 95%CI 1.40-3.25 than females (OR 1.56 95%CI 0.83-2.95, (SNP-gender interaction P = 0.048. We also identified a SNP-SNP interaction between T-cell activation related genes GATA3 and CD81 (interaction P = 0.0003. The fact that bladder cancer incidence is 3-4 times higher in males suggests the involvement of hormone levels. This biologic process-based analysis suggests candidate susceptibility markers and supports the theory that disrupted hormone regulation plays a role in bladder carcinogenesis.

  1. Evaluation of polymorphisms in pbp4 gene and genetic diversity in penicillin-resistant, ampicillin-susceptible Enterococcus faecalis from hospitals in different states in Brazil.

    Science.gov (United States)

    Infante, Victor Hugo Pacagnelli; Conceição, Natália; de Oliveira, Adriana Gonçalves; Darini, Ana Lúcia da Costa

    2016-04-01

    The aim of the present study was to verify whether penicillin-resistant, ampicillin-susceptible Enterococcus faecalis (PRASEF) occurred in Brazil prior to the beginning of the 21st century, and to verify whether ampicillin susceptibility can predict susceptibility to other β-lactams in E. faecalis with this inconsistent phenotype. The presence of polymorphisms in the pbp4 gene and genetic diversity among the isolates were investigated. Of 21 PRASEF analyzed, 5 (23.8%) and 4 (19.0%) were imipenem and piperacillin resistant simultaneously by disk diffusion and broth dilution respectively, contradicting the current internationally accepted standards of susceptibility testing. Sequencing of pbp4 gene revealed an amino acid substitution (Asp-573→Glu) in all PRASEF isolates but not in the penicillin-susceptible, ampicillin-susceptible E. faecalis. Most PRASEF (90.5%) had related pulsed-field gel electrophoresis profiles, but were different from other PRASEF described to date. Results demonstrate that penicillin-resistant, ampicillin-susceptible phenotype was already a reality in the 1990s in E. faecalis isolates in different Brazilian states, and some of these isolates were also imipenem- and piperacillin-resistant; therefore, internationally accepted susceptibility criteria cannot be applied to these isolates. According to pbp4 gene sequencing, this study suggests that a specific amino acid substitution in pbp4 gene found in all PRASEF analyzed is associated with penicillin resistance. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  2. Polymorphisms in miRNA genes and their involvement in autoimmune diseases susceptibility.

    Science.gov (United States)

    Latini, Andrea; Ciccacci, Cinzia; Novelli, Giuseppe; Borgiani, Paola

    2017-08-01

    MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate the expression of multiple protein-encoding genes at the post-transcriptional level. MicroRNAs are involved in different pathways, such as cellular proliferation and differentiation, signal transduction and inflammation, and play crucial roles in the development of several diseases, such as cancer, diabetes, and cardiovascular diseases. They have recently been recognized to play a role also in the pathogenesis of autoimmune diseases. Although the majority of studies are focused on miRNA expression profiles investigation, a growing number of studies have been investigating the role of polymorphisms in miRNA genes in the autoimmune diseases development. Indeed, polymorphisms affecting the miRNA genes can modify the set of targets they regulate or the maturation efficiency. This review is aimed to give an overview about the available studies that have investigated the association of miRNA gene polymorphisms with the susceptibility to various autoimmune diseases and to their clinical phenotypes.

  3. A retinoblastoma orthologue is required for the sensing of a chalone in Dictyostelium discoideum.

    Science.gov (United States)

    Bakthavatsalam, Deenadayalan; White, Michael J V; Herlihy, Sarah E; Phillips, Jonathan E; Gomer, Richard H

    2014-03-01

    Retinoblastoma-like proteins regulate cell differentiation and inhibit cell proliferation. The Dictyostelium discoideum retinoblastoma orthologue RblA affects the differentiation of cells during multicellular development, but it is unclear whether RblA has a significant effect on Dictyostelium cell proliferation, which is inhibited by the secreted proteins AprA and CfaD. We found that rblA⁻ cells in shaking culture proliferate to a higher density, die faster after reaching stationary density, and, after starvation, have a lower spore viability than wild-type cells, possibly because in shaking culture, rblA⁻ cells have both increased cytokinesis and lower extracellular accumulation of CfaD. However, rblA⁻ cells have abnormally slow proliferation on bacterial lawns. Recombinant AprA inhibits the proliferation of wild-type cells but not that of rblA⁻ cells, whereas CfaD inhibits the proliferation of both wild-type cells and rblA⁻ cells. Similar to aprA⁻ cells, rblA⁻ cells have a normal mass and protein accumulation rate on a per-nucleus basis, indicating that RblA affects cell proliferation but not cell growth. AprA also functions as a chemorepellent, and RblA is required for proper AprA chemorepellent activity despite the fact that RblA does not affect cell speed. Together, our data indicate that an autocrine proliferation-inhibiting factor acts through RblA to regulate cell density in Dictyostelium, suggesting that such factors may signal through retinoblastoma-like proteins to control the sizes of structures such as developing organs or tumors.

  4. Identification of susceptibility genes for bipolar affective disorder and schizophrenia on chromosome 22q13

    DEFF Research Database (Denmark)

    Severinsen, Jacob Eg

    2006-01-01

    Linkage analyses suggest that chromosome 22q12-13 may harbor one or more shared susceptibility loci for bipolar affective disorder (BPD) and schizophrenia (SZ). In a study of distantly related cases and control individuals from the Faeroe Islands our group has previously reported that chromosome 22...... samples (total of 1,751 individuals), and by bioinformatic and expression analyses of a subset of disease associated genes and gene variants. In total 67 single nucleotide polymorphisms (SNPs) located in 18 positional candidate genes, and 4 microsattelite markers were investigated, using a Scottish case...

  5. RETRACTED: Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression.

    Science.gov (United States)

    Yang, Chun-Hua; Zhou, Tian-Biao

    2015-12-01

    This article has been included in a multiple retraction: Chun-Hua Yang and Tian-Biao Zhou Association of the ACE I/D gene polymorphism with sepsis susceptibility and sepsis progression Journal of Renin-Angiotensin-Aldosterone System 1470320314568521, first published on February 3, 2015 doi: 10.1177/1470320314568521 This article has been retracted at the request of the Editors and the Publisher. After conducting a thorough investigation, SAGE found that the submitting authors of a number of papers published in the Journal of the Renin-Angiotensin Aldosterone System ( JRAAS) (listed below) had supplied fabricated contact details for their nominated reviewers. The Editors accepted these papers based on the reports supplied by the individuals using these fake reviewer email accounts. After concluding that the peer review process was therefore seriously compromised, SAGE and the journal Editors have decided to retract all affected articles. Online First articles (these articles will not be published in an issue) Wenzhuang Tang, Tian-Biao Zhou, and Zongpei Jiang Association of the angiotensinogen M235T gene polymorphism with risk of diabetes mellitus developing into diabetic nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563426, first published on December 18, 2014 doi: 10.1177/1470320314563426 Tian-Biao Zhou, Hong-Yan Li, Zong-Pei Jiang, Jia-Fan Zhou, Miao-Fang Huang, and Zhi-Yang Zhou Role of renin-angiotensin-aldosterone system inhibitors in radiation nephropathy Journal of Renin-Angiotensin-Aldosterone System 1470320314563424, first published on December 18, 2014 doi: 10.1177/1470320314563424 Weiqiang Zhong, Zongpei Jiang, and Tian-Biao Zhou Association between the ACE I/D gene polymorphism and T2DN susceptibility: The risk of T2DM developing into T2DN in the Asian population Journal of Renin-Angiotensin-Aldosterone System 1470320314566019, first published on January 26, 2015 doi: 10.1177/1470320314566019 Tian-Biao Zhou, Xue-Feng Guo, Zongpei

  6. Mapping of Mcs30, a new mammary carcinoma susceptibility quantitative trait locus (QTL30 on rat chromosome 12: identification of fry as a candidate Mcs gene.

    Directory of Open Access Journals (Sweden)

    Xuefeng Ren

    Full Text Available Rat strains differ dramatically in their susceptibility to mammary carcinogenesis. On the assumption that susceptibility genes are conserved across mammalian species and hence inform human carcinogenesis, numerous investigators have used genetic linkage studies in rats to identify genes responsible for differential susceptibility to carcinogenesis. Using a genetic backcross between the resistant Copenhagen (Cop and susceptible Fischer 344 (F344 strains, we mapped a novel mammary carcinoma susceptibility (Mcs30 locus to the centromeric region on chromosome 12 (LOD score of ∼8.6 at the D12Rat59 marker. The Mcs30 locus comprises approximately 12 Mbp on the long arm of rat RNO12 whose synteny is conserved on human chromosome 13q12 to 13q13. After analyzing numerous genes comprising this locus, we identified Fry, the rat ortholog of the furry gene of Drosophila melanogaster, as a candidate Mcs gene. We cloned and determined the complete nucleotide sequence of the 13 kbp Fry mRNA. Sequence analysis indicated that the Fry gene was highly conserved across evolution, with 90% similarity of the predicted amino acid sequence among eutherian mammals. Comparison of the Fry sequence in the Cop and F344 strains identified two non-synonymous single nucleotide polymorphisms (SNPs, one of which creates a putative, de novo phosphorylation site. Further analysis showed that the expression of the Fry gene is reduced in a majority of rat mammary tumors. Our results also suggested that FRY activity was reduced in human breast carcinoma cell lines as a result of reduced levels or mutation. This study is the first to identify the Fry gene as a candidate Mcs gene. Our data suggest that the SNPs within the Fry gene contribute to the genetic susceptibility of the F344 rat strain to mammary carcinogenesis. These results provide the foundation for analyzing the role of the human FRY gene in cancer susceptibility and progression.

  7. Treatment of retinoblastoma by precision megavoltage radiation therapy

    International Nuclear Information System (INIS)

    Schipper, J.; Peperzeel, H.A. van; Tan, K.E.W.P.

    1985-01-01

    The principal treatment concept in the Utrecht Retinoblastoma Centre is megavoltage irradiation, followed by light coagulation and/or cryotherapy if there is any doubt as to whether the residual tumour is still active. Radiation therapy is administered by means of a simple but highly accurate temporal beam technique. A standardized dose of 45 Gy is given in 15 fractions of 3 Gy at 3 fractions per week. From 1971 to 1982, 39 children with retinoblastoma have been irradiated in at least one eye. Of the 73 affected eyes, 18 were primarily enucleated, one received light coagulation only, and 54 received radiation therapy. Of the 54 irradiated eyes, 32 were additionally treated by light coagulation and/or cryotherapy for suspicious residual tumour (in 29 eyes), recurrent tumour (in 1 eye), and/or new tumour (in 3 eyes) and 10 were ultimately enucleated. Two eyes also received hyperthermia. The percentages of cure of the irradiated eyes with a minimum follow-up of 2 years were 100% (14/14), 100% (9/9,) 83% (10/12), 79% (11/14) and 0% (0/5) in the Reese-Ellsworth groups I to V-A, respectively. Of the saved eyes 95% achieved useful vision. Eighteen eyes developed a clinically detectable radiation cataract; in five of these the lens was aspirated. Cataracts developed exclusively in those lenses of which a posterior portion of more than 1 mm had to be included in the treatment field. The likelihood and the degree of cataract formation was found to be directly related to the dose of radiation to the germinative zone of the lens epithelium. The minimum cataractogenic dose found in this series was 8 Gy. (Auth.)

  8. Treatment of retinoblastoma by precision megavoltage radiation therapy

    Energy Technology Data Exchange (ETDEWEB)

    Schipper, J.; Peperzeel, H.A. van (Rijksuniversiteit Utrecht (Netherlands). Academisch Ziekenhuis); Tan, K.E.W.P. (Royal Dutch Eye Hospital, Utrecht, Netherlands)

    1985-02-01

    The principal treatment concept in the Utrecht Retinoblastoma Centre is megavoltage irradiation, followed by light coagulation and/or cryotherapy if there is any doubt as to whether the residual tumour is still active. Radiation therapy is administered by means of a simple but highly accurate temporal beam technique. A standardized dose of 45 Gy is given in 15 fractions of 3 Gy at 3 fractions per week. From 1971 to 1982, 39 children with retinoblastoma have been irradiated in at least one eye. Of the 73 affected eyes, 18 were primarily enucleated, one received light coagulation only, and 54 received radiation therapy. Of the 54 irradiated eyes, 32 were additionally treated by light coagulation and/or cryotherapy for suspicious residual tumour (in 29 eyes), recurrent tumour (in 1 eye), and/or new tumour (in 3 eyes) and 10 were ultimately enucleated. Two eyes also received hyperthermia. The percentages of cure of the irradiated eyes with a minimum follow-up of 2 years were 100% (14/14), 100% (9/9), 83% (10/12), 79% (11/14) and 0% (0/5) in the Reese-Ellsworth groups I to V-A, respectively. Of the saved eyes 95% achieved useful vision. Eighteen eyes developed a clinically detectable radiation cataract; in five of these the lens was aspirated. Cataracts developed exclusively in those lenses of which a posterior portion of more than 1 mm had to be included in the treatment field. The likelihood and the degree of cataract formation was found to be directly related to the dose of radiation to the germinative zone of the lens epithelium. The minimum cataractogenic dose found in this series was 8 Gy.

  9. Mutation spectrum of RB1 mutations in retinoblastoma cases from Singapore with implications for genetic management and counselling.

    Directory of Open Access Journals (Sweden)

    Swati Tomar

    Full Text Available Retinoblastoma (RB is a rare childhood malignant disorder caused by the biallelic inactivation of RB1 gene. Early diagnosis and identification of carriers of heritable RB1 mutations can improve disease outcome and management. In this study, mutational analysis was conducted on fifty-nine matched tumor and peripheral blood samples from 18 bilateral and 41 unilateral unrelated RB cases by a combinatorial approach of Multiplex Ligation-dependent Probe Amplification (MLPA assay, deletion screening, direct sequencing, copy number gene dosage analysis and methylation assays. Screening of both blood and tumor samples yielded a mutation detection rate of 94.9% (56/59 while only 42.4% (25/59 of mutations were detected if blood samples alone were analyzed. Biallelic mutations were observed in 43/59 (72.9% of tumors screened. There were 3 cases (5.1% in which no mutations could be detected and germline mutations were detected in 19.5% (8/41 of unilateral cases. A total of 61 point mutations were identified, of which 10 were novel. There was a high incidence of previously reported recurrent mutations, occurring at 38.98% (23/59 of all cases. Of interest were three cases of mosaic RB1 mutations detected in the blood from patients with unilateral retinoblastoma. Additionally, two germline mutations previously reported to be associated with low-penetrance phenotypes: missense-c.1981C>T and splice variant-c.607+1G>T, were observed in a bilateral and a unilateral proband, respectively. These findings have implications for genetic counselling and risk prediction for the affected families. This is the first published report on the spectrum of mutations in RB patients from Singapore and shows that further improved mutation screening strategies are required in order to provide a definitive molecular diagnosis for every case of RB. Our findings also underscore the importance of genetic testing in supporting individualized disease management plans for patients and

  10. Genetic susceptibility loci, environmental exposures, and Parkinson's disease: a case-control study of gene-environment interactions.

    Science.gov (United States)

    Chung, Sun Ju; Armasu, Sebastian M; Anderson, Kari J; Biernacka, Joanna M; Lesnick, Timothy G; Rider, David N; Cunningham, Julie M; Ahlskog, J Eric; Frigerio, Roberta; Maraganore, Demetrius M

    2013-06-01

    Prior studies causally linked mutations in SNCA, MAPT, and LRRK2 genes with familial Parkinsonism. Genome-wide association studies have demonstrated association of single nucleotide polymorphisms (SNPs) in those three genes with sporadic Parkinson's disease (PD) susceptibility worldwide. Here we investigated the interactions between SNPs in those three susceptibility genes and environmental exposures (pesticides application, tobacco smoking, coffee drinking, and alcohol drinking) also associated with PD susceptibility. Pairwise interactions between environmental exposures and 18 variants (16 SNPs and two variable number tandem repeats, or "VNTRs") in SNCA, MAPT and LRRK2, were investigated using data from 1098 PD cases from the upper Midwest, USA and 1098 matched controls. Environmental exposures were assessed using a validated telephone interview script. Five pairwise interactions had uncorrected P-values coffee drinking × MAPT H1/H2 haplotype or MAPT rs16940806, and alcohol drinking × MAPT rs2435211. None of these interactions remained significant after Bonferroni correction. Secondary analyses in strata defined by type of control (sibling or unrelated), sex, or age at onset of the case also did not identify significant interactions after Bonferroni correction. This study documented limited pairwise interactions between established genetic and environmental risk factors for PD; however, the associations were not significant after correction for multiple testing. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Dosimetric Study of Current Treatment Options for Radiotherapy in Retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Eldebawy, Eman [Department of Radiation Oncology, McGill University Health Centre, Montreal, Quebec (Canada); Department of Radiation Oncology, Children' s Cancer Hospital, Cairo (Egypt); Parker, William, E-mail: william.parker@mcgill.ca [Department of Medical Physics, McGill University Health Centre, Montreal, Quebec (Canada); Abdel Rahman, Wamied [Department of Medical Physics, McGill University Health Centre, Montreal, Quebec (Canada); Freeman, Carolyn R. [Department of Radiation Oncology, McGill University Health Centre, Montreal, Quebec (Canada)

    2012-03-01

    Purpose: To determine the best treatment technique for patients with retinoblastoma requiring radiotherapy to the whole eye. Methods and Materials: Treatment plans for 3 patients with retinoblastoma were developed using 10 radiotherapy techniques including electron beams, photon beam wedge pair (WP), photon beam three-dimensional conformal radiotherapy (3D-CRT), fixed gantry intensity-modulated radiotherapy (IMRT), photon volumetric arc therapy (VMAT), fractionated stereotactic radiotherapy, and helical tomotherapy (HT). Dose-volume analyses were carried out for each technique. Results: All techniques provided similar target coverage; conformity was highest for VMAT, nine-field (9F) IMRT, and HT (conformity index [CI] = 1.3) and lowest for the WP and two electron techniques (CI = 1.8). The electron techniques had the highest planning target volume dose gradient (131% of maximum dose received [D{sub max}]), and the CRT techniques had the lowest (103% D{sub max}) gradient. The volume receiving at least 20 Gy (V{sub 20Gy}) for the ipsilateral bony orbit was lowest for the VMAT and HT techniques (56%) and highest for the CRT techniques (90%). Generally, the electron beam techniques were superior in terms of brain sparing and delivered approximately one-third of the integral dose of the photon techniques. Conclusions: Inverse planned image-guided radiotherapy delivered using HT or VMAT gives better conformity index, improved orbital bone and brain sparing, and a lower integral dose than other techniques.

  12. Systematic Prioritization and Integrative Analysis of Copy Number Variations in Schizophrenia Reveal Key Schizophrenia Susceptibility Genes

    Science.gov (United States)

    Luo, Xiongjian; Huang, Liang; Han, Leng; Luo, Zhenwu; Hu, Fang; Tieu, Roger; Gan, Lin

    2014-01-01

    Schizophrenia is a common mental disorder with high heritability and strong genetic heterogeneity. Common disease-common variants hypothesis predicts that schizophrenia is attributable in part to common genetic variants. However, recent studies have clearly demonstrated that copy number variations (CNVs) also play pivotal roles in schizophrenia susceptibility and explain a proportion of missing heritability. Though numerous CNVs have been identified, many of the regions affected by CNVs show poor overlapping among different studies, and it is not known whether the genes disrupted by CNVs contribute to the risk of schizophrenia. By using cumulative scoring, we systematically prioritized the genes affected by CNVs in schizophrenia. We identified 8 top genes that are frequently disrupted by CNVs, including NRXN1, CHRNA7, BCL9, CYFIP1, GJA8, NDE1, SNAP29, and GJA5. Integration of genes affected by CNVs with known schizophrenia susceptibility genes (from previous genetic linkage and association studies) reveals that many genes disrupted by CNVs are also associated with schizophrenia. Further protein-protein interaction (PPI) analysis indicates that protein products of genes affected by CNVs frequently interact with known schizophrenia-associated proteins. Finally, systematic integration of CNVs prioritization data with genetic association and PPI data identifies key schizophrenia candidate genes. Our results provide a global overview of genes impacted by CNVs in schizophrenia and reveal a densely interconnected molecular network of de novo CNVs in schizophrenia. Though the prioritized top genes represent promising schizophrenia risk genes, further work with different prioritization methods and independent samples is needed to confirm these findings. Nevertheless, the identified key candidate genes may have important roles in the pathogenesis of schizophrenia, and further functional characterization of these genes may provide pivotal targets for future therapeutics and

  13. O uso da quimioterapia no tratamento do retinoblastoma: avaliação retrospectiva The use of chemotherapy in the treatment of retinoblastoma: retrospective analysis

    Directory of Open Access Journals (Sweden)

    Fernando Leite Kronbauer

    2000-12-01

    Full Text Available Objetivo:Análise retrospectiva de pacientes com retinoblastoma considerando: 1 - estadiamento e apresentação tumoral à tomografia, 2 - proporção de pacientes com margens comprometidas (nervo óptico no exame anatomopatológico dos olhos enucleados e 3-tratamento com quimioterapia. Métodos: Revisados os prontuários de 11 pacientes consecutivos com diagnóstico de retinoblastoma entre fevereiro/98 e setembro/99, tratados conjuntamente no setor de Oncologia Pediátrica e Serviço de Oftalmologia. Foram selecionados aqueles submetidos à quimioterapia com vincristina, etoposida e carboplatina (VEC num total de 7 pacientes. Foram avaliados: apresentação tumoral (estadiamento, resposta à quimioterapia e sobrevida destes pacientes. Resultados: Os 7 pacientes estudados foram diagnosticados entre 15 e 38 meses de idade (média=25,7 meses, sendo 3 unilaterais, 3 bilaterais e 1 trilateral (pinealoblastoma. Todos pacientes foram tratados com quimioterapia (VEC administrados em 2 a 5 ciclos e divididos em 2 grupos: Grupo 1 - Pacientes tratados com quimioterapia primária visando redução tumoral e preservação de 1 dos olhos (5 pacientes; Grupo 2 - Pacientes tratados com quimioterapia agressiva para doença extra-ocular (2 pacientes. Dos 5 pacientes tratados com quimioterapia primária (4 submetidos a enucleação devido ao grande volume tumoral, 4 obtiveram redução tumoral, 2 responderam apenas inicialmente indo à óbito em 10 meses de média e 1 apresentou-se quimiorresistente. Pacientes com tumor bilateral foram submetidos a radioterapia (EBTR no olho menos acometido. O tempo médio de seguimento após quimioterapia primária foi 12,4 meses. Os dois pacientes submetidos à enucleação e quimioterapia adjuvante, apresentavam metástase cerebral e foram a óbito em média 4/5 meses após início do tratamento. Conclusão: Esse estudo revelou que: 1-os casos de retinoblastoma são diagnosticados tardiamente em nosso meio. 2 - A porcentagem

  14. Differential Gene Expression Profile in the Rat Caudal Vestibular Nucleus is Associated with Individual Differences in Motion Sickness Susceptibility.

    Directory of Open Access Journals (Sweden)

    Jun-Qin Wang

    Full Text Available To identify differentially expressed genes associated with motion sickness (MS susceptibility in the rat caudal vestibular nucleus.We identified MS susceptible (MSS and insusceptible (inMSS rats by quantifying rotation-induced MS symptoms: defecation and spontaneous locomotion activity. Microarray analysis was used to screen differentially expressed genes in the caudal vestibular nucleus (CVN after rotation. Plasma stress hormones were identified by radioimmunoassay. Candidate genes were selected by bioinformatics analysis and the microarray results were verified by real-time quantitative-PCR (RT-qPCR methods. By using Elvax implantation, receptor antagonists or recombinant adenovirus targeting the candidate genes were applied to the CVN to evaluate their contribution to MS susceptibility variability. Validity of gene expression manipulation was verified by RT-qPCR and western blot analysis.A total of 304 transcripts were differentially expressed in the MSS group compared with the inMSS group. RT-qPCR analysis verified the expression pattern of candidate genes, including nicotinic cholinergic receptor (nAchR α3 subunit, 5-hydroxytryptamine receptor 4 (5-HT4R, tachykinin neurokinin-1 (NK1R, γ-aminobutyric acid A receptor (GABAAR α6 subunit, olfactory receptor 81 (Olr81 and homology 2 domain-containing transforming protein 1 (Shc1. In MSS animals, the nAchR antagonist mecamylamine significantly alleviated rotation-induced MS symptoms and the plasma β-endorphin response. The NK1R antagonist CP99994 and Olr81 knock-down were effective for the defecation response, while the 5-HT4R antagonist RS39604 and Shc1 over-expression showed no therapeutic effect. In inMSS animals, rotation-induced changes in spontaneous locomotion activity and the plasma β-endorphin level occurred in the presence of the GABAAR antagonist gabazine.Our findings suggested that the variability of the CVN gene expression profile after motion stimulation might be a putative

  15. Glypican-4 gene polymorphism (rs1048369) and susceptibility to Epstein-Barr virus-associated and -negative gastric carcinoma.

    Science.gov (United States)

    Zhao, Danrui; Liu, Shuzhen; Sun, Lingling; Zhao, Zhenzhen; Liu, Song; Kuang, Xiaojing; Shu, Jun; Luo, Bing

    2016-07-15

    Gastric cancer (GC) is one of the most common malignant tumors in China and single nucleotide polymorphisms (SNPs) have been found to be highly related to GC carcinogenesis. Glypican-4 (GPC4), a member of the heparan sulphate proteoglycan family, plays an important role in the regulation of cell growth and differentiation. However, little is known about polymorphisms of GPC4 gene and their associated susceptibility to GC, especially to Epstein-Barr virus-associated GC (EBVaGC). Here we studied the GPC4 polymorphism (rs1048369) in GC individuals, especially those with EBVaGC, and we explored an association between the GPC4 gene polymorphism (rs1048369) and susceptibility to EBVaGC and Epstein-Barr virus-negative GC (EBVnGC) in a population from Northern China. The GPC4 gene polymorphism (rs1048369) was detected in 54 cases of EBVaGC and 73 cases of EBVnGC using polymerase chain reaction (PCR). One hundred and seven peripheral blood samples from healthy individuals were also measured as a control group. There were significant differences in both the genotype and allelic frequency of GPC4 gene (rs1048369) between the EBVaGC and EBVnGC patients. Meanwhile, the distribution of genotype and allelic frequency of GPC4 (rs1048369) differed between EBVaGC and control groups. Distribution of the GPC4 genotype also revealed differences between EBVnGC and control groups, no significant differences in the allelic frequency of the GPC4 gene (rs1048369) were observed. The frequency of the T allele in EBVaGC group was significantly higher than that in control and EBVnGC groups. The GPC4 gene polymorphism and the allele of GPC4 are both associated with susceptibility to EBVaGC. The T allele of GPC4 may represent a risk factor for EBVaGC. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Search of type 2 diabetes susceptibility gene on chromosome 20q

    International Nuclear Information System (INIS)

    Takeuchi, F.; Yanai, K.; Inomata, H.; Kuzuya, N.; Kajio, H.; Honjo, S.; Takeda, N.; Kaburagi, Y.; Yasuda, K.; Shirasawa, S.; Sasazuki, T.; Kato, N.

    2007-01-01

    Significant evidence of linkage to type 2 diabetes (T2D) has been shown in a relatively broad region on chromosome 20q, where the hepatocyte nuclear factor-4α (HNF4A) has been noted as a positional candidate. To systematically evaluate genetic susceptibility to T2D in the relevant region, we examined the disease association by using 1145 SNPs in two-step screening in the Japanese population. The marker screening enabled us to identify significant disease association in the lipopolysaccharide binding protein (LBP) but not in the HNF4A locus. In a 17.7-Mb interval screened, the strongest association was identified for a SNP, rs2232592, located in the intron of LBP, with an estimated odds ratio of 1.73 (95% CI 1.30-2.31) (P 0.0002) in the whole study panel involving 675 case and 474 control subjects. Our data suggest that the LBP gene may confer genetic susceptibility to T2D and this warrants further replication study

  17. Integrative analyses of leprosy susceptibility genes indicate a common autoimmune profile.

    Science.gov (United States)

    Zhang, Deng-Feng; Wang, Dong; Li, Yu-Ye; Yao, Yong-Gang

    2016-04-01

    Leprosy is an ancient chronic infection in the skin and peripheral nerves caused by Mycobacterium leprae. The development of leprosy depends on genetic background and the immune status of the host. However, there is no systematic view focusing on the biological pathways, interaction networks and overall expression pattern of leprosy-related immune and genetic factors. To identify the hub genes in the center of leprosy genetic network and to provide an insight into immune and genetic factors contributing to leprosy. We retrieved all reported leprosy-related genes and performed integrative analyses covering gene expression profiling, pathway analysis, protein-protein interaction network, and evolutionary analyses. A list of 123 differentially expressed leprosy related genes, which were enriched in activation and regulation of immune response, was obtained in our analyses. Cross-disorder analysis showed that the list of leprosy susceptibility genes was largely shared by typical autoimmune diseases such as lupus erythematosus and arthritis, suggesting that similar pathways might be affected in leprosy and autoimmune diseases. Protein-protein interaction (PPI) and positive selection analyses revealed a co-evolution network of leprosy risk genes. Our analyses showed that leprosy associated genes constituted a co-evolution network and might undergo positive selection driven by M. leprae. We suggested that leprosy may be a kind of autoimmune disease and the development of leprosy is a matter of defect or over-activation of body immunity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. A pilot study of hyperfractionated radiotherapy for infants with retinoblastoma

    International Nuclear Information System (INIS)

    Harris, Eleanor E.R.; Meadows, Anna T.; Shields, Jerry; D'Angio, Giulio J.; Goldwein, Joel W.

    1996-01-01

    Purpose: This study was undertaken to assess the use of twice daily fractionated radiotherapy using low doses per fraction in the treatment of intraocular retinoblastoma in infants in terms of local control, ocular complications and bony growth disturbances. Methods: Children were irradiated using standard techniques including en face electrons (3 patients) or opposed lateral photon fields to one or both orbits (7 patients). Patients were treated with 100 cGy twice daily with an inter fraction interval of 4 or more hours to total doses of 43 to 45 Gy. No patients received chemotherapy. Results: Ten children under the age of 13 months were entered onto the twice daily radiation protocol from 4/87 through 6/90. Nine patients presented with nonfamilial bilateral retinoblastoma; one later failed in the pineal region representing trilateral retinoblastoma. The tenth patient had advanced unilateral disease. Of 19 eyes involved with tumor, 13 were group V and all patients had at least one eye with advanced disease (group III-V). Two patients underwent enucleation of the more advanced eye up front and received radiation to the intact eye only. Overall survival was 8 of 10 patients with a median follow-up of 28 months (range 12-47 months). Two patients died of distant metastases, one with local recurrence and one with trilateral disease but local control. Local recurrence after initial external beam radiation therapy only was seen in 8 of 19 eyes (42%). Failures occurred in 6 of 13 group V eyes, 1 of 2 group IV eyes and 1 of 2 group III eyes. Further local therapy included plaque therapy in 3 eyes, cryotherapy in 3 eyes and enucleation in one eye. Surgery was refused for one patient with bilateral recurrences. Ultimate local control after external beam irradiation plus additional local therapies was 16 of 19 eyes (84%). Post-irradiation ocular loss occurred in 5 of 19 eyes. Therefore, overall local control with ocular preservation was achieved in 14 of 19 eyes (74%). Vision

  19. Strain-dependent susceptibility for hypertension in mice resides in the natural killer gene complex

    NARCIS (Netherlands)

    Taherzadeh, Zhila; VanBavel, Ed; de Vos, Judith; Matlung, Hanke L.; van Montfrans, Gert; Brewster, Lizzy M.; Seghers, Leonard; Quax, Paul H. A.; Bakker, Erik N. T. P.

    2010-01-01

    Taherzadeh Z, VanBavel E, de Vos J, Matlung HL, van Montfrans G, Brewster LM, Seghers L, Quax PH, Bakker EN. Strain-dependent susceptibility for hypertension in mice resides in the natural killer gene complex. Am J Physiol Heart Circ Physiol 298: H1273-H1282, 2010. First published February 12, 2010;

  20. Wild rodents as a model to discover genes and pathways underlying natural variation in infectious disease susceptibility.

    Science.gov (United States)

    Turner, A K; Paterson, S

    2013-11-01

    Individuals vary in their susceptibility to infectious disease, and it is now well established that host genetic factors form a major component of this variation. The discovery of genes underlying susceptibility has the potential to lead to improved disease control, through the identification and management of vulnerable individuals and the discovery of novel therapeutic targets. Laboratory rodents have proved invaluable for ascertaining the function of genes involved in immunity to infection. However, these captive animals experience conditions very different to the natural environment, lacking the genetic diversity and environmental pressures characteristic of natural populations, including those of humans. It has therefore often proved difficult to translate basic laboratory research to the real world. In order to further our understanding of the genetic basis of infectious disease resistance, and the evolutionary forces that drive variation in susceptibility, we propose that genetic research traditionally conducted on laboratory animals is expanded to the more ecologically valid arena of natural populations. In this article, we highlight the potential of using wild rodents as a new resource for biomedical research, to link the functional genetic knowledge gained from laboratory rodents with the variation in infectious disease susceptibility observed in humans and other natural populations. © 2013 John Wiley & Sons Ltd.

  1. Polymorphisms in the 3' UTR in the neurocalcin delta gene affect mRNA stability, and confer susceptibility to diabetic nephropathy

    DEFF Research Database (Denmark)

    Kamiyama, Masumi; Kobayashi, Masaaki; Araki, Shin-ichi

    2007-01-01

    Using a large-scale genotyping analysis of gene-based single nucleotide polymorphisms (SNPs) in Japanese type 2 diabetic patients, we have identified a gene encoding neurocalcin delta (NCALD) as a candidate for a susceptibility gene to diabetic nephropathy; the landmark SNP was found in the 3' UT...

  2. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

    Directory of Open Access Journals (Sweden)

    Zheng Lin

    Full Text Available The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2 is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445 and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445 and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605, in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605 may be involved in the susceptibility to paranoid

  3. The interaction of BDNF and NTRK2 gene increases the susceptibility of paranoid schizophrenia.

    Science.gov (United States)

    Lin, Zheng; Su, Yousong; Zhang, Chengfang; Xing, Mengjuan; Ding, Wenhua; Liao, Liwei; Guan, Yangtai; Li, Zezhi; Cui, Donghong

    2013-01-01

    The association between BDNF gene functional Val66Met polymorphism rs6265 and the schizophrenia is far from being consistent. In addition to the heterogeneous in schizophrenia per se leading to the inconsistent results, the interaction among multi-genes is probably playing the main role in the pathogenesis of schizophrenia, but not a single gene. Neurotrophic tyrosine kinase receptor 2 (NTRK2) is the high-affinity receptor of BDNF, and was reported to be associated with mood disorders, though no literature reported the association with schizophrenia. Thus, in the present study, total 402 patients with paranoid schizophrenia (the most common subtype of schizophrenia) and matched 406 healthy controls were recruited to investigate the role of rs6265 in BDNF, three polymorphisms in NTRK2 gene (rs1387923, rs2769605 and rs1565445) and their interaction in the susceptibility to paranoid schizophrenia in a Chinese Han population. We did not observe significant differences in allele and genotype frequencies between patients and healthy controls for all four polymorphisms separately. The haplotype analysis also showed no association between haplotype of NTRK2 genes (rs1387923, rs2769605, and rs1565445) and paranoid schizophrenia. However, we found the association between the interaction of BDNF and NTRK2 with paranoid schizophrenia by using the MDR method followed by conventional statistical analysis. The best gene-gene interaction model was a three-locus model (BDNF rs6265, NTRK2 rs1387923 and NTRK2 rs2769605), in which one low-risk and three high-risk four-locus genotype combinations were identified. Our findings implied that single polymorphism of rs6265 rs1387923, rs2769605, and rs1565445 in BDNF and NTRK2 were not associated with the development of paranoid schizophrenia in a Han population, however, the interaction of BDNF and NTRK2 genes polymorphisms (BDNF-rs6265, NTRK2-rs1387923 and NTRK2-rs2769605) may be involved in the susceptibility to paranoid schizophrenia.

  4. Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.

    Science.gov (United States)

    Xu, Ke; Ma, Lu; Li, Yang; Wang, Fang; Zheng, Gu-Yan; Sun, Zhijun; Jiang, Feng; Chen, Yundai; Liu, Huirong; Dang, Aimin; Chen, Xi; Chun, Jerold; Tian, Xiao-Li

    2015-09-01

    Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension. © 2015 American Heart Association, Inc.

  5. Antimicrobial Susceptibility of Bordetella bronchiseptica Isolates from Swine and Companion Animals and Detection of Resistance Genes.

    Directory of Open Access Journals (Sweden)

    Sandra Prüller

    Full Text Available Bordetella bronchiseptica causes infections of the respiratory tract in swine and other mammals and is a precursor for secondary infections with Pasteurella multocida. Treatment of B. bronchiseptica infections is conducted primarily with antimicrobial agents. Therefore it is essential to get an overview of the susceptibility status of these bacteria. The aim of this study was to comparatively analyse broth microdilution susceptibility testing according to CLSI recommendations with an incubation time of 16 to 20 hours and a longer incubation time of 24 hours, as recently proposed to obtain more homogenous MICs. Susceptibility testing against a panel of 22 antimicrobial agents and two fixed combinations was performed with 107 porcine isolates from different farms and regions in Germany and 43 isolates obtained from companion animals in Germany and other European countries. Isolates with increased MICs were investigated by PCR assays for the presence of resistance genes. For ampicillin, all 107 porcine isolates were classified as resistant, whereas only a single isolate was resistant to florfenicol. All isolates obtained from companion animals showed elevated MICs for β-lactam antibiotics and demonstrated an overall low susceptibility to cephalosporines. Extension of the incubation time resulted in 1-2 dilution steps higher MIC50 values of porcine isolates for seven antimicrobial agents tested, while isolates from companion animals exhibited twofold higher MIC50/90 values only for tetracycline and cefotaxime. For three antimicrobial agents, lower MIC50 and MIC90 values were detected for both, porcine and companion animal isolates. Among the 150 isolates tested, the resistance genes blaBOR-1 (n = 147, blaOXA-2, (n = 4, strA and strB (n = 17, sul1 (n = 10, sul2 (n = 73, dfrA7 (n = 3 and tet(A (n = 8 were detected and a plasmid localisation was identified for several of the resistance genes.

  6. Bipolar disorder: idioms of susceptibility and disease and the role of 'genes' in illness explanations.

    Science.gov (United States)

    Baart, Ingrid; Widdershoven, Guy

    2013-11-01

    This qualitative study explores (1) how members of the Dutch Association for People with Bipolar Disorder explain the affliction of bipolar disorder; (2) the relationship between genetic, environmental and personal factors in these explanations and (3) the relationship between illness explanations, self-management and identity. A total of 40 participants took part in seven different focus group discussions. The results demonstrate that there are two different explanatory idioms, each one centred around an opposing concept, that is, susceptibility and disease. Individuals who construct explanations around the concept of 'disease' attach more importance to 'genes and chemicals' than to environmental components in the onset of the disorder, whereas individuals adhering to the central concept of 'susceptibility' tend to do this much less. Compared with individuals using the 'susceptibility' idiom, those who use a 'disease' idiom tend to observe fewer possibilities for self-management and are less inclined to construct normalcy through a quest for personal growth. Stories of suffering seem more integral to the 'disease' idiom than to the 'susceptibility' idiom. The 'disease' idiom seems less integrated in a contemporary surveillance psychiatric discourse than the 'susceptibility' idiom; however, both vocabularies can offer normative constraints.

  7. The application of nonsense-mediated mRNA decay inhibition to the identification of breast cancer susceptibility genes

    International Nuclear Information System (INIS)

    Johnson, Julie K; Waddell, Nic; Chenevix-Trench, Georgia

    2012-01-01

    Identification of novel, highly penetrant, breast cancer susceptibility genes will require the application of additional strategies beyond that of traditional linkage and candidate gene approaches. Approximately one-third of inherited genetic diseases, including breast cancer susceptibility, are caused by frameshift or nonsense mutations that truncate the protein product [1]. Transcripts harbouring premature termination codons are selectively and rapidly degraded by the nonsense-mediated mRNA decay (NMD) pathway. Blocking the NMD pathway in any given cell will stabilise these mutant transcripts, which can then be detected using gene expression microarrays. This technique, known as gene identification by nonsense-mediated mRNA decay inhibition (GINI), has proved successful in identifying sporadic nonsense mutations involved in many different cancer types. However, the approach has not yet been applied to identify germline mutations involved in breast cancer. We therefore attempted to use GINI on lymphoblastoid cell lines (LCLs) from multiple-case, non- BRCA1/2 breast cancer families in order to identify additional high-risk breast cancer susceptibility genes. We applied GINI to a total of 24 LCLs, established from breast-cancer affected and unaffected women from three multiple-case non-BRCA1/2 breast cancer families. We then used Illumina gene expression microarrays to identify transcripts stabilised by the NMD inhibition. The expression profiling identified a total of eight candidate genes from these three families. One gene, PPARGC1A, was a candidate in two separate families. We performed semi-quantitative real-time reverse transcriptase PCR of all candidate genes but only PPARGC1A showed successful validation by being stabilised in individuals with breast cancer but not in many unaffected members of the same family. Sanger sequencing of all coding and splice site regions of PPARGC1A did not reveal any protein truncating mutations. Haplotype analysis using short

  8. Cancer Risks Associated with Inherited Mutations in Ovarian Cancer Susceptibility Genes Beyond BRCA1 and BRCA2

    Science.gov (United States)

    2016-05-01

    25 other candidate genes in the Fanconi anemia-BRCA pathway: ATR, BABAM1, BAP1, BLM, BRCC3, BRE, CHEK1, ERCC1, ERCC4 (FANCQ), FANCA , FANCB, FANCC...AWARD NUMBER: W81XWH-13-1-0484 TITLE: Cancer Risks Associated with Inherited Mutations in Ovarian Cancer Susceptibility Genes Beyond BRCA1 and...DNA repair genes on small core biopsy specimens iv) begun accessioning samples from the phase 2 rucaparib trial (Ariel 2, NCT01891344). 15

  9. Comprehensive analysis of three TYK2 gene variants in the susceptibility to Chagas disease infection and cardiomyopathy

    Science.gov (United States)

    Carmona, F. David; Dolade, Nuria; Vargas, Sofia; Echeverría, Luis Eduardo; González, Clara Isabel; Martin, Javier

    2018-01-01

    Tyrosine kinase 2 (TYK2) is a member of the Janus kinases family implicated in the signal transduction of type I interferons and several interleukins. It has been described that genetic mutations within TYK2 lead to multiple deleterious effects in the immune response. In this work, we have analyzed three functional independent variants from the frequency spectrum on the TYK2 gene (common and low-frequency variants) suggested to reduce the function of the gene in mediating cytokine signaling and the susceptibility to infections by Trypanosoma cruzi and/or the development of Chagas cardiomyopathy in the Colombian population. A total of 1,323 individuals from a Colombian endemic region for Chagas disease were enrolled in the study. They were classified as seronegative (n = 445), seropositive asymptomatic (n = 336), and chronic Chagas Cardiomyopathy subjects (n = 542). DNA samples were genotyped using TaqMan probes. Our results showed no statistically significant differences between the allelic frequencies of the three analyzed variants when seropositive and seronegative individuals were compared, therefore these variants were not associated with susceptibility to Chagas disease. Moreover, when Chagas cardiomyopathy patients were compared to asymptomatic patients, no significant associations were found. Previous reports highlighted the association of this gene in immune-related disorders under an autoimmunity context, but not predisposing patients to infectious diseases, which is consistent with our findings. Therefore, according to our results, TYK2 gene variants do not seem to play an important role in Chagas disease susceptibility and/or chronic Chagas cardiomyopathy. PMID:29304122

  10. Salvage/Adjuvant Brachytherapy After Ophthalmic Artery Chemosurgery for Intraocular Retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Francis, Jasmine H., E-mail: francij1@mskcc.org [Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Barker, Christopher A.; Wolden, Suzanne L.; McCormick, Beryl; Segal, Kira; Cohen, Gil [Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Gobin, Y. Pierre; Marr, Brian P. [Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Weill-Cornell Medical College, New York-Presbyterian Hospital, New York, New York (United States); Brodie, Scott E. [Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Mount Sinai School of Medicine, New York, New York (United States); Dunkel, Ira J.; Abramson, David H. [Memorial Sloan-Kettering Cancer Center, New York, New York (United States); Weill-Cornell Medical College, New York-Presbyterian Hospital, New York, New York (United States)

    2013-11-01

    Purpose: To evaluate the efficacy and toxicity of brachytherapy after ophthalmic artery chemosurgery (OAC) for retinoblastoma. Methods and Materials: This was a single-arm, retrospective study of 15 eyes in 15 patients treated with OAC followed by brachytherapy at (blinded institution) between May 1, 2006, and December 31, 2012, with a median 19 months' follow-up from plaque insertion. Outcome measurements included patient and ocular survival, visual function, and retinal toxicity measured by electroretinogram (ERG). Results: Brachytherapy was used as adjuvant treatment in 2 eyes and as salvage therapy in 13 eyes of which 12 had localized vitreous seeding. No patients developed metastasis or died of retinoblastoma. The Kaplan-Meier estimate of ocular survival was 79.4% (95% confidence interval 48.7%-92.8%) at 18 months. Three eyes were enucleated, and an additional 6 eyes developed out-of-target volume recurrences, which were controlled with additional treatments. Patients with an ocular complication had a mean interval between last OAC and plaque of 2.5 months (SD 2.3 months), which was statistically less (P=.045) than patients without ocular complication who had a mean interval between last OAC and plaque of 6.5 months (SD 4.4 months). ERG responses from pre- versus postplaque were unchanged or improved in more than half the eyes. Conclusions: Brachytherapy following OAC is effective, even in the presence of vitreous seeding; the majority of eyes maintained stable or improved retinal function following treatment, as assessed by ERG.

  11. Salvage/Adjuvant Brachytherapy After Ophthalmic Artery Chemosurgery for Intraocular Retinoblastoma

    International Nuclear Information System (INIS)

    Francis, Jasmine H.; Barker, Christopher A.; Wolden, Suzanne L.; McCormick, Beryl; Segal, Kira; Cohen, Gil; Gobin, Y. Pierre; Marr, Brian P.; Brodie, Scott E.; Dunkel, Ira J.; Abramson, David H.

    2013-01-01

    Purpose: To evaluate the efficacy and toxicity of brachytherapy after ophthalmic artery chemosurgery (OAC) for retinoblastoma. Methods and Materials: This was a single-arm, retrospective study of 15 eyes in 15 patients treated with OAC followed by brachytherapy at (blinded institution) between May 1, 2006, and December 31, 2012, with a median 19 months' follow-up from plaque insertion. Outcome measurements included patient and ocular survival, visual function, and retinal toxicity measured by electroretinogram (ERG). Results: Brachytherapy was used as adjuvant treatment in 2 eyes and as salvage therapy in 13 eyes of which 12 had localized vitreous seeding. No patients developed metastasis or died of retinoblastoma. The Kaplan-Meier estimate of ocular survival was 79.4% (95% confidence interval 48.7%-92.8%) at 18 months. Three eyes were enucleated, and an additional 6 eyes developed out-of-target volume recurrences, which were controlled with additional treatments. Patients with an ocular complication had a mean interval between last OAC and plaque of 2.5 months (SD 2.3 months), which was statistically less (P=.045) than patients without ocular complication who had a mean interval between last OAC and plaque of 6.5 months (SD 4.4 months). ERG responses from pre- versus postplaque were unchanged or improved in more than half the eyes. Conclusions: Brachytherapy following OAC is effective, even in the presence of vitreous seeding; the majority of eyes maintained stable or improved retinal function following treatment, as assessed by ERG

  12. Danish retinoblastoma patients 1943-2013 - genetic testing and clinical implications

    DEFF Research Database (Denmark)

    Gregersen, Pernille A; Urbak, Steen F; Funding, Mikkel

    2015-01-01

    , the rate has been stable around 1 per 14 000 live births with 95% of the patients surviving their retinoblastoma. Stratifying data on the time of diagnosis and status of genetic testing, the number of screened patients gradually increased from 5% in the beginning of the period to 96% in the last five...... to offspring and elevated risk of second primary cancers, we recommend information and access to genetic counseling and RB1 screening. This has ethical, psychological and possible economic consequences, and should be handled with caution...

  13. Overview of recurrent chromosomal losses in retinoblastoma detected by low coverage next generation sequencing

    Science.gov (United States)

    García-Chequer, A.J.; Méndez-Tenorio, A.; Olguín-Ruiz, G.; Sánchez-Vallejo, C.; Isa, P.; Arias, C.F.; Torres, J.; Hernández-Angeles, A.; Ramírez-Ortiz, M.A.; Lara, C.; Cabrera-Muñoz, M.L.; Sadowinski-Pine, S.; Bravo-Ortiz, J.C.; Ramón-García, G.; Diegopérez-Ramírez, J.; Ramírez-Reyes, G.; Casarrubias-Islas, R.; Ramírez, J.; Orjuela, M.A.; Ponce-Castañeda, M.V.

    2016-01-01

    Genes are frequently lost or gained in malignant tumors and the analysis of these changes can be informative about the underlying tumor biology. Retinoblastoma is a pediatric intraocular malignancy, and since deletions in chromosome 13 have been described in this tumor, we performed genome wide sequencing with the Illumina platform to test whether recurrent losses could be detected in low coverage data from DNA pools of Rb cases. An in silico reference profile for each pool was created from the human genome sequence GRCh37p5; a chromosome integrity score and a graphics 40 Kb window analysis approach, allowed us to identify with high resolution previously reported non random recurrent losses in all chromosomes of these tumors. We also found a pattern of gains and losses associated to clear and dark cytogenetic bands respectively. We further analyze a pool of medulloblastoma and found a more stable genomic profile and previously reported losses in this tumor. This approach facilitates identification of recurrent deletions from many patients that may be biological relevant for tumor development. PMID:26883451

  14. Cis-eQTL analysis and functional validation of candidate susceptibility genes for high-grade serous ovarian cancer.

    Science.gov (United States)

    Lawrenson, Kate; Li, Qiyuan; Kar, Siddhartha; Seo, Ji-Heui; Tyrer, Jonathan; Spindler, Tassja J; Lee, Janet; Chen, Yibu; Karst, Alison; Drapkin, Ronny; Aben, Katja K H; Anton-Culver, Hoda; Antonenkova, Natalia; Baker, Helen; Bandera, Elisa V; Bean, Yukie; Beckmann, Matthias W; Berchuck, Andrew; Bisogna, Maria; Bjorge, Line; Bogdanova, Natalia; Brinton, Louise A; Brooks-Wilson, Angela; Bruinsma, Fiona; Butzow, Ralf; Campbell, Ian G; Carty, Karen; Chang-Claude, Jenny; Chenevix-Trench, Georgia; Chen, Anne; Chen, Zhihua; Cook, Linda S; Cramer, Daniel W; Cunningham, Julie M; Cybulski, Cezary; Dansonka-Mieszkowska, Agnieszka; Dennis, Joe; Dicks, Ed; Doherty, Jennifer A; Dörk, Thilo; du Bois, Andreas; Dürst, Matthias; Eccles, Diana; Easton, Douglas T; Edwards, Robert P; Eilber, Ursula; Ekici, Arif B; Fasching, Peter A; Fridley, Brooke L; Gao, Yu-Tang; Gentry-Maharaj, Aleksandra; Giles, Graham G; Glasspool, Rosalind; Goode, Ellen L; Goodman, Marc T; Grownwald, Jacek; Harrington, Patricia; Harter, Philipp; Hasmad, Hanis Nazihah; Hein, Alexander; Heitz, Florian; Hildebrandt, Michelle A T; Hillemanns, Peter; Hogdall, Estrid; Hogdall, Claus; Hosono, Satoyo; Iversen, Edwin S; Jakubowska, Anna; James, Paul; Jensen, Allan; Ji, Bu-Tian; Karlan, Beth Y; Kruger Kjaer, Susanne; Kelemen, Linda E; Kellar, Melissa; Kelley, Joseph L; Kiemeney, Lambertus A; Krakstad, Camilla; Kupryjanczyk, Jolanta; Lambrechts, Diether; Lambrechts, Sandrina; Le, Nhu D; Lee, Alice W; Lele, Shashi; Leminen, Arto; Lester, Jenny; Levine, Douglas A; Liang, Dong; Lissowska, Jolanta; Lu, Karen; Lubinski, Jan; Lundvall, Lene; Massuger, Leon F A G; Matsuo, Keitaro; McGuire, Valerie; McLaughlin, John R; Nevanlinna, Heli; McNeish, Ian; Menon, Usha; Modugno, Francesmary; Moysich, Kirsten B; Narod, Steven A; Nedergaard, Lotte; Ness, Roberta B; Azmi, Mat Adenan Noor; Odunsi, Kunle; Olson, Sara H; Orlow, Irene; Orsulic, Sandra; Weber, Rachel Palmieri; Pearce, Celeste L; Pejovic, Tanja; Pelttari, Liisa M; Permuth-Wey, Jennifer; Phelan, Catherine M; Pike, Malcolm C; Poole, Elizabeth M; Ramus, Susan J; Risch, Harvey A; Rosen, Barry; Rossing, Mary Anne; Rothstein, Joseph H; Rudolph, Anja; Runnebaum, Ingo B; Rzepecka, Iwona K; Salvesen, Helga B; Schildkraut, Joellen M; Schwaab, Ira; Sellers, Thomas A; Shu, Xiao-Ou; Shvetsov, Yurii B; Siddiqui, Nadeem; Sieh, Weiva; Song, Honglin; Southey, Melissa C; Sucheston, Lara; Tangen, Ingvild L; Teo, Soo-Hwang; Terry, Kathryn L; Thompson, Pamela J; Timorek, Agnieszka; Tsai, Ya-Yu; Tworoger, Shelley S; van Altena, Anne M; Van Nieuwenhuysen, Els; Vergote, Ignace; Vierkant, Robert A; Wang-Gohrke, Shan; Walsh, Christine; Wentzensen, Nicolas; Whittemore, Alice S; Wicklund, Kristine G; Wilkens, Lynne R; Woo, Yin-Ling; Wu, Xifeng; Wu, Anna H; Yang, Hannah; Zheng, Wei; Ziogas, Argyrios; Monteiro, Alvaro; Pharoah, Paul D; Gayther, Simon A; Freedman, Matthew L

    2015-09-22

    Genome-wide association studies have reported 11 regions conferring risk of high-grade serous epithelial ovarian cancer (HGSOC). Expression quantitative trait locus (eQTL) analyses can identify candidate susceptibility genes at risk loci. Here we evaluate cis-eQTL associations at 47 regions associated with HGSOC risk (P≤10(-5)). For three cis-eQTL associations (P<1.4 × 10(-3), FDR<0.05) at 1p36 (CDC42), 1p34 (CDCA8) and 2q31 (HOXD9), we evaluate the functional role of each candidate by perturbing expression of each gene in HGSOC precursor cells. Overexpression of HOXD9 increases anchorage-independent growth, shortens population-doubling time and reduces contact inhibition. Chromosome conformation capture identifies an interaction between rs2857532 and the HOXD9 promoter, suggesting this SNP is a leading causal variant. Transcriptomic profiling after HOXD9 overexpression reveals enrichment of HGSOC risk variants within HOXD9 target genes (P=6 × 10(-10) for risk variants (P<10(-4)) within 10 kb of a HOXD9 target gene in ovarian cells), suggesting a broader role for this network in genetic susceptibility to HGSOC.

  15. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors

    DEFF Research Database (Denmark)

    Nickels, Stefan; Truong, Thérèse; Hein, Rebecca

    2013-01-01

    Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cance...

  16. Evidence of gene-environment interactions between common breast cancer susceptibility loci and established environmental risk factors

    NARCIS (Netherlands)

    Nickels, S.; Truong, T.; Hein, R.; Stevens, K.; Buck, K.; Behrens, S.; Eilber, U.; Schmidt, M.; Haberle, L.; Vrieling, A.; Gaudet, M.; Figueroa, J.; Schoof, N.; Spurdle, A.B.; Rudolph, A.; Fasching, P.A.; Hopper, J.L.; Makalic, E.; Schmidt, D.F.; Southey, M.C.; Beckmann, M.W.; Ekici, A.B.; Fletcher, O.; Gibson, L.; Idos, S. Silva; Peto, J.; Humphreys, M.K.; Wang, J; Cordina-Duverger, E.; Menegaux, F.; Nordestgaard, B.G.; Bojesen, S.E.; Lanng, C.; Anton-Culver, H.; Ziogas, A.; Bernstein, L.; Clarke, C.A.; Brenner, H.; Muller, H.; Arndt, V.; Stegmaier, C.; Brauch, H.; Bruning, T.; Harth, V.; Genica, N.; Mannermaa, A.; Kataja, V.; Kosma, V.M.; Hartikainen, J.M.; Lambrechts, D.; Smeets, D.; Neven, P.; Paridaens, R.; Flesch-Janys, D.; Obi, N.; Wang-Gohrke, S.; Couch, F.J.; Olson, J.E.; Vachon, C.M.; Giles, G.G.; Severi, G.; Baglietto, L.; Offit, K.; John, E.M.; Miron, A.; Andrulis, I.L.; Knight, J.A.; Glendon, G.; Mulligan, A.M.; Chanock, S.J.; Lissowska, J.; Liu, J.; Cox, A; Cramp, H.; Connley, D.; Balasubramanian, S.; Dunning, A.M.; Shah, M.; Trentham-Dietz, A.; Newcomb, P.; Titus, L.; Egan, K.; Cahoon, E.K.; Rajaraman, P.; Sigurdson, A.J.; Doody, M.M.; Guenel, P.; Pharoah, P.D.; Schmidt, M.K.; Hall, P.; Easton, D.F.; Garcia-Closas, M.; Milne, R.L.; Chang-Claude, J.; et al.,

    2013-01-01

    Various common genetic susceptibility loci have been identified for breast cancer; however, it is unclear how they combine with lifestyle/environmental risk factors to influence risk. We undertook an international collaborative study to assess gene-environment interaction for risk of breast cancer.

  17. External beam radiation for retinoblastoma: Results, patterns of failure, and a proposal for treatment guidelines

    International Nuclear Information System (INIS)

    Hernandez, J. Carlos; Brady, Luther W.; Shields, Jerry A.; Shields, Carol L.; Potter, Patrick de; Karlsson, Ulf L.; Markoe, Arnold M.; Amendola, Beatriz E.; Singh, Arun

    1996-01-01

    Purpose: To analyze treatment results and patterns of failure following external beam radiation for retinoblastoma and propose treatment guidelines according to specific clinical variables. Methods and Materials: We analyzed 27 patients (34 eyes) with retinoblastoma who received external beam radiation as initial treatment at Hahnemann University Hospital from October 1980 to December 1991 and have been followed for at least 1 year. Of the 34 eyes, 14 were Groups I-II (Reese-Ellsworth classification), 7 were Group III, and 13 were Groups IV-V. Doses ranged from 34.5-49.5 Gy (mean 44.3 Gy, median 45 Gy) in 1.5-2.0 Gy fractions generally delivered through anterior and lateral wedged pair fields. Results: At a mean follow up of 35.2 months (range 12-93 months), local tumor control was obtained in 44% (15 out of 34) of eyes with external beam radiation alone. Salvage therapy (plaque brachytherapy, cryotherapy, and/or photocoagulation) controlled an additional 10 eyes (29.5%), so that overall ocular survival has been 73.5%. Local tumor control with external beam radiotherapy alone was obtained in 78.5% (11 out of 14) of eyes in Groups I-II, but in only 20% (4 out of 20) of eyes in Groups III-V. A total of 67 existing tumors were identified prior to treatment in the 34 treated eyes and local control with external beam radiation alone was obtained in 87% (46 out of 53) of tumors measuring 15 mm or less and in 50% (7 out of 14) of tumors measuring more than 15 mm. When analyzing patterns of failure in the 19 eyes that relapsed, a total of 28 failure sites were identified and consisted of progression of vitreous seeds in seven instances (25% of failure sites) recurrences from previously existing tumors in 10 instances (36% of failure sites) and development of new tumors in previously uninvolved retina in 11 instances (39% of failure sites). Conclusions: 1) We find that external beam radiation to a dose of 45 Gy in fractions of 1.5 to 2.0 Gy provides adequate tumor control

  18. Optimized lens-sparing treatment of retinoblastoma with electron beams

    International Nuclear Information System (INIS)

    Steenbakkers, Roel J.H.M.; Altschuler, Martin D.; D'Angio, Giulio J.; Goldwein, Joel W.; Kassaee, Alireza

    1997-01-01

    Purpose: The ideal lens-sparing radiotherapy technique for retinoblastoma calls for 100% dose to the entire retina including the ora serrata and zero dose to the lens. Published techniques, most of which use photons, have not accomplished this ideal treatment. We describe here a technique that approaches this ideal configuration using electron beam therapy. Methods and Materials: Dose-modeling calculations were made using a computer program built around a proprietary algorithm. This program calculates 3D dose distribution for electrons and photons and uses the Cimmino feasibility method for the inverse problem of beam weighting to achieve the prescribed dose. The algorithm has been verified in the ocular region by measurements in a RANDO phantom. To search for an ideal lens-sparing beam setup, a stylized phantom of an 8-month-old infant was generated with built-in inhomogeneities, and a phantom of a 5-year-old child was generated from a patient CT series. Results: Of more than 100 different beam setups tested, two 9 MeV electron beams at gantry angles plus and minus 26 degrees from the optic nerve axis achieved the best distribution. Both fields have a lens block and an isocenter between the globe and origin of the optic nerve. When equal doses are given to both fields, the entire extent of the retina (including ora serrata) received 100%, while the lens received 10% or less. Conclusion: The two-oblique-electron-beam technique here described appears to meet most of the stringent dosimetry needed to treat retinoblastoma. It is suitable for a range of ages, from infancy to early childhood years

  19. Success of intra-arterial chemotherapy (chemosurgery) for retinoblastoma: effect of orbitovascular anatomy.

    Science.gov (United States)

    Marr, Brian P; Hung, Crystal; Gobin, Yves P; Dunkel, Ira J; Brodie, Scott E; Abramson, David H

    2012-02-01

    To review results of orbital angiography performed during intra-arterial chemotherapy (chemosurgery) for treatment of retinoblastoma to assess the association of angiographic variability in orbitovascular anatomy with tumor response and outcomes. Medical records and 64 orbital angiograms were reviewed for 56 pediatric patients with retinoblastoma undergoing chemosurgery using a combination of melphalan hydrochloride, topotecan hydrochloride, or carboplatin. The major orbital arteries and capillary blush patterns were graded, and tumor response and recurrence were compared using the log-rank and Fisher exact tests. Statistically significant variables for tumor response were lacrimal artery prominence (P = .001), previous treatment (P = .003), and lacrimal blush (P = .004). The only statistically significant variable for vitreous seed response was ciliary body blush (P = .03). Statistically significant variables influencing time to recurrence and time to enucleation were choroidal blush absence (P = .01) and lacrimal artery presence (P = .03), respectively. The success of intra-arterial chemotherapy is dependent on delivery of drug to the target tumor within the eye via the ophthalmic artery. Because of the small volume of drug used (0.50-1.25 mL per treatment) and the selectivity of catheterization, variables affecting orbital blood flow greatly influence drug delivery and the success of chemosurgery.

  20. Isolated lower extremity metastases, 9 years after initial diagnosis of retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Mulligan, M.E.; Smith, S.E. [University of Maryland, Department of Radiology, Medical School, Baltimore, MD (United States); McCarthy, E.F. [Johns Hopkins Hospital, Department of Pathology, Baltimore, MD (United States)

    2006-10-15

    We report the development of isolated lower extremity metastases, in a child, 9 years after her initial diagnosis and treatment of bilateral infantile retinoblastomas. The radiographic, scintigraphic, computed tomographic, and magnetic resonance imaging findings are discussed. The dominant metastatic focus was blastic, involving the medial cuneiform. Additional occult lesions were found in the base of the second metatarsal, middle cuneiform, navicular and tibial diaphysis. An open biopsy confirmed the diagnosis. The occurrence of late distant metastases is rare in the USA. (orig.)

  1. Assessment of relatedness between neurocan gene as bipolar disorder susceptibility locus and schizophrenia

    Directory of Open Access Journals (Sweden)

    Lilijana Oruč

    2012-11-01

    Full Text Available Large scale genetic association meta-analyses showed that neurocan (NCAN gene polymorphism rs1064395 is susceptibility locus for bipolar disorder. These studies also included patients with bipolar disorder originated from Bosnia and Herzegovina. Followed by theory of shared genetic elements between bipolar disorder and schizophrenia susceptibility, other studies explored several genetic factors with schizophrenia vulnerability as well. In this work, authors investigated the association between previously confirmed bipolar disorder genetic risk factor-neurocan with schizophrenia in a population sample of Bosnia and Herzegovina.Ethical aspects of this research were assessed by Ethics Committee of Clinical Center University of Sarajevo. Blood samples for DNA extraction were taken from the total of 86 patients and healthy individuals who previously signed informed consent. Genotyping for rs 1064395 was done using direct sequencing method. A case-control analysis of common genetic polymorphism within neurocan gene and schizophrenia status in a consecutively sampled patient cohort have been done using Fisher-exact test with odds-ratio calculation. No statistically significant allele and genotype association with disease status was found (p>0.05.Our finding supports the fact that large-scale genetic association studies approach need to be employed when detecting the variants with small additive effect in phenotypes with complex ethiology.

  2. Managing the consequences of aggressive conservative treatment for refractory retinoblastoma with vitreous seeding

    Directory of Open Access Journals (Sweden)

    Aubrey Brink

    2014-08-01

    Full Text Available A 4 year-old girl with bilateral, non-familial retinoblastoma (RB was referred to our care after primary enucleation OS and active tumor OD refractory to multiple therapies (intravenous chemotherapy, laser/cryotherapy, and I-125 plaque radiotherapy. Vitreous seeding OD, initially controlled by several sessions of Ophthalmic Artery Infusion Chemotherapy (OAIC and periocular chemotherapy, recurred shortly thereafter. The patient underwent intravitreal (IVit Melphalan injections achieving tumor control despite the concurrent development of keratopathy, pupillary synechiae, cataract, and necrosis of the inferior fornix and the adjacent orbital fat, all secondary to the treatments administered. Repeated amniotic membrane implants and tarsorrhaphy were performed to alleviate the symptoms. Despite being tumor free for 6 months, a poor fundus view and treatment-related complications prompted us to consider enucleation, but parents declined. Following recent negative magnetic resonance imaging (MRI, her cataract was removed. She was then found to have tumor recurrence. Her eye was enucleated 12 months ago and she recovered well from the surgery. As ocular oncology embarks in eye-preserving treatments for retinoblastoma, it is important to address the cumulative effects and associated impact of such treatments and the possibility of failure.

  3. Chemokine MCP1/CCL2 and RANTES/CCL5 gene polymorphisms influence Henoch–Schönlein purpura susceptibility and severity

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    Hsin-Hui Yu

    2015-04-01

    Conclusion: Our results support the fact that chemokines play important roles in the pathogenesis of HSP. MCP1/CCL2 gene polymorphisms were associated with susceptibility for HSP. RANTES/CCL5 gene polymorphisms may be related to disease severity and HSP nephritis.

  4. Antibiotic Susceptibility, Genetic Diversity, and the Presence of Toxin Producing Genes in Campylobacter Isolates from Poultry.

    Science.gov (United States)

    Lee, Jeeyeon; Jeong, Jiyeon; Lee, Heeyoung; Ha, Jimyeong; Kim, Sejeong; Choi, Yukyung; Oh, Hyemin; Seo, Kunho; Yoon, Yohan; Lee, Soomin

    2017-11-17

    This study examined antibiotic susceptibility, genetic diversity, and characteristics of virulence genes in Campylobacter isolates from poultry. Chicken ( n = 152) and duck ( n = 154) samples were collected from 18 wet markets in Korea. Campylobacter spp. isolated from the carcasses were identified by PCR. The isolated colonies were analyzed for antibiotic susceptibility to chloramphenicol, amikacin, erythromycin, tetracycline, ciprofloxacin, nalidixic acid, and enrofloxacin. The isolates were also used to analyze genetic diversity using the DiversiLab TM system and were tested for the presence of cytolethal distending toxin ( cdt ) genes. Campylobacter spp. were isolated from 45 poultry samples out of 306 poultry samples (14.7%) and the average levels of Campylobacter contamination were 22.0 CFU/g and 366.1 CFU/g in chicken and duck samples, respectively. Moreover, more than 90% of the isolates showed resistance to nalidixic acid and ciprofloxacin. Genetic correlation analysis showed greater than 95% similarity between 84.4% of the isolates, and three cdt genes ( cdtA , cdtB , and cdtC ) were present in 71.1% of Campylobacter isolates. These results indicate that Campylobacter contamination should be decreased to prevent and treat Campylobacter foodborne illness.

  5. Virulence Genes and Antibiotic Susceptibilities of Uropathogenic E. coli Strains.

    Science.gov (United States)

    Uzun, Cengiz; Oncül, Oral; Gümüş, Defne; Alan, Servet; Dayioğlu, Nurten; Küçüker, Mine Anğ

    2015-01-01

    The aim of this study is to detect the presence of and possible relation between virulence genes and antibiotic resistance in E. coli strains isolated from patients with acute, uncomplicated urinary tract infections (UTI). 62 E. coli strains isolated from patients with acute, uncomplicated urinary tract infections (50 strains isolated from acute uncomplicated cystitis cases (AUC); 12 strains from acute uncomplicated pyelonephritis cases (AUP)) were screened for virulence genes [pap (pyelonephritis-associated pili), sfa/foc (S and F1C fimbriae), afa (afimbrial adhesins), hly (hemolysin), cnf1 (cytotoxic necrotizing factor), aer (aerobactin), PAI (pathogenicity island marker), iroN (catecholate siderophore receptor), ompT (outer membrane protein T), usp (uropathogenic specific protein)] by PCR and for antimicrobial resistance by disk diffusion method according to CLSI criteria. It was found that 56 strains (90.3%) carried at least one virulence gene. The most common virulence genes were ompT (79%), aer (51.6%), PAI (51.6%) and usp (56.5%). 60% of the strains were resistant to at least one antibiotic. The highest resistance rates were against ampicillin (79%) and co-trimoxazole (41.9%). Fifty percent of the E. coli strains (31 strains) were found to be multiple resistant. Eight (12.9%) out of 62 strains were found to be ESBL positive. Statistically significant relationships were found between the absence of usp and AMP - SXT resistance, iroN and OFX - CIP resistance, PAI and SXT resistance, cnf1 and AMP resistance, and a significant relationship was also found between the presence of the afa and OFX resistance. No difference between E. coli strains isolated from two different clinical presentations was found in terms of virulence genes and antibiotic susceptibility.

  6. The gene expression profile of resistant and susceptible Bombyx mori strains reveals cypovirus-associated variations in host gene transcript levels.

    Science.gov (United States)

    Guo, Rui; Wang, Simei; Xue, Renyu; Cao, Guangli; Hu, Xiaolong; Huang, Moli; Zhang, Yangqi; Lu, Yahong; Zhu, Liyuan; Chen, Fei; Liang, Zi; Kuang, Sulan; Gong, Chengliang

    2015-06-01

    High-throughput paired-end RNA sequencing (RNA-Seq) was performed to investigate the gene expression profile of a susceptible Bombyx mori strain, Lan5, and a resistant B. mori strain, Ou17, which were both orally infected with B. mori cypovirus (BmCPV) in the midgut. There were 330 and 218 up-regulated genes, while there were 147 and 260 down-regulated genes in the Lan5 and Ou17 strains, respectively. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment for differentially expressed genes (DEGs) were carried out. Moreover, gene interaction network (STRING) analyses were performed to analyze the relationships among the shared DEGs. Some of these genes were related and formed a large network, in which the genes for B. mori cuticular protein RR-2 motif 123 (BmCPR123) and the gene for B. mori DNA replication licensing factor Mcm2-like (BmMCM2) were key genes among the common up-regulated DEGs, whereas the gene for B. mori heat shock protein 20.1 (Bmhsp20.1) was the central gene among the shared down-regulated DEGs between Lan5 vs Lan5-CPV and Ou17 vs Ou17-CPV. These findings established a comprehensive database of genes that are differentially expressed in response to BmCPV infection between silkworm strains that differed in resistance to BmCPV and implied that these DEGs might be involved in B. mori immune responses against BmCPV infection.

  7. Role of MHC-Linked Susceptibility Genes in the Pathogenesis of Human and Murine Lupus

    Directory of Open Access Journals (Sweden)

    Manfred Relle

    2012-01-01

    Full Text Available Systemic lupus erythematosus (SLE is a chronic autoimmune disease characterized by the production of autoantibodies against nuclear antigens and a systemic inflammation that can damage a broad spectrum of organs. SLE patients suffer from a wide variety of symptoms, which can affect virtually almost any tissue. As lupus is difficult to diagnose, the worldwide prevalence of SLE can only be roughly estimated to range from 10 and 200 cases per 100,000 individuals with dramatic differences depending on gender, ethnicity, and location. Although the treatment of this disease has been significantly ameliorated by new therapies, improved conventional drug therapy options, and a trained expert eye, the underlying pathogenesis of lupus still remain widely unknown. The complex etiology reflects the complex genetic background of the disease, which is also not well understood yet. However, in the past few years advances in lupus genetics have been made, notably with the publication of genome-wide association studies (GWAS in humans and the identification of susceptibility genes and loci in mice. This paper reviews the role of MHC-linked susceptibility genes in the pathogenesis of systemic lupus erythematosus.

  8. Knockout of a P-glycoprotein gene increases susceptibility to abamectin and emamectin benzoate in Spodoptera exigua.

    Science.gov (United States)

    Zuo, Y-Y; Huang, J-L; Wang, J; Feng, Y; Han, T-T; Wu, Y-D; Yang, Y-H

    2018-02-01

    P-glycoprotein [P-gp or the ATP-binding cassette transporter B1 (ABCB1)] is an important participant in multidrug resistance of cancer cells, yet the precise function of this arthropod transporter is unknown. The aim of this study was to determine the importance of P-gp for susceptibility to insecticides in the beet armyworm (Spodoptera exigua) using clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9) gene-editing technology. We cloned an open reading frame (ORF) encoding the S. exigua P-gp protein (SeP-gp) predicted to display structural characteristics common to P-gp and other insect ABCB1 transporters. A knockout line with a frame shift deletion of four nucleotides in the SeP-gp ORF was established using the CRISPR/Cas9 gene-editing system to test its potential role in determining susceptibility to chemical insecticides or insecticidal proteins from the bacterium Bacillus thuringiensis (Bt). Results from comparative bioassays demonstrate that knockout of SeP-gp significantly increases susceptibility of S. exigua by around threefold to abamectin and emamectin benzoate (EB), but not to spinosad, chlorfenapyr, beta-cypermethrin, carbosulfan indoxacarb, chlorpyrifos, phoxim, diafenthiuron, chlorfluazuron, chlorantraniliprole or two Bt toxins (Cry1Ca and Cry1Fa). Our data support an important role for SeP-gp in susceptibility of S. exigua to abamectin and EB and imply that overexpression of SeP-gp may contribute to abamectin and EB resistance in S. exigua. © 2017 The Royal Entomological Society.

  9. Association of the solute carrier family 11 member 1 gene polymorphisms with susceptibility to leprosy in a Brazilian sample

    Directory of Open Access Journals (Sweden)

    Maria José Franco Brochado

    2016-02-01

    Full Text Available Natural resistance-associated macrophage protein 1/solute carrier family 11 member 1 gene (Nramp1/Slc11a1 is a gene that controls the susceptibility of inbred mice to intracellular pathogens. Polymorphisms in the human Slc11a1/Nramp1 gene have been associated with host susceptibility to leprosy. This study has evaluated nine polymorphisms of the Slc11a1/Nramp1 gene [(GTn, 274C/T, 469+14G/C, 577-18G/A, 823C/T, 1029 C/T, 1465-85G/A, 1703G/A, and 1729+55del4] in 86 leprosy patients (67 and 19 patients had the multibacillary and the paucibacillary clinical forms of the disease, respectively, and 239 healthy controls matched by age, gender, and ethnicity. The frequency of allele 2 of the (GTn polymorphism was higher in leprosy patients [p = 0.04, odds ratio (OR = 1.49], whereas the frequency of allele 3 was higher in the control group (p = 0.03; OR = 0.66. Patients carrying the 274T allele (p = 0.04; OR = 1.49 and TT homozygosis (p = 0.02; OR = 2.46, such as the 469+14C allele (p = 0.03; OR = 1.53 of the 274C/T and 469+14G/C polymorphisms, respectively, were more frequent in the leprosy group. The leprosy and control groups had similar frequency of the 577-18G/A, 823C/T, 1029C/T, 1465-85G/A, 1703G/A, and 1729+55del4 polymorphisms. The 274C/T polymorphism in exon 3 and the 469+14G/C polymorphism in intron 4 were associated with susceptibility to leprosy, while the allele 2 and 3 of the (GTn polymorphism in the promoter region were associated with susceptibility and protection to leprosy, respectively.

  10. Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis.

    Directory of Open Access Journals (Sweden)

    Nigel P S Crawford

    2007-11-01

    Full Text Available A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b, was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis.

  11. Enrichment of putative PAX8 target genes at serous epithelial ovarian cancer susceptibility loci

    DEFF Research Database (Denmark)

    Kar, Siddhartha P; Adler, Emily; Tyrer, Jonathan

    2017-01-01

    BACKGROUND: Genome-wide association studies (GWAS) have identified 18 loci associated with serous ovarian cancer (SOC) susceptibility but the biological mechanisms driving these findings remain poorly characterised. Germline cancer risk loci may be enriched for target genes of transcription factors...... (TFs) critical to somatic tumorigenesis. METHODS: All 615 TF-target sets from the Molecular Signatures Database were evaluated using gene set enrichment analysis (GSEA) and three GWAS for SOC risk: discovery (2196 cases/4396 controls), replication (7035 cases/21 693 controls; independent from discovery...... to interact with PAX8 in the literature to the PAX8-target set and applying an alternative to GSEA, interval enrichment, further confirmed this association (P=0.006). Fifteen of the 157 genes from this expanded PAX8 pathway were near eight loci associated with SOC risk at P

  12. Ocular toxoplasmosis: susceptibility in respect to the genes encoding the KIR receptors and their HLA class I ligands

    Science.gov (United States)

    Ayo, Christiane Maria; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Brandão de Mattos, Cinara de Cássia; Previato, Mariana; Barbosa, Amanda Pires; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; de Mattos, Luiz Carlos

    2016-01-01

    The objective of this study was to investigate the influence of the genes encoding the KIR receptors and their HLA ligands in the susceptibility of ocular toxoplasmosis. A total of 297 patients serologically-diagnosed with toxoplasmosis were selected and stratified according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping was performed by PCR-SSOP. Statistical analyses were conducted using the Chi-square test, and odds ratio with a 95% confidence interval was also calculated to evaluate the risk association. The activating KIR3DS1 gene was associated with increased susceptibility for ocular toxoplasmosis. The activating KIR together with their HLA ligands (KIR3DS1-Bw4-80Ile and KIR2DS1+/C2++ KIR3DS1+/Bw4-80Ile+) were associated with increased susceptibility for ocular toxoplasmosis and its clinical manifestations. KIR-HLA inhibitory pairs -KIR2DL3/2DL3-C1/C1 and KIR2DL3/2DL3-C1- were associated with decreased susceptibility for ocular toxoplasmosis and its clinical forms, while the KIR3DS1−/KIR3DL1+/Bw4-80Ile+ combination was associated as a protective factor against the development of ocular toxoplasmosis and, in particular, against recurrent manifestations. Our data demonstrate that activating and inhibitory KIR genes may influence the development of ocular toxoplasmosis. PMID:27827450

  13. Age and prior blood feeding of Anopheles gambiae influences their susceptibility and gene expression patterns to ivermectin-containing blood meals.

    Science.gov (United States)

    Seaman, Jonathan A; Alout, Haoues; Meyers, Jacob I; Stenglein, Mark D; Dabiré, Roch K; Lozano-Fuentes, Saul; Burton, Timothy A; Kuklinski, Wojtek S; Black, William C; Foy, Brian D

    2015-10-15

    Ivermectin has been proposed as a novel malaria transmission control tool based on its insecticidal properties and unique route of acquisition through human blood. To maximize ivermectin's effect and identify potential resistance/tolerance mechanisms, it is important to understand its effect on mosquito physiology and potential to shift mosquito population age-structure. We therefore investigated ivermectin susceptibility and gene expression changes in several age groups of female Anopheles gambiae mosquitoes. The effect of aging on ivermectin susceptibility was analyzed in three age groups (2, 6, and 14-days) of colonized female Anopheles gambiaemosquitoes using standard survivorship assays. Gene expression patterns were then analyzed by transcriptome sequencing on an Illumina HiSeq 2500 platform. RT-qPCR was used to validate transcriptional changes and also to examine expression in a different, colonized strain and in wild mosquitoes, both of which blood fed naturally on an ivermectin-treated person. Mosquitoes of different ages and blood meal history died at different frequencies after ingesting ivermectin. Mortality was lowest in 2-day old mosquitoes exposed on their first blood meal and highest in 6-day old mosquitoes exposed on their second blood meal. Twenty-four hours following ivermectin ingestion, 101 and 187 genes were differentially-expressed relative to control blood-fed, in 2 and 6-day groups, respectively. Transcription patterns of select genes were similar in membrane-fed, colonized, and naturally-fed wild vectors. Transcripts from several unexpected functional classes were highly up-regulated, including Niemann-Pick Type C (NPC) genes, peritrophic matrix-associated genes, and immune-response genes, and these exhibited different transcription patterns between age groups, which may explain the observed susceptibility differences. Niemann-Pick Type 2 genes were the most highly up-regulated transcripts after ivermectin ingestion (up to 160 fold) and

  14. MicroRNA gene polymorphisms and environmental factors increase patient susceptibility to hepatocellular carcinoma.

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    Yin-Hung Chu

    Full Text Available BACKGROUND: Micro RNAs (miRNAs are small RNA fragments that naturally exist in the human body. Through various physiological mechanisms, miRNAs can generate different functions for regulating RNA protein levels and balancing abnormalities. Abnormal miRNA expression has been reported to be highly related to several diseases and cancers. Single-nucleotide polymorphisms (SNPs in miRNAs have been reported to increase patient susceptibility and affect patient prognosis and survival. We adopted a case-control research design to verify the relationship between miRNAs and hepatocellular carcinoma. METHODOLOGY/PRINCIPAL FINDINGS: A total of 525 subjects, including 377 controls and 188 hepatocellular carcinoma patients, were selected. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP and real-time PCR were used to analyze miRNA146a (rs2910164, miRNA149 (rs2292832, miRNA196 (rs11614913, and miRNA499 (rs3746444 genetic polymorphisms between the control group and the case group. The results indicate that people who carry the rs3746444 CT or CC genotypes may have a significantly increased susceptibility to hepatocellular carcinoma (adjusted odds ratio [AOR] = 2.84, 95% confidence interval [CI] = 1.88-4.30. In addition, when combined with environmental risk factors, such as smoking and alcohol consumption, interaction effects were observed between gene polymorphisms and environmental factors (odds ratio [OR] = 4.69, 95% CI = 2.52-8.70; AOR = 3.38, 95% CI = 1.68-6.80. CONCLUSIONS: These results suggest that a significant association exists between miRNA499 SNPs and hepatocellular carcinoma. Gene-environment interactions of miRNA499 polymorphisms, smoking, and alcohol consumption might alter hepatocellular carcinoma susceptibility.

  15. Autism genetic database (AGD: a comprehensive database including autism susceptibility gene-CNVs integrated with known noncoding RNAs and fragile sites

    Directory of Open Access Journals (Sweden)

    Talebizadeh Zohreh

    2009-09-01

    Full Text Available Abstract Background Autism is a highly heritable complex neurodevelopmental disorder, therefore identifying its genetic basis has been challenging. To date, numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism, but most discoveries either fail to be replicated or account for a small effect. Thus, in most cases the underlying causative genetic mechanisms are not fully understood. In the present work, the Autism Genetic Database (AGD was developed as a literature-driven, web-based, and easy to access database designed with the aim of creating a comprehensive repository for all the currently reported genes and genomic copy number variations (CNVs associated with autism in order to further facilitate the assessment of these autism susceptibility genetic factors. Description AGD is a relational database that organizes data resulting from exhaustive literature searches for reported susceptibility genes and CNVs associated with autism. Furthermore, genomic information about human fragile sites and noncoding RNAs was also downloaded and parsed from miRBase, snoRNA-LBME-db, piRNABank, and the MIT/ICBP siRNA database. A web client genome browser enables viewing of the features while a web client query tool provides access to more specific information for the features. When applicable, links to external databases including GenBank, PubMed, miRBase, snoRNA-LBME-db, piRNABank, and the MIT siRNA database are provided. Conclusion AGD comprises a comprehensive list of susceptibility genes and copy number variations reported to-date in association with autism, as well as all known human noncoding RNA genes and fragile sites. Such a unique and inclusive autism genetic database will facilitate the evaluation of autism susceptibility factors in relation to known human noncoding RNAs and fragile sites, impacting on human diseases. As a result, this new autism database offers a valuable tool for the research

  16. Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

    International Nuclear Information System (INIS)

    Conde, João; Silva, Susana N; Azevedo, Ana P; Teixeira, Valdemar; Pina, Julieta Esperança; Rueff, José; Gaspar, Jorge F

    2009-01-01

    MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls) to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH). Using unconditional logistic regression we found that MLH3 (L844P, G>A) polymorphism GA (Leu/Pro) and AA (Pro/Pro) genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95) (p = 0.03) and OR = 0.62 (0.41-0.94) (p = 0.03), respectively. Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83), p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49), p = 0.01], GG/AA [OR = 2.11 (1.12-3,98), p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15), p = 0.02] all associated with an increased risk for breast cancer. It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results

  17. Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study

    Directory of Open Access Journals (Sweden)

    Pina Julieta

    2009-09-01

    Full Text Available Abstract Background MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti-recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. Methods We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH. Results Using unconditional logistic regression we found that MLH3 (L844P, G>A polymorphism GA (Leu/Pro and AA (Pro/Pro genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95 (p = 0.03 and OR = 0.62 (0.41-0.94 (p = 0.03, respectively. Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83, p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49, p = 0.01], GG/AA [OR = 2.11 (1.12-3,98, p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15, p = 0.02] all associated with an increased risk for breast cancer. Conclusion It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results.

  18. Genes and pathways underlying susceptibility to impaired lung function in the context of environmental tobacco smoke exposure

    NARCIS (Netherlands)

    K. de Jong (Kim); J.M. Vonk (Judith); M. Imboden (Medea); L. Lahousse (Lies); A. Hofman (Albert); G.G. Brusselle (Guy); N.M. Probst-Hensch (Nicole M.); D.S. Postma (Dirkje); H.M. Boezen (Marike)

    2017-01-01

    textabstractBackground: Studies aiming to assess genetic susceptibility for impaired lung function levels upon exposure to environmental tobacco smoke (ETS) have thus far focused on candidate-genes selected based on a-priori knowledge of potentially relevant biological pathways, such as glutathione

  19. Diffuse chorioretinal atrophy after a single standard low- dose intravitreal melphalan injection in a child with retinoblastoma: a case report.

    Science.gov (United States)

    Chao, An- Ning; Kao, Ling-Yuh; Liu, Laura; Wang, Nan-Kai

    2016-03-15

    Controlling retinoblastoma with seeding is challenging despite advances in treatment modalities. Intravitreal melphalan is an alternative to external beam radiation or enucleation for recurrent or refractory vitreous seeds. Significant ocular side effects following intravitreal melphalan injections are uncommon. Complications have been reported in eyes receiving higher concentrations of melphalan and repetitive injections. We report a case in which diffuse chorioretinal atrophy was developed at the injection site after a single, standard low-dose intravitreal melphalan injection. A 12-month-old female child without a family history of retinoblastoma presented with unilateral group C retinoblastoma in her right eye. A solitary tumour with retinal breaks on the tumour surface, and vitreous seeds overlying the tumour were observed at the 8 o'clock position of the retina. After two cycles of intra-arterial chemotherapy with melphalan, the main tumour displayed significant regression, but the vitreous seeds overlying the main tumour were still active. Because of the persistence of vitreous seeds and the inadequate response to intra-arterial melphalan treatment, intravitreal melphalan (8 μg in 0.05 mL) was injected using a 32-gauge needle 2.5 mm from the 5 o'clock position of the limbus, the meridian opposite to the vitreous seeds. After 1 month, the retina around the injection site demonstrated diffuse retinal pigment epithelium alterations with dense hard exudates. Although the main retinal mass, and vitreous seeds resolved, the hard exudates persisted for more than 2 years after the single low-dose melphalan injection. Intravitreal melphalan injections should be cautiously used for eyes with refractory seeds, particularly when multiple injections are required to control retinoblastoma seeds. Dose- related retinal toxicity could occur in pre-treated eyes even when a relatively low standard dose is used. Such patients should be followed up closely to monitor the

  20. Polymorphisms in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in populations of European ancestry

    Directory of Open Access Journals (Sweden)

    Sousa Inês

    2010-03-01

    Full Text Available Abstract Background Autism spectrum disorders (ASDs are a group of highly heritable neurodevelopmental disorders which are characteristically comprised of impairments in social interaction, communication and restricted interests/behaviours. Several cell adhesion transmembrane leucine-rich repeat (LRR proteins are highly expressed in the nervous system and are thought to be key regulators of its development. Here we present an association study analysing the roles of four promising candidate genes - LRRTM1 (2p, LRRTM3 (10q, LRRN1 (3p and LRRN3 (7q - in order to identify common genetic risk factors underlying ASDs. Methods In order to gain a better understanding of how the genetic variation within these four gene regions may influence susceptibility to ASDs, a family-based association study was undertaken in 661 families of European ancestry selected from four different ASD cohorts. In addition, a case-control study was undertaken across the four LRR genes, using logistic regression in probands with ASD of each population against 295 ECACC controls. Results Significant results were found for LRRN3 and LRRTM3 (P LRRTM3. Conclusions Overall, our findings implicate the neuronal leucine-rich genes LRRN3 and LRRTM3 in ASD susceptibility.

  1. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa

    Science.gov (United States)

    Tosh, Kerrie; Campbell, Sarah J.; Fielding, Katherine; Sillah, Jackson; Bah, Boubacar; Gustafson, Per; Manneh, Kebba; Lisse, Ida; Sirugo, Giorgio; Bennett, Steve; Aaby, Peter; McAdam, Keith P. W. J.; Bah-Sow, Oumou; Lienhardt, Christian; Kramnik, Igor; Hill, Adrian V. S.

    2006-01-01

    The sst1 locus has been identified in a mouse model to control resistance and susceptibility of Mycobacterium tuberculosis infection. Subsequent studies have now identified Ipr1 (intracellular pathogen resistance 1) to be the gene responsible. Ipr1 is encoded within the sst1 locus and is expressed in the tuberculosis lung lesions and macrophages of sst1-resistant, but not sst1-susceptible mice. We have therefore examined the closest human homologue of Ipr1, SP110, for its ability to control susceptibility to M. tuberculosis infection in humans. In a study of families from The Gambia we have identified three polymorphisms that are associated with disease. On examination of additional families from Guinea-Bissau and the Republic of Guinea, two of these associations were independently replicated. These variants are in strong linkage disequilibrium with each other and lie within a 31-kb block of low haplotypic diversity, suggesting that a polymorphism within this region has a role in genetic susceptibility to tuberculosis in humans. PMID:16803959

  2. Testing differential susceptibility: Plasticity genes, the social environment, and their interplay in adolescent response inhibition.

    Science.gov (United States)

    Richards, Jennifer S; Arias Vásquez, Alejandro; van Rooij, Daan; van der Meer, Dennis; Franke, Barbara; Hoekstra, Pieter J; Heslenfeld, Dirk J; Oosterlaan, Jaap; Faraone, Stephen V; Hartman, Catharina A; Buitelaar, Jan K

    2017-06-01

    Impaired inhibitory control is a key feature of attention-deficit/hyperactivity disorder (ADHD). We investigated gene-environment interaction (GxE) as a possible contributing factor to response inhibition variation in context of the differential susceptibility theory. This states individuals carrying plasticity gene variants will be more disadvantaged in negative, but more advantaged in positive environments. Behavioural and neural measures of response inhibition were assessed during a Stop-signal task in participants with (N = 197) and without (N = 295) ADHD, from N = 278 families (age M = 17.18, SD =3.65). We examined GxE between candidate plasticity genes (DAT1, 5-HTT, DRD4) and social environments (maternal expressed emotion, peer affiliation). A DRD4 × Positive peer affiliation interaction was found on the right fusiform gyrus (rFG) activation during successful inhibition. Further, 5-HTT short allele carriers showed increased rFG activation during failed inhibitions. Maternal warmth and positive peer affiliation were positively associated with right inferior frontal cortex activation during successful inhibition. Deviant peer affiliation was positively related to the error rate. While a pattern of differential genetic susceptibility was found, more clarity on the role of the FG during response inhibition is warranted before firm conclusions can be made. Positive and negative social environments were related to inhibitory control. This extends previous research emphasizing adverse environments.

  3. The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.

    Directory of Open Access Journals (Sweden)

    Iñigo Landa

    2009-09-01

    Full Text Available In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9. Functional assays of rs1867277 (NM_004473.3:c.-283G>A within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

  4. The Variant rs1867277 in FOXE1 Gene Confers Thyroid Cancer Susceptibility through the Recruitment of USF1/USF2 Transcription Factors

    Science.gov (United States)

    Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; del Peso, Cristina; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio, Didac; Opocher, Giuseppe; Rodríguez-Antona, Cristina; González-Neira, Anna; Matías-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes

    2009-01-01

    In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30–1.70; P = 5.9×10−9). Functional assays of rs1867277 (NM_004473.3:c.−283G>A) within the FOXE1 5′ UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/αCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era. PMID:19730683

  5. A transposable element insertion in the susceptibility gene CsaMLO8 results in hypocotyl resistance to powdery mildew in cucumber

    NARCIS (Netherlands)

    Berg, J.A.; Appiano, M.; Santillán Martínez, M.I.; Hemans, F.W.K.; Vriezen, W.H.; Visser, R.G.F.; Bai, Y.; Schouten, H.J.

    2015-01-01

    Background - Powdery mildew (PM) is an important disease of cucumber (Cucumis sativus L.). CsaMLO8 was previously identified as a candidate susceptibility gene for PM in cucumber, for two reasons: 1) This gene clusters phylogenetically in clade V, which has previously been shown to harbour all known

  6. Control of cell proliferation, endoreduplication, cell size, and cell death by the retinoblastoma-related pathway in maize endosperm

    KAUST Repository

    Sabelli, Paolo A.; Liu, Yan; Dante, Ricardo Augusto; Lizarraga, Lucina E.; Nguyen, Hong N.; Brown, Sara W.; Klingler, John; Yu, Jingjuan; LaBrant, Evan; Layton, Tracy M.; Feldman, Max; Larkins, Brian A.

    2013-01-01

    , and programmed cell death. Although manipulation of these processes could maximize grain yield, how they are regulated and integrated is poorly understood. We show that the Retinoblastoma-related (RBR) pathway controls key aspects of endosperm development

  7. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis

    DEFF Research Database (Denmark)

    Müller, H; Bracken, A P; Vernell, R

    2001-01-01

    The retinoblastoma protein (pRB) and its two relatives, p107 and p130, regulate development and cell proliferation in part by inhibiting the activity of E2F-regulated promoters. We have used high-density oligonucleotide arrays to identify genes in which expression changed in response to activation...

  8. [The efficacy of large spot indirect ophthalmoscopy laser alone or combined with systemic chemotherapy in retinoblastoma therapy].

    Science.gov (United States)

    Liang, J H; Cheng, Y; Deng, X; Yu, Y Y; Li, X X

    2016-10-11

    Objective: To evaluate the efficacy of large spot indirect ophthalmoscopy laser alone or combined with systemic chemotherapy in the treatment of early and middle stage retinoblastoma. Methods: Retrospective series case study. Clinical data of 21 patients (22 eyes) who were diagnosed as retinoblastoma (RB) in Peking University People's Hospital from March 2009 to August 2014 were collected. Medical and family history, ocular ultrasound, orbital and cranial MRI or CT examination of RB Children were detailed recorded. Ocular examination and laser treatment were performed under general anesthesia, once every 3-4 weeks until the tumor was under control. The observation period was at least 3 months after the last treatment. The ocular examination included intraocular pressure measurement, anterior segment and fundus examination and the fundus photography with Retcam. Laser therapeutic instrument was large spot indirect ophthalmoscopy laser of 810nm wavelength. Results: Of the 21 children, 16 were male and 5 were female. The range of age was 3 to 82 months averaged 17.3 months. Among 22 eyes, four with small tumor, eight with medium tumor, and ten with large tumor. Two eyes underwent laser treatment only and 20 eyes underwent laser treatment combined with systemic chemotherapy. During the average observation period of 33.9 months, 15 tumors were treated successfully, but 7 failed. The total success rate was 68.2%. The number and success rate of small, medium and large tumor eyes were 4 (100%), 5 (62.5%) and 5 (50%), respectively. There was one case of tumor brain metastases, and the classification of contralateral eye of the child was E phase. Iris burns happened in one eye, obvious vitreous proliferation in one eye and mild vitreous hemorrhage occurred in two eyes, which did not affect the treatment of laser. However, obvious tumor hemorrhage happened in two eyes and affected laser therapy. There was no complicated cataract, iatrogenic retinal hole and tumor intravitreal

  9. Long-term visual results in eyes cured for retinoblastoma by radiation

    International Nuclear Information System (INIS)

    Holbek, S.; Ehlers, N.

    1989-01-01

    Twenty-four eyes from 18 patients cured for retinoblastoma by radiation on an average 12 years previously, were re-examined with respect to visual performance. The macular functions, i.e. visual acuity, colour vision and contrast sensitivity demonstrated performances predictable from tumour localization and radiation dose to the macula. The rod functions, i.e. visual field and dark adaptation were found to be relatively resistant to the radiation treatment. A special problem encountered in two-eyed patients was the unavoidable amblyopia dut to unequal handicaps in the two eyes at the vulnerable age. (author)

  10. Long-term visual results in eyes cured for retinoblastoma by radiation

    Energy Technology Data Exchange (ETDEWEB)

    Holbek, S.; Ehlers, N. (Department of Ophthalmology, Aarhus University Hospital, Aarhus (Denmark))

    1989-01-01

    Twenty-four eyes from 18 patients cured for retinoblastoma by radiation on an average 12 years previously, were re-examined with respect to visual performance. The macular functions, i.e. visual acuity, colour vision and contrast sensitivity demonstrated performances predictable from tumour localization and radiation dose to the macula. The rod functions, i.e. visual field and dark adaptation were found to be relatively resistant to the radiation treatment. A special problem encountered in two-eyed patients was the unavoidable amblyopia dut to unequal handicaps in the two eyes at the vulnerable age. (author).

  11. Activation of peroxisome proliferator-activated receptor gamma bypasses the function of the retinoblastoma protein in adipocyte differentiation

    DEFF Research Database (Denmark)

    Hansen, Jacob B.; Petersen, R K; Larsen, B M

    1999-01-01

    The retinoblastoma protein (pRB) is an important regulator of development, proliferation, and cellular differentiation. pRB was recently shown to play a pivotal role in adipocyte differentiation, to interact physically with adipogenic CCAAT/enhancer-binding proteins (C/EBPs), and to positively...

  12. Genetic susceptibility to Grave's disease.

    Science.gov (United States)

    Li, Hong; Chen, Qiuying

    2013-06-01

    The variety of clinical presentations of eye changes in patients with Graves' disease (GD) suggests that complex interactions between genetic, environmental, endogenous and local factors influence the severity of Graves' ophthalmopathy (GO). It is thought that the development of GO might be influenced by genetic factors and environmental factors, such as cigarette smoking. At present, however, the role of genetic factors in the development of GO is not known. On the basis of studies with candidate genes and other genetic approaches, several susceptibility loci in GO have been proposed, including immunological genes, human leukocyte antigen (HLA), cytotoxic T-lymphocyte antigen-4 (CTLA-4), regulatory T-cell genes and thyroid-specific genes. This review gives a brief overview of the current range of major susceptibility genes found for GD.

  13. Data on the recurrence of breast tumors fit a model in which dormant cells are subject to slow attrition but can randomly awaken to become malignant

    DEFF Research Database (Denmark)

    Stein, Wilfred D; Litman, Thomas

    2006-01-01

    appears to be a random event. Inasmuch as the kinetics of cancer recurrence in published data sets closely follows the model found for the appearance of sporadic retinoblastoma, tumor recurrence could be triggered by mutations in awakening- suppressor mechanisms. The retinoblastoma tumor suppressor gene...... was identified by tracing its occurrence in familial retinoblastoma pedigrees. Will it be possible to track the postulated cancer recurrence, awakening suppressor gene(s) in early recurrence breast cancer patients?...

  14. Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity

    International Nuclear Information System (INIS)

    Azmy, Iman AF; Balasubramanian, Saba P; Wilson, Anthony G; Stephenson, Timothy J; Cox, Angela; Brown, Nicola J; Reed, Malcolm WR

    2004-01-01

    Genetic polymorphisms in the promoter region of the tumour necrosis factor (TNF) gene can regulate gene expression and have been associated with inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter of the TNF gene (-308 G>A and -238 G>A) for their role in breast cancer susceptibility and severity by means of an allelic association study. Using a case–control study design, breast cancer patients (n = 709) and appropriate age-matched and sex-matched controls obtained from the Breast Screening Unit (n = 498) were genotyped for these TNF polymorphisms, using a high-throughput allelic discrimination method. Allele frequencies for both polymorphisms were similar in both breast cancer cases and controls. However, the -308 polymorphism was found to be associated with vascular invasion in breast tumours (P = 0.024). Comparison with other standard prognostic indices did not show any association for either genotype. We demonstrated no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF and susceptibility to breast cancer, in a large North European population. However, the -308 G>A polymorphism was found to be associated with the presence of vascular invasion in breast tumours

  15. Exome sequencing reveals frequent deleterious germline variants in cancer susceptibility genes in women with invasive breast cancer undergoing neoadjuvant chemotherapy.

    Science.gov (United States)

    Ellingson, Marissa S; Hart, Steven N; Kalari, Krishna R; Suman, Vera; Schahl, Kimberly A; Dockter, Travis J; Felten, Sara J; Sinnwell, Jason P; Thompson, Kevin J; Tang, Xiaojia; Vedell, Peter T; Barman, Poulami; Sicotte, Hugues; Eckel-Passow, Jeanette E; Northfelt, Donald W; Gray, Richard J; McLaughlin, Sarah A; Moreno-Aspitia, Alvaro; Ingle, James N; Moyer, Ann M; Visscher, Daniel W; Jones, Katie; Conners, Amy; McDonough, Michelle; Wieben, Eric D; Wang, Liewei; Weinshilboum, Richard; Boughey, Judy C; Goetz, Matthew P

    2015-09-01

    When sequencing blood and tumor samples to identify targetable somatic variants for cancer therapy, clinically relevant germline variants may be uncovered. We evaluated the prevalence of deleterious germline variants in cancer susceptibility genes in women with breast cancer referred for neoadjuvant chemotherapy and returned clinically actionable results to patients. Exome sequencing was performed on blood samples from women with invasive breast cancer referred for neoadjuvant chemotherapy. Germline variants within 142 hereditary cancer susceptibility genes were filtered and reviewed for pathogenicity. Return of results was offered to patients with deleterious variants in actionable genes if they were not aware of their result through clinical testing. 124 patients were enrolled (median age 51) with the following subtypes: triple negative (n = 43, 34.7%), HER2+ (n = 37, 29.8%), luminal B (n = 31, 25%), and luminal A (n = 13, 10.5%). Twenty-eight deleterious variants were identified in 26/124 (21.0%) patients in the following genes: ATM (n = 3), BLM (n = 1), BRCA1 (n = 4), BRCA2 (n = 8), CHEK2 (n = 2), FANCA (n = 1), FANCI (n = 1), FANCL (n = 1), FANCM (n = 1), FH (n = 1), MLH3 (n = 1), MUTYH (n = 2), PALB2 (n = 1), and WRN (n = 1). 121/124 (97.6%) patients consented to return of research results. Thirteen (10.5%) had actionable variants, including four that were returned to patients and led to changes in medical management. Deleterious variants in cancer susceptibility genes are highly prevalent in patients with invasive breast cancer referred for neoadjuvant chemotherapy undergoing exome sequencing. Detection of these variants impacts medical management.

  16. The Fanconi anemia family of genes and its correlation with breast cancer susceptibility and breast cancer features.

    Science.gov (United States)

    Barroso, E; Pita, G; Arias, J I; Menendez, P; Zamora, P; Blanco, M; Benitez, J; Ribas, G

    2009-12-01

    Fanconi anemia (FA) family of proteins participates in the DNA repair pathway by homologous recombination, and it is currently formed by 13 genes. Some of these proteins also confer susceptibility to hereditary breast and ovarian cancer (HBOC), since FANCD1 is the BRCA2 breast cancer susceptibility gene, and FANCN/PALB2 and FANCJ/BRIP1 explain 2% of non-BRCA1/2 HBOC families. Thus, there is an important connection between FA and BRCA pathways. In a previous case-control association study analysing FANCA, FANCD2 and FANCL, we reported an association between FANCD2 and sporadic breast cancer (BC) risk (OR = 1.35). In order to know whether variants in other FA genes could also be involved in this association, we have extended our study with the rest of FA genes and some others implicated in the BRCA pathway. We have also analyzed the correlation with survival, nodal metastasis and hormonal receptors (ER- and PR-). A total of 61 SNPs in ten FA genes (FANC-B, -C, -D1, -E, -F, -G, -I, -J, -M, -N) and five FA related genes (ATM, ATR, BRCA1, H2AX and USP1) were studied in a total of 547 consecutive and nonrelated sporadic BC cases and 552 unaffected controls from the Spanish population. Association analyses reported marginal statistically significant results with the minor allele of intronic SNPs in three genes: BRCA1, BRCA2/FANCD1, and ATM. Survival association with SNPs on FANCC and BRCA2/FANCD1 genes were also reported. Sub-group analyses revealed associations between SNPs on FANCI and ATM and nodal metastasis status and between FANCJ/BRIP1 and FANCN/PALB2 and PR- status.

  17. High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma. Part 1: MRI vs. histopathology

    Energy Technology Data Exchange (ETDEWEB)

    Sirin, Selma; Schlamann, Marc; Schweiger, Bernd; Goericke, Sophia L. [University Hospital Essen, Department of Diagnostic and Interventional Radiology and Neuroradiology, Essen (Germany); Metz, Klaus A. [University Hospital Essen, Department of Pathology and Neuropathology, Essen (Germany); Bornfeld, Norbert; Holdt, Markus [University Hospital Essen, Department of Ophthalmology, Essen (Germany); Temming, Petra; Schuendeln, Michael M. [University Hospital Essen, Department of Pediatric Hematology and Oncology, Essen (Germany)

    2015-08-15

    A reliable detection of metastatic risk factors is important for children with retinoblastoma to choose the right therapeutic regimen. First studies using high-resolution magnetic resonance imaging (MRI) with orbit surface coils were promising. The aim of this study was therefore to evaluate the ability of high-resolution MRI to detect metastatic and especially advanced metastatic risk factors in a large group of children with retinoblastoma. One hundred forty-three consecutive children with retinoblastoma (148 enucleated eyes, 64 girls, 79 boys, mean age 19.7 ± 15.3) who received pretherapeutical high-resolution MRI with orbit surface coils on 1.5 T MR scanner systems between 2007 and 2012 and subsequent primary enucleation within 14 days were included in this retrospective study. Image analysis was performed by two neuroradiologists experienced in ocular imaging in consensus. Histopathology served as gold standard. Sensitivity/specificity for the detection of metastatic risk factors using high-resolution MRI with orbit surface coils were 60 %/88.7 % for postlaminar optic nerve infiltration, 65.5 %/95.6 % for choroidal invasion, 100 %/99.3 % for scleral invasion, and 100 %/100 % for peribulbar fat invasion, respectively. The results increased for the detection of advanced metastatic risk factors, 81.8 %/89.1 % for deep postlaminar optic nerve infiltration, 70.6 %/97.6 % for massive choroidal invasion. High-resolution MRI is clinically valuable for the detection of metastatic, especially of advanced metastatic risk factors in children with retinoblastoma. (orig.)

  18. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes

    Science.gov (United States)

    McKay, James D.; Hung, Rayjean J.; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C.; Caporaso, Neil E.; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A.; Qian, David C.; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N.; Bojesen, Stig E.; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C.; Bush, William S.; Tardon, Adonina; Rennert, Gad; Teare, M. Dawn; Field, John K.; Kiemeney, Lambertus A.; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B.; Andrew, Angeline S.; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C.; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S.; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A.; Wilkens, Lynne R.; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F.M.; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael PA; Marcus, Michael W.; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C.; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A.; Barnett, Matt P.; Chen, Chu; Goodman, Gary E.; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H.-Erich; Manz, Judith; Muley, Thomas R.; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A.; Tsao, Ming-Sound; Arnold, Susanne M.; Haura, Eric B.; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M.; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J.; Butler, Lesley M.; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S.; McLaughlin, John; Stevens, Victoria L.; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C.; Obeidat, Ma’en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D.; Wain, Louise V.; Rafnar, Thorunn; Thorgeirsson, Thorgeir E.; Reginsson, Gunnar W.; Stefansson, Kari; Hancock, Dana B.; Bierut, Laura J.; Spitz, Margaret R.; Gaddis, Nathan C.; Lutz, Sharon M.; Gu, Fangyi; Johnson, Eric O.; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F.; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I.

    2017-01-01

    Summary While several lung cancer susceptibility loci have been identified, much of lung cancer heritability remains unexplained. Here, 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated GWAS analysis of lung cancer on 29,266 patients and 56,450 controls. We identified 18 susceptibility loci achieving genome wide significance, including 10 novel loci. The novel loci highlighted the striking heterogeneity in genetic susceptibility across lung cancer histological subtypes, with four loci associated with lung cancer overall and six with lung adenocarcinoma. Gene expression quantitative trait analysis (eQTL) in 1,425 normal lung tissues highlighted RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes, OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer. PMID:28604730

  19. Differences in the gene expression profiles of haemocytes from schistosome-susceptible and -resistant biomphalaria glabrata exposed to Schistosoma mansoni excretory-secretory products.

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    Zahida Zahoor

    Full Text Available During its life cycle, the helminth parasite Schistosoma mansoni uses the freshwater snail Biomphalaria glabrata as an intermediate host to reproduce asexually generating cercariae for infection of the human definitive host. Following invasion of the snail, the parasite develops from a miracidium to a mother sporocyst and releases excretory-secretory products (ESPs that likely influence the outcome of host infection. To better understand molecular interactions between these ESPs and the host snail defence system, we determined gene expression profiles of haemocytes from S. mansoni-resistant or -susceptible strains of B. glabrata exposed in vitro to S. mansoni ESPs (20 μg/ml for 1 h, using a 5K B. glabrata cDNA microarray. Ninety-eight genes were found differentially expressed between haemocytes from the two snail strains, 57 resistant specific and 41 susceptible specific, 60 of which had no known homologue in GenBank. Known differentially expressed resistant-snail genes included the nuclear factor kappa B subunit Relish, elongation factor 1α, 40S ribosomal protein S9, and matrilin; known susceptible-snail specific genes included cathepsins D and L, and theromacin. Comparative analysis with other gene expression studies revealed 38 of the 98 identified genes to be uniquely differentially expressed in haemocytes in the presence of ESPs, thus identifying for the first time schistosome ESPs as important molecules that influence global snail host-defence cell gene expression profiles. Such immunomodulation may benefit the schistosome, enabling its survival and successful development in the snail host.

  20. Two variants on T2DM susceptible gene HHEX are associated with CRC risk in a Chinese population.

    Science.gov (United States)

    Sun, Rui; Liu, Jian-Ping; Gao, Chang; Xiong, Ying-Ying; Li, Min; Wang, Ya-Ping; Su, Yan-Wei; Lin, Mei; Jiang, An-Li; Xiong, Ling-Fan; Xie, Yan; Feng, Jue-Ping

    2016-05-17

    Increasing amounts of evidence has demonstrated that T2DM (Type 2 Diabetes Mellitus) patients have increased susceptibility to CRC (colorectal cancer). As HHEX is a recognized susceptibility gene in T2DM, this work was focused on two SNPs in HHEX, rs1111875 and rs7923837, to study their association with CRC. T2DM patients without CRC (T2DM-only, n=300), T2DM with CRC (T2DM/CRC, n=135), cancer-free controls (Control, n=570), and CRC without T2DM (CRC-only, n=642) cases were enrolled. DNA samples were extracted from the peripheral blood leukocytes of the patients and sequenced by direct sequencing. The χ2 test was used to compare categorical data. We found that in T2DM patients, rs1111875 but not the rs7923837 in HHEX gene was associated with the occurrence of CRC (p= 0.006). for rs1111875, TC/CC patients had an increased risk of CRC (p=0.019, OR=1.592, 95%CI=1.046-2.423). Moreover, our results also indicated that the two variants of HEEX gene could be risk factors for CRC in general population, independent on T2DM (pCRC was observed in TC or TC/CC than CC individuals (pCRC risk was observed in AG, GG, and AG/GG than AA individuals (pCRC susceptibility. Risk effects and the functional impact of these polymorphisms need further validation.

  1. Methodological issues in detecting gene-gene interactions in breast cancer susceptibility: a population-based study in Ontario

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    Onay Venus

    2007-08-01

    Full Text Available Abstract Background There is growing evidence that gene-gene interactions are ubiquitous in determining the susceptibility to common human diseases. The investigation of such gene-gene interactions presents new statistical challenges for studies with relatively small sample sizes as the number of potential interactions in the genome can be large. Breast cancer provides a useful paradigm to study genetically complex diseases because commonly occurring single nucleotide polymorphisms (SNPs may additively or synergistically disturb the system-wide communication of the cellular processes leading to cancer development. Methods In this study, we systematically studied SNP-SNP interactions among 19 SNPs from 18 key genes involved in major cancer pathways in a sample of 398 breast cancer cases and 372 controls from Ontario. We discuss the methodological issues associated with the detection of SNP-SNP interactions in this dataset by applying and comparing three commonly used methods: the logistic regression model, classification and regression trees (CART, and the multifactor dimensionality reduction (MDR method. Results Our analyses show evidence for several simple (two-way and complex (multi-way SNP-SNP interactions associated with breast cancer. For example, all three methods identified XPD-[Lys751Gln]*IL10-[G(-1082A] as the most significant two-way interaction. CART and MDR identified the same critical SNPs participating in complex interactions. Our results suggest that the use of multiple statistical approaches (or an integrated approach rather than a single methodology could be the best strategy to elucidate complex gene interactions that have generally very different patterns. Conclusion The strategy used here has the potential to identify complex biological relationships among breast cancer genes and processes. This will lead to the discovery of novel biological information, which will improve breast cancer risk management.

  2. Differential mRNA expression of seven genes involved in cholesterol metabolism and transport in the liver of atherosclerosis-susceptible and -resistant Japanese quail strains

    Directory of Open Access Journals (Sweden)

    Li Xinrui

    2012-06-01

    Full Text Available Abstract Background Two atherosclerosis-susceptible and -resistant Japanese quail (Coturnix japonica strains obtained by divergent selection are commonly used as models to study atherosclerosis, but no genetic characterization of their phenotypic differences has been reported so far. Our objective was to examine possible differences in the expression of genes involved in cholesterol metabolism and transport in the liver between these two strains and to evaluate the value of this model to analyze the gene system affecting cholesterol metabolism and transport. Methods A factorial study with both strains (atherosclerosis-susceptible versus atherosclerosis-resistant and two diets (control versus cholesterol was carried out. The mRNA concentrations of four genes involved in cholesterol biosynthesis (HMGCR, FDFT1, SQLE and DHCR7 and three genes in cholesterol transport (ABCG5, ABCG8 and APOA1 were assayed using real-time quantitative PCR. Plasma lipids were also assayed. Results Expression of ABCG5 (control diet and ABCG8 (regardless of dietary treatment and expression of HMGCR, FDFT1 and SQLE (regardless of dietary treatment were significantly higher in the atherosclerosis-resistant than in the atherosclerosis-susceptible strain. Plasma triglyceride and LDL levels, and LDL/HDL ratio were significantly higher in the atherosclerosis-susceptible than in the atherosclerosis-resistant strain fed the cholesterol diet. In the atherosclerosis-susceptible strain, ABCG5 expression regressed significantly and positively on plasma LDL level, whereas DHCR7 and SQLE expression regressed significantly and negatively on plasma triglyceride level. Conclusions Our results provide support for the hypothesis that the atherosclerosis-resistant strain metabolizes and excretes cholesterol faster than the atherosclerosis-susceptible strain. We have also demonstrated that these quail strains are a useful model to study cholesterol metabolism and transport in relation with

  3. Stage of presentation and visual outcome of patients screened for familial retinoblastoma: nationwide registration in the Netherlands

    NARCIS (Netherlands)

    Imhof, S. M.; Moll, A. C.; Schouten-van Meeteren, A. Y. N.

    2006-01-01

    In the Netherlands a comprehensive programme for screening just after birth for familial retinoblastoma is taking place. In this report the stage of the disease at the time of detection, by way of screening, and the long term visual outcome in these patients was evaluated. A nationwide,

  4. Association study of candidate genes for susceptibility to schizophrenia and bipolar disorder on chromosome 22Q13

    DEFF Research Database (Denmark)

    Severinsen, Jacob; Binderup, Helle; Mors, Ole

    Chromosome 22q is suspected to harbor risk genes for schizophrenia as well as bipolar affective disorder. This is evidenced through genetic mapping studies, investigations of cytogenetic abnormalities, and direct examination of candidate genes. In a recent study of distantly related patients from...... the Faroe Islands we have obtained evidence suggesting two regions on chromosome 22q13 to potentially harbor susceptibility genes for both schizophrenia and bipolar affective disorder. We have selected a number of candidate genes from these two regions for further analysis, including the neuro-gene WKL1...... and unrelated controls, and in a Scottish case-control sample comprising 200 schizophrenics, 200 bipolar patients and 200 controls. None of the investigated SNPs have so far showed strong evidence of association to either bipolar disorder or schizophrenia....

  5. Homologues of CsLOB1 in citrus function as disease susceptibility genes in citrus canker.

    Science.gov (United States)

    Zhang, Junli; Huguet-Tapia, Jose Carlos; Hu, Yang; Jones, Jeffrey; Wang, Nian; Liu, Sanzhen; White, Frank F

    2017-08-01

    The lateral organ boundary domain (LBD) genes encode a group of plant-specific proteins that function as transcription factors in the regulation of plant growth and development. Citrus sinensis lateral organ boundary 1 (CsLOB1) is a member of the LBD family and functions as a disease susceptibility gene in citrus bacterial canker (CBC). Thirty-four LBD members have been identified from the Citrus sinensis genome. We assessed the potential for additional members of LBD genes in citrus to function as surrogates for CsLOB1 in CBC, and compared host gene expression on induction of different LBD genes. Using custom-designed transcription activator-like (TAL) effectors, two members of the same clade as CsLOB1, named CsLOB2 and CsLOB3, were found to be capable of functioning similarly to CsLOB1 in CBC. RNA sequencing and quantitative reverse transcription-polymerase chain reaction analyses revealed a set of cell wall metabolic genes that are associated with CsLOB1, CsLOB2 and CsLOB3 expression and may represent downstream genes involved in CBC. © 2016 BSPP AND JOHN WILEY & SONS LTD.

  6. Medroxyprogesterone acetate-treated human, primary endometrial epithelial cells reveal unique gene expression signature linked to innate immunity and HIV-1 susceptibility.

    Science.gov (United States)

    Woods, Matthew W; Zahoor, Muhammad Atif; Dizzell, Sara; Verschoor, Chris P; Kaushic, Charu

    2018-01-01

    Medroxyprogesterone acetate (MPA), a progestin-based hormonal contraceptive designed to mimic progesterone, has been linked to increased human immunodeficiency virus (HIV-1) susceptibility. Genital epithelial cells (GECs) form the mucosal lining of the female genital tract (FGT) and provide the first line of protection against HIV-1. The impact of endogenous sex hormones or MPA on the gene expression profile of GECs has not been comprehensively documented. Using microarray analysis, we characterized the transcriptional profile of primary endometrial epithelial cells grown in physiological levels of E2, P4, and MPA. Each hormone treatment altered the gene expression profile of GECs in a unique manner. Interestingly, although MPA is a progestogen, the gene expression profile induced by it was distinct from P4. MPA increased gene expression of genes related to inflammation and cholesterol synthesis linked to innate immunity and HIV-1 susceptibility. The analysis of gene expression profiles provides insights into the effects of sex hormones and MPA on GECs and allows us to posit possible mechanisms of the MPA-mediated increase in HIV-1 acquisition. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Prevalence, Virulence Genes, Antimicrobial Susceptibility, and Genetic Diversity of Bacillus cereus Isolated From Pasteurized Milk in China

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    Tiantian Gao

    2018-03-01

    Full Text Available Bacillus cereus is a common and important food-borne pathogen that can be found in various food products. Due to low-temperature sterilization for a short period of time, pasteurization is not sufficient for complete elimination of B. cereus in milk, thereby cause severe economic loss and food safety problems. It is therefore of paramount importance to perform risk assessment of B. cereus in pasteurized milk. In this study, we isolated B. cereus from pasteurized milk samples in different regions of China, and evaluated the contamination situation, existence of virulence genes, antibiotic resistance profile and genetic polymorphism of B. cereus isolates. Intriguingly, 70 samples (27% were found to be contaminated by B. cereus and the average contamination level was 111 MPN/g. The distribution of virulence genes was assessed toward 10 enterotoxigenic genes (hblA, hblC, hblD, nheA, nheB, nheC, cytK, entFM, bceT, and hlyII and one emetic gene (cesB. Forty five percent strains harbored enterotoxigenic genes hblACD and 93% isolates contained nheABC gene cluster. The positive rate of cytK, entFM, bceT, hlyII, and cesB genes were 73, 96, 75, 54, and 5%, respectively. Antibiotic susceptibility assessment showed that most of the isolates were resistant to β-lactam antibiotics and rifampicin, but susceptible to other antibiotics such as ciprofloxacin, gentamicin and chloramphenicol. Total multidrug-resistant population was about 34%. In addition, B. cereus isolates in pasteurized milk showed a high genetic diversity. In conclusion, our findings provide the first reference on the prevalence, contamination level and characteristics of B. cereus isolated from pasteurized milk in China, suggesting a potential high risk of B. cereus to public health and dairy industry.

  8. Retracted: Association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in a Caucasian population.

    Science.gov (United States)

    Liu, Guohui; Zhou, Tian-Biao; Jiang, Zongpei; Zheng, Dongwen

    2015-03-01

    The association of the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism with type-2 diabetic nephropathy (T2DN) susceptibility and the risk of type-2 diabetes mellitus (T2DM) developing into T2DN in Caucasian populations is still controversial. A meta-analysis was performed to evaluate the association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in Caucasian populations. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases. Sixteen articles were identified for the analysis of the association of ACE I/D gene polymorphism with T2DN susceptibility and the risk of T2DM developing into T2DN in Caucasian populations. ACE I/D gene polymorphism was not associated with T2DN susceptibility and the risk of patients with T2DM developing T2DN in Caucasian populations. Sensitivity analysis according to sample size of case (ACE I/D gene polymorphism was not associated with T2DN susceptibility and the risk of patients with T2DM developing T2DN in Caucasian populations. However, more studies should be performed in the future. © The Author(s) 2014.

  9. Prevalence of variations in melanoma susceptibility genes among Slovenian melanoma families

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    Besic Nikola

    2008-09-01

    Full Text Available Abstract Background Two high-risk genes have been implicated in the development of CM (cutaneous melanoma. Germline mutations of the CDKN2A gene are found in CDK4 gene reported to date. Beside those high penetrance genes, certain allelic variants of the MC1R gene modify the risk of developing the disease. The aims of our study were: to determine the prevalence of germline CDKN2A mutations and variants in members of families with familial CM and in patients with multiple primary CM; to search for possible CDK4 mutations, and to determine the frequency of variations in the MC1R gene. Methods From January 2001 until January 2007, 64 individuals were included in the study. The group included 28 patients and 7 healthy relatives belonging to 25 families, 26 patients with multiple primary tumors and 3 children with CM. Additionally 54 healthy individuals were included as a control group. Mutations and variants of the melanoma susceptibility genes were identified by direct sequencing. Results Seven families with CDKN2A mutations were discovered (7/25 or 28.0%. The L94Q mutation found in one family had not been previously reported in other populations. The D84N variant, with possible biological impact, was discovered in the case of patient without family history but with multiple primary CM. Only one mutation carrier was found in the control group. Further analysis revealed that c.540C>T heterozygous carriers were more common in the group of CM patients and their healthy relatives (11/64 vs. 2/54. One p14ARF variant was discovered in the control group and no mutations of the CDK4 gene were found. Most frequently found variants of the MC1R gene were T314T, V60L, V92M, R151C, R160W and R163Q with frequencies slightly higher in the group of patients and their relatives than in the group of controls, but the difference was statistically insignificant. Conclusion The present study has shown high prevalence of p16INK4A mutations in Slovenian population of

  10. Meta-analysis and genome-wide interpretation of genetic susceptibility to drug addiction

    Science.gov (United States)

    2011-01-01

    Background Classical genetic studies provide strong evidence for heritable contributions to susceptibility to developing dependence on addictive substances. Candidate gene and genome-wide association studies (GWAS) have sought genes, chromosomal regions and allelic variants likely to contribute to susceptibility to drug addiction. Results Here, we performed a meta-analysis of addiction candidate gene association studies and GWAS to investigate possible functional mechanisms associated with addiction susceptibility. From meta-data retrieved from 212 publications on candidate gene association studies and 5 GWAS reports, we linked a total of 843 haplotypes to addiction susceptibility. We mapped the SNPs in these haplotypes to functional and regulatory elements in the genome and estimated the magnitude of the contributions of different molecular mechanisms to their effects on addiction susceptibility. In addition to SNPs in coding regions, these data suggest that haplotypes in gene regulatory regions may also contribute to addiction susceptibility. When we compared the lists of genes identified by association studies and those identified by molecular biological studies of drug-regulated genes, we observed significantly higher participation in the same gene interaction networks than expected by chance, despite little overlap between the two gene lists. Conclusions These results appear to offer new insights into the genetic factors underlying drug addiction. PMID:21999673

  11. Deletion of the Candida glabrata ERG3 and ERG11 genes: effect on cell viability, cell growth, sterol composition, and antifungal susceptibility.

    Science.gov (United States)

    Geber, A; Hitchcock, C A; Swartz, J E; Pullen, F S; Marsden, K E; Kwon-Chung, K J; Bennett, J E

    1995-01-01

    We have cloned and sequenced the structural genes encoding the delta 5,6 sterol desaturase (ERG3 gene) and the 14 alpha-methyl sterol demethylase (ERG11 gene) from Candida glabrata L5 (leu2). Single and double mutants of these genes were created by gene deletion. The phenotypes of these mutants, including sterol profiles, aerobic viabilities, antifungal susceptibilities, and generation times, were studied. Strain L5D (erg3 delta::LEU2) accumulated mainly ergosta-7,22-dien-3 beta-ol, was aerobically viable, and remained susceptible to antifungal agents but had a slower generation time than its parent strain. L5LUD (LEU2 erg11 delta::URA3) strains required medium supplemented with ergosterol and an anaerobic environment for growth. A spontaneous aerobically viable mutant, L5LUD40R (LEU erg11 delta::URA3), obtained from L5LUD (LEU2 erg11 delta::URA3), was found to accumulate lanosterol and obtusifoliol, was resistant to azole antifungal agents, demonstrated some increase in resistance to amphotericin B, and exhibited a 1.86-fold increase in generation time in comparison with L5 (leu2). The double-deletion mutant L5DUD61 (erg3 delta::LEU2 erg11 delta::URA3) was aerobically viable, produced mainly 14 alpha-methyl fecosterol, and had the same antifungal susceptibility pattern as L5LUD40R (LEU2 erg11 delta::URA3), and its generation time was threefold greater than that of L5 (leu2). Northern (RNA) analysis revealed that the single-deletion mutants had a marked increase in message for the undeleted ERG3 and ERG11 genes. These results indicate that differences in antifungal susceptibilities and the restoration of aerobic viability exist between the C. glabrata ergosterol mutants created in this study and those sterol mutants with similar genetic lesions previously reported for Saccharomyces cerevisiae. PMID:8593007

  12. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

    Science.gov (United States)

    McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

    2017-07-01

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  13. Nutlin-3 down-regulates retinoblastoma protein expression and inhibits muscle cell differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Walsh, Erica M. [Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118 (United States); Niu, MengMeng; Bergholz, Johann [Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China (China); Jim Xiao, Zhi-Xiong, E-mail: jxiao@bu.edu [Department of Biochemistry, Boston University School of Medicine, Boston, MA 02118 (United States); Center of Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, 610014 China (China)

    2015-05-29

    The p53 tumor suppressor gene plays a critical role in regulation of proliferation, cell death and differentiation. The MDM2 oncoprotein is a major negative regulator for p53 by binding to and targeting p53 for proteasome-mediated degradation. The small molecule inhibitor, nutlin-3, disrupts MDM2-p53 interaction resulting in stabilization and activation of p53 protein. We have previously shown that nutlin-3 activates p53, leading to MDM2 accumulation as concomitant of reduced retinoblastoma (Rb) protein stability. It is well known that Rb is important in muscle development and myoblast differentiation and that rhabdomyosarcoma (RMS), or cancer of the skeletal muscle, typically harbors MDM2 amplification. In this study, we show that nutlin-3 inhibited myoblast proliferation and effectively prevented myoblast differentiation, as evidenced by lack of expression of muscle differentiation markers including myogenin and myosin heavy chain (MyHC), as well as a failure to form multinucleated myotubes, which were associated with dramatic increases in MDM2 expression and decrease in Rb protein levels. These results indicate that nutlin-3 can effectively inhibit muscle cell differentiation. - Highlights: • Nutlin-3 inhibits myoblast proliferation and prevents differentiation into myotubes. • Nutlin-3 increases MDM2 expression and down-regulates Rb protein levels. • This study has implication in nutlin-3 treatment of rhabdomyosarcomas.

  14. Endostatin gene variation and protein levels in breast cancer susceptibility and severity

    International Nuclear Information System (INIS)

    Balasubramanian, Sabapathy P; Cross, Simon S; Globe, Jenny; Cox, Angela; Brown, Nicola J; Reed, Malcolm W

    2007-01-01

    Endostatin is a potent endogenous anti-angiogenic agent which inhibits tumour growth. A non-synonymous coding polymorphism in the Endostatin gene is thought to affect Endostatin activity. We aimed to determine the role of this Endostatin polymorphism in breast cancer pathogenesis and any influence on serum Endostatin levels in healthy volunteers. Endostatin protein expression on a breast cancer micro array was also studied to determine any relationship to genotype and to breast cancer prognosis. The 4349G > A (coding non-synonymous) polymorphism in exon 42 of the Endostatin gene was genotyped in approximately 846 breast cancer cases and 707 appropriate controls. In a separate healthy cohort of 57 individuals, in addition to genotyping, serum Endostatin levels were measured using enzyme linked immunosorbant assay (ELISA). A semi-quantitative assessment of Endostatin protein expression on immunostained tissue micro arrays (TMA) constructed from breast cancer samples of patients with genotype data was performed. The rare allele (A) was significantly associated with invasive breast cancers compared to non-invasive tumours (p = 0.03), but there was no association with tumour grade, nodal status, vascular invasion or overall survival. There was no association with breast cancer susceptibility. Serum Endostatin levels and Endostatin protein expression on the tissue micro array were not associated with genotype. The Endostatin 4349A allele is associated with invasive breast cancer. The Endostatin 4349G > A polymorphism however does not appear to be associated with breast cancer susceptibility or severity in invasive disease. By studying circulating levels and tumour Endostatin protein expression, we have shown that any influence of this polymorphism is unlikely to be through an effect on the levels of protein produced

  15. Retinoblastoma protein expression is an independent predictor of both radiation response and survival in muscle invasive bladder cancer

    DEFF Research Database (Denmark)

    Agerbæk, Mads; Alsner, Jan; Marcussen, Niels

    2003-01-01

    The objective of the study was to investigate the predictive value of various clinical, biochemical, and histopathological parameters, with special emphasis on the expression of the retinoblastoma protein (pRB), on the radiation response in bladder cancer. In order to obtain a truly objective...

  16. Presence of the KPC carbapenemase gene in Enterobacteriaceae causing bacteremia, and the correlation with in vitro carbapenem susceptibility

    Science.gov (United States)

    During six months, we obtained Enterobacteriaceae isolates from patients with Gram-negative bacteremia at a 1250-bed teaching hospital in St. Louis, Missouri, and compared carbapenem susceptibility with the presence of blaKPC, a transferable carbapenemase gene. Three (1.2%) out of 243 isolates were ...

  17. The gene-immune-behavioral pathway: Gamma-interferon (IFN-γ) simultaneously coordinates susceptibility to infectious disease and harm avoidance behaviors.

    Science.gov (United States)

    MacMurray, James; Comings, David E; Napolioni, Valerio

    2014-01-01

    Cytokine gene variants are known to influence both infectious disease susceptibility and harm-avoidant behaviors, suggesting that these risk variants may be pleiotropically linked to instinctual disease-avoidant traits. The gamma-interferon (IFNG) +874 T>A polymorphism (rs2430561) is an ideal candidate gene variant for immune-behavioral studies. It is a functional SNP, regulating IFNG mRNA expression; it is known to modulate serotonergic activity and is therefore capable of modifying behavior; and it has previously been associated with increased susceptibility to malaria, tuberculosis, leprosy and Chagas disease. We hypothesized that the infectious disease-high-risk IFNG +874 A-allele would be associated with four personality traits previously reported as behavioral defenses against infection: Harm Avoidance (HA), Extraversion (E), Exploratory Excitability (Exp E), and Openness to Experience (O). We tested this hypothesis in a sample of 168 healthy university students from Southern California genotyped for IFNG +874 T>A and evaluated by the Temperament and Character Inventory-Revised (TCI-R) and the NEO Five-Factor Inventory (NEO-FFI). We found that the infectious disease-high-risk IFNG +874 A-allele was associated with increased HA (P=0.001) and decreased E (P=0.030) and Exp E (P=0.030). These findings suggest that the IFNG +874 A gene variant is linked both to infectious disease susceptibility and to proactive behavioral defenses that reduce infection risk in healthy subjects. Copyright © 2013 Elsevier Inc. All rights reserved.

  18. X-ray sensitivity of fibroblasts from patients with hereditary retinoblastoma and their families.

    OpenAIRE

    Pledger, J. V.; Craft, A. W.; Bartlett, K.; Long, D. R.

    1987-01-01

    The in vitro response to X-irradiation of cultured human fibroblasts was studied using a colony forming assay. A comprehensive reference range was established, giving a median D0 value of 98.5 cGy with an interquartile range of 86.5-110.5 cGy. Cells from 3 retinoblastoma family pedigrees were studied and the cell survival after exposure to X-rays was compared between affected (11 samples) and unaffected (26 samples) family members. No significant differences in response to ionising radiation ...

  19. The Circadian Rhythm Gene Arntl2 Is a Metastasis Susceptibility Gene for Estrogen Receptor-Negative Breast Cancer.

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    Ngoc-Han Ha

    2016-09-01

    Full Text Available Breast cancer mortality is primarily due to metastasis rather than primary tumors, yet relatively little is understood regarding the etiology of metastatic breast cancer. Previously, using a mouse genetics approach, we demonstrated that inherited germline polymorphisms contribute to metastatic disease, and that these single nucleotide polymorphisms (SNPs could be used to predict outcome in breast cancer patients. In this study, a backcross between a highly metastatic (FVB/NJ and low metastatic (MOLF/EiJ mouse strain identified Arntl2, a gene encoding a circadian rhythm transcription factor, as a metastasis susceptibility gene associated with progression, specifically in estrogen receptor-negative breast cancer patients. Integrated whole genome sequence analysis with DNase hypersensitivity sites reveals SNPs in the predicted promoter of Arntl2. Using CRISPR/Cas9-mediated substitution of the MOLF promoter, we demonstrate that the SNPs regulate Arntl2 transcription and affect metastatic burden. Finally, analysis of SNPs associated with ARNTL2 expression in human breast cancer patients revealed reproducible associations of ARNTL2 expression quantitative trait loci (eQTL SNPs with disease-free survival, consistent with the mouse studies.

  20. Postenucleation orbits in retinoblastoma: treatment with 125I brachytherapy

    International Nuclear Information System (INIS)

    Stannard, Clare; Sealy, Ross; Hering, Egbert; Hough, Jan; Knowles, Ruth; Lecuona, Karin; Reddi, V. Bala

    2002-01-01

    Purpose: Children with retinoblastoma that extends into or through the choroid, sclera, or optic nerve are at risk of developing orbital disease, as well as metastases. Previously, these enucleated orbits were treated with external beam radiotherapy in addition to chemotherapy. 125 I brachytherapy for tumors in and around the eye was pioneered by Sealy in Cape Town, South Africa, in 1974. In 1983, he developed a technique to irradiate the contents of the orbit while limiting the dose to the bony orbit and eyelids. Methods and Materials: Six nylon tubes containing 125 I seeds were implanted through the eyelids around the periphery of the orbit. Each contained a metal gutter that screens the outer part of the seeds from the bony orbit. A seventh unscreened tube was placed in the center, and a metal disc with 125 I seeds on its posterior surface was secured beneath the eyelids. Between 1983 and 2000, 57 orbits were treated in 56 children with retinoblastoma. Thirty-six were treated prophylactically and 21, with tumor at the resection line of the nerve, extrascleral tumor, or metastases, were treated therapeutically. They received a median dose of 34 Gy in 70 h; 30 also received chemotherapy. Children with tumor at the resection line of the nerve also received treatment to the craniospinal axis. Results: The median follow-up of the 35 patients treated prophylactically was 35 months (range 0-187). Seven patients died, 6 of metastases, at a median of 10 months (range 4-29) after the implant. Eight of the 13 patients with microscopic extraocular tumor survived a median of 29 months (range 5-156). None of the 8 patients presenting with orbital tumor or metastases survived. No orbital recurrences developed in any of the patients. Cosmesis was considerably improved compared with previous forms of irradiation. Conclusion: Orbital brachytherapy is an effective method of irradiating the orbit to prevent recurrent tumor, the treatment time is short, and the cosmesis is much more

  1. Variations in testosterone pathway genes and susceptibility to testicular cancer in Norwegian men.

    Science.gov (United States)

    Kristiansen, W; Aschim, E L; Andersen, J M; Witczak, O; Fosså, S D; Haugen, T B

    2012-12-01

    Imbalance between the oestrogen and androgen levels in utero is hypothesized to influence testicular cancer (TC) risk. Thus, variation in genes involved in the action of sex hormones may contribute to variability of an individual's susceptibility to TC. Mutations in testosterone pathway genes may alter the level of testosterone in vivo and hypothetically the risk of developing TC. Luteinizing hormone receptor (LHR), 5α-reductase II (SRD5A2) and androgen receptor (AR) are key elements in androgen action. A case-control study comprising 651 TC cases and 313 controls in a Norwegian population was conducted for investigation of polymorphisms in the LHR, SRD5A and AR genes and their possible association with TC. A statistical significant difference was observed in patients being heterozygous for the LHR Asn312Ser polymorphism when comparing genotypes between all TC cases and controls (OR = 0.66, 95% CI = 0.48-0.89, p(adj) = 0.049). No statistically significant difference between the histological subtypes seminoma and non-seminoma was observed. Our results may suggest a possible association between genetic variation in the LHR gene and the risk of developing TC. © 2012 The Authors. International Journal of Andrology © 2012 European Academy of Andrology.

  2. Discovering susceptibility genes for allergic rhinitis and allergy using a genome-wide association study strategy.

    Science.gov (United States)

    Li, Jingyun; Zhang, Yuan; Zhang, Luo

    2015-02-01

    Allergic rhinitis and allergy are complex conditions, in which both genetic and environmental factors contribute to the pathogenesis. Genome-wide association studies (GWASs) employing common single-nucleotide polymorphisms have accelerated the search for novel and interesting genes, and also confirmed the role of some previously described genes which may be involved in the cause of allergic rhinitis and allergy. The aim of this review is to provide an overview of the genetic basis of allergic rhinitis and the associated allergic phenotypes, with particular focus on GWASs. The last decade has been marked by the publication of more than 20 GWASs of allergic rhinitis and the associated allergic phenotypes. Allergic diseases and traits have been shown to share a large number of genetic susceptibility loci, of which IL33/IL1RL1, IL-13-RAD50 and C11orf30/LRRC32 appear to be important for more than two allergic phenotypes. GWASs have further reflected the genetic heterogeneity underlying allergic phenotypes. Large-scale genome-wide association strategies are underway to discover new susceptibility variants for allergic rhinitis and allergic phenotypes. Characterization of the underlying genetics provides us with an insight into the potential targets for future studies and the corresponding interventions.

  3. Association between SLC2A9 (GLUT9) gene polymorphisms and gout susceptibility: an updated meta-analysis.

    Science.gov (United States)

    Zhang, Xu; Yang, Xiao; Wang, Mengmeng; Li, Xiaona; Xia, Qing; Xu, Shengqian; Xu, Jianhua; Cai, Guoqi; Wang, Li; Xin, Lihong; Zou, Yanfeng; Pan, Faming

    2016-08-01

    The relationship between the SLC2A9 (solute carrier family 2, member 9) gene polymorphisms and gout was still inconsistent among the individual genetic association studies. Therefore, this present research was aimed to systematically evaluate the association between SLC2A9 gene polymorphisms and gout susceptibility. Relevant studies were enrolled by searching databases systematically. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the associations. The heterogeneity between each of the studies was calculated by using the Q statistic methods, and Begg's funnel plot and Egger's tests were performed to evaluate publication bias. A total of 13 studies investigated four single nucleotide polymorphisms (SNPs) in SLC2A9 were included. In this study, we found that the allele C of rs3733591 was higher in patients than in controls in both all-pooled population [C vs. T: OR (95 % CI) = 1.432 (1.213-1.691)] and Asians-pooled population [C vs. T: OR (95 % CI) = 1.583 (1.365-1.835)]. The allele frequency C of s6449213 was lower in the gout patients than in controls in both all-pooled population and Caucasians-pooled population. Additionally, the allele frequency T of rs16890979 and the allele frequency C of rs1014290 were lower in gout patients than in controls. This study demonstrated that the genetic susceptibility for gout is associated with the SLC2A9 gene polymorphisms. Four of them except for the rs3733591 are protective SNPs in Caucasians, and rs16890979 and rs1014290 are protective SNPs in both Caucasians and Asians, while rs3733591 may be susceptibility SNP in Asians.

  4. Association between single-nucleotide polymorphism in CISH gene and susceptibility to tuberculosis in Chinese Han population.

    Science.gov (United States)

    Zhao, Lan; Chu, Haiqing; Xu, Xiaogang; Yue, Jun; Li, Huiping; Wang, Minggui

    2014-04-01

    The cytokine-inducible SRC homology 2 domain (CISH) gene is up-regulated by IL-2 in response to infection, and inhibits microbial infection. The objective of the present study was to examine whether genetic variants of CISH (SNPs) are associated with increased susceptibility to tuberculosis (TB) in individuals of Chinese Han ethnicity. We sequenced five previously identified SNPs of CISH in patients with TB or healthy controls. Three of the SNPs, rs148685070 [position -639; C/C], rs414171 [position -292; A/T], and rs6768300 [position -163; C/G]) are located in the promoter region, while the fourth (rs2239751 [position +1320; A/C]) near the translation start site, and the fifth (rs622502 [position +3415; C/G]) in the third intron. The AA genotypes of the SNPs rs2239751 and rs414171 were significantly associated with TB. Multivariate logistic regression analysis demonstrated that subjects with the rs414171 AA genotype were more likely to have TB than those with the AT genotype. By contrast, we did not observe genetic variants of the rs148685070 SNP. In conclusion, two genetic variants in CISH gene appear to increase susceptibility to TB in Chinese Han population.

  5. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot"

    DEFF Research Database (Denmark)

    Johnatty, Sharon E; Beesley, Jonathan; Chen, Xiaoqing

    2010-01-01

    We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes...

  6. Identification of IGF1, SLC4A4, WWOX, and SFMBT1 as hypertension susceptibility genes in Han Chinese with a genome-wide gene-based association study.

    Directory of Open Access Journals (Sweden)

    Hsin-Chou Yang

    Full Text Available Hypertension is a complex disorder with high prevalence rates all over the world. We conducted the first genome-wide gene-based association scan for hypertension in a Han Chinese population. By analyzing genome-wide single-nucleotide-polymorphism data of 400 matched pairs of young-onset hypertensive patients and normotensive controls genotyped with the Illumina HumanHap550-Duo BeadChip, 100 susceptibility genes for hypertension were identified and also validated with permutation tests. Seventeen of the 100 genes exhibited differential allelic and expression distributions between patient and control groups. These genes provided a good molecular signature for classifying hypertensive patients and normotensive controls. Among the 17 genes, IGF1, SLC4A4, WWOX, and SFMBT1 were not only identified by our gene-based association scan and gene expression analysis but were also replicated by a gene-based association analysis of the Hong Kong Hypertension Study. Moreover, cis-acting expression quantitative trait loci associated with the differentially expressed genes were found and linked to hypertension. IGF1, which encodes insulin-like growth factor 1, is associated with cardiovascular disorders, metabolic syndrome, decreased body weight/size, and changes of insulin levels in mice. SLC4A4, which encodes the electrogenic sodium bicarbonate cotransporter 1, is associated with decreased body weight/size and abnormal ion homeostasis in mice. WWOX, which encodes the WW domain-containing protein, is related to hypoglycemia and hyperphosphatemia. SFMBT1, which encodes the scm-like with four MBT domains protein 1, is a novel hypertension gene. GRB14, TMEM56 and KIAA1797 exhibited highly significant differential allelic and expressed distributions between hypertensive patients and normotensive controls. GRB14 was also found relevant to blood pressure in a previous genetic association study in East Asian populations. TMEM56 and KIAA1797 may be specific to

  7. Interaction of the retinoblastoma protein with Orc1 and its recruitment to human origins of DNA replication.

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    Ramiro Mendoza-Maldonado

    Full Text Available BACKGROUND: The retinoblastoma protein (Rb is a crucial regulator of cell cycle progression by binding with E2F transcription factor and repressing the expression of a variety of genes required for the G1-S phase transition. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that Rb and E2F1 directly participate in the control of initiation of DNA replication in human HeLa, U2OS and T98G cells by specifically binding to origins of DNA replication in a cell cycle regulated manner. We show that, both in vitro and inside the cells, the largest subunit of the origin recognition complex (Orc1 specifically binds hypo-phosphorylated Rb and that this interaction is competitive with the binding of Rb to E2F1. The displacement of Rb-bound Orc1 by E2F1 at origins of DNA replication marks the progression of the G1 phase of the cell cycle toward the G1-S border. CONCLUSIONS/SIGNIFICANCE: The participation of Rb and E2F1 in the formation of the multiprotein complex that binds origins of DNA replication in mammalian cells appears to represent an effective mechanism to couple the expression of genes required for cell cycle progression to the activation of DNA replication.

  8. Relationship between Angiotensin-Converting Enzyme Insertion/Deletion Gene Polymorphism and Susceptibility of Minimal Change Nephrotic Syndrome: A Meta-Analysis

    Directory of Open Access Journals (Sweden)

    Tian-Biao Zhou

    2011-01-01

    Africans: D: =.81, DD: =.49. Furthermore, the II genotype seemed not to play a protective role against MCNS risk for Asians, Caucasians and Africans (=.12, =.09, =.76, resp.. Interestingly, there was also significant association between ACE I/D gene polymorphism and MCNS susceptibility in overall populations (D: =.007, DD: =.04, II: =.03. Conclusion. D allele or DD genotype might be a significant genetic molecular marker for MCNS susceptibility in Asians and overall populations, but not for Caucasians and Africans. More larger and rigorous genetic epidemiological investigations are required to further explore this association.

  9. Association between Single Nucleotide Polymorphisms in Vitamin D Receptor Gene Polymorphisms and Permanent Tooth Caries Susceptibility to Permanent Tooth Caries in Chinese Adolescent

    Directory of Open Access Journals (Sweden)

    Miao Yu

    2017-01-01

    Full Text Available Purpose. Dental caries is a multifactorial infectious disease. In this study, we investigated whether single nucleotide polymorphisms (SNPs in vitamin D receptor (VDR gene were associated with susceptibility to permanent tooth caries in Chinese adolescents. Method. A total of 200 dental caries patients and 200 healthy controls aged 12 years were genotyped for VDR gene polymorphisms using the PCR-restriction fragment length polymorphism (PCR-RFLP assay. All of them were examined for their oral and dental status with the WHO criteria, and clinical information such as the Decayed Missing Filled Teeth Index (DMFT was evaluated. Genomic DNA was extracted from the buccal epithelial cells. The four polymorphic SNPs (Bsm I, Taq I, Apa I, and Fok I in VDR were assessed for both genotypic and phenotypic susceptibilities. Results. Among the four examined VDR gene polymorphisms, the increased frequency of the CT and CC genotype of the Fok I VDR gene polymorphism was associated with dental caries in 12-year-old adolescent, compared with the controls (X2 = 17.813, p≤0.001. Moreover, Fok I polymorphic allele C frequency was significantly increased in the dental caries cases, compared to the controls (X2 = 14.144, p≤0.001, OR = 1.730, 95% CI = 1.299–2.303. However, the other three VDR gene polymorphisms (Bsm I, Taq I, and Apa I showed no statistically significant differences in the caries groups compared with the controls. Conclusion. VDR-Fok I gene polymorphisms may be associated with susceptibility to permanent tooth caries in Chinese adolescent.

  10. Dissecting functions of the retinoblastoma tumor suppressor and the related pocket proteins by integrating genetic, cell biology, and electrophoretic techniques

    DEFF Research Database (Denmark)

    Hansen, Klaus; Lukas, J; Holm, K

    1999-01-01

    The members of the 'pocket protein' family, comprising the retinoblastoma tumor suppressor (pRB) and its relatives, p107 and p130, negatively regulate cell proliferation and modulate fundamental biological processes including embryonic development, differentiation, homeostatic tissue renewal...

  11. Evaluation of candidate stromal epithelial cross-talk genes identifies association between risk of serous ovarian cancer and TERT, a cancer susceptibility "hot-spot"

    DEFF Research Database (Denmark)

    Johnatty, Sharon E; Beesley, Jonathan; Chen, Xiaoqing

    2010-01-01

    We hypothesized that variants in genes expressed as a consequence of interactions between ovarian cancer cells and the host micro-environment could contribute to cancer susceptibility. We therefore used a two-stage approach to evaluate common single nucleotide polymorphisms (SNPs) in 173 genes in...

  12. Correlation between the Insertion/Deletion Mutations of Prion Protein Gene and BSE Susceptibility and Milk Performance in Dairy Cows

    Directory of Open Access Journals (Sweden)

    Hu Shen-rong

    2013-12-01

    Full Text Available Objective To investigate the 23 bp and 12 bp insertion/deletion (indel mutations within the bovine prion protein (PRNP gene in Chinese dairy cows, and to detect the associations of two indel mutations with BSE susceptibility and milk performance.

  13. The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura

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    Sundholm James

    2004-02-01

    Full Text Available Abstract Background The C677T variant in the methylenetetrahydrofolate reductase (MTHFR gene is associated with increased levels of circulating homocysteine and is a mild risk factor for vascular disease. Migraine, with and without aura (MA and MO, is a prevalent and complex neurovascular disorder that may also be affected by genetically influenced hyperhomocysteinaemia. To determine whether the C677T variant in the MTHFR gene is associated with migraine susceptibility we utilised unrelated and family-based case-control study designs. Methods A total of 652 Caucasian migraine cases were investigated in this study. The MTHFR C677T variant was genotyped in 270 unrelated migraine cases and 270 controls as well as 382 affected subjects from 92 multiplex pedigrees. Results In the unrelated case-control sample we observed an over-representation of the 677T allele in migraine patients compared to controls, specifically for the MA subtype (40% vs. 33% (χ2 = 5.70, P = 0.017. The Armitage test for trend indicated a significant dosage effect of the risk allele (T for MA (χ2 = 5.72, P = 0.017. This linear trend was also present in the independent family-based sample (χ2 = 4.25, Padjusted = 0.039. Overall, our results indicate that the T/T genotype confers a modest, yet significant, increase in risk for the MA subtype (odds ratio: 2.0 – 2.5. No increased risk for the MO subtype was observed (P > 0.05. Conclusions In Caucasians, the C677T variant in the MTHFR gene influences susceptibility to MA, but not MO. Investigation into the enzyme activity of MTHFR and the role of homocysteine in the pathophysiology of migraine is warranted.

  14. RNAi mediated acute depletion of Retinoblastoma protein (pRb promotes aneuploidy in human primary cells via micronuclei formation

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    Iovino Flora

    2009-11-01

    Full Text Available Abstract Background Changes in chromosome number or structure as well as supernumerary centrosomes and multipolar mitoses are commonly observed in human tumors. Thus, centrosome amplification and mitotic checkpoint dysfunctions are believed possible causes of chromosomal instability. The Retinoblastoma tumor suppressor (RB participates in the regulation of synchrony between DNA synthesis and centrosome duplication and it is involved in transcription regulation of some mitotic genes. Primary human fibroblasts were transfected transiently with short interfering RNA (siRNA specific for human pRb to investigate the effects of pRb acute loss on chromosomal stability. Results Acutely pRb-depleted fibroblasts showed altered expression of genes necessary for cell cycle progression, centrosome homeostasis, kinetochore and mitotic checkpoint proteins. Despite altered expression of genes involved in the Spindle Assembly Checkpoint (SAC the checkpoint seemed to function properly in pRb-depleted fibroblasts. In particular AURORA-A and PLK1 overexpression suggested that these two genes might have a role in the observed genomic instability. However, when they were post-transcriptionally silenced in pRb-depleted fibroblasts we did not observe reduction in the number of aneuploid cells. This finding suggests that overexpression of these two genes did not contribute to genomic instability triggered by RB acute loss although it affected cell proliferation. Acutely pRb-depleted human fibroblasts showed the presence of micronuclei containing whole chromosomes besides the presence of supernumerary centrosomes and aneuploidy. Conclusion Here we show for the first time that RB acute loss triggers centrosome amplification and aneuploidy in human primary fibroblasts. Altogether, our results suggest that pRb-depleted primary human fibroblasts possess an intact spindle checkpoint and that micronuclei, likely caused by mis-attached kinetochores that in turn trigger

  15. Glutathione S-transferase genes and the risk of type 2 diabetes mellitus: Role of sexual dimorphism, gene-gene and gene-smoking interactions in disease susceptibility.

    Science.gov (United States)

    Azarova, Iuliia; Bushueva, Olga; Konoplya, Alexander; Polonikov, Alexey

    2018-05-01

    Compromised defense against reactive oxygen species (ROS) is considered important in the pathogenesis of type 2 diabetes mellitus (T2DM); therefore, genes encoding antioxidant defense enzymes may contribute to disease susceptibility. This study investigated whether polymorphisms in genes encoding glutathione S-transferase M1 (GSTM1), T1 (GSTT1), and P1 (GSTP1) jointly contribute to the risk of T2DM. In all, 1120 unrelated Russian subjects (600 T2DM patients, 520 age- and sex-matched healthy subjects), were recruited to the study. Genotyping was performed by multiplex polymerase chain reaction (PCR; del/del polymorphisms of GSTM1 and GSTT1) and TaqMan-based PCR (polymorphisms I105V and A114V of GSTP1). Plasma ROS and glutathione levels in study subjects were analyzed by fluorometric and colorimetric assays, respectively. Genotype del/del GSTT1 was significantly associated with the risk of T2DM (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.17-2.21, P = 0.003). Gender-stratified analysis showed that the deletion genotypes of GSTM1 (OR 1.99, 95% CI 1.30-3.05; P = 0.0002, Q = 0.016) and GSTT1 (OR 2.23, 95% CI 1.22-4.09; P = 0.008, Q = 0.0216), as well as genotype 114A/V of GSTP1 (OR 2.85, 95% CI 1.44-5.62; P = 0.005, Q = 0.02) were associated with an increased risk of T2DM exclusively in males. Three genotype combinations (i.e. GSTM1+ × GSTT1+, GSTM1+ × GSTP1 114A/A and GSTT1+ × GSTP1 114A/A) showed significant associations with a decreased risk of T2DM in males. This study demonstrates, for the first time, that genes encoding glutathione S-transferases jointly contribute to the risk of T2DM, and that their effects on disease susceptibility are gender specific. © 2017 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

  16. Current Trends in the Management of Retinoblastoma

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    Hayyam Kıratlı

    2014-09-01

    Full Text Available Retinoblastoma is the most common primary intraocular malignant tumor of early childhood, and 95% of all cases are diagnosed before the age of 5 years. Tumors are evaluated and classified based on laterality, genetic features, the number, location and size of foci. Currently, systemic and intaarterial chemotherapy are the most commonly used management options worldwide. Group A tumors are treated with focal techniques including transpupillary thermotherapy, cryotherapy, or laser photocoagulation. Groups B and C tumors are managed with systemic chemotherapy and focal consolidation techniques. Group D lesions are best treated with systemic chemotherapy, subtenon carboplatin injection or external beam radiotherapy. Alternatively, groups B, C and D tumors can be primarily treated with intraarterial chemotherapy. Intravitreal melphalan injection can be an alternative treatment for eyes with recurrent or persistent vitreous seeding. Group E eyes are often enucleated, however, depending on the fellow eye, systemic or intraarterial chemotherapy may be administered. Systemic chemotherapy is also mandatory if high-risk histopathological features are found after enucleation. (Turk J Ophthalmol 2014; 44: Supplement 22-8

  17. The Interaction of TXNIP and AFq1 Genes Increases the Susceptibility of Schizophrenia.

    Science.gov (United States)

    Su, Yousong; Ding, Wenhua; Xing, Mengjuan; Qi, Dake; Li, Zezhi; Cui, Donghong

    2017-08-01

    Although previous studies showed the reduced risk of cancer in patients with schizophrenia, whether patients with schizophrenia possess genetic factors that also contribute to tumor suppressor is still unknown. In the present study, based on our previous microarray data, we focused on the tumor suppressor genes TXNIP and AF1q, which differentially expressed in patients with schizophrenia. A total of 413 patients and 578 healthy controls were recruited. We found no significant differences in genotype, allele, or haplotype frequencies at the selected five single nucleotide polymorphisms (SNPs) (rs2236566 and rs7211 in TXNIP gene; rs10749659, rs2140709, and rs3738481 in AF1q gene) between patients with schizophrenia and controls. However, we found the association between the interaction of TXNIP and AF1q with schizophrenia by using the MDR method followed by traditional statistical analysis. The best gene-gene interaction model identified was a three-locus model TXNIP (rs2236566, rs7211)-AF1q (rs2140709). After traditional statistical analysis, we found the high-risk genotype combination was rs2236566 (GG)-rs7211(CC)-rs2140709(CC) (OR = 1.35 [1.03-1.76]). The low-risk genotype combination was rs2236566 (GT)-rs7211(CC)-rs2140709(CC) (OR = 0.67 [0.49-0.91]). Our finding suggested statistically significant role of interaction of TXNIP and AF1q polymorphisms (TXNIP-rs2236566, TXNIP-rs7211, and AF1q-rs2769605) in schizophrenia susceptibility.

  18. Circadian gene variants and susceptibility to type 2 diabetes: a pilot study.

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    M Ann Kelly

    Full Text Available Disruption of endogenous circadian rhythms has been shown to increase the risk of developing type 2 diabetes, suggesting that circadian genes might play a role in determining disease susceptibility. We present the results of a pilot study investigating the association between type 2 diabetes and selected single nucleotide polymorphisms (SNPs in/near nine circadian genes. The variants were chosen based on their previously reported association with prostate cancer, a disease that has been suggested to have a genetic link with type 2 diabetes through a number of shared inherited risk determinants.The pilot study was performed using two genetically homogeneous Punjabi cohorts, one resident in the United Kingdom and one indigenous to Pakistan. Subjects with (N = 1732 and without (N = 1780 type 2 diabetes were genotyped for thirteen circadian variants using a competitive allele-specific polymerase chain reaction method. Associations between the SNPs and type 2 diabetes were investigated using logistic regression. The results were also combined with in silico data from other South Asian datasets (SAT2D consortium and white European cohorts (DIAGRAM+ using meta-analysis. The rs7602358G allele near PER2 was negatively associated with type 2 diabetes in our Punjabi cohorts (combined odds ratio [OR] = 0.75 [0.66-0.86], p = 3.18 × 10(-5, while the BMAL1 rs11022775T allele was associated with an increased risk of the disease (combined OR = 1.22 [1.07-1.39], p = 0.003. Neither of these associations was replicated in the SAT2D or DIAGRAM+ datasets, however. Meta-analysis of all the cohorts identified disease associations with two variants, rs2292912 in CRY2 and rs12315175 near CRY1, although statistical significance was nominal (combined OR = 1.05 [1.01-1.08], p = 0.008 and OR = 0.95 [0.91-0.99], p = 0.015 respectively.None of the selected circadian gene variants was associated with type 2 diabetes with study-wide significance after meta-analysis. The nominal

  19. Estudo do raspado de conjuntiva de pacientes tratados de retinoblastoma: Etapa II -- citologia Study of conjunctival scrape smears in patients treated for retinoblastoma: Phase II - cytology

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    Maria Carmen Menezes Santos

    2002-06-01

    Full Text Available Objetivo: A citologia da conjuntiva humana tem sido amplamente estu-dada. A falta de dados sobre as características do raspado ocular em pacientes tratados de retinoblastoma submetidos à enucleação e radioterapia foi o que motivou este estudo. Métodos: Foram examinadas 114 órbitas de 58 pacientes. Este trabalho apresenta os resultados da citologia conjuntival, em 4 condições, com e sem enucleação, com e sem radioterapia. Resultados: No infiltrado leucocitário das órbitas com bulbo ocular predominaram os linfócitos e nas demais, os polimorfonucleares neutrófilos. De maneira geral, as alterações das células epiteliais mais encontradas nas lâminas dos esfregaços conjuntivais de órbitas irradiadas foram: células com núcleo aumentado e nucléolo proeminente e com hialinização do citoplasma. Conclusão: Os achados citológicos do raspado conjuntival não indicaram perfil característico e distinto para cada grupo.Purpose: Human conjunctival cytology has been extensively studied. Lack of data about the characteristics of conjunctival smears in patients treated for retinoblastoma who underwent enucleation and radiotherapy motivated this study. Methods: A previously studied group of 114 orbits of 58 patients was examined. The authors present the results of conjunctival cytology in 4 different situations, with and without enucleation, with and without radiotherapy. Results: In the leukocytic infiltrate in orbits with ocular bulbi predominated the lymphocyte, while in the others predominated the polymorphonuclear neutrophil. In general, the majority of epithelial cell alterations seen in the conjunctival smears of irradiated orbits were: cell with large nuclei, prominent nucleoli, and cytoplasmatic hyalinization. Conclusion: The cytological findings of the conjunctival smears do not indicate a characteristic and distinct pattern for each group.

  20. A meta-analysis of adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility

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    Xiuju Chen

    2016-01-01

    Full Text Available Several studies have investigated the correlation between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk. However, the results were not conclusive with each other. Therefore, to overcome this obstacle, we performed this meta-analysis to further explicate the adiponectin gene rs22411766 T>G polymorphism and ischemic stroke susceptibility. Case-control or cohort studies focused on adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk were electronic searched in the databases of Medline, Pubmed, Cochrane library, Excerpta Medica database(EMBASE and China National Knowledge Infrastructure (CNKI. All the potentially relevant studies were included in this meta-analysis. The association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke was expressed by odds ratio with its confidence interval. Publication bias has been assessed by begg’s funnel plot. All the analyses have been performed by Revman 5.1 statistical software. Finally, a total of six studies with 1,345 cases and 1,421 controls were included in this meta-analysis. Our results demonstrated that there was a significant association between adiponectin gene rs22411766 T>G polymorphism and ischemic stroke risk (p<0.05. People with G single nucleotide of adiponectin gene have the increased risk of developing ischemic stroke compared to T single nucleotide.

  1. Vitamin D Receptor Gene Polymorphisms Influence T1D Susceptibility among Pakistanis

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    Maryam Mukhtar

    2017-01-01

    Full Text Available Background. The vitamin D receptor (VDR gene regulates insulin secretion from the pancreas and acts as a mediator of the immune response through vitamin D. Polymorphism in VDR causes alterations in the functioning of vitamin D, leading to type 1 diabetes (T1D predisposition. The aim of the present study was to determine VDR gene polymorphism in association with T1D in Pakistanis. Methods. The association was evaluated by selecting rs2228570 (FokΙ, rs7975232 (ApaΙ, and rs731236 (TaqΙ polymorphic sites in 102 patients and 100 controls. Genotypes were identified by DNA sequencing and PCR-RFLP. Results. The allelic and genotypic frequencies of FokΙ and ApaI were significantly associated with T1D (p0.05. CCGC, CCGG, CCTC, and CCTG haplotypes were significantly associated with disease development (p<0.05. However, CTGG haplotype was protective towards T1D (p<0.01. Conclusion. VDR polymorphisms were identified as susceptible regions for T1D development in the Pakistani population.

  2. [Correlation between HLA-DB1 genes and susceptibility to echinococcosis in Tibetan population in Tibetan Plateau].

    Science.gov (United States)

    Shu-Feng, Gao; Xiu-Min, Han; Xue-Fei, Zhang; Yong-Shun, Wang; Wei, Wang; Ya-Min, Guo; Yong-Shou, Li

    2017-10-23

    To determine the susceptibility genes and resistance genes in HLA-DRB1 alleles in Tibetan patients with cystic and alveolar hydatid diseases, so as to provide the references for the research of the genetic characteristics and infection mechanism of Tibetan hydatid diseases. The case control method was applied. The Tibetan patients with cystic and alveolar hydatid diseases (63 and 73 cases respectively) in Yushu and Guoluo Tibetan Autonomous Prefecture, and unrelated healthy people (60 cases) in this area were selected as the study subjects. The polymerase chain reaction-sequence based typing (PCR-SBT) technique was applied for genotyping of HLA-DRB1, and the comparison of the gene frequency. The frequency of HLA-DRB1*04 in the alveolar/cystic echinococcosis group was lower than that in the control group ( χ 2 = 4.71, 4.31, both P < 0.05). HLA-DRB1*04 genotypes may be associated with the resistance of cystic and alveolar echinococcosis and its resistance genes.

  3. Differential susceptibility to plasticity: a 'missing link' between gene-culture co-evolution and neuropsychiatric spectrum disorders?

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    Wurzman Rachel

    2012-04-01

    Full Text Available Abstract Brüne's proposal that erstwhile 'vulnerability' genes need to be reconsidered as 'plasticity' genes, given the potential for certain environments to yield increased positive function in the same domain as potential dysfunction, has implications for psychiatric nosology as well as a more dynamic understanding of the relationship between genes and culture. In addition to validating neuropsychiatric spectrum disorder nosologies by calling for similar methodological shifts in gene-environment-interaction studies, Brüne's position elevates the importance of environmental contexts - inclusive of socio-cultural variables - as mechanisms that contribute to clinical presentation. We assert that when models of susceptibility to plasticity and neuropsychiatric spectrum disorders are concomitantly considered, a new line of inquiry emerges into the co-evolution and co-determination of socio-cultural contexts and endophenotypes. This presents potentially unique opportunities, benefits, challenges, and responsibilities for research and practice in psychiatry. Please see related manuscript: http://www.biomedcentral.com/1741-7015/10/38

  4. [Eyeball salvage treatment or enucleation for advanced retinoblastoma].

    Science.gov (United States)

    Qian, J; Xue, K

    2016-10-11

    The management of retinoblastoma (RB) has dramatically changed over the past two decades. The introduction of chemotherapy has transformed treatment algorithms completely. Chemotherapy is currently used as a first line approach for children with RB and can be delivered by intravenous, intra-arterial and intravitreal routes. However, there still remains some controversy on the treatment of advanced RB, especially in eyeball salvage. This article described domestic and international approaches to eyeball salvage treatment. We would like to further discuss our opinion on the management of advanced RB based on our clinical experience for attracting more clinical concern on this issue. Many factors should be considered when choosing the appropriate conservative therapy. The choice of eyeball salvage treatment not only depends upon the tumor staging and laterality but also upon compliance and economic factors. Doctors and parents should not blindly pursue eye saving. However, there are still cases where enucleation is definitely the treatment of choice. (Chin J Ophthalmol, 2016, 52: 728-732) .

  5. Variants in toll-like receptor 9 gene influence susceptibility to tuberculosis in a Mexican population.

    Science.gov (United States)

    Torres-García, Diana; Cruz-Lagunas, Alfredo; García-Sancho Figueroa, Ma Cecilia; Fernández-Plata, Rosario; Baez-Saldaña, Renata; Mendoza-Milla, Criselda; Barquera, Rodrigo; Carrera-Eusebio, Aida; Ramírez-Bravo, Salomón; Campos, Lizeth; Angeles, Javier; Vargas-Alarcón, Gilberto; Granados, Julio; Gopal, Radha; Khader, Shabaana A; Yunis, Edmond J; Zuñiga, Joaquin

    2013-09-21

    The control of Mycobacterium tuberculosis (Mtb) infection begins with the recognition of mycobacterial structural components by toll like receptors (TLRs) and other pattern recognition receptors. Our objective was to determine the influence of TLRs polymorphisms in the susceptibility to develop tuberculosis (TB) in Amerindian individuals from a rural area of Oaxaca, Mexico with high TB incidence. We carried out a case-control association community based study, genotyping 12 polymorphisms of TLR2, TLR4, TLR6 and TLR9 genes in 90 patients with confirmed pulmonary TB and 90 unrelated exposed but asymptomatic household contacts. We found a significant increase in the frequency of the allele A of the TLR9 gene polymorphism rs352139 (A>G) in the group of TB patients (g.f. = 0.522) when compared with controls (g.f. = 0.383), (Pcorr = 0.01, OR = 1.75). Under the recessive model (A/G + A/A vs G/G) this polymorphism was also significantly associated with TB (Pcorr = 0.01, OR= 2.37). The association of the SNP rs352139 was statistically significant after adjustment by age, gender and comorbidities by regression logistic analysis (Dominant model: p value = 0.016, OR = 2.31; Additive model: p value = 0.023, OR = 1.68). The haplotype GAA of TLR9 SNPs was also associated with TB susceptibility (Pcorr = 0.02). Differences in the genotype or allele frequencies of TLR2, TLR4 and TLR6 polymorphisms between TB patients and healthy contacts were not detected. Our study suggests that the allele A of the intronic polymorphism rs352139 on TLR9 gene might contribute to the risk of developing TB in Mexican Amerindians.

  6. Polymorphism of Gene and Association with Susceptibility to Digestive Disorders in Rabbit

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    Yu Yang

    2013-04-01

    Full Text Available NLR family pyrin domain containing 3 (NLRP3 is a key component of the inflammasome, whose assembly is a crucial part of the innate immune response. The aim of the present study was to evaluate the association between exon 3 polymorphisms of NLRP3 and the susceptibility to digestive disorders in rabbits. In total, five coding single-nucleotide polymorphisms (cSNPs were identified; all of which are synonymous. Among them, c.456 C> and c.594 G> were further genotyped for association analysis based on case-control design (n =162 vs n =102. Meanwhile, growing rabbits were experimentally induced to digestive disorders by feeding a fiber-deficient diet, subsequently they were subjected to mRNA expression analysis. Association analysis revealed that haplotype H1 (the two cSNPs: GT played a potential protective role against digestive disorders (p<0.001. The expression of NLRP3 in the group H1HX1 (H1HX1 is composed of H1H1, H1H3 and H1H4 was the lowest among four groups which were classified by different types of diplotypes. Those results suggested that the NLRP3 gene was significantly associated with susceptibility to digestive disorders in rabbit.

  7. Functional complementation studies identify candidate genes and common genetic variants associated with ovarian cancer survival

    DEFF Research Database (Denmark)

    Quaye, Lydia; Dafou, Dimitra; Ramus, Susan J

    2009-01-01

    ) [hazard ratio (HR) = 1.13 (95% CI: 1.00-1.27), P = 0.042] and two tSNPs in the retinoblastoma binding protein (RBBP8) gene [HR = 0.85 (95% CI: 0.75-0.95), P = 0.007 and HR = 0.83 (95% CI: 0.71-0.95), P = 0.009]. After adjusting for multiple prognostic factors in a multivariate Cox regression analysis...

  8. Radiation regression patterns after cobalt plaque insertion for retinoblastoma

    International Nuclear Information System (INIS)

    Buys, R.J.; Abramson, D.H.; Ellsworth, R.M.; Haik, B.

    1983-01-01

    An analysis of 31 eyes of 30 patients who had been treated with cobalt plaques for retinoblastoma disclosed that a type I radiation regression pattern developed in 15 patients; type II, in one patient, and type III, in five patients. Nine patients had a regression pattern characterized by complete destruction of the tumor, the surrounding choroid, and all of the vessels in the area into which the plaque was inserted. This resulting white scar, corresponding to the sclerae only, was classified as a type IV radiation regression pattern. There was no evidence of tumor recurrence in patients with type IV regression patterns, with an average follow-up of 6.5 years, after receiving cobalt plaque therapy. Twenty-nine of these 30 patients had been unsuccessfully treated with at least one other modality (ie, light coagulation, cryotherapy, external beam radiation, or chemotherapy)

  9. Radiation regression patterns after cobalt plaque insertion for retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Buys, R.J.; Abramson, D.H.; Ellsworth, R.M.; Haik, B.

    1983-08-01

    An analysis of 31 eyes of 30 patients who had been treated with cobalt plaques for retinoblastoma disclosed that a type I radiation regression pattern developed in 15 patients; type II, in one patient, and type III, in five patients. Nine patients had a regression pattern characterized by complete destruction of the tumor, the surrounding choroid, and all of the vessels in the area into which the plaque was inserted. This resulting white scar, corresponding to the sclerae only, was classified as a type IV radiation regression pattern. There was no evidence of tumor recurrence in patients with type IV regression patterns, with an average follow-up of 6.5 years, after receiving cobalt plaque therapy. Twenty-nine of these 30 patients had been unsuccessfully treated with at least one other modality (ie, light coagulation, cryotherapy, external beam radiation, or chemotherapy).

  10. Assessing SNP-SNP interactions among DNA repair, modification and metabolism related pathway genes in breast cancer susceptibility.

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    Yadav Sapkota

    Full Text Available Genome-wide association studies (GWASs have identified low-penetrance common variants (i.e., single nucleotide polymorphisms, SNPs associated with breast cancer susceptibility. Although GWASs are primarily focused on single-locus effects, gene-gene interactions (i.e., epistasis are also assumed to contribute to the genetic risks for complex diseases including breast cancer. While it has been hypothesized that moderately ranked (P value based weak single-locus effects in GWASs could potentially harbor valuable information for evaluating epistasis, we lack systematic efforts to investigate SNPs showing consistent associations with weak statistical significance across independent discovery and replication stages. The objectives of this study were i to select SNPs showing single-locus effects with weak statistical significance for breast cancer in a GWAS and/or candidate-gene studies; ii to replicate these SNPs in an independent set of breast cancer cases and controls; and iii to explore their potential SNP-SNP interactions contributing to breast cancer susceptibility. A total of 17 SNPs related to DNA repair, modification and metabolism pathway genes were selected since these pathways offer a priori knowledge for potential epistatic interactions and an overall role in breast carcinogenesis. The study design included predominantly Caucasian women (2,795 cases and 4,505 controls from Alberta, Canada. We observed two two-way SNP-SNP interactions (APEX1-rs1130409 and RPAP1-rs2297381; MLH1-rs1799977 and MDM2-rs769412 in logistic regression that conferred elevated risks for breast cancer (P(interaction<7.3 × 10(-3. Logic regression identified an interaction involving four SNPs (MBD2-rs4041245, MLH1-rs1799977, MDM2-rs769412, BRCA2-rs1799943 (P(permutation = 2.4 × 10(-3. SNPs involved in SNP-SNP interactions also showed single-locus effects with weak statistical significance, while BRCA2-rs1799943 showed stronger statistical significance (P

  11. Polymorphisms in the CISH gene are associated with susceptibility to tuberculosis in the Chinese Han population.

    Science.gov (United States)

    Ji, Lin-dan; Xu, Wei-nan; Chai, Peng-fei; Zheng, Wei; Qian, Hai-xia; Xu, Jin

    2014-12-01

    A recent multi-center case-control study identified several single nucleotide polymorphisms (SNPs) within the cytokine-inducible SRC homology 2 domain (CISH) gene that are associated with susceptibility to tuberculosis (TB) in both African and Asian populations. To acquire a more robust and well-powered estimate of the putative influence of these SNPs on TB susceptibility, we conducted a well-designed case-control study in the Chinese Han population. We genotyped 3 previously identified SNPs within CISH in 600 patients with pulmonary TB and 618 healthy controls, and we calculated the pooled P-values and ORs of several studies that have also been conducted in the Chinese populations. The results of the case-control study showed that the C allele of rs2239751 and the T allele of rs414171 are associated with TB susceptibility, and this association exists only in women and young adults. The pooled analysis indicated that both SNPs are significantly associated with TB in the global populations and Chinese populations. The current study confirms that variants of CISH are associated with susceptibility to TB, suggesting that negative regulators of cytokine signaling may have a role in immunity against TB infection. We hypothesize that CISH and estrogen may interact in the cytokine-dependent regulation of the immune system. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Cell size checkpoint control by the retinoblastoma tumor suppressor pathway.

    Science.gov (United States)

    Fang, Su-Chiung; de los Reyes, Chris; Umen, James G

    2006-10-13

    Size control is essential for all proliferating cells, and is thought to be regulated by checkpoints that couple cell size to cell cycle progression. The aberrant cell-size phenotypes caused by mutations in the retinoblastoma (RB) tumor suppressor pathway are consistent with a role in size checkpoint control, but indirect effects on size caused by altered cell cycle kinetics are difficult to rule out. The multiple fission cell cycle of the unicellular alga Chlamydomonas reinhardtii uncouples growth from division, allowing direct assessment of the relationship between size phenotypes and checkpoint function. Mutations in the C. reinhardtii RB homolog encoded by MAT3 cause supernumerous cell divisions and small cells, suggesting a role for MAT3 in size control. We identified suppressors of an mat3 null allele that had recessive mutations in DP1 or dominant mutations in E2F1, loci encoding homologs of a heterodimeric transcription factor that is targeted by RB-related proteins. Significantly, we determined that the dp1 and e2f1 phenotypes were caused by defects in size checkpoint control and were not due to a lengthened cell cycle. Despite their cell division defects, mat3, dp1, and e2f1 mutants showed almost no changes in periodic transcription of genes induced during S phase and mitosis, many of which are conserved targets of the RB pathway. Conversely, we found that regulation of cell size was unaffected when S phase and mitotic transcription were inhibited. Our data provide direct evidence that the RB pathway mediates cell size checkpoint control and suggest that such control is not directly coupled to the magnitude of periodic cell cycle transcription.

  13. Extended biofilm susceptibility assay for Staphylococcus aureus bovine mastitis isolates: evidence for association between genetic makeup and biofilm susceptibility.

    Science.gov (United States)

    Melchior, M B; van Osch, M H J; Lam, T J G M; Vernooij, J C M; Gaastra, W; Fink-Gremmels, J

    2011-12-01

    Staphylococcus aureus is one of the most prevalent causes of bovine mastitis. The antimicrobial treatment of this disease is currently based on antimicrobial susceptibility tests according to Clinical and Laboratory Standards Institute standards. However, various authors have shown a discrepancy between the results of this standard susceptibility test and the actual cure rate of the applied antimicrobial treatment. Increasing evidence suggests that in vivo biofilm formation by Staph. aureus, which is not assessed in the antimicrobial susceptibility tests, is associated with this problem, resulting in disappointing cure rates, especially for infections of longer duration. Previous data obtained with a limited number of strains showed that the extended biofilm antimicrobial susceptibility (EBS) assay reveals differences between strains, which cannot be derived from a standard susceptibility test or from a 24-h biofilm susceptibility test. The objective of this study was to test a collection of Staph. aureus bovine mastitis strains in the EBS assay and to model the effect of antimicrobial exposure, duration of antimicrobial exposure, and genotype profile of the strains on antimicrobial susceptibility. With the results from a previous study with the same collection of strains, the effect of genotype represented by accessory gene regulator gene (agr-type), the presence of insertional sequence 257 (IS257), intercellular adhesion (ica), and the β-lactamase (blaZ) gene were entered as explanatory factors in a logistic regression model. The agr locus of Staph. aureus controls the expression of most of the virulence factors, represses the transcription of several cell wall-associated proteins, and activates several exoproteins during the post-exponential phase. The IS257 gene has been related to biofilm formation in vitro and was found earlier in 50% of the agr-type 2 strains. The ica gene cluster encodes for the production of an extracellular polysaccharide adhesin, termed

  14. Prevalence and spectrum of large deletions or duplications in the major long QT syndrome-susceptibility genes and implications for long QT syndrome genetic testing.

    Science.gov (United States)

    Tester, David J; Benton, Amber J; Train, Laura; Deal, Barbara; Baudhuin, Linnea M; Ackerman, Michael J

    2010-10-15

    Long QT syndrome (LQTS) is a cardiac channelopathy associated with syncope, seizures, and sudden death. Approximately 75% of LQTS is due to mutations in genes encoding for 3 cardiac ion channel α-subunits (LQT1 to LQT3). However, traditional mutational analyses have limited detection capabilities for atypical mutations such as large gene rearrangements. We set out to determine the prevalence and spectrum of large deletions/duplications in the major LQTS-susceptibility genes in unrelated patients who were mutation negative after point mutation analysis of LQT1- to LQT12-susceptibility genes. Forty-two unrelated, clinically strong LQTS patients were analyzed using multiplex ligation-dependent probe amplification, a quantitative fluorescent technique for detecting multiple exon deletions and duplications. The SALSA multiplex ligation-dependent probe amplification LQTS kit from MRC-Holland was used to analyze the 3 major LQTS-associated genes, KCNQ1, KCNH2, and SCN5A, and the 2 minor genes, KCNE1 and KCNE2. Overall, 2 gene rearrangements were found in 2 of 42 unrelated patients (4.8%, confidence interval 1.7 to 11). A deletion of KCNQ1 exon 3 was identified in a 10-year-old Caucasian boy with a corrected QT duration of 660 ms, a personal history of exercise-induced syncope, and a family history of syncope. A deletion of KCNQ1 exon 7 was identified in a 17-year-old Caucasian girl with a corrected QT duration of 480 ms, a personal history of exercise-induced syncope, and a family history of sudden cardiac death. In conclusion, because nearly 5% of patients with genetically elusive LQTS had large genomic rearrangements involving the canonical LQTS-susceptibility genes, reflex genetic testing to investigate genomic rearrangements may be of clinical value. Copyright © 2010 Elsevier Inc. All rights reserved.

  15. Mannose-binding lectin gene, MBL2, polymorphisms are not associated with susceptibility to invasive pneumococcal disease in children

    DEFF Research Database (Denmark)

    Lundbo, Lene Fogt; Harboe, Zitta Barrella; Clausen, Louise Nygaard

    2014-01-01

    BACKGROUND: Most children are transiently colonized with Streptococcus pneumoniae, but very few develop invasive pneumococcal disease (IPD). Host genetic variation of innate immunity may predispose to IPD. We investigated the effect of genetic variation in the mannose-binding lectin gene, MBL2......, on susceptibility and disease severity of IPD in previously healthy children aged

  16. Phylogenetic diversity, antimicrobial susceptibility and virulence gene profiles of Brachyspira hyodysenteriae isolates from pigs in Germany.

    Directory of Open Access Journals (Sweden)

    Jessica Joerling

    Full Text Available Swine dysentery (SD is an economically important diarrheal disease in pigs caused by different strongly hemolytic Brachyspira (B. species, such as B. hyodysenteriae, B. suanatina and B. hampsonii. Possible associations of epidemiologic data, such as multilocus sequence types (STs to virulence gene profiles and antimicrobial susceptibility are rather scarce, particularly for B. hyodysenteriae isolates from Germany. In this study, B. hyodysenteriae (n = 116 isolated from diarrheic pigs between 1990 and 2016 in Germany were investigated for their STs, susceptibility to the major drugs used for treatment of SD (tiamulin and valnemulin and genes that were previously linked with virulence and encode for hemolysins (tlyA, tlyB, tlyC, hlyA, BHWA1_RS02885, BHWA1_RS09085, BHWA1_RS04705, and BHWA1_RS02195, outer membrane proteins (OMPs (bhlp16, bhlp17.6, bhlp29.7, bhmp39f, and bhmp39h as well as iron acquisition factors (ftnA and bitC. Multilocus sequence typing (MLST revealed that 79.4% of the isolates belonged to only three STs, namely ST52 (41.4%, ST8 (12.1%, and ST112 (25.9% which have been observed in other European countries before. Another 24 isolates belonged to twelve new STs (ST113-118, ST120-123, ST131, and ST193. The temporal distribution of STs revealed the presence of new STs as well as the regular presence of ST52 over three decades (1990s-2000s. The proportion of strains that showed resistance to both tiamulin und valnemulin (39.1% varied considerably among the most frequent STs ranging from 0% (0/14 isolates resistant in ST8 isolates to 46.7% (14/30, 52.1% (25/48, and 85.7% (6/7 in isolates belonging to ST112, ST52, and ST114, respectively. All hemolysin genes as well as the iron-related gene ftnA and the OMP gene bhlp29.7 were regularly present in the isolates, while the OMP genes bhlp17.6 and bhmp39h could not be detected. Sequence analysis of hemolysin genes of selected isolates revealed co-evolution of tlyB, BHWA1_RS02885, BHWA1_RS

  17. Phylogenetic diversity, antimicrobial susceptibility and virulence gene profiles of Brachyspira hyodysenteriae isolates from pigs in Germany

    Science.gov (United States)

    Joerling, Jessica; Barth, Stefanie A.; Schlez, Karen; Willems, Hermann

    2018-01-01

    Swine dysentery (SD) is an economically important diarrheal disease in pigs caused by different strongly hemolytic Brachyspira (B.) species, such as B. hyodysenteriae, B. suanatina and B. hampsonii. Possible associations of epidemiologic data, such as multilocus sequence types (STs) to virulence gene profiles and antimicrobial susceptibility are rather scarce, particularly for B. hyodysenteriae isolates from Germany. In this study, B. hyodysenteriae (n = 116) isolated from diarrheic pigs between 1990 and 2016 in Germany were investigated for their STs, susceptibility to the major drugs used for treatment of SD (tiamulin and valnemulin) and genes that were previously linked with virulence and encode for hemolysins (tlyA, tlyB, tlyC, hlyA, BHWA1_RS02885, BHWA1_RS09085, BHWA1_RS04705, and BHWA1_RS02195), outer membrane proteins (OMPs) (bhlp16, bhlp17.6, bhlp29.7, bhmp39f, and bhmp39h) as well as iron acquisition factors (ftnA and bitC). Multilocus sequence typing (MLST) revealed that 79.4% of the isolates belonged to only three STs, namely ST52 (41.4%), ST8 (12.1%), and ST112 (25.9%) which have been observed in other European countries before. Another 24 isolates belonged to twelve new STs (ST113-118, ST120-123, ST131, and ST193). The temporal distribution of STs revealed the presence of new STs as well as the regular presence of ST52 over three decades (1990s–2000s). The proportion of strains that showed resistance to both tiamulin und valnemulin (39.1%) varied considerably among the most frequent STs ranging from 0% (0/14 isolates resistant) in ST8 isolates to 46.7% (14/30), 52.1% (25/48), and 85.7% (6/7) in isolates belonging to ST112, ST52, and ST114, respectively. All hemolysin genes as well as the iron-related gene ftnA and the OMP gene bhlp29.7 were regularly present in the isolates, while the OMP genes bhlp17.6 and bhmp39h could not be detected. Sequence analysis of hemolysin genes of selected isolates revealed co-evolution of tlyB, BHWA1_RS02885, BHWA1_RS

  18. Immunogenetics and genetic susceptibility in the pathogenesis of autoimmune hepatitis

    Directory of Open Access Journals (Sweden)

    Das Anup K

    2014-11-01

    Full Text Available vAutoimmune hepatitis is a progressive liver disease. Its pathogenesis is unclear, but needs a ‘trigger’ to initiate the disease in a genetically susceptible person. The susceptibility is partly related to MHCII class genes, and more so with human leukocyte antigen (HLA. Several mechanisms have been proposed which, however, cannot fully explain the immunologic findings in autoimmune hepatitis. The susceptibility to any autoimmune disease is determined by several factors where genetic and immunological alterations, along with, environmental factor are active. MHCII antigens as a marker for AIH, or a predictor of treatment response and prognosis has been investigated. Since MHCII antigens show significant ethnic heterogeneity, mutations in MHCII may merely act as only precursors of the surface markers of immune cells, which can be of significance, because the changes in HLA and MHC are missing in certain populations. One such marker is the CTLA-4 (CD152 gene mutation, reported in the phenotypes representing susceptibility to AIH. Other candidate genes of cytokines, TNF, TGF-beta1 etc, have also been investigated but with unvalidated results. Paediatric AIH show differences in genetic susceptibility. Genetic susceptibility or resistance to AIH may be associated with polypeptides in DRB1 with certain amino-acid sequences. Understanding which genes are implicated in genesis and/or disease progression will obviously help to identify key pathways in AIH and provide better insights into its pathogenesis. But studies to identify responsible genes are complex because of the complex trait of AIH.

  19. Impact of passive smoking, cooking with solid fuel exposure, and MBL/MASP-2 gene polymorphism upon susceptibility to tuberculosis

    Directory of Open Access Journals (Sweden)

    Mengshi Chen

    2014-12-01

    Conclusions: Passive smoking, cooking with solid fuel, and polymorphisms of MBL (rs7096206 and MASP-2 (rs6695096 genes were associated with susceptibility to TB in non-smokers, and there were gene–environment interactions among them. Further studies are needed to explore details of the mechanisms of association.

  20. Epistatic interaction between haplotypes of the ghrelin ligand and receptor genes influence susceptibility to myocardial infarction and coronary artery disease.

    Science.gov (United States)

    Baessler, Andrea; Fischer, Marcus; Mayer, Bjoern; Koehler, Martina; Wiedmann, Silke; Stark, Klaus; Doering, Angela; Erdmann, Jeanette; Riegger, Guenter; Schunkert, Heribert; Kwitek, Anne E; Hengstenberg, Christian

    2007-04-15

    Data from both experimental models and humans provide evidence that ghrelin and its receptor, the growth hormone secretagogue receptor (ghrelin receptor, GHSR), possess a variety of cardiovascular effects. Thus, we hypothesized that genetic variants within the ghrelin system (ligand ghrelin and its receptor GHSR) are associated with susceptibility to myocardial infarction (MI) and coronary artery disease (CAD). Seven single nucleotide polymorphisms (SNPs) covering the GHSR region as well as eight SNPs across the ghrelin gene (GHRL) region were genotyped in index MI patients (864 Caucasians, 'index MI cases') from the German MI family study and in matched controls without evidence of CAD (864 Caucasians, 'controls', MONICA Augsburg). In addition, siblings of these MI patients with documented severe CAD (826 'affected sibs') were matched likewise with controls (n = 826 Caucasian 'controls') and used for verification. The effect of interactions between genetic variants of both genes of the ghrelin system was explored by conditional classification tree models. We found association of several GHSR SNPs with MI [best SNP odds ratio (OR) 1.7 (1.2-2.5); P = 0.002] using a recessive model. Moreover, we identified a common GHSR haplotype which significantly increases the risk for MI [multivariate adjusted OR for homozygous carriers 1.6 (1.1-2.5) and CAD OR 1.6 (1.1-2.5)]. In contrast, no relationship between genetic variants and the disease could be revealed for GHRL. However, the increase in MI/CAD frequency related to the susceptible GHSR haplotype was abolished when it coincided with a common GHRL haplotype. Multivariate adjustments as well as permutation-based methods conveyed the same results. These data are the first to demonstrate an association of SNPs and haplotypes within important genes of the ghrelin system and the susceptibility to MI, whereas association with MI/CAD could be identified for genetic variants across GHSR, no relationship could be revealed for GHRL

  1. Significant association of interleukin-4 gene intron 3 VNTR polymorphism with susceptibility to knee osteoarthritis.

    Science.gov (United States)

    Yigit, Serbulent; Inanir, Ahmet; Tekcan, Akın; Tural, Ercan; Ozturk, Gokhan Tuna; Kismali, Gorkem; Karakus, Nevin

    2014-03-01

    Interleukin-4 (IL-4) is a strong chondroprotective cytokine and polymorphisms within this gene may be a risk factor for osteoarthritis (OA). We aimed to investigate genotype and allele frequencies of IL-4 gene intron 3 variable number of tandem repeats (VNTR) polymorphism in patients with knee OA in a Turkish population. The study included 202 patients with knee OA and 180 healthy controls. Genomic DNA was isolated and IL-4 gene 70 bp VNTR polymorphism determined by using polymerase chain reaction (PCR) with specific primers followed by restriction fragment length polymorphism (RFLP) analysis. Our result show that there was statistically significant difference between knee OA patients and control group with respect to IL-4 genotype distribution and allele frequencies (p=0.000, OR: 0.20, 95% CI: 0.10-0.41, OR: 0.22, 95% CI: 0.12-0.42, respectively). Our findings suggest that there is an association of IL-4 gene intron 3 VNTR polymorphism with susceptibility of a person for development of knee OA. As a result, IL-4 gene intron 3 VNTR polymorphism could be a genetic marker in OA in a Turkish study population. This is the first association study that evaluates the associations between IL-4 gene VNTR polymorphism and knee OA. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  2. Fractionated stereotaxic radiotherapy in the treatment of the retinoblastoma: preliminary results; Radiotherapie stereotaxique fractionnee dans le traitement du retinoblastome: resultats preliminaires

    Energy Technology Data Exchange (ETDEWEB)

    Pica, A. [Centre Hospitalier Universitaire Vaudois (CHUV), Service de Radiotherapie, Lausanne (Switzerland); Moeckli, R.; Do, H. [Institut de Radiophysique Appliquee, Lausanne (Switzerland); Balmer, A.; Munier, F. [Hopital ophtalmique Jules-Gonin, Lausanne (Switzerland); Chollet Rivier, M. [Centre Hospitalier Universitaire Vaudois (CHUV), Service d' Anesthesie, Lausanne (Switzerland)

    2006-11-15

    The objective of this study is to evaluate the impact in term of morbidity at short and long term and the response to the fractionated stereotaxic radiotherapy with a micro multi slides collimator in the treatment of the retinoblastoma. (N.C.)

  3. Post-transcriptional gene expression control by NANOS is up-regulated and functionally important in pRb-deficient cells.

    Science.gov (United States)

    Miles, Wayne O; Korenjak, Michael; Griffiths, Lyra M; Dyer, Michael A; Provero, Paolo; Dyson, Nicholas J

    2014-10-01

    Inactivation of the retinoblastoma tumor suppressor (pRb) is a common oncogenic event that alters the expression of genes important for cell cycle progression, senescence, and apoptosis. However, in many contexts, the properties of pRb-deficient cells are similar to wild-type cells suggesting there may be processes that counterbalance the transcriptional changes associated with pRb inactivation. Therefore, we have looked for sets of evolutionary conserved, functionally related genes that are direct targets of pRb/E2F proteins. We show that the expression of NANOS, a key facilitator of the Pumilio (PUM) post-transcriptional repressor complex, is directly repressed by pRb/E2F in flies and humans. In both species, NANOS expression increases following inactivation of pRb/RBF1 and becomes important for tissue homeostasis. By analyzing datasets from normal retinal tissue and pRb-null retinoblastomas, we find a strong enrichment for putative PUM substrates among genes de-regulated in tumors. These include pro-apoptotic genes that are transcriptionally down-regulated upon pRb loss, and we characterize two such candidates, MAP2K3 and MAP3K1, as direct PUM substrates. Our data suggest that NANOS increases in importance in pRb-deficient cells and helps to maintain homeostasis by repressing the translation of transcripts containing PUM Regulatory Elements (PRE). © 2014 The Authors.

  4. Correlation between conventional MR imaging combined with diffusion-weighted imaging and histopathologic findings in eyes primarily enucleated for advanced retinoblastoma. A retrospective study

    Energy Technology Data Exchange (ETDEWEB)

    Cui, Yanfen [Shanghai Jiao Tong University School of Medicine, Department of Radiology, Xinhua Hospital, Shanghai (China); Shanxi Medical University, Department of Radiology, Shanxi Province Cancer Hospital, Taiyuan (China); Luo, Ran; Liu, Huanhuan; Zhang, Caiyuan; Zhang, Zhongyang; Wang, Dengbin [Shanghai Jiao Tong University School of Medicine, Department of Radiology, Xinhua Hospital, Shanghai (China); Wang, Ruifen [Shanghai Jiao Tong University School of Medicine, Department of Pathology, Xinhua Hospital, Shanghai (China)

    2018-02-15

    To determine the diagnostic accuracy of conventional MRI in detecting tumour invasion of advanced intraocular retinoblastoma and to correlate ADC values with high-risk prognostic parameters. The sensitivities, specificities, positive predictive values (PPV), negative predictive values (NPV) and accuracies of MRI in detecting tumour-extent parameters of 63 retinoblastomas were determined. Furthermore, ADC values were correlated with high-risk prognostic parameters. MRI detected postlaminar optic nerve with a sensitivity of 73.3% (95% CI 44.9-92.2%) and a specificity of 89.6% (77.3-96.5%), while the specificity for choroidal invasion was only 31.8% (13.9-54.9%). Likewise, MRI failed to predicted early optic nerve invasion in terms of low sensitivity and PPV. In contrast, scleral and ciliary body invasion could be correctly excluded with high NPV. ADC values were significantly lower in patients with undifferentiated tumours, large tumour size, as with optic nerve and scleral invasion (all p < 0.05). However, no correlation was found between ADC values and the degree of choroidal or ciliary body infiltration. Additionally, ADC values were negatively correlated with Ki-67 index (r = -0.62, P = 0.002). Conventional MRI has some limitations in reliably predicting microscopic infiltration, with the diagnostic efficiency showing room for improvement, whereas ADC values correlated well with certain high-risk prognostic parameters for retinoblastoma. (orig.)

  5. Relationship Between LAPTM4B Gene Polymorphism and Susceptibility of Malignant Melanoma in Chinese Patients

    Directory of Open Access Journals (Sweden)

    Meng Zhang

    2014-10-01

    Full Text Available Lysosomal-associated protein transmembrane 4 beta (LAPTM4B is known as an oncogene associated with many human malignant tumors. There are two alleles of the gene, LAPTM4B*1 and LAPTM4B*2. Previous studies have shown that LAPTM4B polymorphism contributes to the risk of many cancers. This case-control study was to investigate the relationship between LAPTM4B gene polymorphism and susceptibility of malignant melanoma. The genotypes of LAPTM4B were determined in 617 control subjects and 220 patients with malignant melanoma by utilizing polymerase chain reaction based on specific primers. The genotypic distribution of LAPTM4B and Hardy–Weinberg equilibrium were analyzed by χ2 test. Odds ratio and 95% confidence interval was calculated by unconditional logistic regression. The distributions of LAPTM4B genotypes were significantly different between melanoma patients (45.9% for *1/1, 46.4% for *1/2 and 7.7 for *2/2 and controls (54.5% for *1/1, 39.9% for *1/2 and 5.7 for *2/2. LAPTM4B *1/2 and LAPTM4B *2/2 had a 1.396-fold and 1.619-fold higher risk for melanoma occurrence than *1/1, and subjects with LAPTM4B*2 have a 1.308-fold higher risk than LAPTM4B*1 carriers. No association between LAPTM4B genotypes and gender, age, subtype, Clark level of invasion, Breslow thickness, ulceration, clinical stage, and C-KIT, BRAF gene mutation status was observed. LAPTM4B*2 is associated with the high risk of malignant melanoma and carrying LAPTM4B *2 may be a susceptible factor to Chinese melanoma patients.

  6. Variants in toll-like receptor 9 gene influence susceptibility to tuberculosis in a Mexican population

    Science.gov (United States)

    2013-01-01

    Background The control of Mycobacterium tuberculosis (Mtb) infection begins with the recognition of mycobacterial structural components by toll like receptors (TLRs) and other pattern recognition receptors. Our objective was to determine the influence of TLRs polymorphisms in the susceptibility to develop tuberculosis (TB) in Amerindian individuals from a rural area of Oaxaca, Mexico with high TB incidence. Methods We carried out a case–control association community based study, genotyping 12 polymorphisms of TLR2, TLR4, TLR6 and TLR9 genes in 90 patients with confirmed pulmonary TB and 90 unrelated exposed but asymptomatic household contacts. Results We found a significant increase in the frequency of the allele A of the TLR9 gene polymorphism rs352139 (A>G) in the group of TB patients (g.f. = 0.522) when compared with controls (g.f. = 0.383), (Pcorr = 0.01, OR = 1.75). Under the recessive model (A/G + A/A vs G/G) this polymorphism was also significantly associated with TB (Pcorr = 0.01, OR= 2.37). The association of the SNP rs352139 was statistically significant after adjustment by age, gender and comorbidities by regression logistic analysis (Dominant model: p value = 0.016, OR = 2.31; Additive model: p value = 0.023, OR = 1.68). The haplotype GAA of TLR9 SNPs was also associated with TB susceptibility (Pcorr = 0.02). Differences in the genotype or allele frequencies of TLR2, TLR4 and TLR6 polymorphisms between TB patients and healthy contacts were not detected. Conclusions Our study suggests that the allele A of the intronic polymorphism rs352139 on TLR9 gene might contribute to the risk of developing TB in Mexican Amerindians. PMID:24053111

  7. Genetic factors affecting radiosensitivity and cancer predisposition: application of a continuous low dose-rate irradiation colony formation assay to select radiosensitive retinoblastoma family members for correction with a cDNA library

    International Nuclear Information System (INIS)

    Wilson, P.F.; Nagasawa, H.; Bedford, J.S.; Little, J.B.

    2003-01-01

    Full text: The aim of this study is to identify new or undescribed functions of radiosensitivity and genomic instability genes using a continuous low dose-rate colony formation assay. This assay expands on the standard colony formation assay, whereby colony formation ability (retention of proliferative capacity) is measured during continuous low dose-rate irradiation rather than 10-14 days following the completion of such exposures. This approach has previously employed by the Bedford laboratory to identify a Prkdc (DNA-PKcs) mutant of CHO cells, irs-20. In this study we examine the growth response of fibroblasts derived from recently identified radiosensitive retinoblastoma family members, both affected probands and their unaffected parents, and various apparently normal fibroblast lines obtained from the NIGMS Human Genetic Cell Repository (Coriell Medical Institute, Camden, NJ). Colony formation was assayed by plating single cells, exposing them at 37 deg C to continuous Cs-137 gamma irradiation at dose rates of 0.5-8.5 cGy/h, and scoring survivors as colonies with >100 viable cells. The retinoblastoma family members display severely limited growth (survival less than 10E-3) at dose rates greater than 2-2.5 cGy/h, while the apparently normal cell lines do not display such inhibited growth until 6-7 cGy/h. Two of the retinoblastoma family cell lines, MF-6F and MF-15F (both unaffected but radiosensitive parents), were selected as targets of transfection with a viral cDNA library (ViraPort human cDNA library, Stratagene Cloning Systems, La Jolla, CA) and subjected to a ∼3 cGy/h selection dose rate, where uncorrected survival relative to normal cells is lower by a factor of 50-150. Colonies recovered will provide valuable information regarding the genetic nature of their radiosensitivity (possibly involving chromosome stability, DNA repair, and/or cell cycle regulatory pathways), that may influence risks for cancer and heritable effects for a previously

  8. Genetic variation in the NBS1, MRE11, RAD50 and BLM genes and susceptibility to non-Hodgkin lymphoma

    Directory of Open Access Journals (Sweden)

    Gascoyne Randy D

    2009-11-01

    Full Text Available Abstract Background Translocations are hallmarks of non-Hodgkin lymphoma (NHL genomes. Because lymphoid cell development processes require the creation and repair of double stranded breaks, it is not surprising that disruption of this type of DNA repair can cause cancer. The members of the MRE11-RAD50-NBS1 (MRN complex and BLM have central roles in maintenance of DNA integrity. Severe mutations in any of these genes cause genetic disorders, some of which are characterized by increased risk of lymphoma. Methods We surveyed the genetic variation in these genes in constitutional DNA of NHL patients by means of gene re-sequencing, then conducted genetic association tests for susceptibility to NHL in a population-based collection of 797 NHL cases and 793 controls. Results 114 SNPs were discovered in our sequenced samples, 61% of which were novel and not previously reported in dbSNP. Although four variants, two in RAD50 and two in NBS1, showed association results suggestive of an effect on NHL, they were not significant after correction for multiple tests. Conclusion These results suggest an influence of RAD50 and NBS1 on susceptibility to diffuse large B-cell lymphoma and marginal zone lymphoma. Larger association and functional studies could confirm such a role.

  9. Investigation on the association between NLRP3 gene polymorphisms and susceptibility to primary gout.

    Science.gov (United States)

    Wang, L F; Ding, Y J; Zhao, Q; Zhang, X L

    2015-12-09

    We conducted a case-control study to investigate the association between 3 common NALP3 polymorphisms (rs10754558, rs7512998, and rs12137901) and the susceptibility to primary gout. A total of 320 patients with primary gout and 320 controls were included in this study. The genotyping of NALP3 rs10754558, rs7512998, and rs12137901 were conducted by polymerase chain reaction-restriction fragment length polymorphism. Comparison analysis showed that primary gout patients were more likely to have higher body mass index, prevalence of hypertension, blood glucose, triglycerides, urea nitrogen, and uric acid (P gene polymorphisms and the risk of primary gout.

  10. Associations between CD36 gene polymorphisms and susceptibility to coronary artery heart disease

    International Nuclear Information System (INIS)

    Zhang, Y.; Ling, Z.Y.; Deng, S.B.; Du, H.A.; Yin, Y.H.; Yuan, J.; She, Q.; Chen, Y.Q.

    2014-01-01

    Associations between polymorphisms of the CD36 gene and susceptibility to coronary artery heart disease (CHD) are not clear. We assessed allele frequencies and genotype distributions of CD36 gene polymorphisms in 112 CHD patients and 129 control patients using semi-quantitative polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Additionally, we detected CD36 mRNA expression by real-time quantitative PCR, and we quantified plasma levels of oxidized low-density lipoprotein (ox-LDL) using an enzyme-linked immunosorbent assay (ELISA). There were no significant differences between the two groups (P>0.05) in allele frequencies of rs1761667 or in genotype distribution and allele frequencies of rs3173798. The genotype distribution of rs1761667 significantly differed between CHD patients and controls (P=0.034), with a significantly higher frequency of the AG genotype in the CHD group compared to the control group (P=0.011). The plasma levels of ox-LDL in patients with the AG genotype were remarkably higher than those with the GG and AA genotypes (P=0.010). In a randomized sample taken from patients in the two groups, the CD36 mRNA expression of the CHD patients was higher than that of the controls. In CHD patients, the CD36 mRNA expression in AG genotype patients was remarkably higher than in those with an AA genotype (P=0.005). After adjusted logistic regression analysis, the AG genotype of rs1761667 was associated with an increased risk of CHD (OR=2.337, 95% CI=1.336-4.087, P=0.003). In conclusion, the rs1761667 polymorphism may be closely associated with developing CHD in the Chongqing Han population of China, and an AG genotype may be a genetic susceptibility factor for CHD

  11. Associations between CD36 gene polymorphisms and susceptibility to coronary artery heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Y.; Ling, Z.Y.; Deng, S.B.; Du, H.A.; Yin, Y.H.; Yuan, J.; She, Q.; Chen, Y.Q. [Department of Cardiology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing (China)

    2014-08-08

    Associations between polymorphisms of the CD36 gene and susceptibility to coronary artery heart disease (CHD) are not clear. We assessed allele frequencies and genotype distributions of CD36 gene polymorphisms in 112 CHD patients and 129 control patients using semi-quantitative polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Additionally, we detected CD36 mRNA expression by real-time quantitative PCR, and we quantified plasma levels of oxidized low-density lipoprotein (ox-LDL) using an enzyme-linked immunosorbent assay (ELISA). There were no significant differences between the two groups (P>0.05) in allele frequencies of rs1761667 or in genotype distribution and allele frequencies of rs3173798. The genotype distribution of rs1761667 significantly differed between CHD patients and controls (P=0.034), with a significantly higher frequency of the AG genotype in the CHD group compared to the control group (P=0.011). The plasma levels of ox-LDL in patients with the AG genotype were remarkably higher than those with the GG and AA genotypes (P=0.010). In a randomized sample taken from patients in the two groups, the CD36 mRNA expression of the CHD patients was higher than that of the controls. In CHD patients, the CD36 mRNA expression in AG genotype patients was remarkably higher than in those with an AA genotype (P=0.005). After adjusted logistic regression analysis, the AG genotype of rs1761667 was associated with an increased risk of CHD (OR=2.337, 95% CI=1.336-4.087, P=0.003). In conclusion, the rs1761667 polymorphism may be closely associated with developing CHD in the Chongqing Han population of China, and an AG genotype may be a genetic susceptibility factor for CHD.

  12. Comparison of the diagnostic value of MR imaging and ophthalmoscopy for the staging of retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Khurana, Aman; Wan, Wenshuai; Yeom, Kristen [Stanford University, Department of Radiology, Stanford, CA (United States); Eisenhut, Christina A. [Technical University of Munich, Department of Radiology, Munich (Germany); Ebrahimi, Katayoon B. [Johns Hopkins University, Department of Ocular Oncology, Baltimore, MD (United States); Patel, Chirag [University of California Davis, Department of Radiology, Davis, CA (United States); O' Brien, Joan M. [University of Pennsylvania, Department of Ophthalmology, Philadelphia, PA (United States); Daldrup-Link, Heike E. [Stanford University, Department of Radiology, Stanford, CA (United States); Stanford University, Department of Radiology, Pediatric Radiology Section, Lucile Packard Children' s Hospital, Stanford, CA (United States)

    2013-05-15

    To compare the diagnostic value of magnetic resonance (MR) imaging and ophthalmoscopy for staging of retinoblastoma. MR and ophthalmoscopic images of 36 patients who underwent enucleation were evaluated retrospectively following institutional review board approval. Histopathology being the standard of reference, the sensitivity and specificity of both diagnostic modalities were compared regarding growth pattern, iris neoangiogenesis, retinal detachment, vitreous seeds and optic nerve invasion. Data were analysed via McNemar's test. Both investigations showed no significant difference in accuracy for the detection of different tumour growth patterns (P = 0.80). Vitreous seeding detection was superior by ophthalmoscopy (P < 0.001). For prelaminar optic nerve invasion, MR imaging showed similar sensitivity as ophthalmoscopy but increased specificity of 40 % (CI 0.12-0.74) vs. 20 % (0.03-0.56). MR detected optic nerve involvement past the lamina cribrosa with a sensitivity of 80 % (0.28-0.99) and a specificity of 74 % (0.55-0.88). The absence of optic nerve enhancement excluded histopathological infiltration, but the presence of optic nerve enhancement included a high number of false positives (22-24 %). Ophthalmoscopy remains the method of choice for determining extent within the globe while MR imaging is useful for evaluating extraocular tumour extension. Thus, both have their own strengths and contribute uniquely to the staging of retinoblastoma. (orig.)

  13. p73 gene in dopaminergic neurons is highly susceptible to manganese neurotoxicity.

    Science.gov (United States)

    Kim, Dong-Suk; Jin, Huajun; Anantharam, Vellareddy; Gordon, Richard; Kanthasamy, Arthi; Kanthasamy, Anumantha G

    2017-03-01

    Chronic exposure to elevated levels of manganese (Mn) has been linked to a Parkinsonian-like movement disorder, resulting from dysfunction of the extrapyramidal motor system within the basal ganglia. However, the exact cellular and molecular mechanisms of Mn-induced neurotoxicity remain elusive. In this study, we treated C57BL/6J mice with 30mg/kg Mn via oral gavage for 30 days. Interestingly, in nigral tissues of Mn-exposed mice, we found a significant downregulation of the truncated isoform of p73 protein at the N-terminus (ΔNp73). To further determine the functional role of Mn-induced p73 downregulation in Mn neurotoxicity, we examined the interrelationship between the effect of Mn on p73 gene expression and apoptotic cell death in an N27 dopaminergic neuronal model. Consistent with our animal study, 300μM Mn treatment significantly suppressed p73 mRNA expression in N27 dopaminergic cells. We further determined that protein levels of the ΔNp73 isoform was also reduced in Mn-treated N27 cells and primary striatal cultures. Furthermore, overexpression of ΔNp73 conferred modest cellular protection against Mn-induced neurotoxicity. Taken together, our results demonstrate that Mn exposure downregulates p73 gene expression resulting in enhanced susceptibility to apoptotic cell death. Thus, further characterization of the cellular mechanism underlying p73 gene downregulation will improve our understanding of the molecular underpinnings of Mn neurotoxicity. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Datasets in Gene Expression Omnibus used in the study ORD-020969: Genomic effects of androstenedione and sex-specific liver cancer susceptibility in mice

    Data.gov (United States)

    U.S. Environmental Protection Agency — Datasets in Gene Expression Omnibus used in the study ORD-020969: Genomic effects of androstenedione and sex-specific liver cancer susceptibility in mice. This...

  15. Ciprofloxacin susceptibility of Pseudomonas aeruginosa isolates from keratitis

    DEFF Research Database (Denmark)

    Lomholt, JA; Kilian, Mogens

    2003-01-01

    keratitis, endophthalmitis, contact lens associated red eye (CLARE), and contact lens storage cases showed MIC values below 1 mg/l. Several allelic forms of gyrA and a single variation in the mexR gene product were detected in 10 ciprofloxacin susceptible strains. CONCLUSIONS: The vast majority of eye......AIM: To examine the ciprofloxacin susceptibility of 106 Pseudomonas aeruginosa eye isolates from the United Kingdom, Denmark, India, the United States, and Australia, and to determine the molecular mechanisms of resistance. METHODS: Ciprofloxacin susceptibility was tested by an agar dilution method...... isolates of P aeruginosa from European countries are fully susceptible to ciprofloxacin and the concentration of ciprofloxacin eye drops used for local treatment (3000 mg/l) exceeds MIC values for strains recorded as resistant. Mutations in more than one target gene were associated with higher MIC values....

  16. Ciprofloxacin susceptibility of Pseudomonas aeruginosa isolates from keratitis

    DEFF Research Database (Denmark)

    Lomholt, JA; Kilian, Mogens

    2003-01-01

    AIM: To examine the ciprofloxacin susceptibility of 106 Pseudomonas aeruginosa eye isolates from the United Kingdom, Denmark, India, the United States, and Australia, and to determine the molecular mechanisms of resistance. METHODS: Ciprofloxacin susceptibility was tested by an agar dilution method...... keratitis, endophthalmitis, contact lens associated red eye (CLARE), and contact lens storage cases showed MIC values below 1 mg/l. Several allelic forms of gyrA and a single variation in the mexR gene product were detected in 10 ciprofloxacin susceptible strains. CONCLUSIONS: The vast majority of eye...... isolates of P aeruginosa from European countries are fully susceptible to ciprofloxacin and the concentration of ciprofloxacin eye drops used for local treatment (3000 mg/l) exceeds MIC values for strains recorded as resistant. Mutations in more than one target gene were associated with higher MIC values....

  17. Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19

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    Ferrell Robert E

    2011-01-01

    Full Text Available Abstract Background Abdominal aortic aneurysm (AAA is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM database. Methods Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22 were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies. Results Several SNPs were nominally associated with AAA (p CEBPG, peptidase D (PEPD, and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non-aneurysmal tissue samples. Conclusions Association testing

  18. Detecting differential allelic expression using high-resolution melting curve analysis: application to the breast cancer susceptibility gene CHEK2

    Directory of Open Access Journals (Sweden)

    Sinilnikova Olga

    2011-05-01

    Full Text Available Abstract Background The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified. Methods We implemented an assay based on high-resolution melting (HRM curve analysis and developed an analysis tool for DAE assessment. Results We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs. Conclusions Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.

  19. Rare MDM4 gene amplification in colorectal cancer: The principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable.

    Science.gov (United States)

    Suda, Tetsuji; Yoshihara, Mitsuyo; Nakamura, Yoshiyasu; Sekiguchi, Hironobu; Godai, Ten-I; Sugano, Nobuhiro; Tsuchida, Kazuhito; Shiozawa, Manabu; Sakuma, Yuji; Tsuchiya, Eiju; Kameda, Yoichi; Akaike, Makoto; Matsukuma, Shoichi; Miyagi, Yohei

    2011-07-01

    MDM4, a homolog of MDM2, is considered a key negative regulator of p53. Gene amplification of MDM4 has been identified in a variety of tumors. MDM2 or MDM4 gene amplification is only associated with the wild-type TP53 gene in retinoblastomas, thus the amplification of the two genes is mutually exclusive. Previously, we demonstrated that MDM2 amplification and TP53 alteration were not mutually exclusive in colorectal cancer, and we identified a subset of colorectal cancer patients without alterations in either the TP53 or the MDM2 gene. In this study, we investigated the gene amplification status of MDM4 in the same set of colorectal cancer cases. Unexpectedly, MDM4 amplification was rare, detected in only 1.4% (3 out of 211) of colorectal cancer cases. All the three gene-amplified tumors also harbored TP53-inactivating mutations. This contradicts the simple mutually exclusive relationship observed in retinoblastomas. Surprisingly, two of the three MDM4-amplified tumors also demonstrated MDM2 amplification. Paradoxically, the MDM4 protein levels were decreased in the tumor tissue of the gene-amplified cases compared with levels in the matched normal mucosa. We speculate that MDM4 might play a role in colorectal carcinogenesis that is not limited to negative regulation of p53 in combination with MDM2. The functional significance of MDM4 is still unclear and further studies are needed.

  20. Relevance of CT and MRI in retinoblastoma for the diagnosis of postlaminar invasion with normal-size optic nerve: a retrospective study of 150 patients with histological comparison

    International Nuclear Information System (INIS)

    Brisse, Herve J.; Guesmi, Myriam; Neuenschwander, Sylvia; Aerts, Isabelle; Sastre-Garau, Xavier; Savignoni, Alexia; Asselain, Bernard; Bours, Daniele; Lumbroso-Le Rouic, Livia; Desjardins, Laurence; Doz, Francois

    2007-01-01

    Detection of optic nerve invasion is mandatory in children primarily enucleated for retinoblastoma to ensure a free resection margin. To assess the accuracy of CT and MRI for the detection of postlaminar invasion in normal-size nerves. A total of 150 patients enucleated for retinoblastoma were included. Imaging data (119 CT and 46 MRI) were retrospectively reviewed and compared with histological findings. Abnormal contrast enhancement of the optic nerve was used as diagnostic criterion for invasion. The associations between postlaminar invasion and several indirect signs were also assessed. Statistical analysis was performed with the Kruskal-Wallis and Fisher exact tests. Postlaminar invasion on histology was observed in 8% (12/150). The sensitivity, specificity, accuracy and negative and positive predictive values were 60%, 95%, 91%, 95% and 60% for MRI, and 0%, 100%, 94% and 94% (PPV not assessable) for CT, respectively. Tumour diameter was the only indirect radiological sign significantly associated with postlaminar optic nerve invasion (P=0.002). Our results suggest that MRI is more relevant than CT for preoperative detection of optic nerve invasion in patients with retinoblastoma. Tumour diameter is the only indirect sign significantly associated with postlaminar invasion. (orig.)

  1. Relevance of CT and MRI in retinoblastoma for the diagnosis of postlaminar invasion with normal-size optic nerve: a retrospective study of 150 patients with histological comparison

    Energy Technology Data Exchange (ETDEWEB)

    Brisse, Herve J.; Guesmi, Myriam; Neuenschwander, Sylvia [Institute Curie, Department of Radiology, Paris (France); Aerts, Isabelle [Institute Curie, Department of Paediatric Oncology, Paris (France); Sastre-Garau, Xavier [Institute Curie, Department of Pathology, Paris (France); Savignoni, Alexia; Asselain, Bernard; Bours, Daniele [Institute Curie, Department of Biostatistics, Paris (France); Lumbroso-Le Rouic, Livia; Desjardins, Laurence [Institute Curie, Department of Ocular Oncology, Paris (France); Doz, Francois [Institute Curie, Department of Paediatric Oncology, Paris (France); Faculty of Medicine, Department of Paediatrics, Paris (France)

    2007-07-15

    Detection of optic nerve invasion is mandatory in children primarily enucleated for retinoblastoma to ensure a free resection margin. To assess the accuracy of CT and MRI for the detection of postlaminar invasion in normal-size nerves. A total of 150 patients enucleated for retinoblastoma were included. Imaging data (119 CT and 46 MRI) were retrospectively reviewed and compared with histological findings. Abnormal contrast enhancement of the optic nerve was used as diagnostic criterion for invasion. The associations between postlaminar invasion and several indirect signs were also assessed. Statistical analysis was performed with the Kruskal-Wallis and Fisher exact tests. Postlaminar invasion on histology was observed in 8% (12/150). The sensitivity, specificity, accuracy and negative and positive predictive values were 60%, 95%, 91%, 95% and 60% for MRI, and 0%, 100%, 94% and 94% (PPV not assessable) for CT, respectively. Tumour diameter was the only indirect radiological sign significantly associated with postlaminar optic nerve invasion (P=0.002). Our results suggest that MRI is more relevant than CT for preoperative detection of optic nerve invasion in patients with retinoblastoma. Tumour diameter is the only indirect sign significantly associated with postlaminar invasion. (orig.)

  2. Disease susceptibility of the human macula: differential gene transcription in the retinal pigmented epithelium/choroid.

    Science.gov (United States)

    Radeke, Monte J; Peterson, Katie E; Johnson, Lincoln V; Anderson, Don H

    2007-09-01

    The discoveries of gene variants associated with macular diseases have provided valuable insight into their molecular mechanisms, but they have not clarified why the macula is particularly vulnerable to degenerative disease. Its predisposition may be attributable to specialized structural features and/or functional properties of the underlying macular RPE/choroid. To examine the molecular basis for the macula's disease susceptibility, we compared the gene expression profile of the human RPE/choroid in the macula with the profile in the extramacular region using DNA microarrays. Seventy-five candidate genes with differences in macular:extramacular expression levels were identified by microarray analysis, of which 29 were selected for further analysis. Quantitative PCR confirmed that 21 showed statistically significant differences in expression. Five genes were expressed at higher levels in the macula. Two showed significant changes in the macular:extramacular expression ratio; another two exhibited changes in absolute expression level, as a function of age or AMD. Several of the differentially expressed genes have potential relevance to AMD pathobiology. One is an RPE cell growth factor (TFPI2), five are extracellular matrix components (DCN, MYOC, OGN, SMOC2, TFPI2), and six are related to inflammation (CCL19, CCL26, CXCL14, SLIT2) and/or angiogenesis (CXCL14, SLIT2, TFPI2, WFDC1). The identification of regional differences in gene expression in the RPE/choroid is a first step in clarifying the macula's propensity for degeneration. These findings lay the groundwork for further studies into the roles of the corresponding gene products in the normal, aged, and diseased macula.

  3. Tumor regression patterns in retinoblastoma

    International Nuclear Information System (INIS)

    Zafar, S.N.; Siddique, S.N.; Zaheer, N.

    2016-01-01

    To observe the types of tumor regression after treatment, and identify the common pattern of regression in our patients. Study Design: Descriptive study. Place and Duration of Study: Department of Pediatric Ophthalmology and Strabismus, Al-Shifa Trust Eye Hospital, Rawalpindi, Pakistan, from October 2011 to October 2014. Methodology: Children with unilateral and bilateral retinoblastoma were included in the study. Patients were referred to Pakistan Institute of Medical Sciences, Islamabad, for chemotherapy. After every cycle of chemotherapy, dilated funds examination under anesthesia was performed to record response of the treatment. Regression patterns were recorded on RetCam II. Results: Seventy-four tumors were included in the study. Out of 74 tumors, 3 were ICRB group A tumors, 43 were ICRB group B tumors, 14 tumors belonged to ICRB group C, and remaining 14 were ICRB group D tumors. Type IV regression was seen in 39.1% (n=29) tumors, type II in 29.7% (n=22), type III in 25.6% (n=19), and type I in 5.4% (n=4). All group A tumors (100%) showed type IV regression. Seventeen (39.5%) group B tumors showed type IV regression. In group C, 5 tumors (35.7%) showed type II regression and 5 tumors (35.7%) showed type IV regression. In group D, 6 tumors (42.9%) regressed to type II non-calcified remnants. Conclusion: The response and success of the focal and systemic treatment, as judged by the appearance of different patterns of tumor regression, varies with the ICRB grouping of the tumor. (author)

  4. Differential expression of Toll-like receptor pathway genes in chicken embryo fibroblasts from chickens resistant and susceptible to Marek's disease.

    Science.gov (United States)

    Haunshi, Santosh; Cheng, Hans H

    2014-03-01

    The Toll-like receptor (TLR) signaling pathway is one of the innate immune defense mechanisms against pathogens in vertebrates and invertebrates. However, the role of TLR in non-MHC genetic resistance or susceptibility to Marek's disease (MD) in the chicken is yet to be elucidated. Chicken embryo fibroblast (CEF) cells from MD susceptible and resistant lines were infected either with Marek's disease virus (MDV) or treated with polyionosinic-polycytidylic acid, a synthetic analog of dsRNA, and the expression of TLR and pro-inflammatory cytokines was studied at 8 and 36 h posttreatment by quantitative reverse transcriptase PCR. Findings of the present study reveal that MDV infection and polyionosinic-polycytidylic acid treatment significantly elevated the mRNA expression of TLR3, IL6, and IL8 in both susceptible and resistant lines. Furthermore, basal expression levels in uninfected CEF for TLR3, TLR7, and IL8 genes were significantly higher in resistant chickens compared with those of susceptible chickens. Our results suggest that TLR3 together with pro-inflammatory cytokines may play a significant role in genetic resistance to MD.

  5. An international survey of classification and treatment choices for group D retinoblastoma

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    Jasmine H Francis

    2017-06-01

    Full Text Available AIM: To determine which IIRC scheme was used by retinoblastoma centers worldwide and the percentage of D eyes treated primarily with enucleation versus globe salvaging therapies as well as to correlate trends in treatment choice to IIRC version used and geographic region. METHODS: An anonymized electronic survey was offered to 115 physicians at 39 retinoblastoma centers worldwide asking about IIRC classification schemes and treatment patterns used between 2008 and 2012. Participants were asked to record which version of the IIRC was used for classification, how many group D eyes were diagnosed, and how many eyes were treated with enucleation versus globe salvaging therapies. Averages of eyes per treatment modality were calculated and stratified by both IIRC version and geographic region. Statistical significance was determined by Chi-square, ANOVA and Kruskal-Wallis tests using Prism. RESULTS: The survey was completed by 29% of physicians invited to participate. Totally 1807 D eyes were diagnosed. Regarding IIRC system, 27% of centers used the Children’s Hospital of Los Angeles (CHLA version, 33% used the Children’s Oncology Group (COG version, 23% used the Philadelphia version, and 17% were unsure. The rate for primary enucleation varied between 0 and 100% and the mean was 29%. By IIRC version, primary enucleation rates were: Philadelphia, 8%; COG, 34%; and CHLA, 37%. By geographic region, primary enucleation rates were: Latin America, 57%; Asia, 40%; Europe, 36%; Africa, 10%, US, 8%; and Middle East, 8%. However, systemic chemoreduction was used more often than enucleation in all regions except Latin America with a mean of 57% per center (P<0.0001. CONCLUSION: Worldwide there is no consensus on which IIRC version is used, systemic chemoreduction was the most frequently used initial treatment during the study period followed by enucleation and primary treatment modality, especially enucleation, varied greatly with regards to IIRC version

  6. Estudo do raspado de conjuntiva e margem palpebral de pacientes tratados de retinoblastoma: etapa I - Microflora aeróbica Study of the conjunctival scrape and eyelid margin smears in patients treated for retinoblastoma: phase I - Aerobic microflora

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    Maria Carmen Menezes Santos

    2002-03-01

    Full Text Available Objetivo: A queixa de secreção ocular é muito freqüente entre os pacientes tratados de retinoblastoma submetidos à enucleação e radioterapia. A falta de dados sobre a microflora em pacientes nessas condições foi o que motivou este estudo. Métodos: Foram examinadas 114 órbitas de 58 pacientes. Este trabalho apresenta os resultados das culturas para bactérias aeróbicas e fungos, de conjuntiva e margem palpebral em 4 condições, com e sem enucleação, com e sem radioterapia. Procedeu-se à identificação dos microrganismos de acordo com o Protocolo do National Committee for Clinical Laboratory Standards e os esfregaços para citologia foram submetidos às colorações de Gram e Leishman. Resultados: A presença de microrganismos foi mais freqüente nas cavidades anoftálmicas irradiadas, tanto na conjuntiva (54,5% quanto na margem palpebral (63,6%, porém sem diferença estatisticamente significante. Além disso, em órbitas com bulbo ocular, a radiação, na fase tardia, representou um fator limitante da presença de microrganismos na conjuntiva e na margem palpebral, mas sem diferença estatisticamente significante. O Staphylococcus coagulase negativa foi o microrganismo mais freqüente na conjuntiva e margem palpebral de todos os grupos. Houve crescimento de fungo, Candida tropicalis, em apenas um caso. Conclusões: Sugere-se o uso de colírios antibióticos em pacientes tratados de retinoblastoma, portadores de cavidade anoftálmica, irradiada ou não.Purpose: Conjunctival discharge is a common complaint among patients treated for retinoblastoma who underwent enucleation and radiotherapy. Lack of data about the microflora in those patients motivated this study. Methods: One hundred and fourteen orbits of 58 patients were examined. The authors present the results of aerobic bacterial and fungal culture of conjunctival and eyelid margin smears, as well as conjunctival cytology, in 4 different conditions: with and without

  7. Timecourse microarray analyses reveal global changes in gene expression of susceptible Glycine max (soybean) roots during infection by Heterodera glycines (soybean cyst nematode).

    Science.gov (United States)

    Alkharouf, Nadim W; Klink, Vincent P; Chouikha, Imed B; Beard, Hunter S; MacDonald, Margaret H; Meyer, Susan; Knap, Halina T; Khan, Rana; Matthews, Benjamin F

    2006-09-01

    Changes in gene expression within roots of Glycine max (soybean), cv. Kent, susceptible to infection by Heterodera glycines (the soybean cyst nematode [SCN]), at 6, 12, and 24 h, and 2, 4, 6, and 8 days post-inoculation were monitored using microarrays containing more than 6,000 cDNA inserts. Replicate, independent biological samples were examined at each time point. Gene expression was analyzed statistically using T-tests, ANOVA, clustering algorithms, and online analytical processing (OLAP). These analyses allow the user to query the data in several ways without importing the data into third-party software. RT-PCR confirmed that WRKY6 transcription factor, trehalose phosphate synthase, EIF4a, Skp1, and CLB1 were differentially induced across most time-points. Other genes induced across most timepoints included lipoxygenase, calmodulin, phospholipase C, metallothionein-like protein, and chalcone reductase. RT-PCR demonstrated enhanced expression during the first 12 h of infection for Kunitz trypsin inhibitor and sucrose synthase. The stress-related gene, SAM-22, phospholipase D and 12-oxophytodienoate reductase were also induced at the early time-points. At 6 and 8 dpi there was an abundance of transcripts expressed that encoded genes involved in transcription and protein synthesis. Some of those genes included ribosomal proteins, and initiation and elongation factors. Several genes involved in carbon metabolism and transport were also more abundant. Those genes included glyceraldehyde 3-phosphate dehydrogenase, fructose-bisphosphate aldolase and sucrose synthase. These results identified specific changes in gene transcript levels triggered by infection of susceptible soybean roots by SCN.

  8. Whole Genome Association Study in a Homogenous Population in Shandong Peninsula of China Reveals JARID2 as a Susceptibility Gene for Schizophrenia

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    Yang Liu

    2009-01-01

    Full Text Available DNA pooling can provide an economic and efficient way to detect susceptibility loci to complex diseases. We carried out a genome screen with 400 microsatellite markers spaced at approximately 10 cm in two DNA pools consisting of 119 schizophrenia (SZ patients and 119 controls recruited from a homogenous population in the Chang Le area of the Shandong peninsula of China. Association of D6S289, a dinucleotide repeat polymorphism in the JARID2 gene with SZ, was found and confirmed by individual genotyping (X2=17.89; P=.047. In order to refine the signal, we genotyped 14 single nucleotide polymorphisms (SNPs covering JARID2 and the neighboring gene, DNTBP1, in an extended sample of 309 cases and 309 controls from Shandong peninsula (including the samples from the pools. However, rs2235258 and rs9654600 in JARID2 showed association in allelic, genotypic and haplotypic tests with SZ patients from Chang Le area. This was not replicates in the extended sample, we conclude that JARID2 could be a susceptibility gene for SZ.

  9. Whole Genome Association Study in a Homogenous Population in Shandong Peninsula of China Reveals JARID2 as a Susceptibility Gene for Schizophrenia

    Science.gov (United States)

    Liu, Yang; Chen, Gang; Norton, Nadine; Liu, Wenmin; Zhu, Haining; Zhou, Peng; Luan, Meng; Yang, Shulin; Chen, Xing; Carroll, Liam; Williams, Nigel M.; O'Donovan, Michael C.; Kirov, George; Owen, Michael J.

    2009-01-01

    DNA pooling can provide an economic and efficient way to detect susceptibility loci to complex diseases. We carried out a genome screen with 400 microsatellite markers spaced at approximately 10 cm in two DNA pools consisting of 119 schizophrenia (SZ) patients and 119 controls recruited from a homogenous population in the Chang Le area of the Shandong peninsula of China. Association of D6S289, a dinucleotide repeat polymorphism in the JARID2 gene with SZ, was found and confirmed by individual genotyping (X2 = 17.89; P = .047). In order to refine the signal, we genotyped 14 single nucleotide polymorphisms (SNPs) covering JARID2 and the neighboring gene, DNTBP1, in an extended sample of 309 cases and 309 controls from Shandong peninsula (including the samples from the pools). However, rs2235258 and rs9654600 in JARID2 showed association in allelic, genotypic and haplotypic tests with SZ patients from Chang Le area. This was not replicates in the extended sample, we conclude that JARID2 could be a susceptibility gene for SZ. PMID:19884986

  10. Aldosterone synthase gene is not a major susceptibility gene for progression of chronic kidney disease in patients with autosomal dominant polycystic kidney disease

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    Gnanasambandan Ramanathan

    2017-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is the most common heritable kidney disease and is characterized by bilateral renal cysts. Hypertension is a frequent cause of chronic kidney disease (CKD and mortality in patients with ADPKD. The aldosterone synthase gene polymorphisms of the renin-angiotensin-aldosterone system have been extensively studied as hypertension candidate genes. The present study is aimed to investigate the potential modifier effect of CYP11B2 gene on the progression of CKD in ADPKD. One hundred and two ADPKD patients and 106 healthy controls were recruited based on Ravine inclusion and exclusion criteria. The three tag-SNPs within CYP11B2 gene (rs3802230, rs4543, and rs4544 were genotyped using FRET-based KASPar method. Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Mantel- Haenszel stratified analysis was used to explore confounding and interaction effects of these polymorphisms. Of the three tag-SNPs genotyped, rs4544 polymorphism was monomorphic and rs3802230 deviated Hardy-Weinberg equilibrium. The CYP11B2 tag-SNPs did not show significant association with ADPKD or CKD. Further, these polymorphisms did not exhibit confounding effect on the relationship between CKD progression and hypertension. Our results suggest that aldosterone synthase gene is not a major susceptibility gene for progression of CKD in South Indian ADPKD patients.

  11. The VNTR Polymorphism of the DC-SIGNR Gene and Susceptibility to HIV-1 Infection: A Meta-Analysis

    OpenAIRE

    Li, Hui; Yu, Xiao-Min; Wang, Jia-Xin; Hong, Ze-Hui; Tang, Nelson Leung-Sang

    2012-01-01

    BACKGROUND: Dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin related (DC-SIGNR) can bind to the human immunodeficiency virus-1 (HIV-1) gp120 envelope glycoprotein and is thus important for the host-pathogen interaction in HIV-1 infection. Studies of the association between the variable number tandem repeat (VNTR) polymorphism of the DC-SIGNR gene and HIV-1 susceptibility have produced controversial results. METHODS AND FINDINGS: We conducted a meta-analysis of th...

  12. An epistatic interaction between the PAX8 and STK17B genes in papillary thyroid cancer susceptibility.

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    Iñigo Landa

    Full Text Available Papillary Thyroid Cancer (PTC is a heterogeneous and complex disease; susceptibility to PTC is influenced by the joint effects of multiple common, low-penetrance genes, although relatively few have been identified to date. Here we applied a rigorous combined approach to assess both the individual and epistatic contributions of genetic factors to PTC susceptibility, based on one of the largest series of thyroid cancer cases described to date. In addition to identifying the involvement of TSHR variation in classic PTC, our pioneer study of epistasis revealed a significant interaction between variants in STK17B and PAX8. The interaction was detected by MD-MBR (p = 0.00010 and confirmed by other methods, and then replicated in a second independent series of patients (MD-MBR p = 0.017. Furthermore, we demonstrated an inverse correlation between expression of PAX8 and STK17B in a set of cell lines derived from human thyroid carcinomas. Overall, our work sheds additional light on the genetic basis of thyroid cancer susceptibility, and suggests a new direction for the exploration of the inherited genetic contribution to disease using association studies.

  13. The Canine POMC Gene, Obesity in Labrador Retrievers and Susceptibility to Diabetes Mellitus.

    Science.gov (United States)

    Davison, L J; Holder, A; Catchpole, B; O'Callaghan, C A

    2017-03-01

    Diabetes mellitus (DM) in dogs is a common endocrinopathy with a complex genetic architecture. Disease susceptibility in several breeds is associated with polymorphisms in immune response genes, but in the Labrador retriever breed, no genetic associations with DM have been identified. A deletion in the pro-opiomelanocortin (POMC) gene in Labrador retrievers is associated with increased appetite and risk of obesity. To characterize the POMC deletion in Labrador retrievers, to develop a simple genetic test for this mutation, and to test the hypothesis that the POMC gene deletion is associated with an increased risk of DM in this breed. Sixty-one non-diabetic Labrador retrievers aged >6 years and 57 Labrador retrievers with DM. Case-control genotyping study to compare the frequency of the POMC deletion in dogs with and without DM. After polymerase chain reaction (PCR) and sequencing to characterize the mutation, a PCR-based test was developed and validated using 2 different restriction fragment length polymorphism assays. A 14-base-pair deletion was confirmed and localized to exon 3 of the canine POMC gene. A PCR-based test for the deletion was successfully developed. There was no association between the presence of the POMC deletion mutation and DM in this population of Labrador retriever dogs (P = .31). This study adds to the existing scientific literature indicating that there is little evidence for a direct link between obesity and DM in dogs. Copyright © 2016 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  14. Structure models of G72, the product of a susceptibility gene to schizophrenia.

    Science.gov (United States)

    Kato, Yusuke; Fukui, Kiyoshi

    2017-02-01

    The G72 gene is one of the most susceptible genes to schizophrenia and is contained exclusively in the genomes of primates. The product of the G72 gene modulates the activity of D-amino acid oxidase (DAO) and is a small protein prone to aggregate, which hampers its structural studies. In addition, lack of a known structure of a homologue makes it difficult to use the homology modelling method for the prediction of the structure. Thus, we first developed a hybrid ab initio approach for small proteins prior to the prediction of the structure of G72. The approach uses three known ab initio algorithms. To evaluate the hybrid approach, we tested our prediction of the structure of the amino acid sequences whose structures were already solved and compared the predicted structures with the experimentally solved structures. Based on these comparisons, the average accuracy of our approach was calculated to be ∼5 Å. We then applied the approach to the sequence of G72 and successfully predicted the structures of the N- and C-terminal domains (ND and CD, respectively) of G72. The predicted structures of ND and CD were similar to membrane-bound proteins and adaptor proteins, respectively. © The Authors 2016. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  15. The Association between NOS3 Gene Polymorphisms and Hypoxic-Ischemic Encephalopathy Susceptibility and Symptoms in Chinese Han Population

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    Yongqin Wu

    2016-01-01

    Full Text Available Endothelial NOS (NOS3 has a potential role in the prevention of neuronal injury in hypoxic-ischemic encephalopathy (HIE. Thus, we aimed to explore the association between NOS3 gene polymorphisms and HIE susceptibility and symptoms in a Chinese Han population. Three single nucleotide polymorphisms (SNPs in the NOS3 gene, rs1800783, rs1800779, and rs2070744, were detected in 226 children with HIE and 212 healthy children in a Chinese Han population. Apgar scores and magnetic resonance image scans were used to estimate the symptoms and brain damage. The association analyses were conducted by using SNPStats and SPSS 18.0 software. The genotype and allele distributions of rs1800779 and rs1799983 displayed no significant differences between the patients and the controls, while the rs2070744 allele distribution was significantly different (corrected P=0.009. For clinical characteristics, the rs2070744 genotype distribution was significantly different in patients with different Apgar scores (≤5, TT/TC/CC = 6/7/5; 6~7, TT/TC/CC = 17/0/0; 8~9, TT/TC/CC = 6/2/0; 10, TT/TC/CC = 7/1/0; corrected P=0.006 in the 1001 to 1449 g birth weight subgroup. The haplotype test did not show any associations with the risk and clinical characteristics of HIE. The results suggest that NOS3 gene SNP rs2070744 was significantly associated with HIE susceptibility and symptom expression in Chinese Han population.

  16. [Association of polymorphisms in signal transducer and activator of transcription 4 gene and the susceptibility to unexplained recurrent spontaneous abortions].

    Science.gov (United States)

    Li, Yin-Guang; You, Ze-Shan; Wu, Zai-Gui; Li, Zhu-Yu; Li, Jie; Zhang, Xiu-Ming; Fang, Li-Yuan; Jiang, Li

    2013-09-01

    To investigate the association between the polymorphisms of signal transducer and activator of transcription 4 (STAT4) gene and the susceptibility to unexplained recurrent spontaneous abortion(URSA). PCR-restriction fragment length polymorphism (PCR-RFLP) was used to detect genotype 3 loca (rs7574865 G/T, rs10181656 C/G and rs16833431 C/T) polymorphism of STAT4 in 246 URSA cases (URSA group) and 183 normal controls (control group) . (1)The frequencies of rs7574865 were genotype G/G of 36.2% (89/246) in URSA group and 46.4% (85/183) in control group, genotype G/T of 47.2% (116/246) in URSA group and 45.4% (83/183) in control group, and genotype T/T of 16.7% (41/246) in URSA group and 8.2% (15/183) in control group, which reached statistical difference (P rs7574865 T allele and rs10181656 G allele increased the risk of URSA (OR = 1.51, 1.44, all P rs7574865 G/T and rs10181656 C/G showed haplotype G-T conferring the susceptibility to URSA (OR = 1.49, P < 0.01), but haplotype C-G could provide protection on URSA (OR = 0.68, P < 0.01). Polymorphisms of STAT4 gene might confer the susceptibility to URSA by altering STAT4 function and (or) its expression.

  17. Reconstruction of severe anophthalmic orbits and atresic eye sockets after enucleation and irradiation of retinoblastoma by vascular anastomosed free dorsalis pedis flaps' transplantation.

    Science.gov (United States)

    Bi, Xiaoping; Fan, Xianqun; Zhou, Huifang; Shi, Wodong; Xiao, Caiwen; Lin, Min; Li, Zhenkang

    2011-05-01

    Retinoblastoma is a common malignant intraocular tumor in childhood, and most patients require enucleation or exenteration even with irradiation. Severe anophthalmic orbits and atresic eye sockets are not rare. We conducted a retrospective study to evaluate the results of surgical management of reconstruction of severe anophthalmic orbits and atresic eye sockets with vascular anastomosed free dorsalis pedis flap transplantation. There were 5 patients (5 eyes) who underwent reconstructive surgery of severe anophthalmic orbits and atresic eye sockets after enucleation and irradiation of retinoblastoma in our hospital during the 3 years. All patients had enucleation and irradiation immediately after the retinoblastoma was diagnosed and had never worn artificial eyes because of the atresic eye sockets. Vascular anastomosed free dorsalis pedis flaps, whose dimensions were typically 6.5 × 5.5 cm(2), were transplanted to reconstruct the severe anophthalmic orbits and atresic eye sockets. The donor sites were covered by free abdominal skin flaps. All the vascular anastomosed free dorsalis pedis flaps were valid after more than 6 months of follow-up. And then all the 5 patients underwent secondary autogenous dermal fat implantation to augment the supraorbital area depression. After the 2-stage reconstruction surgery, the dimensions of the eye sockets were adequate, and all patients were able to wear their prosthesis and had a satisfactory cosmetic result. Implantation of alloplastic materials is not recommended because of insufficient blood supply of the irradiated orbital area.

  18. Polymorphisms in voltage-gated sodium channel gene and susceptibility of Aedes albopictus to insecticides in three districts of northern West Bengal, India.

    Science.gov (United States)

    Chatterjee, Moytrey; Ballav, Sudeep; Maji, Ardhendu K; Basu, Nandita; Sarkar, Biplab Chandra; Saha, Pabitra

    2018-01-01

    The control and prevention of dengue largely depends on vector control measures, environmental management, and personal protection. Dengue control programmes are facing great challenges due to development of insecticide resistance among vector mosquitoes. Information on susceptibility status to different insecticides is important for national programmes to formulate vector control strategies. We have studied the larval susceptibility of Aedes albopictus to temephos and adult susceptibility to 4% DDT, 0.05% deltamethrin, and 5% malathion as per WHO protocols in the northern districts of West Bengal. Polymorphisms in the VGSC gene were studied by direct sequencing of PCR products. The Ae. albopictus larval population showed sensitive [Resistance Ratio (RR99)resistance (510) to temephos at different study sites. Adult bioassay results revealed that Ae. albopictus was highly resistant to DDT [Corrected Mortality (CM) 98%), except in Dhupguri where a low level of resistance to deltamethrin (CM = 96.25%) was recorded. None of the six important kdr mutations (S953P, I975M/V, L978, V980G, F1474C, D1703Y) were found in the VGSC of studied mosquitoes, but we identified 11 synonymous and 1 non-synonymous mutation in the VGSC gene. The higher susceptibility level to deltamethrin and malathion, along with the absence of important kdr mutations indicates that these two insecticides are still effective against Ae. albopictus in the study areas. The susceptibility status of temephos should be monitored closely as low to moderate levels of resistance were observed in few sites. A similar study is recommended for monitoring and early detection of insecticide resistance in other parts of the country.

  19. Antimicrobial susceptibility and antibiotic resistance gene transfer analysis of foodborne, clinical, and environmental Listeria spp. isolates including Listeria monocytogenes.

    Science.gov (United States)

    Bertsch, David; Muelli, Mirjam; Weller, Monika; Uruty, Anaïs; Lacroix, Christophe; Meile, Leo

    2014-02-01

    The aims of this study were to assess antibiotic resistance pheno- and genotypes in foodborne, clinical, and environmental Listeria isolates, as well as to elucidate the horizontal gene transfer potential of detected resistance genes. A small fraction of in total 524 Listeria spp. isolates (3.1%) displayed acquired antibiotic resistance mainly to tetracycline (n = 11), but also to clindamycin (n = 4) and trimethoprim (n = 3), which was genotypically confirmed. In two cases, a tetracycline resistance phenotype was observed together with a trimethoprim resistance phenotype, namely in a clinical L. monocytogenes strain and in a foodborne L. innocua isolate. Depending on the applied guidelines, a differing number of isolates (n = 2 or n = 20) showed values for ampicillin that are on the edge between intermediate susceptibility and resistance. Transferability of the antibiotic resistance genes from the Listeria donors, elucidated in vitro by filter matings, was demonstrated for genes located on transposons of the Tn916 family and for an unknown clindamycin resistance determinant. Transfer rates of up to 10(-5) transconjugants per donor were obtained with a L. monocytogenes recipient and up to 10(-7) with an Enterococcus faecalis recipient, respectively. Although the prevalence of acquired antibiotic resistance in Listeria isolates from this study was rather low, the transferability of these resistances enables further spread in the future. This endorses the importance of surveillance of L. monocytogenes and other Listeria spp. in terms of antibiotic susceptibility. © 2014 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

  20. Functional characterization of JMJD2A, a histone deacetylase- and retinoblastoma-binding protein.

    Science.gov (United States)

    Gray, Steven G; Iglesias, Antonio H; Lizcano, Fernando; Villanueva, Raul; Camelo, Sandra; Jingu, Hisaka; Teh, Bin T; Koibuchi, Noriyuki; Chin, William W; Kokkotou, Efi; Dangond, Fernando

    2005-08-05

    To effectively direct targeted repression, the class I histone deacetylases (HDACs) associate with many important regulatory proteins. In this paper we describe the molecular characterization of a member of the Jumonji domain 2 (JMJD2) family of proteins, and demonstrate its binding to both class I HDACs and the retinoblastoma protein (pRb). JMJD2 proteins are characterized by the presence of two leukemia-associated protein/plant homeodomain (LAP/PHD) zinc fingers, one JmjN, one JmjC (containing an internal retinoblastoma-binding protein 2 (RBBP2)-like sequence), and two Tudor domains. The first member of this group, JMJD2A, is widely expressed in human tissues and cell lines, and high endogenous expression of JMJD2A mRNA was found in several cell types, including human T-cell lymphotropic virus 1 (HTLV-1)-infected cell lines. JMJD2A and JMJD2B exhibit cell type-specific responses to the HDAC inhibitor trichostatin A. We show that the JMJD2A protein associates in vivo with pRb and class I HDACs, and mediates repression of E2F-regulated promoters. In HTLV-1 virus-infected cells, we find that JMJD2A binds to the viral Tax protein. Antibodies to JMJD2A recognize the native protein but also a half-sized protein fragment, the latter up-regulated in THP-1 cells during the G(2)/M phase of the cell cycle. The ability of JMJD2A to associate with pRb and HDACs and potentiate pRb-mediated repression of E2F-regulated promoters implies an important role for this protein in cell proliferation and oncogenesis.