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Sample records for retinoblastoma protein-related p130

  1. 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...

  2. 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

  3. 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

  4. 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.)

  5. Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4

    DEFF Research Database (Denmark)

    Farkas, Thomas; Hansen, Klaus; Holm, Karin

    2002-01-01

    The "pocket proteins" pRb (retinoblastoma tumor suppressor protein), p107, and p130 regulate cell proliferation via phosphorylation-sensitive interactions with E2F transcription factors and other proteins. We previously identified 22 in vivo phosphorylation sites in human p130, including three...

  6. Phosphorylation-dependent and -independent functions of p130 cooperate to evoke a sustained G1 block

    DEFF Research Database (Denmark)

    Hansen, Klaus; Farkas, T; Lukas, J

    2001-01-01

    The retinoblastoma (pRb)-related p130 pocket protein is a regulator of cell growth and differentiation, and a candidate tumour suppressor. Both pRb and p130 operate through interactions with cellular proteins, including the E2F transcription factors. While such interactions are controlled...

  7. 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

  8. Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation.

    Science.gov (United States)

    Capasso, Stefania; Alessio, Nicola; Di Bernardo, Giovanni; Cipollaro, Marilena; Melone, Mariarosa Ab; Peluso, Gianfranco; Giordano, Antonio; Galderisi, Umberto

    2014-01-01

    Bone marrow adipose tissue (BMAT) is different from fat found elsewhere in the body, and only recently have some of its functions been investigated. BMAT may regulate bone marrow stem cell niche and plays a role in energy storage and thermogenesis. BMAT may be involved also in obesity and osteoporosis onset. Given the paramount functions of BMAT, we decided to better clarify the human bone marrow adipogenesis by analyzing the role of the retinoblastoma gene family, which are key players in cell cycle regulation. Our data provide evidence that the inactivation of RB1 or RB2/P130 in uncommitted bone marrow stromal cells (BMSC) facilitates the first steps of adipogenesis. In cultures with silenced RB1 or RB2/P130, we observed an increase of clones with adipogenic potential and a higher percentage of cells accumulating lipid droplets. Nevertheless, the absence of RB1 or RB2/P130 impaired the terminal adipocyte differentiation and gave rise to dysregulated adipose cells, with alteration in lipid uptake and release. For the first time, we evidenced that RB2/P130 plays a role in bone marrow adipogenesis. Our data suggest that while the inactivation of retinoblastoma proteins may delay the onset of last cell division and allow more BMSC to be committed to adipocyte, it did not allow a permanent cell cycle exit, which is a prerequisite for adipocyte terminal maturation.

  9. RBL2/p130 is a direct AKT target and is required to induce apoptosis upon AKT inhibition in lung cancer and mesothelioma cell lines.

    Science.gov (United States)

    Pentimalli, Francesca; Forte, Iris M; Esposito, Luca; Indovina, Paola; Iannuzzi, Carmelina A; Alfano, Luigi; Costa, Caterina; Barone, Daniela; Rocco, Gaetano; Giordano, Antonio

    2018-04-02

    The retinoblastoma (RB) protein family includes RB1/p105, RBL1/p107, and RBL2/p130, which are key factors in cell-cycle regulation and stand at the crossroads of multiple pathways dictating cell fate decisions. The role of RB proteins in apoptosis is controversial because they can inhibit or promote apoptosis depending on the context, on the apoptotic stimuli and on their intrinsic status, impacting on the response to antitumoral treatments. Here we identified RBL2/p130 as a direct substrate of the AKT kinase, a key antiapoptotic factor hyperactive in multiple cancer types. We showed that RBL2/p130 and AKT1 physically interact and AKT phosphorylates RBL2/p130 Ser941, located in the pocket domain, but not when this residue is mutated into Ala. We found that pharmacological inhibition of AKT, through the highly selective AKT inhibitor VIII (AKTiVIII), impairs RBL2/p130 Ser941 phosphorylation and increases RBL2/p130 stability, mRNA expression and nuclear levels in both lung cancer and mesothelioma cell lines, mirroring the more extensively studied effects on the p27 cell-cycle inhibitor. Consistently, AKT inhibition reduced cell viability, induced cell accumulation in G0/G1, and triggered apoptosis, which proved to be largely dependent on RBL2/p130 itself, as shown upon RBL2/p130 silencing. AKT inhibition induced RBL2/p130-dependent apoptosis also in HEK-293 cells, in which re-expression of a short hairpin-resistant RBL2/p130 was able to rescue AKTiVIII-induced apoptosis upon RBL2/p130 silencing. Our data also showed that the combination of AKT and cyclin-dependent kinases (CDK) inhibitors, which converge on the re-activation of RBL2/p130 antitumoral potential, could be a promising anticancer strategy.

  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. 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

  12. 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

  13. 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....

  14. 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.)

  15. 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.

  16. 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.)

  17. 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.

  18. Low- and high-risk human papillomavirus E7 proteins regulate p130 differently

    International Nuclear Information System (INIS)

    Barrow-Laing, Lisa; Chen Wei; Roman, Ann

    2010-01-01

    The E7 protein of high-risk human papillomaviruses (HR HPVs) targets pRb family members (pRb, p107 and p130) for degradation; low-risk (LR) HPV E7 only targets p130 for degradation. The effect of HR HPV 16 E7 and LR HPV 6 E7 on p130 intracellular localization and half-life was examined. Nuclear/cytoplasmic fractionation and immunofluorescence showed that, in contrast to control and HPV 6 E7-expressing cells, a greater amount of p130 was present in the cytoplasm in the presence of HPV 16 E7. The half-life of p130, relative to control cells, was decreased in the cytoplasm in the presence of HPV 6 E7 or HPV 16 E7, but only decreased by HPV 6 E7 in the nucleus. Inhibition of proteasomal degradation extended the half-life of p130, regardless of intracellular localization. These results suggest that there may be divergent mechanisms by which LR and HR HPV E7 target p130 for degradation.

  19. 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.

  20. Interaction between focal adhesion kinase and Crk-associated tyrosine kinase substrate p130Cas.

    Science.gov (United States)

    Polte, T R; Hanks, S K

    1995-11-07

    The focal adhesion kinase (FAK) has been implicated in integrin-mediated signaling events and in the mechanism of cell transformation by the v-Src and v-Crk oncoproteins. To gain further insight into FAK signaling pathways, we used a two-hybrid screen to identify proteins that interact with mouse FAK. The screen identified two proteins that interact with FAK via their Src homology 3 (SH3) domains: a v-Crk-associated tyrosine kinase substrate (Cas), p130Cas, and a still uncharacterized protein, FIPSH3-2, which contains an SH3 domain closely related to that of p130Cas. These SH3 domains bind to the same proline-rich region of FAK (APPKPSR) encompassing residues 711-717. The mouse p130Cas amino acid sequence was deduced from cDNA clones, revealing an overall high degree of similarity to the recently reported rat sequence. Coimmunoprecipitation experiments confirmed that p130Cas and FAK are associated in mouse fibroblasts. The stable interaction between p130Cas and FAK emerges as a likely key element in integrin-mediated signal transduction and further represents a direct molecular link between the v-Src and v-Crk oncoproteins. The Src family kinase Fyn, whose Src homology 2 (SH2) domain binds to the major FAK autophosphorylation site (tyrosine 397), was also identified in the two-hybrid screen.

  1. 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

  2. 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 ...

  3. 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)

  4. 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).

  5. 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)

  6. 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 ...

  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. 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)

  9. 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

  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. Biophysical properties of intrinsically disordered p130Cas substrate domain--implication in mechanosensing.

    Directory of Open Access Journals (Sweden)

    Kinya Hotta

    2014-04-01

    Full Text Available Mechanical stretch-induced tyrosine phosphorylation in the proline-rich 306-residue substrate domain (CasSD of p130Cas (or BCAR1 has eluded an experimentally validated structural understanding. Cellular p130Cas tyrosine phosphorylation is shown to function in areas without internal actomyosin contractility, sensing force at the leading edge of cell migration. Circular dichroism shows CasSD is intrinsically disordered with dominant polyproline type II conformations. Strongly conserved in placental mammals, the proline-rich sequence exhibits a pseudo-repeat unit with variation hotspots 2-9 residues before substrate tyrosine residues. Atomic-force microscopy pulling experiments show CasSD requires minimal extension force and exhibits infrequent, random regions of weak stability. Proteolysis, light scattering and ultracentrifugation results show that a monomeric intrinsically disordered form persists for CasSD in solution with an expanded hydrodynamic radius. All-atom 3D conformer sampling with the TraDES package yields ensembles in agreement with experiment when coil-biased sampling is used, matching the experimental radius of gyration. Increasing β-sampling propensities increases the number of prolate conformers. Combining the results, we conclude that CasSD has no stable compact structure and is unlikely to efficiently autoinhibit phosphorylation. Taking into consideration the structural propensity of CasSD and the fact that it is known to bind to LIM domains, we propose a model of how CasSD and LIM domain family of transcription factor proteins may function together to regulate phosphorylation of CasSD and effect machanosensing.

  12. Analysis of p130 protein and mRNA expression in ten patients with uterine papillary serous carcinoma

    Directory of Open Access Journals (Sweden)

    Shao-ting XU

    2011-11-01

    Full Text Available Objective To examine p130 protein and mRNA expression in uterine papillary serous carcinoma(UPSC and their clinical and pathologic significance.Methods A total of 10 UPSC patients(Stage I were included,with 10 cases of high-level endometrial carcinoma of the same stage taken as the control group and 10 cases of normal proliferative stage endometrium(EM taken as the disease control group.The level of p130 protein expression was determined by hematoxylin and eosin staining,microscopic observation,and immunohistochemistry,whereas the p130 mRNA levels were examined through real-time quantitative reverse transcriptase polymerase chain reaction.The clinicopathologic analysis was carried out in combination with clinical data.Results The p130 protein and p130 mRNA expression levels in the UPSC group(0.46±0.01 and 0.56±0.06,respectively were apparently less than that of the normal proliferative stage endometrium group(0.91±0.04 and 2.81±0.40,respectively;P < 0.01 and also less than those in high-level endometrial carcinoma(P < 0.05.Clinicopathologic analysis shows that all patients are post-menopausal women with symptoms of irregular vaginal bleeding and the average tumor size was 7.5cm(range: 1.2-14.8cm.The pathologic features are same as that of high-level ovarian papillary serous carcinoma.Conclusion Reduced p130 protein and p130 mRNA expression in UPSC might correlate with poor prognosis in UPSC patients.

  13. 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.

  14. Organization of functional domains in the docking protein p130Cas

    International Nuclear Information System (INIS)

    Nasertorabi, Fariborz; Garcia-Guzman, Miguel; Briknarova, Klara; Larsen, Elise; Havert, Marnie L.; Vuori, Kristiina; Ely, Kathryn R.

    2004-01-01

    The docking protein p130Cas becomes phosphorylated upon cell adhesion to extracellular matrix proteins, and is thought to play an essential role in cell transformation. Cas transmits signals through interactions with the Src-homology 3 (SH3) and Src-homology 2 domains of FAK or v-Crk signaling molecules, or with 14-3-3 protein, as well as phosphatases PTP1B and PTP-PEST. The large (130 kDa), multi-domain Cas molecule contains an SH3 domain, a Src-binding domain, a serine-rich protein interaction region, and a C-terminal region that participates in protein interactions implicated in antiestrogen resistance in breast cancer. In this study, as part of a long-term goal to examine the protein interactions of Cas by X-ray crystallography and nuclear magnetic resonance spectroscopy, molecular constructs were designed to express two adjacent domains, the serine-rich domain and the Src-binding domain, that each participate in intermolecular contacts dependent on protein phosphorylation. The protein products are soluble, homogeneous, monodisperse, and highly suitable for structural studies to define the role of Cas in integrin-mediated cell signaling

  15. 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.

  16. A p130Cas tyrosine phosphorylated substrate domain decoy disrupts v-Crk signaling

    Directory of Open Access Journals (Sweden)

    Hanafusa Hidesaburo

    2002-07-01

    Full Text Available Abstract Background The adaptor protein p130Cas (Cas has been shown to be involved in different cellular processes including cell adhesion, migration and transformation. This protein has a substrate domain with up to 15 tyrosines that are potential kinase substrates, able to serve as docking sites for proteins with SH2 or PTB domains. Cas interacts with focal adhesion plaques and is phosphorylated by the tyrosine kinases FAK and Src. A number of effector molecules have been shown to interact with Cas and play a role in its function, including c-crk and v-crk, two adaptor proteins involved in intracellular signaling. Cas function is dependent on tyrosine phosphorylation of its substrate domain, suggesting that tyrosine phosphorylation of Cas in part regulates its control of adhesion and migration. To determine whether the substrate domain alone when tyrosine phosphorylated could signal, we have constructed a chimeric Cas molecule that is phosphorylated independently of upstream signals. Results We found that a tyrosine phosphorylated Cas substrate domain acts as a dominant negative mutant by blocking Cas-mediated signaling events, including JNK activation by the oncogene v-crk in transient and stable lines and v-crk transformation. This block was the result of competition for binding partners as the chimera competed for binding to endogenous c-crk and exogenously expressed v-crk. Conclusion Our approach suggests a novel method to study adaptor proteins that require phosphorylation, and indicates that mere tyrosine phosphorylation of the substrate domain of Cas is not sufficient for its function.

  17. Silencing of RB1 and RB2/P130 during adipogenesis of bone marrow stromal cells results in dysregulated differentiation

    OpenAIRE

    Capasso, Stefania; Alessio, Nicola; Di Bernardo, Giovanni; Cipollaro, Marilena; Melone, Mariarosa A. B.; Peluso, Gianfranco; Giordano, Antonio; Galderisi, Umberto

    2014-01-01

    Bone marrow adipose tissue (BMAT) is different from fat found elsewhere in the body, and only recently have some of its functions been investigated. BMAT may regulate bone marrow stem cell niche and plays a role in energy storage and thermogenesis. BMAT may be involved also in obesity and osteoporosis onset. Given the paramount functions of BMAT, we decided to better clarify the human bone marrow adipogenesis by analyzing the role of the retinoblastoma gene family, which are key players in ce...

  18. Ouabain affects cell migration via Na,K-ATPase-p130cas and via nucleus-centrosome association.

    Directory of Open Access Journals (Sweden)

    Young Ou

    Full Text Available Na,K-ATPase is a membrane protein that catalyzes ATP to maintain transmembrane sodium and potassium gradients. In addition, Na,K-ATPase also acts as a signal-transducing receptor for cardiotonic steroids such as ouabain and activates a number of signalling pathways. Several studies report that ouabain affects cell migration. Here we used ouabain at concentrations far below those required to block Na,K-ATPase pump activity and show that it significantly reduced RPE cell migration through two mechanisms. It causes dephosphorylation of a 130 kD protein, which we identify as p130cas. Src is involved, because Src inhibitors, but not inhibitors of other kinases tested, caused a similar reduction in p130cas phosphorylation and ouabain increased the association of Na,K-ATPase and Src. Knockdown of p130cas by siRNA reduced cell migration. Unexpectedly, ouabain induced separation of nucleus and centrosome, also leading to a block in cell migration. Inhibitor and siRNA experiments show that this effect is mediated by ERK1,2. This is the first report showing that ouabain can regulate cell migration by affecting nucleus-centrosome association.

  19. The emerin-binding transcription factor Lmo7 is regulated by association with p130Cas at focal adhesions

    Directory of Open Access Journals (Sweden)

    Michele A. Wozniak

    2013-08-01

    Full Text Available Loss of function mutations in the nuclear inner membrane protein, emerin, cause X-linked Emery-Dreifuss muscular dystrophy (X-EDMD. X-EDMD is characterized by contractures of major tendons, skeletal muscle weakening and wasting, and cardiac conduction system defects. The transcription factor Lmo7 regulates muscle- and heart-relevant genes and is inhibited by binding to emerin, suggesting Lmo7 misregulation contributes to EDMD disease. Lmo7 associates with cell adhesions and shuttles between the plasma membrane and nucleus, but the regulation and biological consequences of this dual localization were unknown. We report endogenous Lmo7 also associates with focal adhesions in cells, and both co-localizes and co-immunoprecipitates with p130Cas, a key signaling component of focal adhesions. Lmo7 nuclear localization and transcriptional activity increased significantly in p130Cas-null MEFs, suggesting Lmo7 is negatively regulated by p130Cas-dependent association with focal adhesions. These results support EDMD models in which Lmo7 is a downstream mediator of integrin-dependent signaling that allows tendon cells and muscles to adapt to and withstand mechanical stress.

  20. 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

  1. 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...

  2. [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.

  3. 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.

  4. 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....

  5. Retinoblastoma

    Science.gov (United States)

    ... Feb 20, 2018 Gene Therapy May Be a Game-Changer for People With Inherited Retinal Disease Dec 19, 2017 ... the Academy Jobs at the Academy Financial Relationships with Industry Medical Disclaimer Privacy Policy Terms of Service For ...

  6. Retinoblastoma

    Science.gov (United States)

    ... NEI Intranet (Employees Only) *PDF files require the free Adobe® Reader® software for viewing. This website is maintained by the NEI Office of Science Communications, Public Liaison, and Education. Technical questions about this website can be addressed ...

  7. 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

  8. 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....

  9. 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

  10. Integrin αβ1, αvβ, α6β effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance

    International Nuclear Information System (INIS)

    Sansing, Hope A.; Sarkeshik, Ali; Yates, John R.; Patel, Vyomesh; Gutkind, J. Silvio; Yamada, Kenneth M.; Berrier, Allison L.

    2011-01-01

    Research highlights: → Proteomics of clustered integrin αβ1, α v β, α 6 β receptors in oral carcinoma. → p130Cas, Dek, Src and talin regulate oral carcinoma invasion. → p130Cas, talin, Src and zyxin regulate oral carcinoma resistance to cisplatin. -- Abstract: Ligand engagement by integrins induces receptor clustering and formation of complexes at the integrin cytoplasmic face that controls cell signaling and cytoskeletal dynamics critical for adhesion-dependent processes. This study searches for a subset of integrin effectors that coordinates both tumor cell invasion and resistance to the chemotherapeutic drug cisplatin in oral carcinomas. Candidate integrin effectors were identified in a proteomics screen of proteins recruited to clustered integrin αβ1, α v β or α 6 β receptors in oral carcinomas. Proteins with diverse functions including microtubule and actin binding proteins, and factors involved in trafficking, transcription and translation were identified in oral carcinoma integrin complexes. Knockdown of effectors in the oral carcinoma HN12 cells revealed that p130Cas, Dek, Src and talin were required for invasion through Matrigel. Disruption of talin or p130Cas by RNA interference increased resistance to cisplatin, whereas targeting Dek, Src or zyxin reduced HN12 resistance to cisplatin. Analysis of the spreading of HN12 cells on collagen I and laminin I revealed that a decrease in p130Cas or talin expression inhibited spreading on both matrices. Interestingly, a reduction in zyxin expression enhanced spreading on laminin I and inhibited spreading on collagen I. Reduction of Dek, Src, talin or zyxin expression reduced HN12 proliferation by 30%. Proliferation was not affected by a reduction in p130Cas expression. We conclude that p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin.

  11. Integrin {alpha}{beta}1, {alpha}{sub v}{beta}, {alpha}{sub 6}{beta} effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance

    Energy Technology Data Exchange (ETDEWEB)

    Sansing, Hope A. [Department of Oral and Craniofacial Biology, Louisiana State University Health Sciences Center-New Orleans, School of Dentistry, New Orleans, LA (United States); Sarkeshik, Ali; Yates, John R. [Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA (United States); Patel, Vyomesh; Gutkind, J. Silvio [Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Yamada, Kenneth M. [Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Berrier, Allison L., E-mail: allison.berrier@gmail.com [Department of Oral and Craniofacial Biology, Louisiana State University Health Sciences Center-New Orleans, School of Dentistry, New Orleans, LA (United States)

    2011-03-11

    Research highlights: {yields} Proteomics of clustered integrin {alpha}{beta}1, {alpha}{sub v}{beta}, {alpha}{sub 6}{beta} receptors in oral carcinoma. {yields} p130Cas, Dek, Src and talin regulate oral carcinoma invasion. {yields} p130Cas, talin, Src and zyxin regulate oral carcinoma resistance to cisplatin. -- Abstract: Ligand engagement by integrins induces receptor clustering and formation of complexes at the integrin cytoplasmic face that controls cell signaling and cytoskeletal dynamics critical for adhesion-dependent processes. This study searches for a subset of integrin effectors that coordinates both tumor cell invasion and resistance to the chemotherapeutic drug cisplatin in oral carcinomas. Candidate integrin effectors were identified in a proteomics screen of proteins recruited to clustered integrin {alpha}{beta}1, {alpha}{sub v}{beta} or {alpha}{sub 6}{beta} receptors in oral carcinomas. Proteins with diverse functions including microtubule and actin binding proteins, and factors involved in trafficking, transcription and translation were identified in oral carcinoma integrin complexes. Knockdown of effectors in the oral carcinoma HN12 cells revealed that p130Cas, Dek, Src and talin were required for invasion through Matrigel. Disruption of talin or p130Cas by RNA interference increased resistance to cisplatin, whereas targeting Dek, Src or zyxin reduced HN12 resistance to cisplatin. Analysis of the spreading of HN12 cells on collagen I and laminin I revealed that a decrease in p130Cas or talin expression inhibited spreading on both matrices. Interestingly, a reduction in zyxin expression enhanced spreading on laminin I and inhibited spreading on collagen I. Reduction of Dek, Src, talin or zyxin expression reduced HN12 proliferation by 30%. Proliferation was not affected by a reduction in p130Cas expression. We conclude that p130Cas, Src and talin function in both oral carcinoma invasion and resistance to cisplatin.

  12. 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...

  13. 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)

  14. 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...

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.)

  1. p130Cas scaffolds the signalosome to direct adaptor-effector cross talk during Kaposi's sarcoma-associated herpesvirus trafficking in human microvascular dermal endothelial cells.

    Science.gov (United States)

    Bandyopadhyay, Chirosree; Veettil, Mohanan Valiya; Dutta, Sujoy; Chandran, Bala

    2014-12-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) interacts with cell surface receptors, such as heparan sulfate, integrins (α3β1, αVβ3, and αVβ5), and EphrinA2 (EphA2), and activates focal adhesion kinase (FAK), Src, phosphoinositol 3-kinase (PI3-K), c-Cbl, and RhoA GTPase signal molecules early during lipid raft (LR)-dependent productive macropinocytic entry into human dermal microvascular endothelial cells. Our recent studies have identified CIB1 as a signal amplifier facilitating EphA2 phosphorylation and subsequent cytoskeletal cross talk during KSHV macropinocytosis. Although CIB1 lacks an enzymatic activity and traditional adaptor domain or known interacting sequence, it associated with the KSHV entry signal complex and the CIB1-KSHV association was sustained over 30 min postinfection. To identify factors scaffolding the EphA2-CIB1 signal axis, the role of major cellular scaffold protein p130Cas (Crk-associated substrate of Src) was investigated. Inhibitor and small interfering RNA (siRNA) studies demonstrated that KSHV induced p130Cas in an EphA2-, CIB1-, and Src-dependent manner. p130Cas and Crk were associated with KSHV, LRs, EphA2, and CIB1 early during infection. Live-cell microscopy and biochemical studies demonstrated that p130Cas knockdown did not affect KSHV entry but significantly reduced productive nuclear trafficking of viral DNA and routed KSHV to lysosomal degradation. p130Cas aided in scaffolding adaptor Crk to downstream guanine nucleotide exchange factor phospho-C3G possibly to coordinate GTPase signaling during KSHV trafficking. Collectively, these studies demonstrate that p130Cas acts as a bridging molecule between the KSHV-induced entry signal complex and the downstream trafficking signalosome in endothelial cells and suggest that simultaneous targeting of KSHV entry receptors with p130Cas would be an attractive potential avenue for therapeutic intervention in KSHV infection. Eukaryotic cell adaptor molecules, without any intrinsic

  2. 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 ...

  3. 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

  4. 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

  5. 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.

  6. 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).

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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 ...

  12. 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.

  13. 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, ...

  14. 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

  15. Conservation and divergence of C-terminal domain structure in the retinoblastoma protein family

    Energy Technology Data Exchange (ETDEWEB)

    Liban, Tyler J.; Medina, Edgar M.; Tripathi, Sarvind; Sengupta, Satyaki; Henry, R. William; Buchler, Nicolas E.; Rubin, Seth M. (UCSC); (Duke); (MSU)

    2017-04-24

    The retinoblastoma protein (Rb) and the homologous pocket proteins p107 and p130 negatively regulate cell proliferation by binding and inhibiting members of the E2F transcription factor family. The structural features that distinguish Rb from other pocket proteins have been unclear but are critical for understanding their functional diversity and determining why Rb has unique tumor suppressor activities. We describe here important differences in how the Rb and p107 C-terminal domains (CTDs) associate with the coiled-coil and marked-box domains (CMs) of E2Fs. We find that although CTD–CM binding is conserved across protein families, Rb and p107 CTDs show clear preferences for different E2Fs. A crystal structure of the p107 CTD bound to E2F5 and its dimer partner DP1 reveals the molecular basis for pocket protein–E2F binding specificity and how cyclin-dependent kinases differentially regulate pocket proteins through CTD phosphorylation. Our structural and biochemical data together with phylogenetic analyses of Rb and E2F proteins support the conclusion that Rb evolved specific structural motifs that confer its unique capacity to bind with high affinity those E2Fs that are the most potent activators of the cell cycle.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.)

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Interactions of the integrin subunit beta1A with protein kinase B/Akt, p130Cas and paxillin contribute to regulation of radiation survival

    DEFF Research Database (Denmark)

    Seidler, Julia; Durzok, Rita; Brakebusch, Cord

    2005-01-01

    25beta1B cells, which express mutant beta1B-integrins, were compared in terms of radiation survival and beta1-integrin signaling. MATERIALS AND METHODS: Cells grown on fibronectin, collagen-III, laminin, vitronectin, anti-beta1-integrin-IgG (beta1-IgG) or poly-l-lysine were irradiated with 0-6Gy...... and phosphorylation were analyzed by Western blot technique. RESULTS: Adhesion of GD25beta1A cells to extracellular matrix proteins or beta1-IgG resulted in growth factor-independent radiation survival. In contrast, serum starved GD25beta1B cells showed a significant (Pradiation survival on all...... phosphorylation. Phosphorylated p130Cas and paxillin subsequently prevented activation of cell death-regulating JNK. CONCLUSIONS: The data show that beta1-integrin-mediated signaling through the cytoplasmic integrin domains is critical for efficient pro-survival regulation after irradiation. Profound knowledge...

  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. 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.

  16. 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.

  17. Current Trends in the Management of Retinoblastoma

    Directory of Open Access Journals (Sweden)

    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

  18. 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

  19. 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.

  20. 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

  1. [Pathological profiles of retinoblastoma in Senegal].

    Science.gov (United States)

    Dial, C; Doh, K; Thiam, I; Ndoye Roth, P; Moreira, C; Woto-Gaye, G

    2016-11-01

    Describe the macroscopic and microscopic profiles of retinoblastoma (RB) in Senegal and correlate histological criteria with progression to establish severity factors. We realized a retrospective study over 10 years (January 2005-December 2014). Only patients (n=67) who underwent histological analysis of the enucleation specimen (n=68) were followed until the end of the study. The tumor measured an average of 3.8cm (2/4.5). Endophytic tumor development was observed in 55 cases (80.8%), exophytic in 6 cases (8.9%) and mixed in 7 cases (10.3%). Retinal detachment was present in 13 cases (19.2%). The RB was well differentiated in 11 cases (16.2%), moderately differentiated in 31 cases (45.6%) and undifferentiated in 26 cases. Optic nerve (ON) invasion was present in 18 cases (26.5%). The tumor was extraretinal in 37 cases (54.4%). The anterior chamber was invaded in 6 cases (8.8%). The global survival at 2 years was 84% and 70% at 5 years. On multivariate analysis, well differentiated tumors and stage pT1 were associated with remission. Retrolaminar ON invasion, massive choroidal invasion and stage pT3 were risk factors for recurrence. Poor tumor differentiation, invasion of the ON resection margin, tumor invasion through the sclera, and stage pT4 were predictive of death. The pathologist is a principal actor in the management of RB because his account guide the post-surgical management strategy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  2. 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 ...

  3. 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'

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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¡¦ ...

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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....

  16. 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.

  17. 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

  18. 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)

  19. 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.

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

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    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.

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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

  8. Peso y talla en niños con retinoblastoma

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    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.

  9. 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

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

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    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

  11. 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.

  12. 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.

  13. 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)

  14. New research progress of microRNAs in retinoblastoma

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    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.

  15. 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.

  16. 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

  17. 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

  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. 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.

  20. 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.

  1. 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.

  2. 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%

  3. Tratamento conservador em retinoblastoma intra-ocular Conservative treatment for intraocular retinoblastoma

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    Clélia Maria Erwenne

    2003-12-01

    bilaterais foram conservados 48,9% dos olhos tratados. Entre os unilaterais, para os mesmos estádios obteve-se: I 0/0; II 2/2 (100,0%; III 1/3 (33,3%; IV 1/3 (33,3%; V 0/7 (0%. Considerando-se o total de unilaterais foram conservados 26,6% dos olhos. Não se observou nefro ou ototoxicidade às drogas neste grupo.PURPOSE: To report the results of conservation of the ocular globe after treatment with carboplatin and laser; with or without the use of other forms of local treatment or radiotherapy, if necessary. METHODS: All eyes, initially untreated, were evaluated using indirect ophthalmology under inhalation anesthesia in an outpatient clinic treatment setting. They were categorized according to the Reese-Ellsworth system; thereafter, the patients were evaluated clinically by a pediatric oncologist. The patients received the first cycle of chemotherapy consisting of intravenous carboplatin 200 mg/m², vincristine 1.5 mg/m² and etoposide 150 mg/m², for three days. This was followed by other cycles with intervals of between 21 and 28 days. From 7 to 15 days after the end of the chemotherapy cycle, another indirect ophthalmoscopy under inhalation anesthesia was performed, with documentation of the findings and laser hyperthermia application, using a Diode laser, 810 nm, continuous pulse with a large spot size. The procedure (chemotherapy and laser was repeated until complete cicatrization of all lesions was observed, or until the need for another treatment modality such as radiotherapy or enucleation became apparent. Follow-up examinations every two months during the first year and three months thereafter were done for review and for treatment of recurrent or new lesions. Pediatric oncology follow-up was also done throughout the entire initial assessment and follow-up period. RESULTS: We treated a total of 62 patients with retinoblastoma, of whom 32 were male and 30 female. Fifteen were unilateral and 47 were bilateral with a total of 107 eyes. The mean age was 16.9 months (2

  4. 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.

  5. 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

  6. 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)

  7. 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).

  8. 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

  9. 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.)

  10. 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.

  11. 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

  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. 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.

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

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    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

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

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    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

  16. 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

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

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    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.

  18. 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)

  19. [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) .

  20. Retinoblastoma: Achieving new standards with methods of chemotherapy

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    Swathi Kaliki

    2015-01-01

    Full Text Available The management of retinoblastoma (RB has dramatically changed over the past two decades from previous radiotherapy methods to current chemotherapy strategies. RB is a remarkably chemotherapy-sensitive tumor. Chemotherapy is currently used as a first-line approach for children with this malignancy and can be delivered by intravenous, intra-arterial, periocular, and intravitreal routes. The choice of route for chemotherapy administration depends upon the tumor laterality and tumor staging. Intravenous chemotherapy (IVC is used most often in bilateral cases, orbital RB, and as an adjuvant treatment in high-risk RB. Intra-arterial chemotherapy (IAC is used in cases with group C or D RB and selected cases of group E tumor. Periocular chemotherapy is used as an adjunct treatment in eyes with group D and E RB and those with persistent/recurrent vitreous seeds. Intravitreal chemotherapy is reserved for eyes with persistent/recurrent vitreous seeds. In this review, we describe the various forms of chemotherapy used in the management of RB. A database search was performed on PubMed, using the terms "RB," and "treatment," "chemotherapy," "systemic chemotherapy," "IVC," "IAC," "periocular chemotherapy," or "intravitreal chemotherapy." Relevant English language articles were extracted, reviewed, and referenced appropriately.

  1. Expression and clinical significance of Pax6 gene in retinoblastoma

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    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.

  2. The genetic alteration of retinoblastoma gene in esophageal cancer

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    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. Dosimetric intercomparison between protons and electrons therapies applied to retinoblastoma

    International Nuclear Information System (INIS)

    Braga, Flavia Vieira

    2008-01-01

    In this work we propose a construction of a simple human eye model in order to simulate the dosimetric response for a treatment with protons and electrons in a retinoblastoma cancer. The computational tool used in this simulation was the Geant4 code, in the version 4.9.1, all these package are free and permit simulate the interaction of radiation with matter. In our simulation we use a box with 4 cm side, with water, for represent the human eye. The simulation was performed considering mono energetics beams of protons and electrons with energy range between 50 and 70 MeV for protons and 2 and 10 MeV for electrons. The simulation was based on the advanced hadron therapy example of the Geant 4 code. In these example the phantom is divided in voxels with 0.2 mm side and it is generated the energy deposited in each voxel. The simulation results show the energy deliver in each voxel, with these energie we can calculate the dose deposited in that region. We can see the dose profile of, proton and electron, and we can see in both cases that for protons the position of delivered dose is well know, that happen in the position where the proton stop, for electrons the energies is delivered along the way and pass the desired position for high dose deposition. (author)

  4. Retinoblastoma loss modulates DNA damage response favoring tumor progression.

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    Marcos Seoane

    Full Text Available Senescence is one of the main barriers against tumor progression. Oncogenic signals in primary cells result in oncogene-induced senescence (OIS, crucial for protection against cancer development. It has been described in premalignant lesions that OIS requires DNA damage response (DDR activation, safeguard of the integrity of the genome. Here we demonstrate how the cellular mechanisms involved in oncogenic transformation in a model of glioma uncouple OIS and DDR. We use this tumor type as a paradigm of oncogenic transformation. In human gliomas most of the genetic alterations that have been previously identified result in abnormal activation of cell growth signaling pathways and deregulation of cell cycle, features recapitulated in our model by oncogenic Ras expression and retinoblastoma (Rb inactivation respectively. In this scenario, the absence of pRb confers a proliferative advantage and activates DDR to a greater extent in a DNA lesion-independent fashion than cells that express only HRas(V12. Moreover, Rb loss inactivates the stress kinase DDR-associated p38MAPK by specific Wip1-dependent dephosphorylation. Thus, Rb loss acts as a switch mediating the transition between premalignant lesions and cancer through DDR modulation. These findings may have important implications for the understanding the biology of gliomas and anticipate a new target, Wip1 phosphatase, for novel therapeutic strategies.

  5. Autologous fat graft in irradiated orbit postenucleation for retinoblastoma.

    Science.gov (United States)

    Klinger, Francesco; Maione, Luca; Vinci, Valeriano; Lisa, Andrea; Barbera, Federico; Balia, Laura; Caviggioli, Fabio; Di Maria, Alessandra

    2018-01-05

    Autologous fat grafting has been extensively and successfully adopted in a number of pathologic conditions in regenerative surgery especially on irradiated fields in order to improve pain symptoms and tissue trophism promoting scar release. In the present study, we report our experience with autologous fat grafting for the treatment of postirradiation fibrosis and pain on three consecutive patients undergoing orbital enucleation for locally advanced retinoblastoma (RB) and subsequent radiotherapy. We selected three consecutive patients who underwent orbital enucleation for locally advanced RB and subsequent local radiotherapy showing severe reduction in orbital volume and eyelid length and retraction due to fibrosis, spontaneous local pain exacerbated after digital pressure with no possibility to place an ocular implant. They underwent autologous fat grafting in the orbital cavity and results were evaluated by clinical examination at 5 and 14 days, and 1, 3, 6 months, and 1 year after surgery. A significant release of scar retraction, reduction of fibrosis and orbital rim contraction together with an important improvement of pain symptoms was observed in all patients. The local changes observed enabled an ease placement of an ocular prosthetic implant (implant). No local or systemic complication occurred. Fat grafting is a promising treatment for patients showing radiotherapy related complication in the orbital area and it should be adopted by all oculoplastic surgeon in order to improve pain syndrome creating the ideal local conditions for the placement of an ocular prosthetic implant.

  6. 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.

  7. Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins

    International Nuclear Information System (INIS)

    Montoya-Durango, Diego E.; Liu, Yongqing; Teneng, Ivo; Kalbfleisch, Ted; Lacy, Mary E.; Steffen, Marlene C.; Ramos, Kenneth S.

    2009-01-01

    Long interspersed nuclear elements (LINEs or L1 elements) are targeted for epigenetic silencing during early embryonic development and remain inactive in most cells and tissues. Here we show that E2F-Rb family complexes participate in L1 elements epigenetic regulation via nucleosomal histone modifications and recruitment of histone deacetylases (HDACs) HDAC1 and HDAC2. Our experiments demonstrated that (i) Rb and E2F interact with human and mouse L1 elements, (ii) L1 elements are deficient in both heterochromatin-associated histone marks H3 tri methyl K9 and H4 tri methyl K20 in Rb family triple knock out (Rb, p107, and p130) fibroblasts (TKO), (iii) L1 promoter exhibits increased histone H3 acetylation in the absence of HDAC1 and HDAC2 recruitment, (iv) L1 expression in TKO fibroblasts is upregulated compared to wild type counterparts, (v) L1 expression increases in the presence of the HDAC inhibitor TSA. On the basis of these findings we propose a model in which L1 sequences throughout the genome serve as centers for heterochromatin formation in an Rb family-dependent manner. As such, Rb proteins and L1 elements may play key roles in heterochromatin formation beyond pericentromeric chromosomal regions. These findings describe a novel mechanism of L1 reactivation in mammalian cells mediated by failure of corepressor protein recruitment by Rb, loss of histone epigenetic marks, heterochromatin formation, and increased histone H3 acetylation.

  8. Epigenetic control of mammalian LINE-1 retrotransposon by retinoblastoma proteins

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    Montoya-Durango, Diego E. [Department of Biochemistry and Molecular Biology and Center for Genetics and Molecular Medicine, University of Louisville School of Medicine Health Sciences Center, Louisville, KY 40202 (United States); Liu, Yongqing [James Graham Brown Cancer Center and Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine Health Sciences Center, Louisville, KY 40202 (United States); Teneng, Ivo; Kalbfleisch, Ted; Lacy, Mary E.; Steffen, Marlene C. [Department of Biochemistry and Molecular Biology and Center for Genetics and Molecular Medicine, University of Louisville School of Medicine Health Sciences Center, Louisville, KY 40202 (United States); Ramos, Kenneth S., E-mail: kenneth.ramos@louisville.edu [Department of Biochemistry and Molecular Biology and Center for Genetics and Molecular Medicine, University of Louisville School of Medicine Health Sciences Center, Louisville, KY 40202 (United States)

    2009-06-01

    Long interspersed nuclear elements (LINEs or L1 elements) are targeted for epigenetic silencing during early embryonic development and remain inactive in most cells and tissues. Here we show that E2F-Rb family complexes participate in L1 elements epigenetic regulation via nucleosomal histone modifications and recruitment of histone deacetylases (HDACs) HDAC1 and HDAC2. Our experiments demonstrated that (i) Rb and E2F interact with human and mouse L1 elements, (ii) L1 elements are deficient in both heterochromatin-associated histone marks H3 tri methyl K9 and H4 tri methyl K20 in Rb family triple knock out (Rb, p107, and p130) fibroblasts (TKO), (iii) L1 promoter exhibits increased histone H3 acetylation in the absence of HDAC1 and HDAC2 recruitment, (iv) L1 expression in TKO fibroblasts is upregulated compared to wild type counterparts, (v) L1 expression increases in the presence of the HDAC inhibitor TSA. On the basis of these findings we propose a model in which L1 sequences throughout the genome serve as centers for heterochromatin formation in an Rb family-dependent manner. As such, Rb proteins and L1 elements may play key roles in heterochromatin formation beyond pericentromeric chromosomal regions. These findings describe a novel mechanism of L1 reactivation in mammalian cells mediated by failure of corepressor protein recruitment by Rb, loss of histone epigenetic marks, heterochromatin formation, and increased histone H3 acetylation.

  9. 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.

  10. 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

  11. 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.

  12. 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)

  13. 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

  14. 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....

  15. 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...

  16. 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

  17. [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.

  18. Discharge and infection in retinoblastoma post-enucleation sockets.

    Science.gov (United States)

    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' characteristics, cleaning habits of the prosthesis, frequency of socket irritation, discharge, and infection, and use of antibiotics. With ordinal logistic regression analysis, factors related to the outcome parameters (frequency of irritation, mucoid and purulent discharge) were identified. In a subset of young asymptomatic and symptomatic patients, a swab culture of the socket was performed to determine the presence of microorganisms. A total of 186 patients or their parents (mean age of the patients: 17.3 years, ranging from 0.8 to 88.3 years) filled out the questionnaire. Irritation, mucoid discharge, and purulent discharge were frequently (once a month or more often) experienced in 75 (39.5%), 127 (66.8%), and 15 (13.2%) sockets, respectively. Younger age was associated with a higher frequency of mucoid and purulent discharge. Radiation therapy, chemotherapy, gender, age at surgery, cleaning frequency, and nocturnal wear were not associated with the outcome parameters. In a subgroup of 26 patients, the sockets were swabbed and cultured. All symptomatic patients had a positive bacterial culture versus 15% (2/13) of the asymptomatic patients ( P socket infection. These complaints were found to decrease with increasing age, but did not seem to be influenced by cleaning or wearing habits. Symptomatic sockets, with and without discharge, were correlated with the presence of pathogenic bacteria for which local antibiotic treatment seemed effective in most cases.

  19. 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.

  20. Quality of life of adult retinoblastoma survivors in the Netherlands

    Directory of Open Access Journals (Sweden)

    Cohen-Kettenis Peggy T

    2007-06-01

    Full Text Available Abstract Background To assess the quality of life (QoL and predictors thereof in Dutch adult hereditary and non-hereditary retinoblastoma (RB survivors. Methods In this population-based cross-sectional study, a generic QoL questionnaire (SF-36 and a disease-specific interview were administered to 87 adult RB survivors aged 18 to 35 years. Their QoL data were compared with those of a Dutch healthy reference group. Among the RB hereditary/non-hereditary survivors, the QoL was compared and predictors for QoL were identified by linear multiple regression analyses. Results As a group, RB survivors scored significantly lower than the reference group on the SF-36 subscale 'mental health' (t = -27, df = 86, p Conclusion In this exploratory study, it appears that the group of adult RB survivors experience a relatively good overall but slightly decreased QoL compared with the reference group. However, they report more problems with regard to their mental health (anxiety, feelings of depression, and loss of control. Hereditary RB survivors differ significantly from non-hereditary RB survivors only in 'general health'. Bullying in childhood and subjective experience of impairment are the main predictors of a worse QoL. In order to prevent worsening of QoL, or perhaps to improve it, clinicians should make an inventory of these issues at an early stage. We recommend further research to assess the specific psychological factors that may lead to mental health problems in this population.

  1. Intra-arterial chemotherapy for retinoblastoma: First Indian report

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    Pukhraj Rishi

    2015-01-01

    Full Text Available Aim: To describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC for retinoblastoma (RB in Indian eyes. Materials and Methods: Single center, retrospective interventional case series of 6 eyes with RB who underwent IAC using Melphalan (3 mg/5 mg/7.5 mg and topetecan (1 mg (n = 4 or melphalan (3 mg/5 mg/7.5 mg alone (n = 2 between December 2013 and June 2014. In all, 17 IAC procedures were performed using selective ophthalmic artery cannulation. Treatment outcomes were evaluated in terms of tumor control, vitreous and subretinal seeds control and globe salvage rates. Results: IAC was employed as primary (n = 1 or secondary (n = 5 modality of treatment. Each eye received mean 3 IAC sessions (median: 3; range: 1-4 sessions. Eyes were classified according to international classification of RB as Group B (n = 1, C (n = 1, D (n = 2 and E (n = 2. Following IAC, complete regression of the main tumor was seen in 3 cases (50%, partial regression in 2 (33%, while 1 case (15% showed no response. Of 4 eyes with subretinal seeds, 1 (25% eye had complete regression while 3 (75% eyes had partial regression. Of 5 eyes with vitreous seeds, 2 (40% eyes had complete regression while 3 (60% eyes had a partial response. Globe salvage was achieved in 5 of 6 eyes (83%. Diffuse choroidal atrophy and vitreous hemorrhage were observed in 1 (17% eye, each. No hematologic toxicity or cerebro-vascular events were observed. Mean follow-up period was 5.5 months (median: 6 months, range: 1-6 months. Conclusion: IAC is an effective therapy for globe preservation in eyes with RB. Larger studies with longer follow-up are required to validate these results.

  2. 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

  3. 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.

  4. 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.)

  5. 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.

  6. 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...

  7. 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...

  8. 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.

  9. 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.)

  10. 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...

  11. 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...

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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).

  17. 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

  18. 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.

  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. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. Discharge and infection in retinoblastoma post-enucleation sockets

    Directory of Open Access Journals (Sweden)

    Mourits DL

    2017-03-01

    Full Text Available Daphne L Mourits,1 Dyonne T Hartong,1 Andries E Budding,2 Machteld I Bosscha,1 H Stevie Tan,1 Annette C Moll1 1Department of Ophthalmology, VU University Medical Center, 2Department of Microbiology, Academic Medical Center, Amsterdam, the Netherlands Purpose: To investigate the causes and treatment options for socket discharge and infection in patients enucleated for retinoblastoma (Rb. Methods: 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’ characteristics, cleaning habits of the prosthesis, frequency of socket irritation, discharge, and infection, and use of antibiotics. With ordinal logistic regression analysis, factors related to the outcome parameters (frequency of irritation, mucoid and purulent discharge were identified. In a subset of young asymptomatic and symptomatic patients, a swab culture of the socket was performed to determine the presence of microorganisms. Results: A total of 186 patients or their parents (mean age of the patients: 17.3 years, ranging from 0.8 to 88.3 years filled out the questionnaire. Irritation, mucoid discharge, and purulent discharge were frequently (once a month or more often experienced in 75 (39.5%, 127 (66.8%, and 15 (13.2% sockets, respectively. Younger age was associated with a higher frequency of mucoid and purulent discharge. Radiation therapy, chemotherapy, gender, age at surgery, cleaning frequency, and nocturnal wear were not associated with the outcome parameters. In a subgroup of 26 patients, the sockets were swabbed and cultured. All symptomatic patients had a positive bacterial culture versus 15% (2/13 of the asymptomatic patients (P<0.001. Common cold was correlated with both symptoms and presence of bacteria. Haemophilus influenzae and Staphylococcus aureus were the species most frequently cultured. Conclusion: Ocular prosthesis-wearing patients often experienced mucoid

  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. 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.

  8. Radiation therapy for retinoblastoma: a retrospective review of 120 patients

    International Nuclear Information System (INIS)

    Pradhan, Deepak G.; Sandridge, Amy L.; Mullaney, Paul; Abboud, Emad; Karcioglu, Zeynel A.; Kandil, Alaa; Mustafa, Mahmoud M.; Gray, Alan J.

    1997-01-01

    Purpose: To characterize the patient population and treatment outcomes in patients with Retinoblastoma (RB) referred for External Beam Orbital Radiotherapy (EBORT) to King Faisal Specialist Hospital and Research Centre (KFSH and RC), Riyadh, Saudi Arabia from 1976 to 1993. Methods and Materials: A retrospective study of 120 patients with RB affecting a total of 192 eyes. Patients were divided into three groups. Group A are 60 patients (64 eyes) treated with EBORT to the intact eye to preserve vision. Reese-Ellsworth (RE) Staging was: 1: 12%; 2: 10%; 3: 12%; 4: 23%; and 5: 43%. Twenty-eight patients (47%) also received Vincristine, Adriamycin, and Cyclophosphamide chemotherapy (C/T). Mean follow-up, per patient, was 48.5 months. Standard treatment until 1992 was 45 Gy in 12 fractions of 3.75 Gy, three times weekly over 18 days. Assuming the α/β ratio for early effects and tumor control at 10, Tk = 21 days, T pot = 5 days, then the Biological Equivalent Dose (BED) was 62 Gy 10 for early effects, and 101 Gy 3 for late effects. Group B are 28 patients (28 eyes) treated for curative intent with EBORT to the orbit for locally advanced disease, usually after enucleation (24 eyes). Nineteen patients (83%) also had C/T. Mean follow-up was 22.6 months. Group C are 37 patients with advanced disease treated with radiotherapy for palliation. Seventeen (46%) also received C/T. Mean follow-up was 11.7 months. Results: Group A-following EBORT useful vision was retained in RE Stage 1 to 5: 7 of 7, 6 of 6, 4 of 8, 10 of 15, and 7 of 28 eyes, respectively. There was no significant difference between patients who received adjuvant chemotherapy and those who did not. Complications included cataract (27%), retinopathy (25%), vitreous hemorrhage (19%), and orbital deformities (11%). In Group B the local control rate was 71%. In Group C, 10 (27%) of the 37 patients were alive at last contact, and 27 (73%) were either terminal or dead of disease. None of Group A or B patients had

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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.)

  14. 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...

  15. 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.

  16. 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)

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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...

  2. 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)

  3. 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

  4. 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...

  5. 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

    Directory of Open Access Journals (Sweden)

    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.

  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. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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

  12. A delayed diagnosis of unsuspected retinoblastoma in an in vitro fertilisation infant with retinopathy of prematurity

    Institute of Scientific and Technical Information of China (English)

    Tian Tian; Xun-Da Ji; Qi Zhang; Jie Peng; Pei-Quan Zhao

    2016-01-01

    Dear Editor,Iam Dr.Tian Tian,from the Department of Ophthalmology,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai,China.I write to present a rare case report of a delayed diagnosis of unsuspected retinoblastoma(RB)in an in vitro fertilisation(IVF)infant with retinopathy of prematurity.The simultaneous presentation of RB and prematurity of retinopathy(ROP)in an IVF infant is very rare.The relationship between RB and IVF is still indeterminate and mechanisms that lead to ocular or systemic abnormalities

  13. 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...

  14. 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)

  15. 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).

  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. 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 ...

  18. 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

  19. 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.

  20. 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.

  1. 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.)

  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. 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.

  4. 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)

  5. 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

  6. 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

  7. 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.

  8. 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...

  9. 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)

  10. 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,

  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. 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

  13. 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

  14. Dosimetric intercomparison between protons and electrons therapies applied to retinoblastoma; Intercomparacao dosimetrica entre terapias de protons e eletrons aplicada ao retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Braga, Flavia Vieira

    2008-07-01

    In this work we propose a construction of a simple human eye model in order to simulate the dosimetric response for a treatment with protons and electrons in a retinoblastoma cancer. The computational tool used in this simulation was the Geant4 code, in the version 4.9.1, all these package are free and permit simulate the interaction of radiation with matter. In our simulation we use a box with 4 cm side, with water, for represent the human eye. The simulation was performed considering mono energetics beams of protons and electrons with energy range between 50 and 70 MeV for protons and 2 and 10 MeV for electrons. The simulation was based on the advanced hadron therapy example of the Geant 4 code. In these example the phantom is divided in voxels with 0.2 mm side and it is generated the energy deposited in each voxel. The simulation results show the energy deliver in each voxel, with these energie we can calculate the dose deposited in that region. We can see the dose profile of, proton and electron, and we can see in both cases that for protons the position of delivered dose is well know, that happen in the position where the proton stop, for electrons the energies is delivered along the way and pass the desired position for high dose deposition. (author)

  15. 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

  16. 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.

  17. Retinoblastoma protein co-purifies with proteasomal insulin-degrading enzyme: Implications for cell proliferation control

    Energy Technology Data Exchange (ETDEWEB)

    Radulescu, Razvan T., E-mail: ratura@gmx.net [Molecular Concepts Research (MCR), Muenster (Germany); Duckworth, William C. [Department of Medicine, Phoenix VA Health Care System, Phoenix, AZ (United States); Levy, Jennifer L. [Research Service, Phoenix VA Health Care System, Phoenix, AZ (United States); Fawcett, Janet, E-mail: janet.fawcett@va.gov [Research Service, Phoenix VA Health Care System, Phoenix, AZ (United States)

    2010-04-30

    Previous investigations on proteasomal preparations containing insulin-degrading enzyme (IDE; EC 3.4.24.56) have invariably yielded a co-purifying protein with a molecular weight of about 110 kDa. We have now found both in MCF-7 breast cancer and HepG2 hepatoma cells that this associated molecule is the retinoblastoma tumor suppressor protein (RB). Interestingly, the amount of RB in this protein complex seemed to be lower in HepG2 vs. MCF-7 cells, indicating a higher (cytoplasmic) protein turnover in the former vs. the latter cells. Moreover, immunofluorescence showed increased nuclear localization of RB in HepG2 vs. MCF-7 cells. Beyond these subtle differences between these distinct tumor cell types, our present study more generally suggests an interplay between RB and IDE within the proteasome that may have important growth-regulatory consequences.

  18. External radiotherapy for circumscribed choroidal haemangiomas using a modified retinoblastoma technique

    International Nuclear Information System (INIS)

    Eide, N.; Syrdalen, P.; Tausjoe, J.; Tveraa, K.

    1995-01-01

    This report describes two cases of circumscribed choroidal haemangiomas involving the fovea, complicated by serous retinal detachment. Laser photocoagulation, generally accepted as the treatment of choice for choroidal haemangioma, was considered either to be of no visual benefit or a risk for jeopardizing vision further due to the subfoveolar lesions. Fractionated radiotherapy using a lens-sparing, modified retinoblastoma technique, was given, using circular fields of 15 mm diameter. The dose was 24 Gy in 8 fractions. In both eyes the retina reattached completely. The visual acuity improved markedly in the first, and was restored to the prior level in the second. Normalization of a high intraocular pressure was also achieved in the second case. We believe this method to be a reasonable and effective therapy for some choroidal haemangiomas after careful individual consideration. (au) 17 refs

  19. 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.

  20. 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.

  1. 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.

  2. An international survey of classification and treatment choices for group D retinoblastoma

    Directory of Open Access Journals (Sweden)

    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

  3. Glycodendrimeric phenylporphyrins as new candidates for retinoblastoma PDT: blood carriers and photodynamic activity in cells.

    Science.gov (United States)

    Wang, Ze-Jian; Chauvin, Benoît; Maillard, Philippe; Hammerer, Fabien; Carez, Danièle; Croisy, Alain; Sandré, Catherine; Chollet-Martin, Sylvie; Prognon, Patrice; Paul, Jean-Louis; Blais, Jocelyne; Kasselouri, Athena

    2012-10-03

    Photodynamic therapy (PDT) has recently been proposed as a possible indication in the conservative treatment of hereditary retinoblastoma. In order to create photosensitizers with enhanced targeting ability toward retinoblastoma cells, meso-tetraphenylporphyrins bearing one glycodendrimeric moiety have been synthesized. The binding properties to plasma proteins and photodynamic activity of two monodendrimeric porphyrins bearing three mannose units via monoethylene glycol (1) or diethylene glycol (2) linkers have been compared to that of the non-dendrimeric tri-substituted derivative [TPP(p-Deg-O-α-ManOH)(3)]. The dendrimeric structure was found to highly increase the binding affinity to plasma proteins and to modify to some extent plasma distribution. HDL and to a lesser extent LDL have been shown to be the main carriers of dendrimeric and non-dendrimeric compounds. The phototoxicity observed for the two glycodendrimers (1) and (2) (LD(50)=0.5 μM) in Y79 cells is of the same order of magnitude that for TPP(p-Deg-O-α-ManOH)(3) (LD(50)=0.7 μM), with a similar cellular uptake level for (1) and a lower for (2). A serum content increase from 2% to 20% (v/v) in the incubation medium was found to inhibit both cellular uptake and photoactivity of dendrimeric derivatives, whereas those of TPP(p-Deg-O-α-ManOH)(3) remained little affected. Specificities of glycodendrimeric porphyrins, combining a lower cellular uptake together with a higher affinity toward plasma proteins, make these derivatives possible candidates for a vascular targeting PDT. Copyright © 2012 Elsevier B.V. All rights reserved.

  4. 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

  5. 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.

  6. 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

  7. 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.

  8. Proton and electron deep dose profiles for retinoblastoma based on GEANT 4 code

    International Nuclear Information System (INIS)

    Braga, Flavia V.; Campos, Tarcisio P.R. de; Ribeiro, Kilder L.

    2009-01-01

    Herein, the dosimetry responses to a retinoblastoma proton and electron radiation therapy were investigated. The computational tool applied to this simulation was the Geant4 code, version 4.9.1. The code allows simulating the charge particle interaction with eyeball tissue. In the present simulation, a box of 4 cm side water filled had represented the human eye. The simulation was performed considering mono energetic beams of protons and electrons with spectra of 57 to 70 MeV for protons and 2 to 8 MeV for electrons. The simulation was guide by the advanced hadron therapy example distributed with the Geant4 code. The phantom was divided in voxels with 0.2 mm side. The energy deposited in each voxel was evaluated taken the direct beam at one face. The simulation results show the delivery energy and therefore the dose deposited in each voxel. The deep dose profiles to proton and electron were plotted. The well known Bragg peak was reproduced for protons. The maximum delivered dose defined the position at the proton stopped. However, to electrons, the absorbed energies were delivered along its path producing a more continuous distribution following the water depth, but also being stopped in the end of its path. (author)

  9. 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

  10. MiR-200c suppresses the migration of retinoblastoma cells by reversing epithelial mesenchymal transition

    Directory of Open Access Journals (Sweden)

    Xiao-Lei Shao

    2017-08-01

    Full Text Available AIM: To analyze the relationship between clinical features and epithelial mesenchymal transition (EMT in retinoblastoma (RB, further to investigate whether miR-200c regulates the EMT and migration of RB cells. METHODS: Expression of EMT-related markers and tumor-related factors were detected by immuno-histochemistry analysis in RB tissue from 29 cases. Correlations between their expression and clinical characteristics were analyzed. The regulation effects of miR-200c on EMT-related markers, tumor-related factors were observed in mRNA level and protein level by real-time polymerase chain reaction (PCR and Western blot, respectively, in Y79 and Weri-rb1 cells. Its effects on migration force of these RB cell lines were also detected with Transwell test. RESULTS: Lower expression of E-cadherin was present in the cases with malignant prognosis. MiR-200c promoted the expression of E-cadherin and decreased the expression of Vimentin and N-cadherin in Y79 and Weri-rb1 cells. Migration force of RB cells could be inhibited by miR-200c. CONCLUSION: EMT might be associated with bad prognosis in RB. MiR-200c suppresses the migration of retinoblastomatous cells by reverse EMT.

  11. RETINOBLASTOMA IN INDIA: Clinical Presentation and Outcome in 1,457 Patients (2,074 Eyes).

    Science.gov (United States)

    Kaliki, Swathi; Patel, Anamika; Iram, Sadiya; Ramappa, George; Mohamed, Ashik; Palkonda, Vijay A R

    2017-11-23

    To study the clinical presentation, treatment, and outcome of patients with retinoblastoma (RB) in India. Retrospective study of 1,457 patients with RB (2,074 eyes). The mean age at presentation of RB was 29 months (median, 24 months; range, presentation of RB in 57% (n = 834) and bilateral in 43% (n = 623). Familial RB was present in 4% (n = 55). The most common presenting complaints included leukocoria (n = 1,100; 75%), proptosis (n = 91; 6%), strabismus (n = 77; 5%), and red eye (n = 68; 5%). Most (n = 1,889; 91%) tumors were intraocular in location, and 185 (n = 185; 9%) had extraocular tumor extension at presentation. The most common modalities of primary treatment-included systemic chemotherapy (n = 1,171; 60%) and enucleation (n = 674; 35%). At a mean follow-up period of 44 months (median, 30 months; range, 3-234 months), 92% (n = 1,206) were alive, and 108 (8%) patients died because of RB. Based on Kaplan-Meier analysis, the survival at 1, 3, 5, and 10 years was 94%, 91%, 90%, and 89%, respectively. The most common presenting signs of RB in Asian Indian population are leukocoria and proptosis. With appropriate treatment, the survival rate is favorable at 92%.

  12. Interaction of fish aryl hydrocarbon receptor paralogs (AHR1 and AHR2) with the retinoblastoma protein

    Energy Technology Data Exchange (ETDEWEB)

    Merson, Rebeka R., E-mail: rmerson@ric.edu [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States); Biology Department, Rhode Island College, 500 Mt. Pleasant Ave., Providence, RI 02908 (United States); Karchner, Sibel I.; Hahn, Mark E. [Biology Department, Woods Hole Oceanographic Institution, Woods Hole, MA 02543 (United States)

    2009-08-13

    The aryl hydrocarbon receptor (AHR) mediates the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related compounds. In some mammalian cell lines, TCDD induces G1 cell cycle arrest, which depends on an interaction between the AHR and the retinoblastoma tumor suppressor (RB). Mammals possess one AHR, whereas fishes possess two or more AHR paralogs that differ in the domains important for AHR-RB interactions in mammals. To test the hypothesis that fish AHR paralogs differ in their ability to interact with RB, we cloned RB cDNA from Atlantic killifish, Fundulus heteroclitus, and studied the interactions of killifish RB protein with killifish AHR1 and AHR2. In coimmunoprecipitation experiments, in vitro-expressed killifish RB coprecipitated with both AHR1 and AHR2. Consistent with these results, both killifish AHR1 and AHR2 interacted with RB in mammalian two-hybrid assays. These results suggest that both fish AHR1 and AHR2 paralogs may have the potential to influence cell proliferation through interactions with RB.

  13. Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining

    Directory of Open Access Journals (Sweden)

    Rebecca Cook

    2015-03-01

    Full Text Available Deficiencies in DNA double-strand break (DSB repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1 is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ. Support of cNHEJ involves a mechanism independent of RB1’s cell-cycle function and depends on its amino terminal domain with which it binds to NHEJ components XRCC5 and XRCC6. Cells with engineered loss of RB family function as well as cancer-derived cells with mutational RB1 loss show substantially reduced levels of cNHEJ. RB1 variants disabled for the interaction with XRCC5 and XRCC6, including a cancer-associated variant, are unable to support cNHEJ despite being able to confer cell-cycle control. Our data identify RB1 loss as a candidate driver of structural genomic instability and a causative factor for cancer somatic heterogeneity and evolution.

  14. Expressions of matrix metalloproteinase-2 and extracellular matrix metalloproteinase inducer in retinoblastoma

    Directory of Open Access Journals (Sweden)

    Yu-Hong Cheng

    2015-07-01

    Full Text Available AIM: To investigate expressions of matrix metalloproteinase-2(MMP-2and extracellular matrix metalloproteinase inducer(EMMPRINin retinoblastoma(Rband the relationships between MMP-2, EMMPRIN and tumor development.METHODS:Immunohistochemical technique was used to detect expressions of MMP-2 and EMMPRIN in 39 cases of paraffin embedded Rb samples. Quantitative analysis of expressions of MMP-2 and EMMPRIN were assessed by measuring the mean gray scale of Rb tissue with LEICA IM50 Color Pathologic Analysis System. The differences of expressions of MMP-2 and EMMPRIN in each clinical and pathological stage were statistically analyzed, and the same step was also undertaken to study the relationship between Rb with MMP-2 positive expression and that with EMMPRIN positive expression.RESULTS: The positive expression rate of MMP-2 was 90%(Gray value: 109.64±14.52; 35/39, and that of EMMPRIN was 85%(Gray value: 108.01±13.60; 33/39. The expressions of MMP-2 and EMMPRIN were significantly higher in tumors of glaucomatous stage(Gray value: 108.21±11.47 and 107.56±14.32than those in intraocular stage(Gray value: 121.13±11.32 and 119.34±12.66; PPPPPPCONCLUSION: The positive expression levels of MMP-2 and EMMPRIN may correlate with tumor infiltration and metastasis.

  15. Proton and electron deep dose profiles for retinoblastoma based on GEANT 4 code

    Energy Technology Data Exchange (ETDEWEB)

    Braga, Flavia V., E-mail: flaviafisica@gmail.co [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Programa de Pos-graduacao em Ciencias e Tecnicas Nucleares; Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizonte, MG (Brazil); Campos, Tarcisio P.R. de [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Programa de Pos-graduacao em Ciencias e Tecnicas Nucleares; Ribeiro, Kilder L., E-mail: kilderlr@gmail.co [Universidade Estadual de Feira de Santana (UEFS), BA (Brazil). Dept. de Fisica

    2009-07-01

    Herein, the dosimetry responses to a retinoblastoma proton and electron radiation therapy were investigated. The computational tool applied to this simulation was the Geant4 code, version 4.9.1. The code allows simulating the charge particle interaction with eyeball tissue. In the present simulation, a box of 4 cm side water filled had represented the human eye. The simulation was performed considering mono energetic beams of protons and electrons with spectra of 57 to 70 MeV for protons and 2 to 8 MeV for electrons. The simulation was guide by the advanced hadron therapy example distributed with the Geant4 code. The phantom was divided in voxels with 0.2 mm side. The energy deposited in each voxel was evaluated taken the direct beam at one face. The simulation results show the delivery energy and therefore the dose deposited in each voxel. The deep dose profiles to proton and electron were plotted. The well known Bragg peak was reproduced for protons. The maximum delivered dose defined the position at the proton stopped. However, to electrons, the absorbed energies were delivered along its path producing a more continuous distribution following the water depth, but also being stopped in the end of its path. (author)

  16. 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.

  17. 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

  18. 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.

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

    Science.gov (United States)

    van Dijk, Jennifer; Oostrom, Kim J; Huisman, Jaap; Moll, Annette C; Cohen-Kettenis, Peggy T; Ringens, Peter J; Imhof, Saskia M

    2010-01-01

    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. In this population-based cross-sectional study, content analysis was used to extract data on perceived restrictions and worries, from semi-structured interviews held with 156 RB survivors aged 8-35 years. The International Classification of Functioning Disabilities and Health (ICF) was used as a framework. Of all survivors, 55% perceive RB-related restrictions in daily life activities (school, professional career, mobility, self-care, intimate relationships). Young/adolescent survivors (6%) and adult survivors (15%) frequently report anxiety about developing a second primary tumor (SPT). Compared with the general population, RB survivors did not differ in rates of employment or marital status. However, special educational services were more frequently offered, and the level of completed education was lower. RB has influenced the lives of most survivors and, even though their prognosis was good, illness-related restrictions are common. Especially fear of developing SPT and of further loss of vision are important life-long problems, and many survivors had special education needs. The ICF might serve as a bridge between families and professionals, because this classification may facilitate early detection of problems. Copyright 2009 Wiley-Liss, Inc.

  20. A Bistable Circuit Involving SCARECROW-RETINOBLASTOMA Integrates Cues to Inform Asymmetric Stem Cell Division

    Science.gov (United States)

    Cruz-Ramírez, Alfredo; Díaz-Triviño, Sara; Blilou, Ikram; Grieneisen, Verônica A.; Sozzani, Rosangela; Zamioudis, Christos; Miskolczi, Pál; Nieuwland, Jeroen; Benjamins, René; Dhonukshe, Pankaj; Caballero-Pérez, Juan; Horvath, Beatrix; Long, Yuchen; Mähönen, Ari Pekka; Zhang, Hongtao; Xu, Jian; Murray, James A.H.; Benfey, Philip N.; Bako, Laszlo; Marée, Athanasius F.M.; Scheres, Ben

    2012-01-01

    SUMMARY In plants, where cells cannot migrate, asymmetric cell divisions (ACDs) must be confined to the appropriate spatial context. We investigate tissue-generating asymmetric divisions in a stem cell daughter within the Arabidopsis root. Spatial restriction of these divisions requires physical binding of the stem cell regulator SCARECROW (SCR) by the RETINOBLASTOMA-RELATED (RBR) protein. In the stem cell niche, SCR activity is counteracted by phosphorylation of RBR through a cyclinD6;1-CDK complex. This cyclin is itself under transcriptional control of SCR and its partner SHORT ROOT (SHR), creating a robust bistable circuit with either high or low SHR-SCR complex activity. Auxin biases this circuit by promoting CYCD6;1 transcription. Mathematical modeling shows that ACDs are only switched on after integration of radial and longitudinal information, determined by SHR and auxin distribution, respectively. Coupling of cell-cycle progression to protein degradation resets the circuit, resulting in a “flip flop” that constrains asymmetric cell division to the stem cell region. PMID:22921914

  1. Dosimetric evaluation in heterogeneous tissue of anterior electron beam irradiation for treatment of retinoblastoma

    International Nuclear Information System (INIS)

    Kirsner, S.M.; Hogstrom, K.R.; Kurup, R.G.; Moyers, M.F.

    1987-01-01

    A dosimetric study of anterior electron beam irradiation for treatment of retinoblastoma was performed to evaluate the influence of tissue heterogeneities on the dose distribution within the eye and the accuracy of the dose calculated by a pencil beam algorithm. Film measurements were made in a variety of polystyrene phantoms and in a removable polystyrene eye incorporated into a tissue substitute phantom constructed from a human skull. Measurements in polystyrene phantoms were used to demonstrate the algorithm's ability to predict the effect of a lens block placed in the beam, as well as the eye's irregular surface shape. The eye phantom was used to measure dose distributions within the eye in both the sagittal and transverse planes in order to test the algorithm's ability to predict the dose distribution when bony heterogeneities are present. Results show (1) that previous treatment planning conclusions based on flat, uniform phantoms for central-axis depth dose are adequate; (2) that a three-dimensional heterogeneity correction is required for accurate dose calculations; and (3) that if only a two-dimensional heterogeneity correction is used in calculating the dose, it is more accurate for the sagittal than the transverse plane

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. [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

  7. Access to the ophthalmic artery by retrograde approach through the posterior communicating artery for intra-arterial chemotherapy of retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Pham, Chi-Tuan; Blanc, Raphael; Pistocchi, Silvia; Bartolini, Bruno; Piotin, Michel [Fondation Rothschild Hospital, Department of Interventional Neuroradiology, Paris (France); Lumbroso-Le Rouic, Livia [Institut Curie, Department of Ocular Oncology, Paris (France)

    2012-08-15

    Intra-arterial infusion of chemotherapy into the ophthalmic artery for treatment of retinoblastoma has been realized after catheterization of the internal carotid and temporary balloon occlusion beyond the orifice of the ophthalmic artery, or more recently after superselective canulation of the ophthalmic artery by a microcatheter. The superselective catheterization of the ophthalmic artery could be cumbersome because of the implantation of the ostium on the carotid siphon or because of the tortuosity of the carotid siphon. We report our experience of using a retrograde approach through the posterior communicating artery that allows a more direct angle of access to the origin of the ophthalmic artery. (orig.)

  8. 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....

  9. A protein relational database and protein family knowledge bases to facilitate structure-based design analyses.

    Science.gov (United States)

    Mobilio, Dominick; Walker, Gary; Brooijmans, Natasja; Nilakantan, Ramaswamy; Denny, R Aldrin; Dejoannis, Jason; Feyfant, Eric; Kowticwar, Rupesh K; Mankala, Jyoti; Palli, Satish; Punyamantula, Sairam; Tatipally, Maneesh; John, Reji K; Humblet, Christine

    2010-08-01

    The Protein Data Bank is the most comprehensive source of experimental macromolecular structures. It can, however, be difficult at times to locate relevant structures with the Protein Data Bank search interface. This is particularly true when searching for complexes containing specific interactions between protein and ligand atoms. Moreover, searching within a family of proteins can be tedious. For example, one cannot search for some conserved residue as residue numbers vary across structures. We describe herein three databases, Protein Relational Database, Kinase Knowledge Base, and Matrix Metalloproteinase Knowledge Base, containing protein structures from the Protein Data Bank. In Protein Relational Database, atom-atom distances between protein and ligand have been precalculated allowing for millisecond retrieval based on atom identity and distance constraints. Ring centroids, centroid-centroid and centroid-atom distances and angles have also been included permitting queries for pi-stacking interactions and other structural motifs involving rings. Other geometric features can be searched through the inclusion of residue pair and triplet distances. In Kinase Knowledge Base and Matrix Metalloproteinase Knowledge Base, the catalytic domains have been aligned into common residue numbering schemes. Thus, by searching across Protein Relational Database and Kinase Knowledge Base, one can easily retrieve structures wherein, for example, a ligand of interest is making contact with the gatekeeper residue.

  10. 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

  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.

    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

  12. External beam irradiation for retinoblastoma: patterns of failure and dose-response analysis

    International Nuclear Information System (INIS)

    Foote, R.L.; Garretson, B.R.; Schomberg, P.J.; Buskirk, S.J.; Robertson, D.M.; Earle, J.D.

    1989-01-01

    Eighteen children with retinoblastoma (25 eyes) were treated with external beam radiation at the Mayo Clinic between January 1977 and January 1987; 15 eyes were in groups I to III and 10 were in groups IV and V. The median number of tumors per eye was 3. Radiation therapy consisted of 4- or 6-MV photons. Doses varied from 39 to 51 Gy in 1.8- to 3.0-Gy fractions. Fourteen eyes were treated through lateral fields by anterior segment-sparing techniques, and 11 eyes were treated by an anterior approach with no attempt at anterior segment sparing. All patients survived (median follow-up, 31.5 months). Cataracts developed in five eyes at a median of 23 months, four in eyes treated with anterior segment-sparing techniques. Of the 15 group I to III eyes, 6 required additional treatment; 4 were salvaged with cryotherapy or photocoagulation and 2 were enucleated. Of the 10 group IV and V eyes, 8 required additional treatment; 4 were salvaged with cryotherapy or photocoagulation, 1 with persistent disease is being followed closely, and 3 were enucleated. Ten (71%) of the 14 eyes treated with anterior segment-sparing techniques required additional treatment. Four (36%) of the 11 eyes treated with an anterior approach required additional treatment. Ninety percent of the tumors 10 disc diameters or smaller (1 disc diameter = 1.6 mm) were controlled independently of dose and fractionation used when they were not in the low-dose area of the anterior retina of an eye treated with an anterior segment-sparing technique. We find that use of lateral, anterior segment-sparing techniques has a high risk of anterior retinal tumor development and cataract formation and should be abandoned in favor of techniques that treat the entire retina

  13. External beam irradiation for retinoblastoma: patterns of failure and dose-response analysis

    Energy Technology Data Exchange (ETDEWEB)

    Foote, R.L.; Garretson, B.R.; Schomberg, P.J.; Buskirk, S.J.; Robertson, D.M.; Earle, J.D.

    1989-03-01

    Eighteen children with retinoblastoma (25 eyes) were treated with external beam radiation at the Mayo Clinic between January 1977 and January 1987; 15 eyes were in groups I to III and 10 were in groups IV and V. The median number of tumors per eye was 3. Radiation therapy consisted of 4- or 6-MV photons. Doses varied from 39 to 51 Gy in 1.8- to 3.0-Gy fractions. Fourteen eyes were treated through lateral fields by anterior segment-sparing techniques, and 11 eyes were treated by an anterior approach with no attempt at anterior segment sparing. All patients survived (median follow-up, 31.5 months). Cataracts developed in five eyes at a median of 23 months, four in eyes treated with anterior segment-sparing techniques. Of the 15 group I to III eyes, 6 required additional treatment; 4 were salvaged with cryotherapy or photocoagulation and 2 were enucleated. Of the 10 group IV and V eyes, 8 required additional treatment; 4 were salvaged with cryotherapy or photocoagulation, 1 with persistent disease is being followed closely, and 3 were enucleated. Ten (71%) of the 14 eyes treated with anterior segment-sparing techniques required additional treatment. Four (36%) of the 11 eyes treated with an anterior approach required additional treatment. Ninety percent of the tumors 10 disc diameters or smaller (1 disc diameter = 1.6 mm) were controlled independently of dose and fractionation used when they were not in the low-dose area of the anterior retina of an eye treated with an anterior segment-sparing technique. We find that use of lateral, anterior segment-sparing techniques has a high risk of anterior retinal tumor development and cataract formation and should be abandoned in favor of techniques that treat the entire retina.

  14. Localized whole eye radiotherapy for retinoblastoma using a 125I applicator, 'claws'

    International Nuclear Information System (INIS)

    Stannard, Clare; Sealy, Rossall; Hering, Egbert; Korrubel, Jan; Hill, John; Barron, Adrian; Knowles, Ruth

    2001-01-01

    Purpose: To treat children with retinoblastoma, who require whole eye radiotherapy, with a specially designed 125 I applicator that irradiates the eye while sparing the surrounding tissues. Methods and Materials: Under general anesthesia, a pericorneal ring is attached to the 4 extraocular muscles, and 4 appendages, each loaded with 125 I seeds, are inserted beneath the conjunctiva in-between each pair of muscles and attached anteriorly to the ring. Twenty-nine eyes were treated. Eighteen received a median dose of 28 Gy during 91 hours and 11 received 40 Gy during 122 hours, when the relative biologic effectiveness was taken as 1 instead of 1.5. Six had received prior chemotherapy. Results: Twenty-four eyes were followed up for 2-157 months (median 29). Although 22 eyes responded, local control was achieved in 13 patients, 3 of whom required additional treatment for new tumors; a further 3 required additional treatment for tumor recurrence as well as new tumors. One of these eyes was enucleated for neovascular glaucoma. All 6 Group I-III eyes and 6 of 18 Group V eyes were retained for 2-157 months (median 39), with good vision in 10 eyes. Three developed cataracts 7, 8, and 12 years later, 1 of which has been removed. Conclusions: This is a new way of irradiating the whole eye with a minimal dose to the surrounding tissues. The treatment time is only 5 days. It is effective in Groups I-III, but only 33% of Group V eyes retained vision. No late cosmetic defects occurred

  15. Radiation therapy for retinoblastoma: comparison of results with lens-sparing versus lateral beam techniques

    International Nuclear Information System (INIS)

    McCormick, B.; Ellsworth, R.; Abramson, D.; Haik, B.; Tome, M.; Grabowski, E.; LoSasso, T.

    1988-01-01

    From 1979 through 1986, 170 children were seen at our institution diagnosed with retinoblastoma. Sixty-six of the children with involvement of 121 eyes, were referred for definitive external beam radiation to one or both eyes. During the study period, two distinct radiation techniques were used. From 1980 through mid-1984, a lens-sparing technique included an anterior electron beam with a contact lens mounted lead shield, combined with a lateral field, was used. Since mid-1984, a modified lateral beam technique has been used, mixing lateral electrons and superior and inferior lateral oblique split beam wedged photons. Doses prescribed were similar for both techniques, ranging from 3,850 to 5,000 cGy in 4 to 5 weeks. The lens-sparing and the modified lateral techniques are compared for local control. For eyes with Group I through III disease, the lens-sparing technique resulted in local control in 33% of the eyes treated, where the modified lateral technique controlled 83% of the eyes treated (p = .006). Mean time to relapse was identical in both groups, that is 24 and 26 months respectively. Most relapses were successfully treated with further local therapy, including laser or cryosurgery, or 60Co plaques. Five eyes required enucleation following initial treatment with the lens-sparing technique, but none thus far with the lateral beam technique. For eyes with Group IV and V disease, no significant differences were found between the two techniques in terms of local control or eventual need for enucleation. With a mean follow-up time of 33 months for the entire group, the 4-year survival is 93%. Two of the 4 deaths are due to second primary tumor, and all 4 have occurred in the lens-sparing group. Because follow-up time is more limited in the lateral beam group, this is not statistically significant and direct survival comparisons are premature

  16. Hepatitis C virus induces E6AP-dependent degradation of the retinoblastoma protein.

    Directory of Open Access Journals (Sweden)

    Tsubasa Munakata

    2007-09-01

    Full Text Available Hepatitis C virus (HCV is a positive-strand RNA virus that frequently causes persistent infections and is uniquely associated with the development of hepatocellular carcinoma. While the mechanism(s by which the virus promotes cancer are poorly defined, previous studies indicate that the HCV RNA-dependent RNA polymerase, nonstructural protein 5B (NS5B, forms a complex with the retinoblastoma tumor suppressor protein (pRb, targeting it for degradation, activating E2F-responsive promoters, and stimulating cellular proliferation. Here, we describe the mechanism underlying pRb regulation by HCV and its relevance to HCV infection. We show that the abundance of pRb is strongly downregulated, and its normal nuclear localization altered to include a major cytoplasmic component, following infection of cultured hepatoma cells with either genotype 1a or 2a HCV. We further demonstrate that this is due to NS5B-dependent ubiquitination of pRb and its subsequent degradation via the proteasome. The NS5B-dependent ubiquitination of pRb requires the ubiquitin ligase activity of E6-associated protein (E6AP, as pRb abundance was restored by siRNA knockdown of E6AP or overexpression of a dominant-negative E6AP mutant in cells containing HCV RNA replicons. E6AP also forms a complex with pRb in an NS5B-dependent manner. These findings suggest a novel mechanism for the regulation of pRb in which the HCV NS5B protein traps pRb in the cytoplasm, and subsequently recruits E6AP to this complex in a process that leads to the ubiquitination of pRb. The disruption of pRb/E2F regulatory pathways in cells infected with HCV is likely to promote hepatocellular proliferation and chromosomal instability, factors important for the development of liver cancer.

  17. A tool for planning retinoblastoma services in sub-Saharan Africa.

    Science.gov (United States)

    Hampejsková, Lindsay; Bascaran, Covadonga; Zondervan, Marcia

    2017-04-01

    Cancer care remains inadequate in low-middle income countries (LMICs). Children with cancer have 80% chance of surviving in high-income countries compared to 20% in LMICs. Retinoblastoma (RB), an aggressive eye cancer of childhood and top childhood cancer in sub-Saharan Africa (SSA), has a low survival rate, due to a delay in diagnosis and abandonment of treatment. The purpose of this study is to provide a tool for planning human resources required to manage RB in SSA. Online tool was developed with 19 modifiable fields and 23 estimates. Routine data were used to populate modifiable fields: population, birthrate, infant mortality rate, and total fertility rate. Values were held constant: frequency, 1:17,000; familial cases, 8%; unilateral RB, 74%; extraocular disease, 70%; and survival postextraocular treatment, 10%. One thousand twenty-three RB incident and familial cases are estimated each year across Ethiopia, Ghana, Malawi, Nigeria, Tanzania, Uganda, Zambia, and Zimbabwe: 75 familial, 700 unilateral, 717 extraocular disease, and 645 palliative. Nigeria represents 431 cases and Zimbabwe 33 cases. Over the eight countries, a total of 41,558 patient visits are estimated each year consisting of unilateral enucleation, follow-up visits, intensive treatment, and familial screening, with a total of 2,802 prosthetic eyes being required each year. In the absence of data, estimates are essential for planning countrywide medical services. More attention is needed around planning for services from the Ministry level including emphasis on building multidisciplinary teams for diseases such as RB, including countrywide database and integrated clinical practice guidelines among all levels of care. © 2016 Wiley Periodicals, Inc.

  18. 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.

  19. 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.)

  20. 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.)

  1. 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.

  2. Health-related quality of life of child and adolescent retinoblastoma survivors in the Netherlands

    Directory of Open Access Journals (Sweden)

    Bezemer Pieter D

    2007-12-01

    Full Text Available Abstract Background To assess health-related quality of life (HRQoL in children (8–11 years and adolescents (12–18 years who survived retinoblastoma (RB, by means of the KIDSCREEN self-report questionnaire and the proxy-report version. Methods This population-based cross-sectional study (participation rate 70% involved 65 RB survivors (8–18 years and their parents. Child/adolescents' and parents' perception of their youth's HRQoL was assessed using the KIDSCREEN, and the results were compared with Dutch reference data. Relations with gender, age, marital status of the parents, and visual acuity were analyzed. Results RB survivors reported better HRQoL than did the Dutch reference group on the dimensions "moods and emotions" and "autonomy". Increased ratings of HRQoL in RB survivors were mainly seen in perceptions of the younger children and adolescent girls. RB survivors with normal visual acuity scored higher on "physical well-being" than visually impaired survivors. Age was negatively associated with the dimensions "psychological well-being", "self-perception" (according to the child and parent reports and "parent relations and home life" (according to the child. "Self-perception" was also negatively associated with visual acuity (according to the child. Only parents of young boys surviving RB reported lower on "autonomy" than the reference group, and parents of low visual acuity and blind RB survivors reported higher on "autonomy" than parents of visually unimpaired survivors. Survivors' perceptions and parents' perceptions correlated poorly on all HRQoL dimensions. Conclusion RB survivors reported a very good HRQoL compared with the Dutch reference group. The perceptions related to HRQoL differ substantially between parents and their children, i.e. parents judge the HRQoL of their child to be relatively poorer. Although the results are reassuring, additional factors of HRQoL that may have more specific relevance, such as psychological

  3. In vitro sensitivity of normal and hereditary retinoblastoma fibroblasts to DNA-damaging agents

    International Nuclear Information System (INIS)

    Woods, W.G.; Byrne, T.D.

    1986-01-01

    We investigated the ability of nine fibroblast cell strains from patients with the hereditary form of retinoblastoma (RB) to handle various types of DNA-damaging agents and compared the results with those obtained in nine normal strains. Cell strains were exposed to gamma-radiation, which causes DNA scission; actinomycin D, a DNA-intercalating agent; and mitomycin C, a bifunctional alkylating agent leading to DNA-DNA cross-linking. Cell strains were studied for their ability to survive in a cytotoxicity assay. Nine normal strains exhibited a mean D0 (inverse of the slope of the straight line portion of the survival curve) of 134-178 cGy after radiation exposure, compared to a range of 119-186 cGy in the nine RB strains (P = 0.33). Similarly, exposure to actinomycin D led to D0 values of 0.024-0.069 microgram/ml in the nine normal strains and D0 values of 0.016-0.067 microgram/ml in the RB strains (P = 0.64). The nine RB strains did exhibit a small overall increase in sensitivity after exposure to mitomycin C, with D0 values ranging from 0.14-0.32 microgram/ml versus 0.19-0.66 microgram/ml in the nine normal strains (P = 0.002); however, when the two most resistant normal strains were excluded from analysis, results were similar. Three RB cell strains derived from individuals who had either developed second cancers or who had a family history of additional sarcomas consistently exhibited increases in sensitivity to all three DNA-damaging agents studied compared with other hereditary RB cell strains as well as normal strains. The results suggest that normal human fibroblast cell strains exhibit a wide response to DNA-damaging agents, especially chemical agents. Most hereditary RB strains exhibit sensitivity well within the normal range; however, strains from RB patients predisposed to second cancers exhibit increases in sensitivity to DNA-damaging agents

  4. Mutation risk associated with paternal and maternal age in a cohort of retinoblastoma survivors.

    Science.gov (United States)

    Mills, Melissa B; Hudgins, Louanne; Balise, Raymond R; Abramson, David H; Kleinerman, Ruth A

    2012-07-01

    Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in

  5. 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

    Directory of Open Access Journals (Sweden)

    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

  6. Treatment planning with protons for pediatric retinoblastoma, medulloblastoma, and pelvic sarcoma: How do protons compare with other conformal techniques?

    International Nuclear Information System (INIS)

    Lee, Catherine T.; Bilton, Stephen D.; Famiglietti, Robin M.; Riley, Beverly A.; Mahajan, Anita; Chang, Eric L.; Maor, Moshe H.; Woo, Shiao Y.; Cox, James D.; Smith, Alfred R.

    2005-01-01

    Purpose: To calculate treatment plans and compare the dose distributions and dose-volume histograms (DVHs) for photon three-dimensional conformal radiation therapy (3D-CRT), electron therapy, intensity-modulated radiation therapy (IMRT), and standard (nonintensity modulated) proton therapy in three pediatric disease sites. Methods and Materials: The tumor volumes from 8 patients (3 retinoblastomas, 2 medulloblastomas, and 3 pelvic sarcomas) were studied retrospectively to compare DVHs from proton therapy with 3D-CRT, electron therapy, and IMRT. In retinoblastoma, several planning techniques were analyzed: A single electron appositional beam was compared with a single 3D-CRT lateral beam, a 3D-CRT anterior beam paired with a lateral beam, IMRT, and protons. In medulloblastoma, three posterior fossa irradiation techniques were analyzed: 3D-CRT, IMRT, and protons. Craniospinal irradiation (which consisted of composite plans of both the posterior fossa and craniospinal components) was also evaluated, primarily comparing spinal irradiation using 3D-CRT electrons, 3D-CRT photons, and protons. Lastly, in pelvic sarcoma, 3D-CRT, IMRT, and proton plans were assessed. Results: In retinoblastoma, protons resulted in the best target coverage combined with the most orbital bone sparing (10% was the mean orbital bone volume irradiated at ≥5 Gy for protons vs. 25% for 3D-CRT electrons, 69% for IMRT, 41% for a single 3D lateral beam, 51% for a 3D anterolateral beam with a lens block, and 65% for a 3D anterolateral beam without a lens block). A single appositional electron field was the next best technique followed by other planning approaches. In medulloblastoma, for posterior fossa and craniospinal irradiation, protons resulted in the least dose to the cochlea (for only posterior fossa irradiation at ≥20 Gy, 34% was the mean cochlear volume irradiated for protons, 87% for IMRT, 89% for 3D-CRT) and hypothalamus-pituitary axis (for only posterior fossa irradiation at ≥10 Gy

  7. Ophthalmic Vascular Events after Primary Unilateral Intra-arterial Chemotherapy for Retinoblastoma in Early and Recent Eras.

    Science.gov (United States)

    Dalvin, Lauren A; Ancona-Lezama, David; Lucio-Alvarez, J Antonio; Masoomian, Babak; Jabbour, Pascal; Shields, Carol L

    2018-06-16

    To assess risk factors for ophthalmic vascular events after intra-arterial chemotherapy (IAC) for retinoblastoma. Retrospective cohort study. Patients who received unilateral IAC as primary treatment for retinoblastoma from January 1, 2009, to November 30, 2017, at a single center. Records were reviewed for patient demographics, tumor features, IAC parameters, and treatment-related vascular events in the early IAC era (2009-2011) compared with the recent era (2012-2017) using the t test and Fisher exact test. Change in event rates over time was assessed using Poisson regression analysis, with Spearman's rho used to test correlation. Rate of IAC-induced ophthalmic vascular events. There were 243 chemotherapy infusions in 76 eyes of 76 patients, divided into early (22 eyes, 57 infusions) and recent (54 eyes, 186 infusions) eras. Intra-arterial chemotherapy consisted of melphalan (243 infusions), topotecan (124 infusions), and carboplatin (9 infusions). A comparison (early vs. recent era) revealed fewer mean number of infusions (2.6 vs. 3.4, P = 0.02) with similar mean patient age and presenting tumor features. Event rates decreased over time (P early era vs. recent era) in the recent era (59% vs. 9% per eye, 23% vs. 3% per infusion, P age (P = 0.75), tumor diameter (P = 0.32), tumor thickness (P = 0.59), or cumulative dosage of melphalan (P = 0.13) or topotecan (P = 0.59). There were no IAC-induced vascular events in 72 infusions of 21 consecutively treated eyes in 2016 to 2017. Ophthalmic vascular events after IAC have decreased from the early era (2009-2011) through the current era (2012-2017) at this center. Experience performing this highly specialized procedure could be an important factor predicting IAC-related vascular events. Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  8. The Modern Role of Radiation Therapy in Treating Advanced-Stage Retinoblastoma: Long-Term Outcomes and Racial Differences

    Energy Technology Data Exchange (ETDEWEB)

    Orman, Amber [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Koru-Sengul, Tulay [Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida (United States); Miao, Feng [Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida (United States); Markoe, Arnold [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States); Panoff, Joseph E., E-mail: jpanoff@med.miami.edu [Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida (United States)

    2014-12-01

    Purpose/Objective(s): To evaluate the effects of various patient characteristics and radiation therapy treatment variables on outcomes in advanced-stage retinoblastoma. Methods and Materials: This was a retrospective review of 41 eyes of 30 patients treated with external beam radiation therapy between June 1, 1992, and March 31, 2012, with a median follow-up time of 133 months (11 years). Outcome measures included overall survival, progression-free survival, local control, eye preservation rate, and toxicity. Results: Over 90% of the eyes were stage V. Definitive external beam radiation therapy (EBRT) was delivered in 43.9% of eyes, adjuvant EBRT in 22% of eyes, and second-line/salvage EBRT in 34.1% of eyes. A relative lens sparing (RLS) technique was used in 68.3% of eyes and modified lens sparing (MLS) in 24.4% of eyes. Three eyes were treated with other techniques. Doses ≥45 Gy were used in 68.3% of eyes. Chemotherapy was a component of treatment in 53.7% of eyes. The 10-year overall survival was 87.7%, progression-free survival was 80.5%, and local control was 87.8%. White patients had significantly better overall survival than did African-American patients in univariate analysis (hazard ratio 0.09; 95% confidence interval 0.01-0.84; P=.035). Toxicity was seen in 68.3% of eyes, including 24.3% with isolated acute dermatitis. Conclusions: External beam radiation therapy continues to be an effective treatment modality for advanced retinoblastoma, achieving excellent long-term local control and survival with low rates of treatment-related toxicity and secondary malignancy.

  9. BAG3 protects against hyperthermic stress by modulating NF-κB and ERK activities in human retinoblastoma cells.

    Science.gov (United States)

    Yunoki, Tatsuya; Tabuchi, Yoshiaki; Hayashi, Atsushi; Kondo, Takashi

    2015-03-01

    BCL2-associated athanogene 3 (BAG3), a co-chaperone of HSP70, is a cytoprotective and anti-apoptotic protein that acts against various stresses, including heat stress. Here, we examined the effect of BAG3 on the sensitivity of human retinoblastoma cells to hyperthermia (HT). We examined the effects of BAG3 knockdown on the sensitivity of Y79 and WERI-Rb-1cells to HT (44 °C, 1 h) by evaluating apoptosis and cell proliferation using western blotting, real-time quantitative PCR (qPCR), flow cytometry, and a WST-8 assay kit. Furthermore, we examined the effects of activating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) using western blotting and real time qPCR. HT induced considerable apoptosis along with the activation of caspase-3 and chromatin condensation. The sensitivity of Y79 and WERI-Rb-1 cells to HT was significantly enhanced by BAG3 knockdown. Compared to HT alone, the combination of BAG3 knockdown and HT reduced phosphorylation of the inhibitors of kappa B α (IκBα) and p65, a subunit of NF-κB, and degraded IκB kinase γ (IKKγ) during the recovery period after HT. Furthermore, BAG3 knockdown increased the HT-induced phosphorylation of ERK after HT treatment, and the ERK inhibitor U0126 significantly improved the viability of the cells treated with a combination of BAG3 knockdown and HT. The silencing of BAG3 seems to enhance the effects of HT, at least in part, by maintaining HT-induced inactivity of NF-κB and the phosphorylation of ERK. These findings indicate that BAG3 may be a potential molecular target for modifying the outcomes of HT in retinoblastoma.

  10. Retinoblastoma protein expression and radiation response in muscle-invasive bladder cancer

    International Nuclear Information System (INIS)

    Pollack, Alan; Czerniak, Bogdan; Zagars, Gunar K.; Hu Shixue; Wu, Catherine S.; Dinney, Colin P.N.; Chyle, Valerian; Benedict, William F.

    1997-01-01

    Purpose: The retinoblastoma protein (pRB) is a key regulator of the G1 cell cycle checkpoint and has been implicated as having a role in G1 arrest and apoptosis induced by radiation damage. In this report we examine the association between pRB expression and radiation response in patients treated between 1960 and 1983 with preoperative radiotherapy (50 Gy in 25 fractions) followed 4-6 weeks later by radical cystectomy. The correlation of pRB to patient outcome and how this relationship is complimentary to that seen with p53 staining status is also described. Methods and Materials: Immunohistochemical staining of pRB and p53 in paraffin-embedded tumor sections using WL-1 anti-RB and DO1 anti-p53 antibodies was considered adequate in 98 and 97 pretreatment tumor samples, respectively. There were 46 patients with clinical Stage T2, 28 with Stage T3a, and 24 with Stage T3b disease. The median age was 62 years and follow-up for those living was 85 months. Results: Staining for pRB was negative in 30% of the cases. Correlations were observed between pRB negativity and high pretreatment apoptosis level (p = 0.06), locally advanced clinical stage (p = 0.01), increased clinical-to-pathologic downstaging (p = 0.014), and more pathologic complete responses (Path-CRs; p = 0.019). Several other factors were tested and were not associated with pRB status, including p53 expression. RB status was the only pretreatment prognostic factor in the univariate analyses that correlated with downstaging and was independently associated with Path-CR using multivariate logistic regression. Despite these significant relationships, no correlations with patient outcome were observed when the entire cohort was analyzed. Restriction of the analyses to Stage T3b patients, however, revealed that pRB negativity predicted for enhanced distant metastasis freedom (p = 0.006, log rank) and overall survival (p 0.02). The overexpression of p53 also correlated with distant metastasis freedom and overall

  11. 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.

  12. 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.)

  13. 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.

  14. 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.)

  15. 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.)

  16. Identification of the proteins related to SET-mediated hepatic cytotoxicity of trichloroethylene by proteomic analysis.

    Science.gov (United States)

    Ren, Xiaohu; Yang, Xifei; Hong, Wen-Xu; Huang, Peiwu; Wang, Yong; Liu, Wei; Ye, Jinbo; Huang, Haiyan; Huang, Xinfeng; Shen, Liming; Yang, Linqing; Zhuang, Zhixiong; Liu, Jianjun

    2014-05-16

    Trichloroethylene (TCE) is an effective solvent for a variety of organic materials. Since the wide use of TCE as industrial degreasing of metals, adhesive paint and polyvinyl chloride production, TCE has turned into an environmental and occupational toxicant. Exposure to TCE could cause severe hepatotoxicity; however, the toxic mechanisms of TCE remain poorly understood. Recently, we reported that SET protein mediated TCE-induced cytotoxicity in L-02 cells. Here, we further identified the proteins related to SET-mediated hepatic cytotoxicity of TCE using the techniques of DIGE (differential gel electrophoresis) and MALDI-TOF-MS/MS. Among the 20 differential proteins identified, 8 were found to be modulated by SET in TCE-induced cytotoxicity and three of them (cofilin-1, peroxiredoxin-2 and S100-A11) were validated by Western-blot analysis. The functional analysis revealed that most of the identified SET-modulated proteins are apoptosis-associated proteins. These data indicated that these proteins may be involved in SET-mediated hepatic cytotoxicity of TCE in L-02 cells. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  17. Identifying biological concepts from a protein-related corpus with a probabilistic topic model

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    Lu Xinghua

    2006-02-01

    Full Text Available Abstract Background Biomedical literature, e.g., MEDLINE, contains a wealth of knowledge regarding functions of proteins. Major recurring biological concepts within such text corpora represent the domains of this body of knowledge. The goal of this research is to identify the major biological topics/concepts from a corpus of protein-related MEDLINE© titles and abstracts by applying a probabilistic topic model. Results The latent Dirichlet allocation (LDA model was applied to the corpus. Based on the Bayesian model selection, 300 major topics were extracted from the corpus. The majority of identified topics/concepts was found to be semantically coherent and most represented biological objects or concepts. The identified topics/concepts were further mapped to the controlled vocabulary of the Gene Ontology (GO terms based on mutual information. Conclusion The major and recurring biological concepts within a collection of MEDLINE documents can be extracted by the LDA model. The identified topics/concepts provide parsimonious and semantically-enriched representation of the texts in a semantic space with reduced dimensionality and can be used to index text.

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

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    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

  19. 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

  20. Overexpression of Cdk5 or non-phosphorylatable retinoblastoma protein protects septal neurons from oxygen-glucose deprivation.

    Science.gov (United States)

    Panickar, Kiran S; Nonner, Doris; White, Michael G; Barrett, John N

    2008-09-01

    Activation of cyclin dependent kinases (Cdks) contributes to neuronal death following ischemia. We used oxygen-glucose deprivation (OGD) in septal neuronal cultures to test for possible roles of cell cycle proteins in neuronal survival. Increased cdc2-immunoreactive neurons were observed at 24 h after the end of 5 h OGD. Green fluorescent protein (GFP) or GFP along with a wild type or dominant negative form of the retinoblastoma protein (Rb), or cyclin-dependent kinase5 (Cdk5), were overexpressed using plasmid constructs. Following OGD, when compared to controls, neurons expressing both GFP and dominant negative Rb, RbDeltaK11, showed significantly less damage using microscopy imaging. Overexpression of Rb-wt did not affect survival. Surprisingly, overexpression of Cdk5-wild type significantly protected neurons from process disintegration but Cdk5T33, a dominant negative Cdk5, gave little or no protection. Thus phosphorylation of the cell cycle regulator, Rb, contributes to death in OGD in septal neurons but Cdk5 can have a protective role.

  1. Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Q. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China); Wang, L.X. [Department of Pharmacology, School of Medicine, Shandong University, Jinan (China); Zeng, J.P. [Department of Biochemistry, School of Medicine, Shandong University, Jinan (China); Liu, X.J.; Liang, X.M.; Zhou, Y.B. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China)

    2013-09-06

    Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis.

  2. Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

    International Nuclear Information System (INIS)

    Wang, Q.; Wang, L.X.; Zeng, J.P.; Liu, X.J.; Liang, X.M.; Zhou, Y.B.

    2013-01-01

    Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis

  3. Structure-function analysis of the retinoblastoma tumor suppressor protein – is the whole a sum of its parts?

    Directory of Open Access Journals (Sweden)

    Dick Frederick A

    2007-09-01

    Full Text Available Abstract Biochemical analysis of the retinoblastoma protein's function has received considerable attention since it was cloned just over 20 years ago. During this time pRB has emerged as a key regulator of the cell division cycle and its ability to block proliferation is disrupted in the vast majority of human cancers. Much has been learned about the regulation of E2F transcription factors by pRB in the cell cycle. However, many questions remain unresolved and researchers continue to explore this multifunctional protein. In particular, understanding how its biochemical functions contribute to its role as a tumor suppressor remains to be determined. Since pRB has been shown to function as an adaptor molecule that links different proteins together, or to particular promoters, analyzing pRB by disrupting individual protein interactions holds tremendous promise in unraveling the intricacies of its function. Recently, crystal structures have reported how pRB interacts with some of its molecular partners. This information has created the possibility of rationally separating pRB functions by studying mutants that disrupt individual binding sites. This review will focus on literature that investigates pRB by isolating functions based on binding sites within the pocket domain. This article will also discuss the prospects for using this approach to further explore the unknown functions of pRB.

  4. Interaction of the retinoblastoma protein with Orc1 and its recruitment to human origins of DNA replication.

    Directory of Open Access Journals (Sweden)

    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.

  5. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells

    Science.gov (United States)

    Labrecque, Mark P.; Takhar, Mandeep K.; Nason, Rebecca; Santacruz, Stephanie; Tam, Kevin J.; Massah, Shabnam; Haegert, Anne; Bell, Robert H.; Altamirano-Dimas, Manuel; Collins, Colin C.; Lee, Frank J.S.; Prefontaine, Gratien G.; Cox, Michael E.; Beischlag, Timothy V.

    2016-01-01

    Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies. PMID:27015368

  6. Characterization and Molecular Mechanism of Peptide-Conjugated Gold Nanoparticle Inhibiting p53-HDM2 Interaction in Retinoblastoma

    Directory of Open Access Journals (Sweden)

    Sushma Kalmodia

    2017-12-01

    Full Text Available Inhibition of the interaction between p53 and HDM2 is an effective therapeutic strategy in cancers that harbor a wild-type p53 protein such as retinoblastoma (RB. Nanoparticle-based delivery of therapeutic molecules has been shown to be advantageous in localized delivery, including to the eye, by overcoming ocular barriers. In this study, we utilized biocompatible gold nanoparticles (GNPs to deliver anti-HDM2 peptide to RB cells. Characterization studies suggested that GNP-HDM2 was stable in biologically relevant solvents and had optimal cellular internalization capability, the primary requirement of any therapeutic molecule. GNP-HDM2 treatment in RB cells in vitro suggested that they function by arresting RB cells at the G2M phase of the cell cycle and initiating apoptosis. Analysis of molecular changes in GNP-HDM2-treated cells by qRT-PCR and western blotting revealed that the p53 protein was upregulated; however, transactivation of its downstream targets was minimal, except for the PUMA-BCl2 and Bax axis. Global gene expression and in silico bioinformatic analysis of GNP-HDM2-treated cells suggested that upregulation of p53 might presumptively mediate apoptosis through the induction of p53-inducible miRNAs.

  7. 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.

  8. A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites.

    Science.gov (United States)

    Sellers, W R; Rodgers, J W; Kaelin, W G

    1995-01-01

    An intact T/E1A-binding domain (the pocket) is necessary, but not sufficient, for the retinoblastoma protein (RB) to bind to DNA-protein complexes containing E2F and for RB to induce a G1/S block. Indirect evidence suggests that the binding of RB to E2F may, in addition to inhibiting E2F transactivation function, generate a complex capable of functioning as a transrepressor. Here we show that a chimera in which the E2F1 transactivation domain was replaced with the RB pocket could, in a DNA-binding and pocket-dependent manner, mimic the ability of RB to repress transcription and induce a cell cycle arrest. In contrast, a transdominant negative E2F1 mutant that is capable of blocking E2F-dependent transactivation did not. Fusion of the RB pocket to a heterologous DNA-binding domain unrelated to E2F likewise generated a transrepressor protein when scored against a suitable reporter. These results suggest that growth suppression by RB is due, at least in part, to transrepression mediated by the pocket domain bound to certain promoters via E2F. Images Fig. 4 Fig. 5 PMID:8524800

  9. Structural changes of the macula and optic nerve head in the remaining eyes after enucleation for retinoblastoma: an optical coherence tomography study.

    Science.gov (United States)

    Said, Azza Mohamed Ahmed; Elbayomi, Ahmed Mohamed; Shaat, Ashraf Abdelsalam Kandeel

    2017-12-16

    To describe objectively the possible structural changes of the macula and optic nerve head in the free eyes of unilateral cured retinoblastoma patients and, also after enucleation using spectral domain optical coherence tomography. A cross sectional study involving 60 patients subdivided into three groups; 15 unilateral RB patients in whom enucleation was indicated as a sole treatment performed earlier in life [(study group (I)], 15 unilateral RB patients who had completely regressed disease with a preserved eye [(study group (II)] and 30 age and sex matched healthy controls. The remaining and free eyes in study groups and right eyes of control group had full ophthalmological examination, static automated perimetry and optical coherence tomography of the macula and optic nerve head. In study group (II); a significant thinning of total macula, central fovea, ganglion cell layer (GCL), ganglion cell complex (GCC), and some sectors of outer nuclear layer (P- values ≤0.05) was found with no significant difference in peripapillary nerve fiber layer (pRNFL) thickness and optic nerve head parameters compared to the control group and the study group (I). A significantly thickened total macula, GCL, GCC, and pRNFL in study group (I) compared to study group (II). Thickened pRNFL was significantly correlated to standard automated perimetry pattern deviations. No significant difference was found between study group (I) and control group. Retinoblastoma eyes characterized by thinning of central fovea, GCL, GCC compared to the control group. After unilateral enucleation, increased GCC and pRNFL thicknesses were detected compared to retinoblastoma group.

  10. 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.

  11. 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.

  12. Intra-arterial chemotherapy for retinoblastoma: Two-year results from tertiary eye-care center in India

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    Pukhraj Rishi

    2017-01-01

    Full Text Available Aim: The aim of this study is to describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC for intraocular retinoblastoma (RB. Materials and Methods: A retrospective, interventional series of 10 eyes with RB which underwent IAC using melphalan (5 mg/7.5 mg and topotecan (1 mg, or melphalan (5 mg/7.5 mg alone. Treatment outcomes were evaluated in terms of tumor control, vitreous seeds (VS and subretinal seeds (SRS control, and globe salvage rates. Results: Ten eyes of 10 patients underwent 38 IAC sessions (mean = 3.8; median = 4; range = 3–5 sessions. Following IAC, complete regression of main tumor was seen in 9 eyes (90% and partial regression in 1 (10%. All four eyes with SRS showed complete regression (100%. Of 5 eyes with VS, 3 eyes (60% showed complete regression, 1 eye (20% showed relapse, while 1 eye (20% showed no response. Globe salvage was achieved in 8 of 10 eyes (80%. Complications included transient ophthalmic artery narrowing (n = 2, branched retinal vein occlusion (n = 1, forehead skin pigmentation (n = 1, and vitreous hemorrhage (n = 2. There was no case of stroke, hemiplegia, metastasis, or death. Transient hematological changes included relative pancytopenia (n = 4, relative leukopenia (n = 5, and relative thrombocytopenia (n = 4. Mean follow-up was 26 months (median = 28, range = 13–36 from the initiation of first IAC. Conclusions: IAC is an effective therapy for globe preservation in eyes with intraocular RB, in the setting of a developing country like India. Larger studies with longer follow-up are required to validate these results.

  13. Control of cell proliferation, endoreduplication, cell size, and cell death by the retinoblastoma-related pathway in maize endosperm

    KAUST Repository

    Sabelli, Paolo A.

    2013-04-22

    The endospermof cereal grains is one of the most valuable products of modern agriculture. Cereal endosperm development comprises different phases characterized by mitotic cell proliferation, endoreduplication, the accumulation of storage compounds, 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 in maize. Down-regulation of RBR1 by RNAi resulted in up-regulation of RBR3-type genes, as well as the MINICHROMOSOME MAINTENANCE 2-7 gene family and PROLIFERATING CELL NUCLEAR ANTIGEN, which encode essential DNA replication factors. Both the mitotic and endoreduplication cell cycles were stimulated. Developing transgenic endosperm contained 42-58% more cells and ~70% more DNA than wild type, whereas there was a reduction in cell and nuclear sizes. In addition, cell death was enhanced. The DNA content of mature endosperm increased 43% upon RBR1 downregulation, whereas storage protein content and kernel weight were essentially not affected. Down-regulation of both RBR1 and CYCLIN DEPENDENT KINASE A (CDKA);1 indicated that CDKA;1 is epistatic to RBR1 and controls endoreduplication through an RBR1- dependent pathway. However, the repressive activity of RBR1 on downstream targets was independent from CDKA;1, suggesting diversification of RBR1 activities. Furthermore, RBR1 negatively regulated CDK activity, suggesting the presence of a feedback loop. These results indicate that the RBR1 pathway plays a major role in regulation of different processes during maize endosperm development and suggest the presence of tissue/organlevel regulation of endosperm/seed homeostasis.

  14. 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

  15. A novel 1050nm handheld OCT imaging system for pediatric retinoblastoma patients: technology development and clinical study (Conference Presentation)

    Science.gov (United States)

    Nadiarnykh, Oleg; Moll, Annette C.; de Boer, Johannes F.

    2016-03-01

    We demonstrate a novel optical coherence tomography system specifically developed and validated for clinical imaging of retinoblastoma tumors in pediatric patients. The existing treatment options for this malignant tumor of the retina aim at reduction of tumor (re)growth risks, and vision preservation. The choice of optimal treatment strongly depends on skilled and detailed clinical assessment. Due to the limitations of the existing real-time diagnostic tools the patients at risk are periodically monitored with retinal imaging to confirm the absence of new tumor seedings. Three-dimensional visualization of tissue layer and microvasculature at improved axial and lateral resolution of interference-based OCT imaging provides sensitivity for detection of vital tumor tissue concurrent with local treatment. Our METC-approved system accommodates for the range of optical parameters of infants' eyes, and uses the 1050nm wavelength to access the deeper choroid layers of retina. The prototype is designed for patients in supine position under general anesthesia, where ergonomic handheld module is connected to fiber-based optical setup via umbilical cord. The system conforms to clinical safety requirements, including fully isolated low-voltage electric circuit. Focusing is performed with a mechanically tunable lens, where resolution is 6 µm axially, and varies with focusing at 10-18µm laterally. We will present optical design, performance limitations, and results of the ongoing clinical study, including the increased OCT diagnostic sensitivity in three dimensions in comparison with the established clinical imaging modalities. We will discuss images of early, active, and treated tumors, as well as follow-up on patients after local and systemic treatments.

  16. 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

  17. T1 Gd-enhanced compared with CISS sequences in retinoblastoma: superiority of T1 sequences in evaluation of tumour extension

    Energy Technology Data Exchange (ETDEWEB)

    Gizewski, Elke R.; Wanke, Isabel; Guengoer, Ali-Riza; Forsting, Michael [University Hospital, Department of Diagnostic and Interventional Neuroradiology, Essen (Germany); Jurklies, Christine [University Hospital Essen, Department of Ophthalmology (Germany)

    2005-01-01

    Background As adequate therapy for retinoblastoma in young children depends on infiltration of extra-retinal structures, diagnostic modalities play an essential role. Methods: In this widely extended study, 80 children with retinoblastoma were studied with MRI (standard fat-suppressed Gd-enhanced T1, T2 thin-slice sequences (additionally with small loop surface coil), constructive interference in steady state (CISS) sequence covering the orbita). The images were analysed by two blinded neuroradiologists. Histology was used as the gold standard. MRI assumed infiltration of extra-retinal structures in 13 of 80 patients of which ten were confirmed by histology. Affected extra-retinal structures were: optic nerve (five, of which two were on CISS and three on T1 with higher image resolution using the surface coil), scleral infiltration (five, of which four on CISS and T1) and ciliary body infiltration (one on CISS and T1). Another 61 enucleated patients did not have any extra-retinal infiltration in histology. The CISS sequence with multiplanar reconstruction was mainly helpful in revealing exact three-dimensional tumour extension with excellent clinical acceptance and pre-surgical planning but T1 fat-suppressed Gd-enhanced images were superior in revealing exact tumour extension. CISS sequences allow to produce excellent anatomical images and to perform multiplanar reconstruction to better demonstrate tumour extension. However, T1-weighted sequences after contrast application are more sensitive (60 versus 40%) in detecting infiltration of the optic nerve but equal in detecting scleral infiltration. (orig.)

  18. Preliminary Experience in Treatment of Papillary and Macular Retinoblastoma: Evaluation of Local Control and Local Complications After Treatment With Linear Accelerator-Based Stereotactic Radiotherapy With Micromultileaf Collimator as Second-Line or Salvage Treatment After Chemotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Pica, Alessia, E-mail: Alessia.Pica@chuv.ch [Department of Radiation Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland); Moeckli, Raphael [University Institute for Radiation Physics, Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland); Balmer, Aubin [Department of Radiation Oncology, Jules Gonin Eye Hospital, Lausanne (Switzerland); Beck-Popovic, Maja [Unit of Pediatric Oncology, University of Lausanne, Lausanne (Switzerland); Chollet-Rivier, Madeleine [Department of Anesthesiology, University of Lausanne, Lausanne (Switzerland); Do, Huu-Phuoc [University Institute for Radiation Physics, Centre Hospitalier Universitaire Vaudois, Lausanne (Switzerland); Weber, Damien C. [Department of Radiation Oncology, Geneva University Hospital, University of Geneva, Geneva (Switzerland); Munier, Francis L. [Department of Radiation Oncology, Jules Gonin Eye Hospital, Lausanne (Switzerland)

    2011-12-01

    Purpose: To determine the local control and complication rates for children with papillary and/or macular retinoblastoma progressing after chemotherapy and undergoing stereotactic radiotherapy (SRT) with a micromultileaf collimator. Methods and Materials: Between 2004 and 2008, 11 children (15 eyes) with macular and/or papillary retinoblastoma were treated with SRT. The mean age was 19 months (range, 2-111). Of the 15 eyes, 7, 6, and 2 were classified as International Classification of Intraocular Retinoblastoma Group B, C, and E, respectively. The delivered dose of SRT was 50.4 Gy in 28 fractions using a dedicated micromultileaf collimator linear accelerator. Results: The median follow-up was 20 months (range, 13-39). Local control was achieved in 13 eyes (87%). The actuarial 1- and 2-year local control rates were both 82%. SRT was well tolerated. Late adverse events were reported in 4 patients. Of the 4 patients, 2 had developed focal microangiopathy 20 months after SRT; 1 had developed a transient recurrence of retinal detachment; and 1 had developed bilateral cataracts. No optic neuropathy was observed. Conclusions: Linear accelerator-based SRT for papillary and/or macular retinoblastoma in children resulted in excellent tumor control rates with acceptable toxicity. Additional research regarding SRT and its intrinsic organ-at-risk sparing capability is justified in the framework of prospective trials.

  19. miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jong-Kook [College of Pharmacy, Ohio State University, Columbus, OH 43210 (United States); Henry, Jon C. [Department of Surgery, Ohio State University, Columbus, OH 43210 (United States); Jiang, Jinmai [College of Pharmacy, Ohio State University, Columbus, OH 43210 (United States); Esau, Christine [Regulus Therapeutics, Carlsbad, CA (United States); Gusev, Yuriy [Lombardi Cancer Center, Georgetown University, Washington, DC (United States); Lerner, Megan R. [Veterans Affairs Medical Center, Oklahoma City, OK (United States); Postier, Russell G. [Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK (United States); Brackett, Daniel J. [Veterans Affairs Medical Center, Oklahoma City, OK (United States); Schmittgen, Thomas D., E-mail: Schmittgen.2@osu.edu [College of Pharmacy, Ohio State University, Columbus, OH 43210 (United States)

    2011-03-25

    Research highlights: {yields} The expression of miR-132 and miR-212 are significantly increased in pancreatic cancer. {yields} miR-132 and miR-212 target the tumor suppressor pRb, resulting in enhanced proliferation. {yields} miR-132 and miR-212 expression is increased by a {beta}2 adrenergic receptor agonist, suggesting a novel mechanism for pancreatic cancer progression. -- Abstract: Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G{sub 2}/M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the {beta}2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The {beta}2 adrenergic pathway may play an important role in this novel mechanism.

  20. miR-132 and miR-212 are increased in pancreatic cancer and target the retinoblastoma tumor suppressor

    International Nuclear Information System (INIS)

    Park, Jong-Kook; Henry, Jon C.; Jiang, Jinmai; Esau, Christine; Gusev, Yuriy; Lerner, Megan R.; Postier, Russell G.; Brackett, Daniel J.; Schmittgen, Thomas D.

    2011-01-01

    Research highlights: → The expression of miR-132 and miR-212 are significantly increased in pancreatic cancer. → miR-132 and miR-212 target the tumor suppressor pRb, resulting in enhanced proliferation. → miR-132 and miR-212 expression is increased by a β2 adrenergic receptor agonist, suggesting a novel mechanism for pancreatic cancer progression. -- Abstract: Numerous microRNAs (miRNAs) are reported as differentially expressed in cancer, however the consequence of miRNA deregulation in cancer is unknown for many miRNAs. We report that two miRNAs located on chromosome 17p13, miR-132 and miR-212, are over-expressed in pancreatic adenocarcinoma (PDAC) tissues. Both miRNAs are predicted to target the retinoblastoma tumor suppressor, Rb1. Validation of this interaction was confirmed by luciferase reporter assay and western blot in a pancreatic cancer cell line transfected with pre-miR-212 and pre-miR-132 oligos. Cell proliferation was enhanced in Panc-1 cells transfected with pre-miR-132/-212 oligos. Conversely, antisense oligos to miR-132/-212 reduced cell proliferation and caused a G 2 /M cell cycle arrest. The mRNA of a number of E2F transcriptional targets were increased in cells over expressing miR-132/-212. Exposing Panc-1 cells to the β2 adrenergic receptor agonist, terbutaline, increased the miR-132 and miR-212 expression by 2- to 4-fold. We report that over-expression of miR-132 and miR-212 result in reduced pRb protein in pancreatic cancer cells and that the increase in cell proliferation from over-expression of these miRNAs is likely due to increased expression of several E2F target genes. The β2 adrenergic pathway may play an important role in this novel mechanism.

  1. Dosage-sensitive function of retinoblastoma related and convergent epigenetic control are required during the Arabidopsis life cycle.

    Directory of Open Access Journals (Sweden)

    Amal J Johnston

    2010-06-01

    Full Text Available The plant life cycle alternates between two distinct multi-cellular generations, the reduced gametophytes and the dominant sporophyte. Little is known about how generation-specific cell fate, differentiation, and development are controlled by the core regulators of the cell cycle. In Arabidopsis, RETINOBLASTOMA RELATED (RBR, an evolutionarily ancient cell cycle regulator, controls cell proliferation, differentiation, and regulation of a subset of Polycomb Repressive Complex 2 (PRC2 genes and METHYLTRANSFERASE 1 (MET1 in the male and female gametophytes, as well as cell fate establishment in the male gametophyte. Here we demonstrate that RBR is also essential for cell fate determination in the female gametophyte, as revealed by loss of cell-specific marker expression in all the gametophytic cells that lack RBR. Maintenance of genome integrity also requires RBR, because diploid plants heterozygous for rbr (rbr/RBR produce an abnormal portion of triploid offspring, likely due to gametic genome duplication. While the sporophyte of the diploid mutant plants phenocopied wild type due to the haplosufficiency of RBR, genetic analysis of tetraploid plants triplex for rbr (rbr/rbr/rbr/RBR revealed that RBR has a dosage-dependent pleiotropic effect on sporophytic development, trichome differentiation, and regulation of PRC2 subunit genes CURLY LEAF (CLF and VERNALIZATION 2 (VRN2, and MET1 in leaves. There were, however, no obvious cell cycle and cell proliferation defects in these plant tissues, suggesting that a single functional RBR copy in tetraploids is capable of maintaining normal cell division but is not sufficient for distinct differentiation and developmental processes. Conversely, in leaves of mutants in sporophytic PRC2 subunits, trichome differentiation was also affected and expression of RBR and MET1 was reduced, providing evidence for a RBR-PRC2-MET1 regulatory feedback loop involved in sporophyte development. Together, dosage-sensitive RBR

  2. A role for the retinoblastoma protein as a regulator of mouse osteoblast cell adhesion: implications for osteogenesis and osteosarcoma formation.

    Directory of Open Access Journals (Sweden)

    Bernadette Sosa-García

    2010-11-01

    Full Text Available The retinoblastoma protein (pRb is a cell cycle regulator inactivated in most human cancers. Loss of pRb function results from mutations in the gene coding for pRb or for any of its upstream regulators. Although pRb is predominantly known as a cell cycle repressor, our data point to additional pRb functions in cell adhesion. Our data show that pRb regulates the expression of a wide repertoire of cell adhesion genes and regulates the assembly of the adherens junctions required for cell adhesion. We conducted our studies in osteoblasts, which depend on both pRb and on cell-to-cell contacts for their differentiation and function. We generated knockout mice in which the RB gene was excised specifically in osteoblasts using the cre-lox P system and found that osteoblasts from pRb knockout mice did not assemble adherens junction at their membranes. pRb depletion in wild type osteoblasts using RNAi also disrupted adherens junctions. Microarrays comparing pRb-expressing and pRb-deficient osteoblasts showed that pRb controls the expression of a number of cell adhesion genes, including cadherins. Furthermore, pRb knockout mice showed bone abnormalities consistent with osteoblast adhesion defects. We also found that pRb controls the function of merlin, a well-known regulator of adherens junction assembly, by repressing Rac1 and its effector Pak1. Using qRT-PCR, immunoblots, co-immunoprecipitation assays, and immunofluorescent labeling, we observed that pRb loss resulted in Rac1 and Pak1 overexpression concomitant with merlin inactivation by Pak1, merlin detachment from the membrane, and adherens junction loss. Our data support a pRb function in cell adhesion while elucidating the mechanism for this function. Our work suggests that in some tumor types pRb inactivation results in both a loss of cell cycle control that promotes initial tumor growth as well as in a loss of cell-to-cell contacts, which contributes to later stages of metastasis.

  3. Retinoblastoma treatment: impact of the glycolytic inhibitor 2-deoxy-d-glucose on molecular genomics expression in LHBETATAG retinal tumors

    Directory of Open Access Journals (Sweden)

    Piña Y

    2012-05-01

    involved in its in vitro and in vivo activity in inhibiting tumor cell growth.Keywords: retinoblastoma, hypoxia, genetic expression, glycolytic inhibitor, 2-DG

  4. 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

  5. Oxysterol-binding protein-related protein (ORP) 9 is a PDK-2 substrate and regulates Akt phosphorylation.

    Science.gov (United States)

    Lessmann, Eva; Ngo, Mike; Leitges, Michael; Minguet, Susana; Ridgway, Neale D; Huber, Michael

    2007-02-01

    The oxysterol-binding protein and oxysterol-binding protein-related protein family has been implicated in lipid transport and metabolism, vesicle trafficking and cell signaling. While investigating the phosphorylation of Akt/protein kinase B in stimulated bone marrow-derived mast cells, we observed that a monoclonal antibody directed against phospho-S473 Akt cross-reacted with oxysterol-binding protein-related protein 9 (ORP9). Further analysis revealed that mast cells exclusively express ORP9S, an N-terminal truncated version of full-length ORP9L. A PDK-2 consensus phosphorylation site in ORP9L and OPR9S at S287 (VPEFS(287)Y) was confirmed by site-directed mutagenesis. In contrast to Akt, increased phosphorylation of ORP9S S287 in stimulated mast cells was independent of phosphatidylinositol 3-kinase but sensitive to inhibition of conventional PKC isotypes. PKC-beta dependence was confirmed by lack of ORP9S phosphorylation at S287 in PKC-beta-deficient, but not PKC-alpha-deficient, mast cells. Moreover, co-immunoprecipitation of PKC-beta and ORP9S, and in vitro phosphorylation of ORP9S in this complex, argued for direct phosphorylation of ORP9S by PKC-beta, introducing ORP9S as a novel PKC-beta substrate. Akt was also detected in a PKC-beta/ORP9S immune complex and phosphorylation of Akt on S473 was delayed in PKC-deficient mast cells. In HEK293 cells, RNAi experiments showed that depletion of ORP9L increased Akt S473 phosphorylation 3-fold without affecting T308 phosphorylation in the activation loop. Furthermore, mammalian target of rapamycin was implicated in ORP9L phosphorylation in HEK293 cells. These studies identify ORP9 as a PDK-2 substrate and negative regulator of Akt phosphorylation at the PDK-2 site.

  6. High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma. Part 2: new vs. old imaging concept

    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

    High-resolution magnetic resonance imaging (MRI) is recommended for the evaluation of metastatic risk factors in children with retinoblastoma according to recent guidelines. The aim of this study was to compare diagnostic accuracy of a new imaging concept with two orbit surface coils to that of an old imaging concept with one orbit surface coil. One hundred forty-three patients (148 eyes, 64 girls, 79 boys) underwent high-resolution MRI on 1.5 T scanners using orbit surface coils. The old imaging concept (one orbit surface coil focusing on the (most) effected eye additionally to the standard head coil) was used in 100 patients/103 eye; the new imaging concept (two orbit surface coils (each focusing on one eye) additionally to the standard head coil) in 43 patients/45 eyes. Image analysis was performed by two neuroradiologists in consensus. Histopathology served as gold standard. Detection rate for choroidal invasion was higher for the new compared to that for the old imaging concept (sensitivity/specificity 87.5/94.6 % vs. 57.1/96.1 % for choroidal invasion and 100/97.5 % vs. 58.3/97.7 % for massive choroidal invasion, respectively). Sensitivity and specificity for the detection of postlaminar optic nerve infiltration, peribulbar fat, and scleral invasion were comparable in both imaging concepts; however positive predictive value was higher in the new imaging concept (new vs. old imaging concept: 60 vs. 31.6 % for postlaminar and deep postlaminar optic nerve infiltration, respectively, and 100 vs. 66.7 % for scleral invasion). The new imaging concept shows a trend towards improving the accuracy of detecting metastatic risk factors in children with retinoblastoma and is therefore recommended for pretherapeutic imaging and follow-up. (orig.)

  7. Flavopiridol induces apoptosis in glioma cell lines independent of retinoblastoma and p53 tumor suppressor pathway alterations by a caspase-independent pathway.

    Science.gov (United States)

    Alonso, Michelle; Tamasdan, Cristina; Miller, Douglas C; Newcomb, Elizabeth W

    2003-02-01

    Flavopiridol is a synthetic flavone, which inhibits growth in vitro and in vivo of several solid malignancies such as renal, prostate, and colon cancers. It is a potent cyclin-dependent kinase inhibitor presently in clinical trials. In this study, we examined the effect of flavopiridol on a panel of glioma cell lines having different genetic profiles: five of six have codeletion of p16(INK4a) and p14(ARF); three of six have p53 mutations; and one of six shows overexpression of mouse double minute-2 (MDM2) protein. Independent of retinoblastoma and p53 tumor suppressor pathway alterations, flavopiridol induced apoptosis in all cell lines but through a caspase-independent mechanism. No cleavage products for caspase 3 or its substrate poly(ADP-ribose) polymerase or caspase 8 were detected. The pan-caspase inhibitor Z-VAD-fmk did not inhibit flavopiridol-induced apoptosis. Mitochondrial damage measured by cytochrome c release and transmission electron microscopy was not observed in drug-treated glioma cells. In contrast, flavopiridol treatment induced translocation of apoptosis-inducing factor from the mitochondria to the nucleus. The proteins cyclin D(1) and MDM2 involved in the regulation of retinoblastoma and p53 activity, respectively, were down-regulated early after flavopiridol treatment. Given that MDM2 protein can confer oncogenic properties under certain circumstances, loss of MDM2 expression in tumor cells could promote increased chemosensitivity. After drug treatment, a low Bcl-2/Bax ratio was observed, a condition that may favor apoptosis. Taken together, the data indicate that flavopiridol has activity against glioma cell lines in vitro and should be considered for clinical development in the treatment of glioblastoma multiforme.

  8. High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma. Part 2: new vs. old imaging concept

    International Nuclear Information System (INIS)

    Sirin, Selma; Schlamann, Marc; Schweiger, Bernd; Goericke, Sophia L.; Metz, Klaus A.; Bornfeld, Norbert; Holdt, Markus; Temming, Petra; Schuendeln, Michael M.

    2015-01-01

    High-resolution magnetic resonance imaging (MRI) is recommended for the evaluation of metastatic risk factors in children with retinoblastoma according to recent guidelines. The aim of this study was to compare diagnostic accuracy of a new imaging concept with two orbit surface coils to that of an old imaging concept with one orbit surface coil. One hundred forty-three patients (148 eyes, 64 girls, 79 boys) underwent high-resolution MRI on 1.5 T scanners using orbit surface coils. The old imaging concept (one orbit surface coil focusing on the (most) effected eye additionally to the standard head coil) was used in 100 patients/103 eye; the new imaging concept (two orbit surface coils (each focusing on one eye) additionally to the standard head coil) in 43 patients/45 eyes. Image analysis was performed by two neuroradiologists in consensus. Histopathology served as gold standard. Detection rate for choroidal invasion was higher for the new compared to that for the old imaging concept (sensitivity/specificity 87.5/94.6 % vs. 57.1/96.1 % for choroidal invasion and 100/97.5 % vs. 58.3/97.7 % for massive choroidal invasion, respectively). Sensitivity and specificity for the detection of postlaminar optic nerve infiltration, peribulbar fat, and scleral invasion were comparable in both imaging concepts; however positive predictive value was higher in the new imaging concept (new vs. old imaging concept: 60 vs. 31.6 % for postlaminar and deep postlaminar optic nerve infiltration, respectively, and 100 vs. 66.7 % for scleral invasion). The new imaging concept shows a trend towards improving the accuracy of detecting metastatic risk factors in children with retinoblastoma and is therefore recommended for pretherapeutic imaging and follow-up. (orig.)

  9. Stages of Retinoblastoma

    Science.gov (United States)

    ... of the ultrasound monitor . The picture can be printed to be looked at later. MRI (magnetic resonance ... procedures may be used in the staging process: Bone scan : A procedure to check if there are ...

  10. Treatment Option Overview (Retinoblastoma)

    Science.gov (United States)

    ... of the ultrasound monitor . The picture can be printed to be looked at later. MRI (magnetic resonance ... procedures may be used in the staging process: Bone scan : A procedure to check if there are ...

  11. General Information about Retinoblastoma

    Science.gov (United States)

    ... of the ultrasound monitor . The picture can be printed to be looked at later. MRI (magnetic resonance ... procedures may be used in the staging process: Bone scan : A procedure to check if there are ...

  12. Treatment Options for Retinoblastoma

    Science.gov (United States)

    ... factors affect prognosis (chance of recovery) and treatment options. The prognosis (chance of recovery ) and treatment options ... or in other places in the body. Treatment Option Overview Key Points There are different types of ...

  13. Assessment of early-stage optic nerve invasion in retinoblastoma using high-resolution 1.5 Tesla MRI with surface coils: a multicentre, prospective accuracy study with histopathological correlation

    Energy Technology Data Exchange (ETDEWEB)

    Brisse, Herve J. [Institut Curie, Department of Radiology, Paris (France); Institut CURIE, Imaging Department, Paris (France); Graaf, Pim de; Rodjan, Firazia; Jong, Marcus C. de; Castelijns, Jonas A. [VU University Medical Center, Department of Radiology, Amsterdam (Netherlands); Galluzzi, Paolo [Neuroimaging and Neurointerventional Unit (NINT) Azienda Ospedaliera e Universitaria Senese, Siena (Italy); Cosker, Kristel; Savignoni, Alexia [Institut Curie, Department of Biostatistics, Paris (France); Maeder, Philippe [Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Department of Radiology, Lausanne (Switzerland); Goericke, Sophia [University Hospital Essen, Institute of Diagnostic and Interventional Radiology and Neuroradiology, Essen (Germany); Aerts, Isabelle [Institut Curie, Department of Pediatric Oncology, Paris (France); Desjardins, Laurence [Institut Curie, Department of Ophthalmology, Paris (France); Moll, Annette C. [VU University Medical Center, Department of Ophthalmology, Amsterdam (Netherlands); Hadjistilianou, Theodora [Azienda Ospedaliera Universitaria Senese, Department of Ophthalmology, Siena (Italy); Toti, Paolo [University of Siena, Department of Medical Biotechnologies, Pathology Unit, Siena (Italy); Valk, Paul van der [VU University Medical Center, Department of Pathology, Amsterdam (Netherlands); Sastre-Garau, Xavier [Institut Curie, Department of Biopathology, Paris (France); Collaboration: European Retinoblastoma Imaging Collaboration (ERIC)

    2015-05-01

    To assess the accuracy of high-resolution (HR) magnetic resonance imaging (MRI) in diagnosing early-stage optic nerve (ON) invasion in a retinoblastoma cohort. This IRB-approved, prospective multicenter study included 95 patients (55 boys, 40 girls; mean age, 29 months). 1.5-T MRI was performed using surface coils before enucleation, including spin-echo unenhanced and contrast-enhanced (CE) T1-weighted sequences (slice thickness, 2 mm; pixel size <0.3 x 0.3 mm{sup 2}). Images were read by five neuroradiologists blinded to histopathologic findings. ROC curves were constructed with AUC assessment using a bootstrap method. Histopathology identified 41 eyes without ON invasion and 25 with prelaminar, 18 with intralaminar and 12 with postlaminar invasion. All but one were postoperatively classified as stage I by the International Retinoblastoma Staging System. The accuracy of CE-T1 sequences in identifying ON invasion was limited (AUC = 0.64; 95 % CI, 0.55 - 0.72) and not confirmed for postlaminar invasion diagnosis (AUC = 0.64; 95 % CI, 0.47 - 0.82); high specificities (range, 0.64 - 1) and negative predictive values (range, 0.81 - 0.97) were confirmed. HR-MRI with surface coils is recommended to appropriately select retinoblastoma patients eligible for primary enucleation without the risk of IRSS stage II but cannot substitute for pathology in differentiating the first degrees of ON invasion. (orig.)

  14. Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System

    Directory of Open Access Journals (Sweden)

    Kexin Zhao

    2017-05-01

    Full Text Available Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs by Niemann-Pick C1 (NPC1. However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4-phosphate-, and vesicle-associated membrane protein-associated protein (VAP-binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles.

  15. Proteomic analysis identifies insulin-like growth factor-binding protein-related protein-1 as a podocyte product.

    Science.gov (United States)

    Matsumoto, Takayuki; Hess, Sonja; Kajiyama, Hiroshi; Sakairi, Toru; Saleem, Moin A; Mathieson, Peter W; Nojima, Yoshihisa; Kopp, Jeffrey B

    2010-10-01

    The podocyte secretory proteome may influence the phenotype of adjacent podocytes, endothelial cells, parietal epithelial cells, and tubular epithelial cells but has not been systematically characterized. We have initiated studies to characterize this proteome, with the goal of further understanding the podocyte cell biology. We cultured differentiated conditionally immortalized human podocytes and subjected the proteins in conditioned medium to mass spectrometry. At a false discovery rate of factor-binding protein-related protein-1 (IGFBP-rP1), was expressed in mRNA and protein of cultured podocytes. In addition, transforming growth factor-β1 stimulation increased IGFBP-rP1 in conditioned medium. We analyzed IGFBP-rP1 glomerular expression in a mouse model of human immunodeficiency virus-associated nephropathy. IGFBP-rP1 was absent from podocytes of normal mice and was expressed in podocytes and pseudocrescents of transgenic mice, where it was coexpressed with desmin, a podocyte injury marker. We conclude that IGFBP-rP1 may be a product of injured podocytes. Further analysis of the podocyte secretory proteome may identify biomarkers of podocyte injury.

  16. Molecular Mechanism of BCAR3-p130Cas in Breast Cancer

    Science.gov (United States)

    2013-05-01

    and requests for materials should be addressed to S.J.R. ( email : sriedl@sanfordburnham.org). NATURE COMMUNICATIONS | 4:1681 | DOI: 10.1038/ncomms2687...North Torrey Pines Road, La Jolla, CA 92037 ( Email : sriedl@sanfordburnham.org). NSP-CAS Protein Complexes: Emerging Signaling Modules in Cancer Yann...Signalling to actin: role of C3G, a multitasking guanine-nucleotide-exchange factor. Biosci Rep. 2011;31:231-44. 32. Kiyokawa E, Hashimoto Y, Kobayashi S

  17. Identification of a genetic interaction between the tumor suppressor EAF2 and the retinoblastoma protein (Rb) signaling pathway in C. elegans and prostate cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Cai, Liquan; Wang, Dan [Department of Urology, The University of Pittsburgh, 5200 Centre Avenue, Pittsburgh, PA 15216 (United States); Fisher, Alfred L., E-mail: fishera2@uthscsa.edu [Division of Geriatrics, Gerontology, and Palliative Medicine, Department of Medicine, UTHSCSA, San Antonio, TX 78229 (United States); Center for Healthy Aging, UTHSCSA, San Antonio, TX 78229 (United States); GRECC, STVAHCS, San Antonio, TX 78229 (United States); Wang, Zhou, E-mail: wangz2@upmc.edu [Department of Urology, The University of Pittsburgh, 5200 Centre Avenue, Pittsburgh, PA 15216 (United States); GRECC, STVAHCS, San Antonio, TX 78229 (United States)

    2014-05-02

    Highlights: • RNAi screen identified genetic enhancers for the C. elegans homolog of EAF2. • EAF2 and RBBP4 proteins physically bind to each other and alter transcription. • Overexpression of EAF2 and RBBP4 induces the cell death in prostate cancer cells. - Abstract: The tumor suppressor EAF2 is regulated by androgen signaling and associated with prostate cancer. While EAF2 and its partner ELL have been shown to be members of protein complexes involved in RNA polymerase II transcriptional elongation, the biologic roles for EAF2 especially with regards to the development of cancer remains poorly understood. We have previously identified the eaf-1 gene in Caenorhabditiselegans as the ortholog of EAF2, and shown that eaf-1 interacts with the ELL ortholog ell-1 to control development and fertility in worms. To identify genetic pathways that interact with eaf-1, we screened RNAi libraries consisting of transcription factors, phosphatases, and chromatin-modifying factors to identify genes which enhance the effects of eaf-1(tm3976) on fertility. From this screen, we identified lin-53, hmg-1.2, pha-4, ruvb-2 and set-6 as hits. LIN-53 is the C. elegans ortholog of human retinoblastoma binding protein 4/7 (RBBP 4/7), which binds to the retinoblastoma protein and inhibits the Ras signaling pathway. We find that lin-53 showed a synthetic interaction with eaf-1(tm3976) where knockdown of lin-53 in an eaf-1(tm3976) mutant resulted in sterile worms. This phenotype may be due to cell death as the treated worms contain degenerated embryos with increased expression of the ced-1:GFP cell death marker. Further we find that the interaction between eaf-1 and lin-53/RBBP4/7 also exists in vertebrates, which is reflected by the formation of a protein complex between EAF2 and RBBP4/7. Finally, overexpression of either human EAF2 or RBBP4 in LNCaP cells induced the cell death while knockdown of EAF2 in LNCaP enhanced cell proliferation, indicating an important role of EAF2 in

  18. Laminarin based AgNPs using brown seaweed Turbinaria ornata and its induction of apoptosis in human retinoblastoma Y79 cancer cell lines

    Science.gov (United States)

    Remya, R. R.; Radhika Rajasree, S. R.; Suman, T. Y.; Aranganathan, L.; Gayathri, S.; Gobalakrishnan, M.; Karthih, M. G.

    2018-03-01

    Biosynthesis of nanoparticles using isolated compounds from various sources is accepting interest due to their broad array of biological activities and biocompatibility. This paper presents a simple; cost effective and green synthesis of silver nanoparticles (AgNPs) using the polysaccharide, laminarin a storage compound obtained from the brown algae Turbinaria ornata (T. ornata). Initially, the water soluble polysaccharide, laminarin was extracted, purified and analyzed using Matrix Assisted Laser Desorption Ionization Time-of-Flight Mass Spectroscopy (MALDI-TOF MS) and Proton Nuclear Magnetic Resonance (1H NMR). Further, the silver nanoparticles (AgNPs) were synthesized using the isolated laminarin and were characterized by Ultraviolet - visible (UV-vis) spectrophotometer, colour value analysis, Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD) and High Resolution Transmission Electron Microscopy (HR-TEM). The free radical scavenging activities were performed and the effect of cytotoxicity against retinoblastoma Y79 cell lines was also evaluated by in vitro studies. Induction of apoptosis was evident by the percentage of cells arrested in G2/M phase using flow cytometry analysis and was further confirmed by DNA fragmentation study which identified the presence of double strand break.

  19. 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.

  20. Programa nacional de prevención y consejería genética del retinoblastoma mediante detección de mutaciones en el gen rb.

    OpenAIRE

    Frayle, H.; Guevara, G.

    2011-01-01

    El retinoblastoma es un raro tumor ocular que se diagnostica en los niños, 40% de los casos se consideran hereditarios y 60% esporádicos. El modelo genético propuesto por Knudson involucra
    una la doble mutación inactivante del gen Rb, exclusivamente somática en los esporádicos y germinal más somática en los hereditarios. Esta investigacin tuvo como objetivo caracterizar las mutaciones en el gen Rb mediante secuenciación directa y evaluar su utilidad en la consejería genética....

  1. Monte Carlo study for designing a dedicated “D”-shaped collimator used in the external beam radiotherapy of retinoblastoma patients

    Energy Technology Data Exchange (ETDEWEB)

    Mayorga, P. A. [FISRAD S.A.S., CR 64 A No. 22 - 41, Bogotá D C, Colombia and Departamento de Física Atómica, Molecular y Nuclear, Universidad de Granada, E-18071 Granada (Spain); Brualla, L.; Sauerwein, W. [NCTeam, Strahlenklinik, Universitätsklinikum Essen, Hufelandstraße 55, D-45122 Essen (Germany); Lallena, A. M., E-mail: lallena@ugr.es [Departamento de Física Atómica, Molecular y Nuclear, Universidad de Granada, E-18071 Granada (Spain)

    2014-01-15

    Purpose: Retinoblastoma is the most common intraocular malignancy in the early childhood. Patients treated with external beam radiotherapy respond very well to the treatment. However, owing to the genotype of children suffering hereditary retinoblastoma, the risk of secondary radio-induced malignancies is high. The University Hospital of Essen has successfully treated these patients on a daily basis during nearly 30 years using a dedicated “D”-shaped collimator. The use of this collimator that delivers a highly conformed small radiation field, gives very good results in the control of the primary tumor as well as in preserving visual function, while it avoids the devastating side effects of deformation of midface bones. The purpose of the present paper is to propose a modified version of the “D”-shaped collimator that reduces even further the irradiation field with the scope to reduce as well the risk of radio-induced secondary malignancies. Concurrently, the new dedicated “D”-shaped collimator must be easier to build and at the same time produces dose distributions that only differ on the field size with respect to the dose distributions obtained by the current collimator in use. The scope of the former requirement is to facilitate the employment of the authors' irradiation technique both at the authors' and at other hospitals. The fulfillment of the latter allows the authors to continue using the clinical experience gained in more than 30 years. Methods: The Monte Carlo codePENELOPE was used to study the effect that the different structural elements of the dedicated “D”-shaped collimator have on the absorbed dose distribution. To perform this study, the radiation transport through a Varian Clinac 2100 C/D operating at 6 MV was simulated in order to tally phase-space files which were then used as radiation sources to simulate the considered collimators and the subsequent dose distributions. With the knowledge gained in that study, a new

  2. 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.

  3. 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.

  4. Role of immunoexpression of cyclin D1, D3, retinoblastoma (Rb mutant and clinical risk factors on complete mole as risk factors of persistent mole

    Directory of Open Access Journals (Sweden)

    Yudi M Hidayat

    2015-10-01

    Full Text Available Introduction: Changes in complete hydatidiform mole (CHM that become persistent are difficult to handle because the malignant pathogenesis of CHM is still unclear. The growth of abnormal cells in CHM is thought to be caused by cell cycle abnormalities. Some components that play a role in this phase include cyclin D and retinoblastoma (Rb. The aim of our study was to determine the role of clinical risk factors, as well as cyclin D1, cyclin D3 and Rb-protein, in the occurrence of persistent moles. Materials and Method: This study involves 68 CHM cases at Dr. Hasan Sadikin Hospital from 2007–2011. The protein expression of cyclin D1, cyclin D3, and Rb were determined by immunohistochemistry. The results were analyzed by comparing the two groups of CHM that became persistent to those that returned to normal, as determined by a Mochizuki regression curve assessment. Results: 20 cases (29% of CHM became persistent and that 48 cases (71% returned to normal. Significant clinical variables were age (p 0.05. Conclusion: There is a strong relationship between clinical risk factors of age, excessive proliferation histopathology, serum βhCG levels ≥100,000 mU/mL, cyclin D1 and Rb mutations with the incidence of persistent moles after the evacuation of the CHM. We proposed a model to predict the risks of persistent moles with a cut-off point of 2.384, which can be used as a reference for patients with CHM.

  5. A novel 1050nm handheld OCT imaging system for pediatric retinoblastoma patients: translation from laboratory bench to clinical study (Conference Presentation)

    Science.gov (United States)

    Nadiarnykh, Oleg; Moll, Annette C.; de Boer, Johannes F.

    2016-03-01

    We demonstrate a novel optical coherence tomography system specifically developed and validated for clinical imaging of retinoblastoma tumors in pediatric patients. The existing treatment options for this malignant tumor of the retina aim at reduction of tumor (re)growth risks, and vision preservation. The choice of optimal treatment strongly depends on skilled and detailed clinical assessment. Currently, the patients at risk are periodically monitored with retinal imaging for possible morphological changes over time, and new tumor seedings, as the existing real-time diagnostic tools are limited. Three-dimensional visualization of tissue layer and microvasculature at improved axial and lateral resolution of interference-based OCT imaging provides sensitivity for detection of vital tumor tissue concurrent with local treatment. Our METC-approved system accommodates for the range of optical parameters of infants' eyes, and uses the 1050nm wavelength to access the deeper choroid layers of retina. The prototype is designed for patients in supine position under general anesthesia, where ergonomic handheld module is connected to fiber-based optical setup via umbilical cord. The system conforms to clinical safety requirements, including fully isolated low-voltage electric circuit. Focusing is performed with a mechanically tunable lens, where resolution is 6 µm axially, and varies with focusing at 10-18µm laterally. We will present optical design, performance limitations, and results of the ongoing clinical study, including the increased OCT diagnostic sensitivity in three dimensions in comparison with the established clinical imaging modalities. We will discuss images of early, active, and treated tumors, as well as follow-up on patients after local and systemic treatments.

  6. 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.

  7. Automatic Segmentation of the Eye in 3D Magnetic Resonance Imaging: A Novel Statistical Shape Model for Treatment Planning of Retinoblastoma

    Energy Technology Data Exchange (ETDEWEB)

    Ciller, Carlos, E-mail: carlos.cillerruiz@unil.ch [Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne (Switzerland); Ophthalmic Technology Group, ARTORG Center of the University of Bern, Bern (Switzerland); Centre d’Imagerie BioMédicale, University of Lausanne, Lausanne (Switzerland); De Zanet, Sandro I.; Rüegsegger, Michael B. [Ophthalmic Technology Group, ARTORG Center of the University of Bern, Bern (Switzerland); Department of Ophthalmology, Inselspital, Bern University Hospital, Bern (Switzerland); Pica, Alessia [Department of Radiation Oncology, Inselspital, Bern University Hospital, Bern (Switzerland); Sznitman, Raphael [Ophthalmic Technology Group, ARTORG Center of the University of Bern, Bern (Switzerland); Department of Ophthalmology, Inselspital, Bern University Hospital, Bern (Switzerland); Thiran, Jean-Philippe [Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne (Switzerland); Signal Processing Laboratory, École Polytechnique Fédérale de Lausanne, Lausanne (Switzerland); Maeder, Philippe [Department of Radiology, Lausanne University Hospital and University of Lausanne, Lausanne (Switzerland); Munier, Francis L. [Unit of Pediatric Ocular Oncology, Jules Gonin Eye Hospital, Lausanne (Switzerland); Kowal, Jens H. [Ophthalmic Technology Group, ARTORG Center of the University of Bern, Bern (Switzerland); Department of Ophthalmology, Inselspital, Bern University Hospital, Bern (Switzerland); and others

    2015-07-15

    Purpose: Proper delineation of ocular anatomy in 3-dimensional (3D) imaging is a big challenge, particularly when developing treatment plans for ocular diseases. Magnetic resonance imaging (MRI) is presently used in clinical practice for diagnosis confirmation and treatment planning for treatment of retinoblastoma in infants, where it serves as a source of information, complementary to the fundus or ultrasonographic imaging. Here we present a framework to fully automatically segment the eye anatomy for MRI based on 3D active shape models (ASM), and we validate the results and present a proof of concept to automatically segment pathological eyes. Methods and Materials: Manual and automatic segmentation were performed in 24 images of healthy children's eyes (3.29 ± 2.15 years of age). Imaging was performed using a 3-T MRI scanner. The ASM consists of the lens, the vitreous humor, the sclera, and the cornea. The model was fitted by first automatically detecting the position of the eye center, the lens, and the optic nerve, and then aligning the model and fitting it to the patient. We validated our segmentation method by using a leave-one-out cross-validation. The segmentation results were evaluated by measuring the overlap, using the Dice similarity coefficient (DSC) and the mean distance error. Results: We obtained a DSC of 94.90 ± 2.12% for the sclera and the cornea, 94.72 ± 1.89% for the vitreous humor, and 85.16 ± 4.91% for the lens. The mean distance error was 0.26 ± 0.09 mm. The entire process took 14 seconds on average per eye. Conclusion: We provide a reliable and accurate tool that enables clinicians to automatically segment the sclera, the cornea, the vitreous humor, and the lens, using MRI. We additionally present a proof of concept for fully automatically segmenting eye pathology. This tool reduces the time needed for eye shape delineation and thus can help clinicians when planning eye treatment and confirming the extent of the tumor.

  8. Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

    Directory of Open Access Journals (Sweden)

    La Torre Agostino

    2010-09-01

    Full Text Available Abstract Background Treatment strategies for Retinoblastoma (RB, the most common primary intraocular tumor in children, have evolved over the past few decades and chemoreduction is currently the most popular treatment strategy. Despite success, systemic chemotherapeutic treatment has relevant toxicity, especially in the pediatric population. Antiangiogenic therapy has thus been proposed as a valuable alternative for pediatric malignancies, in particolar RB. Indeed, it has been shown that vessel density correlates with both local invasive growth and presence of metastases in RB, suggesting that angiogenesis could play a pivotal role for both local and systemic invasive growth in RB. We present here two cases of sporadic, bilateral RB that did not benefit from the conservative treatment and we provide evidence that the VEGF-A pathway is significantly up-regulated in both RB cases along with an over expression of hERG1 K+ channels. Case presentation Two patients showed a sporadic, bilateral RB, classified at Stage II of the Reese-Elsworth Classification. Neither of them got benefits from conservative treatment, and the two eyes were enucleated. In samples from both RB cases we studied the VEGF-A pathway: VEGF-A showed high levels in the vitreous, the vegf-a, flt-1, kdr, and hif1-α transcripts were over-expressed. Moreover, both the transcripts and proteins of the hERG1 K+ channels turned out to be up-regulated in the two RB cases compared to the non cancerous retinal tissue. Conclusions We provide evidence that the VEGF-A pathway is up-regulated in two particular aggressive cases of bilateral RB, which did not experience any benefit from conservative treatment, showing the overexpression of the vegf-a, flt-1, kdr and hif1-α transcripts and the high secretion of VEGF-A. Moreover we also show for the first time that the herg1 gene transcripts and protein are over expressed in RB, as occurs in several aggressive tumors. These results further stress

  9. Automatic Segmentation of the Eye in 3D Magnetic Resonance Imaging: A Novel Statistical Shape Model for Treatment Planning of Retinoblastoma.

    Science.gov (United States)

    Ciller, Carlos; De Zanet, Sandro I; Rüegsegger, Michael B; Pica, Alessia; Sznitman, Raphael; Thiran, Jean-Philippe; Maeder, Philippe; Munier, Francis L; Kowal, Jens H; Cuadra, Meritxell Bach

    2015-07-15

    Proper delineation of ocular anatomy in 3-dimensional (3D) imaging is a big challenge, particularly when developing treatment plans for ocular diseases. Magnetic resonance imaging (MRI) is presently used in clinical practice for diagnosis confirmation and treatment planning for treatment of retinoblastoma in infants, where it serves as a source of information, complementary to the fundus or ultrasonographic imaging. Here we present a framework to fully automatically segment the eye anatomy for MRI based on 3D active shape models (ASM), and we validate the results and present a proof of concept to automatically segment pathological eyes. Manual and automatic segmentation were performed in 24 images of healthy children's eyes (3.29 ± 2.15 years of age). Imaging was performed using a 3-T MRI scanner. The ASM consists of the lens, the vitreous humor, the sclera, and the cornea. The model was fitted by first automatically detecting the position of the eye center, the lens, and the optic nerve, and then aligning the model and fitting it to the patient. We validated our segmentation method by using a leave-one-out cross-validation. The segmentation results were evaluated by measuring the overlap, using the Dice similarity coefficient (DSC) and the mean distance error. We obtained a DSC of 94.90 ± 2.12% for the sclera and the cornea, 94.72 ± 1.89% for the vitreous humor, and 85.16 ± 4.91% for the lens. The mean distance error was 0.26 ± 0.09 mm. The entire process took 14 seconds on average per eye. We provide a reliable and accurate tool that enables clinicians to automatically segment the sclera, the cornea, the vitreous humor, and the lens, using MRI. We additionally present a proof of concept for fully automatically segmenting eye pathology. This tool reduces the time needed for eye shape delineation and thus can help clinicians when planning eye treatment and confirming the extent of the tumor. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Automatic Segmentation of the Eye in 3D Magnetic Resonance Imaging: A Novel Statistical Shape Model for Treatment Planning of Retinoblastoma

    International Nuclear Information System (INIS)

    Ciller, Carlos; De Zanet, Sandro I.; Rüegsegger, Michael B.; Pica, Alessia; Sznitman, Raphael; Thiran, Jean-Philippe; Maeder, Philippe; Munier, Francis L.; Kowal, Jens H.

    2015-01-01

    Purpose: Proper delineation of ocular anatomy in 3-dimensional (3D) imaging is a big challenge, particularly when developing treatment plans for ocular diseases. Magnetic resonance imaging (MRI) is presently used in clinical practice for diagnosis confirmation and treatment planning for treatment of retinoblastoma in infants, where it serves as a source of information, complementary to the fundus or ultrasonographic imaging. Here we present a framework to fully automatically segment the eye anatomy for MRI based on 3D active shape models (ASM), and we validate the results and present a proof of concept to automatically segment pathological eyes. Methods and Materials: Manual and automatic segmentation were performed in 24 images of healthy children's eyes (3.29 ± 2.15 years of age). Imaging was performed using a 3-T MRI scanner. The ASM consists of the lens, the vitreous humor, the sclera, and the cornea. The model was fitted by first automatically detecting the position of the eye center, the lens, and the optic nerve, and then aligning the model and fitting it to the patient. We validated our segmentation method by using a leave-one-out cross-validation. The segmentation results were evaluated by measuring the overlap, using the Dice similarity coefficient (DSC) and the mean distance error. Results: We obtained a DSC of 94.90 ± 2.12% for the sclera and the cornea, 94.72 ± 1.89% for the vitreous humor, and 85.16 ± 4.91% for the lens. The mean distance error was 0.26 ± 0.09 mm. The entire process took 14 seconds on average per eye. Conclusion: We provide a reliable and accurate tool that enables clinicians to automatically segment the sclera, the cornea, the vitreous humor, and the lens, using MRI. We additionally present a proof of concept for fully automatically segmenting eye pathology. This tool reduces the time needed for eye shape delineation and thus can help clinicians when planning eye treatment and confirming the extent of the tumor

  11. 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

  12. Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression

    DEFF Research Database (Denmark)

    Lukas, J; Petersen, B O; Holm, K

    1996-01-01

    The E2F family of transcription factors regulate genes, whose products are essential for progression through the mammalian cell cycle. The transcriptional activity of the E2Fs is inhibited through the specific binding of the retinoblastoma protein, pRB, and the pRB homologs p107 and p130 to their......The E2F family of transcription factors regulate genes, whose products are essential for progression through the mammalian cell cycle. The transcriptional activity of the E2Fs is inhibited through the specific binding of the retinoblastoma protein, pRB, and the pRB homologs p107 and p130...

  13. E2F-5, a new E2F family member that interacts with p130 in vivo

    NARCIS (Netherlands)

    Hijmans, E.M.; Voorhoeve, P.M.; Beijersbergen, R.L.; Veer, L.J. van 't; Bernards, R.A.

    1995-01-01

    E2F DNA binding sites are found in a number of genes whose expression is tightly regulated during the cell cycle. The activity of E2F transcription factors is regulated by association with specific repressor molecules that can bind and inhibit the E2F transactivation domain. For E2F-1, E2F-2, and

  14. External beam orbital radiotherapy (EBORT) in patients with retinoblastoma: a Saudi-Arabian experience with 120 children from 1976 to 1993

    International Nuclear Information System (INIS)

    Pradhan, D.G.; Sandridge, A.; Kandil, A.; Mullaney, P.; Abboud, EB.; Gray, A.J.

    1996-01-01

    Purpose/Objective: To characterize the patient population and treatment options for patients with Retinoblastoma (RB) diagnosed at KKESH and referred for radiation therapy (RT) to KFSH and RC, Riyadh, Saudi Arabia from 1976 to 1993 and to record the treatment outcomes. Material/Methods: A retrospective study of 120 patients (a total of 193 affected eyes) referred for RT. 75% of the eyes were staged Reese-Ellsworth (RE) Stage Va or Vb disease. In 75% family history was available, and showed consanguineous marriages in 65%, (42% first cousins). A familial history of RB was present in 15%. Male:Female ratio 1.8:1.0. Patients were divided into three groups. Group A, 60 patients (64 eyes) were treated with EBORT to the intact eye to preserve vision. 55 of these patients (92%) had bilateral disease and 5 had unilateral disease. 49 patients had one eye already removed as primary treatment. Mean age at diagnosis was 20 months (standard deviation (SD) 24.88), range 0-148. Major presenting symptom was leukokoria in 75% and poor vision in 24%. RE staging was I:12%, II:10%, III:12%, IV:23% and V:43%. 28 of 60 patients (47%) also received chemotherapy (CT) with vincristine, adriamycin and cyclophosphamide (VAC), 7% before, 10% during and 30% after EBORT. Mean follow-up was 48 months, (SD 43.85 months), range was 0-14 years. 4 patients received EBORT to both eyes. Standard treatment until 1992 was 45Gy in 12 fractions of 3.75Gy each, three times a week over 18 days with 6 or 8MV Photons or Cobalt-60. Assuming the (α(β)) ratio for tumor control at 10, Tk = 21 days, Tpot = 5 days then the Biological Equivalent Dose (BED) for this regime 62Gy 10 for early effect and 101Gy 3 for late effects. Since 1992 this has been reduced and is currently BED (early) 54Gy 10 and BED (late) 76Gy 3 (44Gy in 20 fractions in 26 days). Group B consisted of 23 patients (28 eyes) referred for RT to control local disease in the orbit usually after enucleation (23 eyes) and treated with curative intent

  15. Inhibition of HCV replication by oxysterol-binding protein-related protein 4 (ORP4 through interaction with HCV NS5B and alteration of lipid droplet formation.

    Directory of Open Access Journals (Sweden)

    In-Woo Park

    Full Text Available Hepatitis C virus (HCV RNA replication involves complex interactions among the 3'x RNA element within the HCV 3' untranslated region, viral and host proteins. However, many of the host proteins remain unknown. In this study, we devised an RNA affinity chromatography /2D/MASS proteomics strategy and identified nine putative 3' X-associated host proteins; among them is oxysterol-binding protein-related protein 4 (ORP4, a cytoplasmic receptor for oxysterols. We determined the relationship between ORP4 expression and HCV replication. A very low level of constitutive ORP4 expression was detected in hepatocytes. Ectopically expressed ORP4 was detected in the endoplasmic reticulum and inhibited luciferase reporter gene expression in HCV subgenomic replicon cells and HCV core expression in JFH-1-infected cells. Expression of ORP4S, an ORP4 variant that lacked the N-terminal pleckstrin-homology domain but contained the C-terminal oxysterol-binding domain also inhibited HCV replication, pointing to an important role of the oxysterol-binding domain in ORP4-mediated inhibition of HCV replication. ORP4 was found to associate with HCV NS5B and its expression led to inhibition of the NS5B activity. ORP4 expression had little effect on intracellular lipid synthesis and secretion, but it induced lipid droplet formation in the context of HCV replication. Taken together, these results demonstrate that ORP4 is a negative regulator of HCV replication, likely via interaction with HCV NS5B in the replication complex and regulation of intracellular lipid homeostasis. This work supports the important role of lipids and their metabolism in HCV replication and pathogenesis.

  16. Decreased expression of insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) in radiation-induced mouse hepatocellular carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Teishima, Jun [Hiroshima Univ. (Japan). Research Inst. for Radiation Biology and Medicine

    2002-04-01

    Insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) is a member of the IGFBP family, which was called IGFBP-7 or mac25 previously. Decreased expression of IGFBP-rP1 has been shown in breast cancer and prostatic cancer, and tumor suppressive effects of IGFBP-rP1 have been reported in prostatic cancer and osteosarcoma cell lines. In the present study, we investigated whether expression levels of IGFBP-rP1 were related to the development and the growth of radiation-induced hepatomas of B6C3F1 mice. In northern blot analysis, decreased expressions of IGFBP-rP1 gene were shown in radiation-induced mouse hepatomas compared to normal livers. In hepatoma cell lines established from these hepatomas, decreased expressions of IGFBP-rP1 were strongly related to the grade of anchorage-independent growth. In cell lines which were transfected with IGFBP-rP1cDNA, the doubling time of cell growth was increased, and the number and the size of colony formation in soft agar culture were decreased. In tumor formation assay by injecting these cells to B6C3F1 mice subcutaneously, the volume of tumors were decreased. Furthermore, the decreased expression of IGFBP-rP1 gene was observed in human hepatomas by northern blot analysis. These results may suggest that the suppression of IGFBP-rP1 is related to development and progression of mouse and human hepatomas. (author)

  17. Expression of RIZ1 protein (Retinoblastoma-interacting zinc-finger protein 1) in prostate cancer epithelial cells changes with cancer grade progression and is modulated in vitro by DHT and E2.

    Science.gov (United States)

    Rossi, Valentina; Staibano, Stefania; Abbondanza, Ciro; Pasquali, Daniela; De Rosa, Caterina; Mascolo, Massimo; Bellastella, Giuseppe; Visconti, Daniela; De Bellis, Annamaria; Moncharmont, Bruno; De Rosa, Gaetano; Puca, Giovanni Alfredo; Bellastella, Antonio; Sinisi, Antonio Agostino

    2009-12-01

    The nuclear protein methyl-transferase Retinoblastoma-interacting zinc-finger protein 1 (RIZ1) is considered to be a downstream effector of estrogen action in target tissues. Silencing of RIZ1 expression is common in many tumors. We analyzed RIZ1 expression in normal and malignant prostate tissue and evaluated whether estradiol (E2) or dihydrotestosterone (DHT) treatment modulated RIZ1 in cultured prostate epithelial cells (PEC). Moreover, we studied the possible involvement of RIZ1 in estrogen action on the EPN prostate cell line, constitutively expressing both estrogen receptor (ER)-alpha and beta. RIZ1 protein, found in the nucleus of normal PECs by immunohistochemistry, was progressively lost in cancer tissues as the Gleason score increased and was only detected in the cytoplasmic compartment. RIZ1 transcript levels, as assayed by semi-quantitative RT-PCR in primary PEC cultures, were significantly reduced in cancer cells (P DHT treatment significantly increased RIZ1 transcript and protein levels (P DHT or E2 treatment in vitro. Furthermore, the E2 effects on ER-expressing prostate cells involve RIZ1, which confirms a possible role for ER-mediated pathways in a non-classic E(2)-target tissue.

  18. Adenovirus E4 open reading frame 4-induced dephosphorylation inhibits E1A activation of the E2 promoter and E2F-1-mediated transactivation independently of the retinoblastoma tumor suppressor protein

    DEFF Research Database (Denmark)

    Mannervik, M; Fan, S; Ström, A C

    1999-01-01

    of the viral E4 open reading frame 4 (E4-ORF4) protein. This effect does not to require the retinoblastoma protein that previously has been shown to regulate E2F activity. The inhibitory activity of E4-ORF4 appears to be specific because E4-ORF4 had little effect on, for example, E4-ORF6/7 transactivation......Previous studies have shown that the cell cycle-regulated E2F transcription factor is subjected to both positive and negative control by phosphorylation. Here we show that in transient transfection experiments, adenovirus E1A activation of the viral E2 promoter is abrogated by coexpression...... of the E2 promoter. We further show that the repressive effect of E4-ORF4 on E2 transcription works mainly through the E2F DNA-binding sites in the E2 promoter. In agreement with this, we find that E4-ORF4 inhibits E2F-1/DP-1-mediated transactivation. We also show that E4-ORF4 inhibits E2 mRNA expression...

  19. Large-scale proteome analysis of abscisic acid and ABSCISIC ACID INSENSITIVE3-dependent proteins related to desiccation tolerance in Physcomitrella patens

    International Nuclear Information System (INIS)

    Yotsui, Izumi; Serada, Satoshi; Naka, Tetsuji; Saruhashi, Masashi; Taji, Teruaki; Hayashi, Takahisa; Quatrano, Ralph S.; Sakata, Yoichi

    2016-01-01

    tolerance might have evolved in ancestral land plants before the separation of bryophytes and vascular plants. - Highlights: • Large-scale proteomics highlighted proteins related to plant desiccation tolerance. • The proteins were regulated by both the phytohormone ABA and ABI3. • The proteins accumulated in desiccation tolerant cells of both Arabidopsis and moss. • Evolutionary origin of regulatory machinery for desiccation tolerance is proposed.

  20. Modifications to the composition of the hyphal outer layer of Aspergillus fumigatus modulates HUVEC proteins related to inflammatory and stress responses.

    Science.gov (United States)

    Neves, Gabriela Westerlund Peixoto; Curty, Nathália de Andrade; Kubitschek-Barreira, Paula Helena; Fontaine, Thierry; Souza, Gustavo Henrique Martins Ferreira; Cunha, Marcel Lyra; Goldman, Gustavo H; Beauvais, Anne; Latgé, Jean-Paul; Lopes-Bezerra, Leila M

    2017-01-16

    response are unknown. The present work employs a discovery-driven proteomics approach to reveal the role of one important cell wall polysaccharide of A. fumigatus, galactosaminogalactan, in the HUVEC interaction and the consequent mechanisms of endothelial activation. This is the first report of the overall panel of proteins related to the HUVEC response to a specific and purified cell wall component of the angioinvasive fungus A. fumigatus. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Large-scale proteome analysis of abscisic acid and ABSCISIC ACID INSENSITIVE3-dependent proteins related to desiccation tolerance in Physcomitrella patens

    Energy Technology Data Exchange (ETDEWEB)

    Yotsui, Izumi, E-mail: izumi.yotsui@riken.jp [Department of BioScience, Tokyo University of Agriculture 1-1-1 Sakuragaoka, Setagayaku, Tokyo, 156-8502 (Japan); Serada, Satoshi, E-mail: serada@nibiohn.go.jp [Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085 (Japan); Naka, Tetsuji, E-mail: tnaka@nibiohn.go.jp [Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, 7-6-8 Saito-Asagi, Ibaraki, Osaka, 567-0085 (Japan); Saruhashi, Masashi, E-mail: s13db001@mail.saitama-u.ac.jp [Department of BioScience, Tokyo University of Agriculture 1-1-1 Sakuragaoka, Setagayaku, Tokyo, 156-8502 (Japan); Taji, Teruaki, E-mail: t3teruak@nodai.ac.jp [Department of BioScience, Tokyo University of Agriculture 1-1-1 Sakuragaoka, Setagayaku, Tokyo, 156-8502 (Japan); Hayashi, Takahisa, E-mail: t4hayash@nodai.ac.jp [Department of BioScience, Tokyo University of Agriculture 1-1-1 Sakuragaoka, Setagayaku, Tokyo, 156-8502 (Japan); Quatrano, Ralph S., E-mail: rsq@wustl.edu [Department of Biology, Washington University in St. Louis, St. Louis, MO, 63130-4899 (United States); Sakata, Yoichi, E-mail: sakata@nodai.ac.jp [Department of BioScience, Tokyo University of Agriculture 1-1-1 Sakuragaoka, Setagayaku, Tokyo, 156-8502 (Japan)

    2016-03-18

    tolerance might have evolved in ancestral land plants before the separation of bryophytes and vascular plants. - Highlights: • Large-scale proteomics highlighted proteins related to plant desiccation tolerance. • The proteins were regulated by both the phytohormone ABA and ABI3. • The proteins accumulated in desiccation tolerant cells of both Arabidopsis and moss. • Evolutionary origin of regulatory machinery for desiccation tolerance is proposed.

  2. 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...

  3. Heterodimerization of the transcription factors E2F-1 and DP-1 is required for binding to the adenovirus E4 (ORF6/7) protein

    DEFF Research Database (Denmark)

    Helin, K; Harlow, E

    1994-01-01

    Adenovirus infection leads to E1A-dependent activation of the transcription factor E2F. E2F has recently been identified in complexes with cellular proteins such as the retinoblastoma protein (pRB) and the two pRB family members p107 and p130. E1A dissociates E2F from these cellular proteins...

  4. First-line intra-arterial versus intravenous chemotherapy in unilateral sporadic group D retinoblastoma: evidence of better visual outcomes, ocular survival and shorter time to success with intra-arterial delivery from retrospective review of 20 years of treatment.

    Science.gov (United States)

    Munier, Francis L; Mosimann, Pascal; Puccinelli, Francesco; Gaillard, Marie-Claire; Stathopoulos, Christina; Houghton, Susan; Bergin, Ciara; Beck-Popovic, Maja

    2017-08-01

    The introduction of intra-arterial chemotherapy (IAC) as salvage treatment has improved the prognosis for eye conservation in group D retinoblastoma. The aim of this study was to compare the outcomes of consecutive patients with advanced unilateral disease treated with either first-line intravenous chemotherapy (IVC) or first-line IAC. This is a retrospective mono-centric comparative review of consecutive patients. Sporadic unilateral retinoblastoma group D cases treated conservatively at Jules-Gonin Eye Hospital and CHUV between 1997 and 2014. From January 1997 to August 2008, IVC, combined with focal treatments, was the primary treatment approach. From September 2008 to October 2014, IAC replaced IVC as first-line therapy. 48 patients met the inclusion criteria, receiving only either IAC or IVC as primary treatment modality. Outcomes of 23 patients treated by IVC were compared with those of 25 treated by IAC; mean follow-up was 105.3 months (range 29.2-218.6) and 41.7 months (range 19.6-89.5), respectively. Treatment duration was significantly shorter in the IAC group (pchemotherapy treatment. Despite this, the results reported here imply that eyes treated with first-line IAC will have shorter treatment period, better ocular survival and visual acuity than first-line IVC. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  5. SM22α-induced activation of p16INK4a/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of γ-radiation and doxorubicin in HepG2 cells

    International Nuclear Information System (INIS)

    Kim, Tae Rim; Lee, Hee Min; Lee, So Yong; Kim, Eun Jin; Kim, Kug Chan; Paik, Sang Gi; Cho, Eun Wie; Kim, In Gyu

    2010-01-01

    Research highlights: → SM22α overexpression in HepG2 cells leads cells to a growth arrest state, and the treatment of a subclinical dose of γ-radiation or doxorubicin promotes cellular senescence. → SM22α overexpression elevates p16 INK4a followed by pRB activation, but there are no effects on p53/p21 WAF1/Cip1 pathway. → SM22α-induced MT-1G activates p16 INK4a /pRB pathway, which promotes cellular senescence by damaging agents. -- Abstract: Smooth muscle protein 22-alpha (SM22α) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22α overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22α overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of γ-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 μg/ml), compared to control cells. Senescence growth arrest is known to be controlled by p53 phosphorylation/p21 WAF1/Cip1 induction or p16 INK4a /retinoblastoma protein (pRB) activation. SM22α overexpression in HepG2 cells elevated p16 INK4a followed by pRB activation, but did not activate the p53/p21 WAF1/Cip1 pathway. Moreover, MT-1G, which is induced by SM22α overexpression, was involved in the activation of the p16 INK4a /pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents. Our findings provide the first demonstration that SM22α modulates cellular senescence caused by damaging agents via regulation of the p16 INK4a /pRB pathway in HepG2 cells and that these effects of SM22α are partially mediated by MT-1G.

  6. A gene expression signature of retinoblastoma loss-of-function is a predictive biomarker of resistance to palbociclib in breast cancer cell lines and is prognostic in patients with ER positive early breast cancer.

    Science.gov (United States)

    Malorni, Luca; Piazza, Silvano; Ciani, Yari; Guarducci, Cristina; Bonechi, Martina; Biagioni, Chiara; Hart, Christopher D; Verardo, Roberto; Di Leo, Angelo; Migliaccio, Ilenia

    2016-09-13

    Palbociclib is a CDK4/6 inhibitor that received FDA approval for treatment of hormone receptor positive (HR+) HER2 negative (HER2neg) advanced breast cancer. To better personalize patients treatment it is critical to identify subgroups that would mostly benefit from it. We hypothesize that complex alterations of the Retinoblastoma (Rb) pathway might be implicated in resistance to CDK4/6 inhibitors and aim to investigate whether signatures of Rb loss-of-function would identify breast cancer cell lines resistant to palbociclib. We established a gene expression signature of Rb loss-of-function (RBsig) by identifying genes correlated with E2F1 and E2F2 expression in breast cancers within The Cancer Genome Atlas. We assessed the RBsig prognostic role in the METABRIC and in a comprehensive breast cancer meta-dataset. Finally, we analyzed whether RBsig would discriminate palbociclib-sensitive and -resistant breast cancer cells in a large RNA sequencing-based dataset. The RBsig was associated with RB1 genetic status in all tumors (p <7e-32) and in luminal or basal subtypes (p < 7e-11 and p < 0.002, respectively). The RBsig was prognostic in the METABRIC dataset (discovery: HR = 1.93 [1.5-2.4] p = 1.4e-08; validation: HR = 2.01 [1.6-2.5] p = 1.3e-09). Untreated and endocrine treated patients with estrogen receptor positive breast cancer expressing high RBsig had significantly worse recurrence free survival compared to those with low RBsig (HR = 2.37 [1.8 - 3.2] p = 1.87e-08 and HR = 2.62 [1.9- 3.5] p = 8.6e-11, respectively). The RBsig was able to identify palbociclib resistant and sensitive breast cancer cells (ROC AUC = 0,7778). Signatures of RB loss might be helpful in personalizing treatment of patients with HR+/HER2neg breast cancer. Further validation in patients receiving palbociclib is warranted.

  7. SM22{alpha}-induced activation of p16{sup INK4a}/retinoblastoma pathway promotes cellular senescence caused by a subclinical dose of {gamma}-radiation and doxorubicin in HepG2 cells

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Tae Rim; Lee, Hee Min; Lee, So Yong; Kim, Eun Jin; Kim, Kug Chan [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of); Paik, Sang Gi [Department of Biology, School of Biosciences and Biotechnology, Chungnam National University, Daejeon (Korea, Republic of); Cho, Eun Wie, E-mail: ewcho@kribb.re.kr [Daejeon-KRIBB-FHCRC Cooperation Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon (Korea, Republic of); Kim, In Gyu, E-mail: igkim@kaeri.re.kr [Department of Radiation Biology, Environmental Radiation Research Group, Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2010-09-10

    Research highlights: {yields} SM22{alpha} overexpression in HepG2 cells leads cells to a growth arrest state, and the treatment of a subclinical dose of {gamma}-radiation or doxorubicin promotes cellular senescence. {yields} SM22{alpha} overexpression elevates p16{sup INK4a} followed by pRB activation, but there are no effects on p53/p21{sup WAF1/Cip1} pathway. {yields} SM22{alpha}-induced MT-1G activates p16{sup INK4a}/pRB pathway, which promotes cellular senescence by damaging agents. -- Abstract: Smooth muscle protein 22-alpha (SM22{alpha}) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22{alpha} overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 cells. In this study, we demonstrate that SM22{alpha} overexpression leads cells to a growth arrest state and promotes cellular senescence caused by treatment with a subclinical dose of {gamma}-radiation (0.05 and 0.1 Gy) or doxorubicin (0.01 and 0.05 {mu}g/ml), compared to control cells. Senescence growth arrest is known to be controlled by p53 phosphorylation/p21{sup WAF1/Cip1} induction or p16{sup INK4a}/retinoblastoma protein (pRB) activation. SM22{alpha} overexpression in HepG2 cells elevated p16{sup INK4a} followed by pRB activation, but did not activate the p53/p21{sup WAF1/Cip1} pathway. Moreover, MT-1G, which is induced by SM22{alpha} overexpression, was involved in the activation of the p16{sup INK4a}/pRB pathway, which led to a growth arrest state and promoted cellular senescence caused by damaging agents. Our findings provide the first demonstration that SM22{alpha} modulates cellular senescence caused by damaging agents via regulation of the p16{sup INK4a}/pRB pathway in HepG2 cells and that these effects of SM22{alpha} are partially mediated by MT-1G.

  8. Identification of the G13 (cAMP-response-element-binding protein-related protein) gene product related to activating transcription factor 6 as a transcriptional activator of the mammalian unfolded protein response.

    Science.gov (United States)

    Haze, K; Okada, T; Yoshida, H; Yanagi, H; Yura, T; Negishi, M; Mori, K

    2001-04-01

    Eukaryotic cells control the levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element consisting of 19 nt (CCAATN(9)CCACG), the CCACG part of which is considered to provide specificity. We recently identified the basic leucine zipper (bZIP) protein ATF6 as a mammalian UPR-specific transcription factor; ATF6 is activated by ER stress-induced proteolysis and binds directly to CCACG. Here we report that eukaryotic cells express another bZIP protein closely related to ATF6 in both structure and function. This protein encoded by the G13 (cAMP response element binding protein-related protein) gene is constitutively synthesized as a type II transmembrane glycoprotein anchored in the ER membrane and processed into a soluble form upon ER stress as occurs with ATF6. The proteolytic processing of ATF6 and the G13 gene product is accompanied by their relocation from the ER to the nucleus; their basic regions seem to function as a nuclear localization signal. Overexpression of the soluble form of the G13 product constitutively activates the UPR, whereas overexpression of a mutant lacking the activation domain exhibits a strong dominant-negative effect. Furthermore, the soluble forms of ATF6 and the G13 gene product are unable to bind to several point mutants of the cis-acting ER stress response element in vitro that hardly respond to ER stress in vivo. We thus concluded that the two related bZIP proteins are crucial transcriptional regulators of the mammalian UPR, and propose calling the ATF6 gene product ATF6alpha and the G13 gene product ATF6beta.

  9. Helicobacter pylori Outer Membrane Protein-Related Pathogenesis

    Directory of Open Access Journals (Sweden)

    Yuichi Matsuo

    2017-03-01

    Full Text Available Helicobacter pylori colonizes the human stomach and induces inflammation, and in some cases persistent infection can result in gastric cancer. Attachment to the gastric mucosa is the first step in establishing bacterial colonization, and outer membrane proteins (OMPs play a pivotal role in binding to human cells. Some OMP interaction molecules are known in H. pylori, and their associated host cell responses have been gradually clarified. Many studies have demonstrated that OMPs are essential to CagA translocation into gastric cells via the Type IV secretion system of H. pylori. This review summarizes the mechanisms through which H. pylori utilizes OMPs to colonize the human stomach and how OMPs cooperate with the Type IV secretion system.

  10. Rapid detection of RB1 recurrent mutations in retinoblastoma by ...

    Indian Academy of Sciences (India)

    In about half of the patients, one mutation is inherited via the germinal cells, while in the .... mutational hot spots in the RB1 gene, making genetic testing complex and challenging ... by direct sequencing. High normal background in sequenc-.

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

    African Journals Online (AJOL)

    need to develop new therapeutic options to improve the ... derivatives have high therapeutic activity due to their high ... them promising targets for future drug discovery. [8]. Out of the ... and different concentrations of puerarin were added to the ...

  12. A GIANT CONGENITAL ORBITAL TUMOR - AN UNUSUAL PRESENTATION OF RETINOBLASTOMA

    NARCIS (Netherlands)

    ZWAAN, CM; DEWAAL, FC; KOOLE, FD; MENKO, FH; VANDERVALK, P; SLATER, RM; SCHEFFER, H; VANWAVEREN, G; MOLL, AC; SCHOUTENVANMEETEREN, AYN; TAN, KEWP

    1994-01-01

    We report a case of an unusual giant congential tumor presenting in a newborn infant as a large exophytic mass emerging from the left orbit. After enucleation orbital recurrence developed within 14 days. No anti-tumor treatment was given and the child died at the age of 4 weeks. The

  13. 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.

  14. High Dietary Protein Intake and Protein-Related Acid Load on Bone Health.

    Science.gov (United States)

    Cao, Jay J

    2017-12-01

    Consumption of high-protein diets is increasingly popular due to the benefits of protein on preserving lean mass and controlling appetite and satiety. The paper is to review recent clinical research assessing dietary protein on calcium metabolism and bone health. Epidemiological studies show that long-term, high-protein intake is positively associated with bone mineral density and reduced risk of bone fracture incidence. Short-term interventional studies demonstrate that a high-protein diet does not negatively affect calcium homeostasis. Existing evidence supports that the negative effects of the acid load of protein on urinary calcium excretion are offset by the beneficial skeletal effects of high-protein intake. Future research should focus on the role and the degree of contribution of other dietary and physiological factors, such as intake of fruits and vegetables, in reducing the acid load and further enhancing the anabolic effects of protein on the musculoskeletal system.

  15. Proteomics insights: proteins related to larval attachment and metamorphosis of marine invertebrates

    KAUST Repository

    Chandramouli, Kondethimmanahalli

    2014-10-31

    The transition in an animal from a pelagic larval stage to a sessile benthic juvenile typically requires major morphological and behavioral changes. Larval competency, attachment and initiation of metamorphosis are thought to be regulated by intrinsic chemical signals and specific sets of proteins. However, the molecular mechanisms that regulate larval attachment and metamorphosis in marine invertebrates have yet to be fully elucidated. Despite the many challenges associated with analysis of the larvae proteome, recent proteomic technologies have been used to address specific questions in larval developmental biology. These and other molecular studies have generated substantial amount of information of the proteins and molecular pathways involved in larval attachment and metamorphosis. Furthermore, the results of these studies have shown that systematic changes in protein expression patterns and post-translational modifications (PTMs) are crucial for the transition from larva to juvenile. The degeneration of larval tissues is mediated by protein degradation, while the development of juvenile organs may require PTM. In terms of application, the identified proteins may serve as targets for antifouling compounds, and biomarkers for environmental stressors. In this review we highlight the strengths and limitations of proteomic tools in the context of the study of marine invertebrate larval biology.

  16. Proteomics Insights: Proteins related to Larval Attachment and Metamorphosis of Marine Invertebrates

    Directory of Open Access Journals (Sweden)

    KONDETHIMMANAHALLI eCHANDRAMOULI

    2014-10-01

    Full Text Available The transition in an animal from a pelagic larval stage to a sessile benthic juvenile typically requires major morphological and behavioral changes. Larval competency, attachment and initiation of metamorphosis are thought to be regulated by intrinsic chemical signals and specific sets of proteins. However, the molecular mechanisms that regulate larval attachment and metamorphosis in marine invertebrates have yet to be fully elucidated. Despite the many challenges associated with analysis of the larvae proteome, recent proteomic technologies have been used to address specific questions in larval developmental biology. These and other molecular studies have generated substantial amount of information of the proteins and molecular pathways involved in larval attachment and metamorphosis. Furthermore, the results of these studies have shown that systematic changes in protein expression patterns and post-translational modifications (PTM are crucial for the transition from larva to juvenile. The degeneration of larval tissues is mediated by protein degradation, while the development of juvenile organs may require PTM. In terms of application, the identified proteins may serve as targets for antifouling compounds, and biomarkers for environmental stressors. In this review we highlight the strengths and limitations of proteomic tools in the context of the study of marine invertebrate larval biology.

  17. Proteomics insights: proteins related to larval attachment and metamorphosis of marine invertebrates

    KAUST Repository

    Chandramouli, Kondethimmanahalli; Qian, Pei-Yuan; Ravasi, Timothy

    2014-01-01

    The transition in an animal from a pelagic larval stage to a sessile benthic juvenile typically requires major morphological and behavioral changes. Larval competency, attachment and initiation of metamorphosis are thought to be regulated by intrinsic chemical signals and specific sets of proteins. However, the molecular mechanisms that regulate larval attachment and metamorphosis in marine invertebrates have yet to be fully elucidated. Despite the many challenges associated with analysis of the larvae proteome, recent proteomic technologies have been used to address specific questions in larval developmental biology. These and other molecular studies have generated substantial amount of information of the proteins and molecular pathways involved in larval attachment and metamorphosis. Furthermore, the results of these studies have shown that systematic changes in protein expression patterns and post-translational modifications (PTMs) are crucial for the transition from larva to juvenile. The degeneration of larval tissues is mediated by protein degradation, while the development of juvenile organs may require PTM. In terms of application, the identified proteins may serve as targets for antifouling compounds, and biomarkers for environmental stressors. In this review we highlight the strengths and limitations of proteomic tools in the context of the study of marine invertebrate larval biology.

  18. Establishing health standards for indoor foreign proteins related to asthma: Dust mite, cat and cockroach

    Energy Technology Data Exchange (ETDEWEB)

    Platts-Mills, T.A.E.; Chapman, M.D.; Pollart, S.M.; Heymann, P.W.; Luczynska, C.M. (Univ. of Virginia, Charlottesville (United States))

    1990-01-01

    There is no doubt that a large number of individuals become allergic to foreign proteins that are predominantly or exclusively present indoors. In each case this immune response can be demonstrated either by immediate skin test responses or by measuring serum IgE antibodies. It has also been obvious for some time that patients presenting with asthma, perennial rhinitis and atopic dermatitis have an increased prevalence of IgE antibodies to these indoor allergens. More recently several epidemiological surveys have suggested that both mite exposure and IgE antibodies are important risk factors for asthma. The present situation is that assays have been developed capable of measuring the presence of mite, cockroach and cat allergens in house dust. Further clinical studies will be necessary to test the proposed standards for mite allergens and to define risk levels for other allergens.

  19. Chicken genome analysis reveals novel genes encoding biotin-binding proteins related to avidin family

    Directory of Open Access Journals (Sweden)

    Nordlund Henri R

    2005-03-01

    Full Text Available Abstract Background A chicken egg contains several biotin-binding proteins (BBPs, whose complete DNA and amino acid sequences are not known. In order to identify and characterise these genes and proteins we studied chicken cDNAs and genes available in the NCBI database and chicken genome database using the reported N-terminal amino acid sequences of chicken egg-yolk BBPs as search strings. Results Two separate hits showing significant homology for these N-terminal sequences were discovered. For one of these hits, the chromosomal location in the immediate proximity of the avidin gene family was found. Both of these hits encode proteins having high sequence similarity with avidin suggesting that chicken BBPs are paralogous to avidin family. In particular, almost all residues corresponding to biotin binding in avidin are conserved in these putative BBP proteins. One of the found DNA sequences, however, seems to encode a carboxy-terminal extension not present in avidin. Conclusion We describe here the predicted properties of the putative BBP genes and proteins. Our present observations link BBP genes together with avidin gene family and shed more light on the genetic arrangement and variability of this family. In addition, comparative modelling revealed the potential structural elements important for the functional and structural properties of the putative BBP proteins.

  20. Intrinsically disordered proteins--relation to general model expressing the active role of the water environment.

    Science.gov (United States)

    Kalinowska, Barbara; Banach, Mateusz; Konieczny, Leszek; Marchewka, Damian; Roterman, Irena

    2014-01-01

    This work discusses the role of unstructured polypeptide chain fragments in shaping the protein's hydrophobic core. Based on the "fuzzy oil drop" model, which assumes an idealized distribution of hydrophobicity density described by the 3D Gaussian, we can determine which fragments make up the core and pinpoint residues whose location conflicts with theoretical predictions. We show that the structural influence of the water environment determines the positions of disordered fragments, leading to the formation of a hydrophobic core overlaid by a hydrophilic mantle. This phenomenon is further described by studying selected proteins which are known to be unstable and contain intrinsically disordered fragments. Their properties are established quantitatively, explaining the causative relation between the protein's structure and function and facilitating further comparative analyses of various structural models. © 2014 Elsevier Inc. All rights reserved.

  1. GEC1, a protein related to GABARAP, interacts with tubulin and GABAA receptor

    International Nuclear Information System (INIS)

    Mansuy, Virginie; Boireau, Wilfrid; Fraichard, Annick; Schlick, Jean-Luc; Jouvenot, Michele; Delage-Mourroux, Regis

    2004-01-01

    We have previously identified in uterine cells a novel estrogen-regulated gene called gec1. GEC1 presents 87% identity with GABARAP which, so far, was the only protein found to associate with tubulin and GABA A receptor. We demonstrated then that GEC1 interacts in vitro with tubulin and GABA A receptor, and promotes tubulin assembly and microtubule bundling. Since all polyclonal antibodies failed in discrimination of both proteins GEC1 and GABARAP, a GEC1-GFP fusion protein was used to specifically localize GEC1. GEC1-GFP was distributed over the cytoplasm in perinuclear vesicles with a scattered pattern. Overall, our data show that GEC1 could be a new member of the GABARAP family involved in the transport of GABA A receptor

  2. Regulation of the Chlamydomonas Cell Cycle by a Stable, Chromatin-Associated Retinoblastoma Tumor Suppressor Complex

    Czech Academy of Sciences Publication Activity Database

    Olson, B. J. S. C.; Oberholzer, M.; Li, Y.; Zones, J. M.; Kohli, H. S.; Bišová, Kateřina; Fang, S.; Ch.; Meisenhelder, J.; Hunter, T.; Umen, J. G.

    2010-01-01

    Roč. 22, č. 10 (2010), s. 3331-3347 ISSN 1040-4651 Institutional research plan: CEZ:AV0Z50200510 Keywords : GENOME-WIDE ANALYSIS * TRANSCRIPTION FACTOR * GENE-PRODUCT Subject RIV: EE - Microbiology, Virology Impact factor: 9.396, year: 2010

  3. Proton radiation therapy for retinoblastoma: Comparison of various intraocular tumor locations and beam arrangements

    International Nuclear Information System (INIS)

    Krengli, Marco; Hug, Eugen B.; Adams, Judy A.; Smith, Alfred R.; Tarbell, Nancy J.; Munzenrider, John E.

    2005-01-01

    Purpose: To study the optimization of proton beam arrangements for various intraocular tumor locations; and to correlate isodose distributions with various target and nontarget structures. Methods and materials: We considered posterior-central, nasal, and temporal tumor locations, with straight, intrarotated, or extrarotated eye positions. Doses of 46 cobalt grey equivalent (CGE) to gross tumor volume (GTV) and 40 CGE to clinical target volume (CTV) (2 CGE per fraction) were assumed. Using three-dimensional planning, we compared isodose distributions for lateral, anterolateral oblique, and anteromedial oblique beams and dose-volume histograms of CTVs, GTVs, lens, lacrimal gland, bony orbit, and soft tissues. Results: All beam arrangements fully covered GTVs and CTVs with optimal lens sparing. Only 15% of orbital bone received doses ≥20 CGE with a lateral beam, with 20-26 CGE delivered to two of three growth centers. The anterolateral oblique approach with an intrarotated eye resulted in additional reduction of bony volume and exposure of only one growth center. No appreciable dose was delivered to the contralateral eye, brain tissue, or pituitary gland. Conclusions: Proton therapy achieved homogeneous target coverage with true lens sparing. Doses to orbit structures, including bony growth centers, were minimized with different beam arrangements and eye positions. Proton therapy could reduce the risks of second malignancy and cosmetic and functional sequelae

  4. The c-myc oncoprotein forms a specific complex with the product of the retinoblastoma gene

    NARCIS (Netherlands)

    Bernards, R.A.; Rustgi, A.K.; Dyson, N.; Hill, D.

    1991-01-01

    Myc proteins are involved in the regulation of cell proliferation and differentiation. Deregulated expression of myc family genes has been implicated in the genesis of a variety of cancers. Myc proteins share significant sequence homology in the carboxyl terminus with a number of

  5. Arabidopsis RETINOBLASTOMA RELATED directly regulates DNA damage responses through functions beyond cell cycle control

    Czech Academy of Sciences Publication Activity Database

    Horvath, B.M.; Kourová, Hana; Nagy, S.; Nemeth, E.; Magyar, Z.; Papdi, C.; Ahmad, Z.; Sanchez-Perez, G.F.; Perilli, S.; Blilou, I.; Pettko-Szandtner, A.; Darula, Z.; Meszaros, T.; Binarová, Pavla; Bogre, L.; Scheres, B.

    2017-01-01

    Roč. 36, č. 9 (2017), s. 1261-1278 ISSN 0261-4189 R&D Projects: GA ČR GA15-11657S Institutional support: RVO:61388971 Keywords : Arabidopsis * BRCA1 * DNA damage response Subject RIV: EE - Microbiology, Virology OBOR OECD: Microbiology Impact factor: 9.792, year: 2016

  6. The retinoblastoma protein binds to a family of E2F transcription factors

    DEFF Research Database (Denmark)

    Lees, J A; Saito, M; Vidal, M

    1993-01-01

    E2F is a transcription factor that helps regulate the expression of a number of genes that are important in cell proliferation. Recently, several laboratories have isolated a cDNA clone that encodes an E2F-like protein, known as E2F-1. Subsequent characterization of this protein showed that it had...... the properties of E2F, but it was difficult to account for all of the suggested E2F activities through the function of this one protein. Using low-stringency hybridization, we have isolated cDNA clones that encode two additional E2F-like proteins, called E2F-2 and E2F-3. The chromosomal locations of the genes...... protein in vivo. Finally, E2F-2 and E2F-3 were able to activate transcription of E2F-responsive genes in a manner that was dependent upon the presence of at least one functional E2F binding site. These observations suggest that the E2F activities described previously result from the combined action...

  7. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma

    NARCIS (Netherlands)

    Friend, S.H.; Bernards, R.A.; Rogelj, S.; Weinberg, R.A.; Rapaport, J.M.; Albert, D.M.; Dryja, Th.P.

    1986-01-01

    The genomes of various tumor cells contain mutant oncogenes that act dominantly, in that their effects can be observed when they are introduced into non-malignent cells. There is evidence for another class of oncogenes, in which tumour-predisposing mutations are recessive to wild-type alleles.

  8. The promyelocytic leukemia gene product (PML) forms stable complexes with the retinoblastoma protein

    DEFF Research Database (Denmark)

    Alcalay, M; Tomassoni, L; Colombo, E

    1998-01-01

    PML is a nuclear protein with growth-suppressive properties originally identified in the context of the PML-retinoic acid receptor alpha (RAR alpha) fusion protein of acute promyelocytic leukemia. PML localizes within distinct nuclear structures, called nuclear bodies, which are disrupted by the ...

  9. Educação em saúde: experiência com grupo operativo na atenção básica http://dx.doi.org/10.15601/1983-7631/rt.v2n3p130-133

    Directory of Open Access Journals (Sweden)

    Layza Quintão

    2011-12-01

    Full Text Available A educação em saúde é uma prática que está presente na assistência de enfermagem, sob a perspectiva de promoção, prevenção e controle da saúde. A assistência de enfermagem, sistematizada, viabiliza e favorece a adesão ao tratamento de doenças crônicas como diabetes, hipertensão e asma. O objetivo deste estudo foi promover saúde através do processo educativo para a população, utilizando como ferramenta a implementação de Grupos Operativos. Para embasar o planejamento, foi realizado o Diagnóstico Situacional de um dado Centro de Saúde, na grande Belo Horizonte - MG, onde percebeu-se tal necessidade, pela ausência deste tipo de trabalho. Os encontros foram planejados tendo como base os temas, emergidos do próprio grupo, os quais foram organizados, seqüencialmente: conceito, sinais e sintomas, principais complicações, alimentação adequada, medicação, atividade física. Os encontro foram organizados de maneira a serem cumpridas 4 etapas: abertura, com acolhimento dos participantes, abordagem dos conhecimentos já consolidados, exposição do novo tema a ser trabalhado, espaço para dúvidas e atividade avaliativa da apreensão. Foi possível perceber a importância de grupos operativos dentro de uma Unidade de Saúde, pois a partir dele, os indivíduos saem do espaço individual e vão para o coletivo, aderindo melhor ao tratamento.Palavras-chave: prevenção; educação em saúde; qualidade de vida

  10. Retinoblastoma—Health Professional Version

    Science.gov (United States)

    Retinoblastoma is a pediatric cancer. For patients with extraocular retinoblastoma, intensive chemotherapy is required, including high-dose chemotherapy and autologous hematopoietic stem cell rescue. Find evidence-based information on retinoblastoma treatment.

  11. 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.

  12. Corpus vitreum, retina og chorioidea biopsi

    DEFF Research Database (Denmark)

    Scherfig, Erik Christian Høegh

    2002-01-01

    oftalmology, biopsy, choroid, corpus vitreum, retina, malignant melanoma, biopsy technic, retinoblastoma......oftalmology, biopsy, choroid, corpus vitreum, retina, malignant melanoma, biopsy technic, retinoblastoma...

  13. SLDP: a novel protein related to caleosin is associated with the endosymbiotic Symbiodinium lipid droplets from Euphyllia glabrescens.

    Science.gov (United States)

    Pasaribu, Buntora; Lin, I-Ping; Tzen, Jason T C; Jauh, Guang-Yuh; Fan, Tung-Yung; Ju, Yu-Min; Cheng, Jing-O; Chen, Chii-Shiarng; Jiang, Pei-Luen

    2014-10-01

    Intracellular lipid droplets (LDs) have been proposed to play a key role in the mutualistic endosymbiosis between reef-building corals and the dinoflagellate endosymbiont Symbiodinium spp. This study investigates and identifies LD proteins in Symbiodinium from Euphyllia glabrescens. Discontinuous Percoll gradient centrifugation was used to separate Symbiodinium cells from E. glabrescens tentacles. Furthermore, staining with a fluorescent probe, Nile red, indicated that lipids accumulated in that freshly isolated Symbiodinium cells and lipid analyses further showed polyunsaturated fatty acids (PUFA) was abundant. The stable LDs were purified from endosymbiotic Symbiodinium cells. The structural integrity of the Symbiodinium LDs was maintained via electronegative repulsion and steric hindrance possibly provided by their surface proteins. Protein extracts from the purified LDs revealed a major protein band with a molecular weight of 20 kDa, which was termed Symbiodinium lipid droplet protein (SLDP). Interestingly, immunological cross-recognition analysis revealed that SLDP was detected strongly by the anti-sesame and anti-cycad caleosin antibodies. It was suggested that the stable Symbiodinium LDs were sheltered by this unique structural protein and was suggested that SLDP might be homologous to caleosin to a certain extent.

  14. Molecular cloning of a Candida albicans gene (SSB1) coding for a protein related to the Hsp70 family.

    Science.gov (United States)

    Maneu, V; Cervera, A M; Martinez, J P; Gozalbo, D

    1997-06-15

    We have cloned and sequenced a Candida albicans gene (SSB1) encoding a potential member of the heat-shock protein seventy (hsp70) family. The protein encoded by this gene contains 613 amino acids and shows a high degree (85%) of sequence identity to the ssb subfamily (ssb1 and ssb2) of the Saccharomyces cerevisiae hsp70 family. The transcribed mRNA (2.1 kb) is present in similar amounts both in yeast and germ tube cells of C. albicans.

  15. Effect of 21-day head down bed rest on urine proteins related to endothelium: Correlations with changes in carbohydrate metabolism

    Science.gov (United States)

    Kashirina, D.; Pastushkova, L.; Custaud, M. A.; Dobrokhotov, I.; Brzhozovsky, A.; Navasiolava, N.; Nosovsky, A.; Kononikhin, A.; Nikolaev, E.; Larina, I.

    2017-08-01

    We performed liquid chromatography-mass spectrometric study of the urine proteome in 8 healthy volunteers aged between 20 and 44 y.o. who have completed 21-day head-down bed rest. ANDSystem software which builds associative networks was used to identify the urinary proteins functionally related to the endothelium. We identified 7 endothelium-related biological processes, directly linked to 13 urine proteins. We performed manual annotation of the proteins which were the most important in terms of endothelial functions. Analysis of the correlations with biochemical variables revealed a positive correlation between fasting blood glucose and the following urine proteins: albumin, CD44 antigen, endothelial protein C receptor, mucin-1, osteopontin, receptor tyrosine kinase. As well, we found a positive correlation between HOMA-insulin resistance index and the following urine proteins: endothelial protein C receptor and syndecan-4. These results might suggest the involvement of above-mentioned proteins in glucose metabolism and their participation in the response to changes in blood glucose level.

  16. Overexpression of inhibitor of DNA-binding (ID)-1 protein related to angiogenesis in tumor advancement of ovarian cancers

    International Nuclear Information System (INIS)

    Maw, Min Khine; Fujimoto, Jiro; Tamaya, Teruhiko

    2009-01-01

    The inhibitor of DNA-binding (ID) has been involved in cell cycle regulation, apoptosis and angiogenesis. This prompted us to study ID functions in tumor advancement of ovarian cancers. Sixty patients underwent surgery for ovarian cancers. In ovarian cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction. The histoscore with the localization of ID-1 was determined by immunohistochemistry. Patient prognosis was analyzed with a 36-month survival rate. Microvessel counts were determined by immunohistochemistry for CD34 and factor VIII-related antigen. ID-1 histoscores and mRNA levels both significantly (p < 0.001) increased in ovarian cancers according to clinical stage, regardless of histopathological type. Furthermore, 30 patients with high ID-1 expression had a lower survival rate (53%) compared to patients with low ID-1 expression (80%). ID-1 histoscores and mRNA levels significantly (p < 0.0001) correlated with microvessel counts in ovarian cancers. ID-1 increased in ovarian cancer cells during tumor progression. Moreover, ID-1 expression levels correlated with microvessel counts. Therefore, ID-1 might work on tumor advancement via angiogenesis and is considered to be a candidate for a prognostic indicator in ovarian cancers

  17. Sublethal effects of imidacloprid on targeting muscle and ribosomal protein related genes in the honey bee Apis mellifera L.

    Science.gov (United States)

    Wu, Yan-Yan; Luo, Qi-Hua; Hou, Chun-Sheng; Wang, Qiang; Dai, Ping-Li; Gao, Jing; Liu, Yong-Jun; Diao, Qing-Yun

    2017-11-21

    A sublethal concentration of imidacloprid can cause chronic toxicity in bees and can impact the behavior of honey bees. The nectar- and water-collecting, and climbing abilities of bees are crucial to the survival of the bees and the execution of responsibilities in bee colonies. Besides behavioral impact, data on the molecular mechanisms underlying the toxicity of imidacloprid, especially by the way of RNA-seq at the transcriptomic level, are limited. We treated Apis mellifera L. with sublethal concentrations of imidacloprid (0.1, 1 and 10 ppb) and determined the effect on behaviors and the transcriptomic changes. The sublethal concentrations of imidacloprid had a limited impact on the survival and syrup consumption of bees, but caused a significant increase in water consumption. Moreover, the climbing ability was significantly impaired by 10 ppb imidacloprid at 8 d. In the RNA-seq analysis, gene ontology (GO) term enrichment indicated a significant down-regulation of muscle-related genes, which might contribute to the impairment in climbing ability of bees. The enriched GO terms were attributed to the up-regulated ribosomal protein genes. Considering the ribosomal and extra-ribosomal functions of the ribosomal proteins, we hypothesized that imidacloprid also causes cell dysfunction. Our findings further enhance the understanding of imidacloprid sublethal toxicity.

  18. Energy and protein relations in the broiler chicken. 4. Role of sex, line and substrate on in vitro lipogenesis

    International Nuclear Information System (INIS)

    Rosebrough, R.W.; Steele, N.C.; McMurtry, J.P.; Richards, M.P.; Mitchell, A.D.; Calvert, C.C.

    1986-01-01

    Experiments were conducted with dwarf (dw) and normal lines of chickens to determine the effect of sex, diet and line on lipogenesis in the 28-day-old chick. The chicks were fed diets containing 12, 18, 23 and 30% protein. In the first experiment, in vitro lipogenesis (incorporation of [2- 14 C] sodium acetate into hepatic fatty acids) as well as growth from 7 to 28 days of age were determined in males and females of both lines. In the second experiment, only males and females of the dwarf line were fed to determine the relative contribution of acetate and pyruvate to in vitro lipogenesis (incorporation of either [2- 14 C] sodium acetate or [2- 14 C) pyruvate into hepatic fatty acids). Chicks of the dwarf line were smaller than were those of the normal line. Females of both lines were smaller than males. In vitro lipogenesis was lower in the dwarf line; however the rate for both sexes within a given line was equal. An increase in the dietary protein decreased in vitro lipogenesis in both lines. The use of pyruvate as an in vitro precursor indicated that the regulation of lipid and carbohydrate metabolism may be an integrated process involving pyruvate carboxylation and subsequent flux of pyruvate carbon into either glucose or fatty acids. Based on the data presented, there is no evidence to assume, that the dwarf gene per se influences lipogenesis

  19. Functional analysis of P-glycoprotein and multidrug resistance associated protein related multidrug resistance in AML-blasts.

    Science.gov (United States)

    Brügger, D; Herbart, H; Gekeler, V; Seitz, G; Liu, C; Klingebiel, T; Orlikowsky, T; Einsele, H; Denzlinger, C; Bader, P; Niethammer, D; Beck, J F

    1999-05-01

    Despite the high effectiveness of various P-glycoprotein (P-gp) modulating substances in vitro their clinical value e.g. for combination treatment of acute myelogenous leukemias (AML) remains still unclear. This might be explainable by recent findings that other factors than P-gp (e.g. the multidrug resistance associated protein (MRP)) may also be involved in clinical occurring drug resistance. To study P-gp and MRP mediated MDR in AML blasts from patients with relapses at the functional level we measured rhodamine 123 (RHO) efflux in combination with a P-gp specific (SDZ PSC 833) or a MRP specific (MK571) modulator, respectively. Furthermore, direct antineoplastic drug action was monitored by determination of damaged cell fraction of a blast population using flow cytometry. We generally found strongly modulated RHO efflux by SDZ PSC 833 but slight RHO-efflux modulation by MK571 in blasts from relapsed states of AML expressing MDR1 or MRP mRNA at various levels. We could not demonstrate, though, significant PSC 833 or MK571 mediated modulation of the cytotoxic effects of etoposide. The results point to the possibility that combination of etoposide and a modulator might not improve responses to chemotherapy by targeting P-gp or MRP exclusively.

  20. Design and evaluation of antimalarial peptides derived from prediction of short linear motifs in proteins related to erythrocyte invasion.

    Directory of Open Access Journals (Sweden)

    Alessandra Bianchin

    Full Text Available The purpose of this study was to investigate the blood stage of the malaria causing parasite, Plasmodium falciparum, to predict potential protein interactions between the parasite merozoite and the host erythrocyte and design peptides that could interrupt these predicted interactions. We screened the P. falciparum and human proteomes for computationally predicted short linear motifs (SLiMs in cytoplasmic portions of transmembrane proteins that could play roles in the invasion of the erythrocyte by the merozoite, an essential step in malarial pathogenesis. We tested thirteen peptides predicted to contain SLiMs, twelve of them palmitoylated to enhance membrane targeting, and found three that blocked parasite growth in culture by inhibiting the initiation of new infections in erythrocytes. Scrambled peptides for two of the most promising peptides suggested that their activity may be reflective of amino acid properties, in particular, positive charge. However, one peptide showed effects which were stronger than those of scrambled peptides. This was derived from human red blood cell glycophorin-B. We concluded that proteome-wide computational screening of the intracellular regions of both host and pathogen adhesion proteins provides potential lead peptides for the development of anti-malarial compounds.

  1. Effects of immobilization and aerobic training on proteins related to intramuscular substrate storage and metabolism in young and older men.

    Science.gov (United States)

    Vigelsø, Andreas; Gram, Martin; Wiuff, Caroline; Hansen, Christina Neigaard; Prats, Clara; Dela, Flemming; Helge, Jørn Wulff

    2016-03-01

    Aging and inactivity lead to skeletal muscle metabolic inflexibility, but the underlying molecular mechanisms are not entirely elucidated. Therefore, we investigated how muscle lipid and glycogen stores and major regulatory proteins were affected by short-term immobilization followed by aerobic training in young and older men. 17 young (23 ± 1 years, 24 ± 1 kg m(-2), and 20 ± 2% body fat) and 15 older men (68 ± 1 years; 27 ± 1 kg m(-2), and 29 ± 2% body fat) underwent 2 weeks' one leg immobilization followed by 6 weeks' cycle training. Biopsies were obtained from m. vastus lateralis just before immobilization (at inclusion), after immobilization, and the after 6 weeks' training. The biopsies were analyzed for muscle substrates; muscle perilipin protein (PLIN), glycogen synthase (GS), synaptosomal-associated protein of 23 kDa (SNAP23) protein content, and muscle 3-hydroxyacyl-CoA dehydrogenase (HAD) activity The older men had higher intramuscular triglyceride (IMTG) (73 %) and Glycogen (16%) levels compared to the young men, and IMTG tended to increase with immobilization. PLIN2 and 3 protein content increased with immobilization in the older men only. The young men had higher GS (74%) protein compared to the older men. Immobilization decreased and training restored HAD activity, GS and SNAP23 protein content in young and older men. Evidence of age-related metabolic inflexibility is presented, seen as body fat and IMTG accumulation. The question arises as to whether IMTG accumulation in the older men is caused by or leading to the increase in PLIN2 and 3 protein content. Training decreased body fat and IMTG levels in both young and older men; hence, training should be prioritized to reduce the detrimental effect of aging on metabolism.

  2. Effects of immobilization and aerobic training on proteins related to intramuscular substrate storage and metabolism in young and older men

    DEFF Research Database (Denmark)

    Vigelsø Hansen, Andreas; Gram, Martin; Wiuff, Caroline

    2016-01-01

    by aerobic training in young and older men. METHODS: 17 young (23 ± 1 years, 24 ± 1 kg m(-2), and 20 ± 2% body fat) and 15 older men (68 ± 1 years; 27 ± 1 kg m(-2), and 29 ± 2% body fat) underwent 2 weeks' one leg immobilization followed by 6 weeks' cycle training. Biopsies were obtained from m. vastus...... lateralis just before immobilization (at inclusion), after immobilization, and the after 6 weeks' training. The biopsies were analyzed for muscle substrates; muscle perilipin protein (PLIN), glycogen synthase (GS), synaptosomal-associated protein of 23 kDa (SNAP23) protein content, and muscle 3-hydroxyacyl...... GS (74%) protein compared to the older men. Immobilization decreased and training restored HAD activity, GS and SNAP23 protein content in young and older men. CONCLUSION: Evidence of age-related metabolic inflexibility is presented, seen as body fat and IMTG accumulation. The question arises...

  3. Proteome approaches to characterize seed storage proteins related to ditelocentric chromosomes in common wheat (Triticum aestivum L.).

    Science.gov (United States)

    Islam, Nazrul; Woo, Sun-Hee; Tsujimoto, Hisashi; Kawasaki, Hiroshi; Hirano, Hisashi

    2002-09-01

    Changes in protein composition of wheat endosperm proteome were investigated in 39 ditelocentric chromosome lines of common wheat (Triticum aestivum L.) cv. Chinese Spring. Two-dimensional gel electrophoresis followed by Coomassie Brilliant Blue staining has resolved a total of 105 protein spots in a gel. Quantitative image analysis of protein spots was performed by PDQuest. Variations in protein spots between the euploid and the 39 ditelocentric lines were evaluated by spot number, appearance, disappearance and intensity. A specific spot present in all gels was taken as an internal standard, and the intensity of all other spots was calculated as the ratio of the internal standard. Out of the 1755 major spots detected in 39 ditelocentric lines, 1372 (78%) spots were found variable in different spot parameters: 147 (11%) disappeared, 978 (71%) up-regulated and 247 (18%) down-regulated. Correlation studies in changes in protein intensities among 24 protein spots across the ditelocentric lines were performed. High correlations in changes of protein intensities were observed among the proteins encoded by genes located in the homoeologous arms. Locations of structural genes controlling 26 spots were identified in 10 chromosomal arms. Multiple regulators of the same protein located at various chromosomal arms were also noticed. Identification of structural genes for most of the proteins was found difficult due to multiple regulators encoding the same protein. Two novel subunits (1B(Z,) 1BDz), the structure of which are very similar to the high molecular weight glutenin subunit 12, were identified, and the chromosome arm locations of these subunits were assigned.

  4. Proteogenomic Analysis Greatly Expands the Identification of Proteins Related to Reproduction in the Apogamous Fern Dryopteris affinis ssp. affinis.

    Science.gov (United States)

    Grossmann, Jonas; Fernández, Helena; Chaubey, Pururawa M; Valdés, Ana E; Gagliardini, Valeria; Cañal, María J; Russo, Giancarlo; Grossniklaus, Ueli

    2017-01-01

    Performing proteomic studies on non-model organisms with little or no genomic information is still difficult. However, many specific processes and biochemical pathways occur only in species that are poorly characterized at the genomic level. For example, many plants can reproduce both sexually and asexually, the first one allowing the generation of new genotypes and the latter their fixation. Thus, both modes of reproduction are of great agronomic value. However, the molecular basis of asexual reproduction is not well understood in any plant. In ferns, it combines the production of unreduced spores (diplospory) and the formation of sporophytes from somatic cells (apogamy). To set the basis to study these processes, we performed transcriptomics by next-generation sequencing (NGS) and shotgun proteomics by tandem mass spectrometry in the apogamous fern D. affinis ssp. affinis . For protein identification we used the public viridiplantae database (VPDB) to identify orthologous proteins from other plant species and new transcriptomics data to generate a "species-specific transcriptome database" (SSTDB). In total 1,397 protein clusters with 5,865 unique peptide sequences were identified (13 decoy proteins out of 1,410, protFDR 0.93% on protein cluster level). We show that using the SSTDB for protein identification increases the number of identified peptides almost four times compared to using only the publically available VPDB. We identified homologs of proteins involved in reproduction of higher plants, including proteins with a potential role in apogamy. With the increasing availability of genomic data from non-model species, similar proteogenomics approaches will improve the sensitivity in protein identification for species only distantly related to models.

  5. Proteomic analysis of cerebrospinal fluid from children with central nervous system tumors identifies candidate proteins relating to tumor metastatic spread.

    Science.gov (United States)

    Spreafico, Filippo; Bongarzone, Italia; Pizzamiglio, Sara; Magni, Ruben; Taverna, Elena; De Bortoli, Maida; Ciniselli, Chiara M; Barzanò, Elena; Biassoni, Veronica; Luchini, Alessandra; Liotta, Lance A; Zhou, Weidong; Signore, Michele; Verderio, Paolo; Massimino, Maura

    2017-07-11

    Central nervous system (CNS) tumors are the most common solid tumors in childhood. Since the sensitivity of combined cerebrospinal fluid (CSF) cytology and radiological neuroimaging in detecting meningeal metastases remains relatively low, we sought to characterize the CSF proteome of patients with CSF tumors to identify biomarkers predictive of metastatic spread. CSF samples from 27 children with brain tumors and 13 controls (extra-CNS non-Hodgkin lymphoma) were processed using core-shell hydrogel nanoparticles, and analyzed with reverse-phase liquid chromatography/electrospray tandem mass spectrometry (LC-MS/MS). Candidate proteins were identified with Fisher's exact test and/or a univariate logistic regression model. Reverse phase protein array (RPPA), Western blot (WB), and ELISA were used in the training set and in an independent set of CFS samples (60 cases, 14 controls) to validate our discovery findings. Among the 558 non-redundant proteins identified by LC-MS/MS, 147 were missing from the CSF database at http://www.biosino.org. Fourteen of the 26 final top-candidate proteins were chosen for validation with WB, RPPA and ELISA methods. Six proteins (type 1 collagen, insulin-like growth factor binding protein 4, procollagen C-endopeptidase enhancer 1, glial cell-line derived neurotrophic factor receptor α2, inter-alpha-trypsin inhibitor heavy chain 4, neural proliferation and differentiation control protein-1) revealed the ability to discriminate metastatic cases from controls. Combining a unique dataset of CSFs from pediatric CNS tumors with a novel enabling nanotechnology led us to identify CSF proteins potentially related to metastatic status.

  6. iTRAQ-Based Identification of Proteins Related to Muscle Growth in the Pacific Abalone, Haliotis discus hannai

    Directory of Open Access Journals (Sweden)

    Jianfang Huang

    2017-10-01

    Full Text Available The abalone Haliotis discus hannai is an important aquaculture species that is grown for human consumption. However, little is known of the genetic mechanisms governing muscle growth in this species, particularly with respect to proteomics. The isobaric tag for relative and absolute quantitation (iTRAQ method allows for sensitive and accurate protein quantification. Our study was the first to use iTRAQ-based quantitative proteomics to investigate muscle growth regulation in H. discus hannai. Among the 1904 proteins identified from six samples, 125 proteins were differentially expressed in large specimens of H. discus hannai as compared to small specimens. In the large specimens, 47 proteins were upregulated and 78 were downregulated. Many of the significant Kyoto Encyclopedia of Genes and Genomes (KEGG pathways, including these differentially expressed proteins, were closely related to muscle growth, including apoptosis, thyroid hormone signaling, regulation of the actin cytoskeleton, and viral myocarditis (p < 0.05. Our quantitative real-time polymerase chain reaction (qRT-PCR analyses suggested that the alterations in expression levels observed in the differentially expressed proteins were consistent with the alterations observed in the encoding mRNAs, indicating the repeatability of our proteomic approach. Our findings contribute to the knowledge of the molecular mechanisms of muscle growth in H. discus hannai.

  7. Secondary reconstruction of a mobile eye socket 30 years after enucleation of the eyeball for retinoblastoma: a case report.

    Science.gov (United States)

    Okumoto, T; Koike, G; Yoshimura, Y

    2014-03-01

    A mobile eye socket is generally reconstructed by inserting an implant into the scleral pocket immediately after bulbar exenteration, or by attaching the extra-ocular muscles to the implanted artificial eyeball immediately after enucleation. However, exposure of the implanted material and other problems can occur. We achieved satisfactory reconstruction of a mobile eye socket by using an autogenous cartilage graft and a pericranial flap in a patient with long-standing anophthalmia due to enucleation. This case is presented with a review of the relevant literature. Copyright © 2013 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

  8. Retinoblastoma-independent antiproliferative activity of novel intracellular antibodies against the E7 oncoprotein in HPV 16-positive cells

    International Nuclear Information System (INIS)

    Accardi, Luisa; Tommasino, Massimo; Banks, Lawrence; Chirullo, Barbara; Giorgi, Colomba; Donà, Maria Gabriella; Mileo, Anna M; Paggi, Marco G; Federico, Antonio; Torreri, Paola; Petrucci, Tamara C; Accardi, Rosita; Pim, David

    2011-01-01

    'High risk' Human Papillomavirus strains are the causative agents of the vast majority of carcinomas of the uterine cervix. In these tumors, the physical integration of the HPV genome is a frequent, though not invariable occurrence, but the constitutive expression of the E6 and E7 viral genes is always observed, suggesting key roles for the E6 and E7 oncoproteins in the process of malignant transformation. The 'intracellular antibody' technology using recombinant antibodies in single-chain format offers the possibility of targeting a protein in its intracellular environment even at the level of definite domains thus representing a valuable strategy to 'knock out' the function of specific proteins. In this study, we investigate the in vitro activity of two single-chain antibody fragments directed against the 'high-risk' HPV 16 E7 oncoprotein, scFv 43M2 and scFv 51. These scFvs were expressed by retroviral system in different cell compartments of the HPV16-positive SiHa cells, and cell proliferation was analyzed by Colony Formation Assay and EZ4U assay. The binding of these scFvs to E7, and their possible interference with the interaction between E7 and its main target, the tumor suppressor pRb protein, were then investigated by immunoassays, PepSet™technology and Surface Plasmon Resonance. The expression of the two scFvs in the nucleus and the endoplasmic reticulum of SiHa cells resulted in the selective growth inhibition of these cells. Analysis of binding showed that both scFvs bind E7 via distinct but overlapping epitopes not corresponding to the pRb binding site. Nevertheless, the binding of scFv 43M2 to E7 was inhibited by pRb in a non-competitive manner. Based on the overall results, the observed inhibition of HPV-positive SiHa cells proliferation could be ascribed to an interaction between scFv and E7, involving non-pRb targets. The study paves the way for the employment of specific scFvs in immunotherapeutic approaches against the HPV-associated lesions

  9. Role of Changes in the Expression of Cyclins and Retinoblastoma Protein in the Development of Breast Cancer

    National Research Council Canada - National Science Library

    Langan, Thomas

    1999-01-01

    .... Expression of moderate amounts of p16 in breast cancer cell lines with this type of defect suppresses the transformed properties of the cells, preventing growth in soft agar and blocking formation...

  10. Pocket Proteins Suppress Head and Neck Cancer

    Science.gov (United States)

    Shin, Myeong-Kyun; Pitot, Henry C.; Lambert, Paul F.

    2012-01-01

    Head and neck squamous cell carcinomas (HNSCC) is a common cancer in humans long known to be caused by tobacco and alcohol use, but now an increasing percentage of HNSCC is recognized to be caused by the same human papillomaviruses (HPVs) that cause cervical and other anogenital cancers. HPV-positive HNSCCs differ remarkably from HPV-negative HNSCCs in their clinical response and molecular properties. From studies in mice, we know that E7 is the dominant HPV oncoprotein in head and neck cancer. E7 is best known for its ability to inactivate pRb, the product of the retinoblastoma tumor susceptibility gene. However loss of pRb function does not fully account for E7’s potency in causing head and neck cancer. In this study, we characterized the cancer susceptibility of mice deficient in the expression of pRb and either of two related “pocket” proteins, p107 and p130, that are also inactivated by E7. pRb/p107 deficient mice developed head and neck cancer as frequently as do HPV16 E7 transgenic mice. The head and neck epithelia of the pRb/p107 deficient mice also displayed the same acute phenotypes and biomarker readouts as observed in the epithelia of E7 transgenic mice. Mice deficient for pRb and p130 in their head and neck epithelia showed intermediate acute and tumor phenotypes. We conclude that pRb and p107 act together to efficiently suppress head and neck cancer, and are therefore highly relevant targets of HPV16 E7 in its contribution to HPV-positive HNSCC. PMID:22237625

  11. Induction of S-phase entry by E2F transcription factors depends on their nuclear localization

    DEFF Research Database (Denmark)

    Müller, H; Moroni, M C; Vigo, E

    1997-01-01

    The E2F transcription factors are essential for regulating the correct timing of activation of several genes whose products are implicated in cell proliferation and DNA replication. The E2Fs are targets for negative regulation by the retinoblastoma protein family, which includes pRB, p107, and p130......, and they are in a pathway that is frequently found altered in human cancers. There are five members of the E2F family, and they can be divided into two functional subgroups. Whereas, upon overexpression, E2F-1, -2, and -3 induce S phase in quiescent fibroblasts and override G1 arrests mediated by the p16INK4A tumor...... suppressor protein or neutralizing antibodies to cyclin D1, E2F-4 and -5 do not. Using E2F-1 and E2F-4 as representatives of the two subgroups, we showed here, by constructing a set of chimeric proteins, that the amino terminus of E2F-1 is sufficient to confer S-phase-inducing potential as well...

  12. Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects.

    Science.gov (United States)

    Berman, Seth D; West, Julie C; Danielian, Paul S; Caron, Alicia M; Stone, James R; Lees, Jacqueline A

    2009-09-01

    The retinoblastoma tumor-suppressor protein, pRb, is a member of the pocket protein family that includes p107 and p130. These proteins have well-defined roles in regulating entry into and exit from the cell cycle and also have cell cycle-independent roles in facilitating differentiation. Here we investigate the overlap between pocket protein's function during embryonic development by using conditional mutant alleles to generate Rb;p107 double-mutant embryos (DKOs) that develop in the absence of placental defects. These DKOs die between e13.5 and e14.5, much earlier than either the conditional Rb or the germline p107 single mutants, which survive to birth or are largely viable, respectively. Analyses of the e13.5 DKOs shows that p107 mutation exacerbates the phenotypes resulting from pRb loss in the central nervous system and lens, but not in the peripheral nervous system. In addition, these embryos exhibit novel phenotypes, including increased proliferation of blood vessel endothelial cells, and heart defects, including double-outlet right ventricle (DORV). The DORV is caused, at least in part, by a defect in blood vessel endothelial cells and/or heart mesenchymal cells. These findings demonstrate novel, overlapping functions for pRb and p107 in numerous murine tissues.

  13. Dnmt1-dependent Chk1 pathway suppression is protective against neuron division.

    Science.gov (United States)

    Oshikawa, Mio; Okada, Kei; Tabata, Hidenori; Nagata, Koh-Ichi; Ajioka, Itsuki

    2017-09-15

    Neuronal differentiation and cell-cycle exit are tightly coordinated, even in pathological situations. When pathological neurons re-enter the cell cycle and progress through the S phase, they undergo cell death instead of division. However, the mechanisms underlying mitotic resistance are mostly unknown. Here, we have found that acute inactivation of retinoblastoma (Rb) family proteins (Rb, p107 and p130) in mouse postmitotic neurons leads to cell death after S-phase progression. Checkpoint kinase 1 (Chk1) pathway activation during the S phase prevented the cell death, and allowed the division of cortical neurons that had undergone acute Rb family inactivation, oxygen-glucose deprivation (OGD) or in vivo hypoxia-ischemia. During neurogenesis, cortical neurons became protected from S-phase Chk1 pathway activation by the DNA methyltransferase Dnmt1, and underwent cell death after S-phase progression. Our results indicate that Chk1 pathway activation overrides mitotic safeguards and uncouples neuronal differentiation from mitotic resistance. © 2017. Published by The Company of Biologists Ltd.

  14. The E7 oncoprotein of high-risk human papillomavirus type 16 enters the nucleus via a nonclassical Ran-dependent pathway

    International Nuclear Information System (INIS)

    Angeline, Michael; Merle, Eric; Moroianu, Junona

    2003-01-01

    E7, the major transforming protein of high-risk human papillomavirus (HPV), type 16, binds and inactivates the retinoblastoma protein (pRb), and the Rb-related proteins p107 and p130. HPV16 E7 is a nuclear protein lacking a classical basic nuclear localization signal. In this study we investigated the nuclear import of HPV16 E7 oncoprotein in digitonin-permeabilized HeLa cells. HPV16 E7 nuclear import was independent of pRb, as an E7 ΔDLYC variant defective in pRb binding was imported into the nuclei of digitonin-permeabilized cells as efficiently as wild-type E7 in the presence of exogenous cytosol. Interestingly, we discovered that HPV16 E7 is imported into the nuclei via a novel pathway different from those mediated by Kap α2β1 heterodimers, Kap β1, or Kap β2. Nuclear accumulation of E7 required Ran and was not inhibited by the RanG19V-GTP variant, an inhibitor of Kap β mediated import pathways. Together the data suggest that HPV16 E7 translocates through the nuclear pores via a nonclassical Ran-dependent pathway, independent of the main cytosolic Kap β import receptors

  15. Zebrafish usp39 mutation leads to rb1 mRNA splicing defect and pituitary lineage expansion.

    Directory of Open Access Journals (Sweden)

    Yesenia Ríos

    2011-01-01

    Full Text Available Loss of retinoblastoma (Rb tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish ubiquitin specific peptidase 39 (usp39 mutation, the yeast and human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion without apparent changes in major hypothalamic hormonal and regulatory signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130, and cdkn1a (p21 expression. Rb1 mRNA overexpression, or antisense morpholino knockdown of e2f4, partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon. These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis.

  16. Large-scale proteome analysis of abscisic acid and ABSCISIC ACID INSENSITIVE3-dependent proteins related to desiccation tolerance in Physcomitrella patens.

    Science.gov (United States)

    Yotsui, Izumi; Serada, Satoshi; Naka, Tetsuji; Saruhashi, Masashi; Taji, Teruaki; Hayashi, Takahisa; Quatrano, Ralph S; Sakata, Yoichi

    2016-03-18

    Desiccation tolerance is an ancestral feature of land plants and is still retained in non-vascular plants such as bryophytes and some vascular plants. However, except for seeds and spores, this trait is absent in vegetative tissues of vascular plants. Although many studies have focused on understanding the molecular basis underlying desiccation tolerance using transcriptome and proteome approaches, the critical molecular differences between desiccation tolerant plants and non-desiccation plants are still not clear. The moss Physcomitrella patens cannot survive rapid desiccation under laboratory conditions, but if cells of the protonemata are treated by the phytohormone abscisic acid (ABA) prior to desiccation, it can survive 24 h exposure to desiccation and regrow after rehydration. The desiccation tolerance induced by ABA (AiDT) is specific to this hormone, but also depends on a plant transcription factor ABSCISIC ACID INSENSITIVE3 (ABI3). Here we report the comparative proteomic analysis of AiDT between wild type and ABI3 deleted mutant (Δabi3) of P. patens using iTRAQ (Isobaric Tags for Relative and Absolute Quantification). From a total of 1980 unique proteins that we identified, only 16 proteins are significantly altered in Δabi3 compared to wild type after desiccation following ABA treatment. Among this group, three of the four proteins that were severely affected in Δabi3 tissue were Arabidopsis orthologous genes, which were expressed in maturing seeds under the regulation of ABI3. These included a Group 1 late embryogenesis abundant (LEA) protein, a short-chain dehydrogenase, and a desiccation-related protein. Our results suggest that at least three of these proteins expressed in desiccation tolerant cells of both Arabidopsis and the moss are very likely to play important roles in acquisition of desiccation tolerance in land plants. Furthermore, our results suggest that the regulatory machinery of ABA- and ABI3-mediated gene expression for desiccation tolerance might have evolved in ancestral land plants before the separation of bryophytes and vascular plants. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Phosphorylation of intracellular proteins related to the multihormonal regulation of prolactin: comparison of normal anterior pituitary cells in culture with the tumor-derived GH cell lines

    International Nuclear Information System (INIS)

    Beretta, L.; Boutterin, M.C.; Sobel, A.

    1988-01-01

    We have previously identified a group of cytoplasmic phosphoproteins (proteins 1-11) whose phosphorylation could be related, on a pharmacological basis, to the multihormonal regulation of PRL synthesis and release in the anterior pituitary tumor-derived GH cell lines. Phosphoproteins with identical migration properties on two-dimensional electrophoresis gels were also detectable in normal rat anterior pituitary cells in culture. We designed appropriate culture and [ 32 P] phosphate-labeling conditions allowing to analyze the regulation of the phosphorylation of these proteins in normal pituitary cells. TRH, 12-O-tetradecanoylphorbol-13-acetate, and vasoactive intestinal peptide induced the same qualitative changes in phosphorylation of proteins 1-11 in normal as in GH cells. Quantitative differences observed are most likely due to the heterogeneity of primary pituitary cultures. Phosphorylation changes affecting proteins 14-16, not previously detected in GH cells, were also observed with normal anterior pituitary cells. GH cell lines have lost the sensitivity of pituitary lactotrophs for dopamine, an important physiological inhibitor of PRL synthesis and release. In normal anterior pituitary cells in culture, dopamine inhibited also the TRH-stimulated phosphorylation of proteins 1-10, thus strengthening the correlation between phosphorylation of these proteins and multihormonal regulation of pituitary cell functions. Our results indicate: 1) that the same phosphoproteins as in GH cells are related to the multihormonal regulation of nontumoral, normal anterior pituitary cells in culture; 2) that dopamine acts by interfering with the phosphorylation of these proteins

  18. Identification of Proteins Related to Epigenetic Regulation in the Malignant Transformation of Aberrant Karyotypic Human Embryonic Stem Cells by Quantitative Proteomics

    Science.gov (United States)

    Sun, Yi; Yang, Yixuan; Zeng, Sicong; Tan, Yueqiu; Lu, Guangxiu; Lin, Ge

    2014-01-01

    Previous reports have demonstrated that human embryonic stem cells (hESCs) tend to develop genomic alterations and progress to a malignant state during long-term in vitro culture. This raises concerns of the clinical safety in using cultured hESCs. However, transformed hESCs might serve as an excellent model to determine the process of embryonic stem cell transition. In this study, ITRAQ-based tandem mass spectrometry was used to quantify normal and aberrant karyotypic hESCs proteins from simple to more complex karyotypic abnormalities. We identified and quantified 2583 proteins, and found that the expression levels of 316 proteins that represented at least 23 functional molecular groups were significantly different in both normal and abnormal hESCs. Dysregulated protein expression in epigenetic regulation was further verified in six pairs of hESC lines in early and late passage. In summary, this study is the first large-scale quantitative proteomic analysis of the malignant transformation of aberrant karyotypic hESCs. The data generated should serve as a useful reference of stem cell-derived tumor progression. Increased expression of both HDAC2 and CTNNB1 are detected as early as the pre-neoplastic stage, and might serve as prognostic markers in the malignant transformation of hESCs. PMID:24465727

  19. Is Meeting the Recommended Dietary Allowance (RDA) for Protein Related to Body Composition among Older Adults?: Results from the Cardiovascular Health of Seniors and Built Environment Study.

    Science.gov (United States)

    Beasley, J M; Deierlein, A L; Morland, K B; Granieri, E C; Spark, A

    2016-01-01

    Studies suggest protein intake may be associated with lower body weight, but protein has also been associated with preservation of lean body mass. Understanding the role of protein in maintaining health for older adults is important for disease prevention among this population. Cross-sectional study of the relationship of dietary protein on body composition. New York City community centers. 1,011 Black, White, and Latino urban men and women 60-99 years of age. Protein intake was assessed using two interviewer-administered 24-hour recalls, and body composition was assessed using bioelectrical impedance analysis (BIA) of fat mass (kg) (FM), fat free mass (kg) (FFM), and impedance resistance (Ohms). Indices of FM and FFM were calculated by dividing BIA measurements by height squared (m2), and percent FFM was calculated by dividing FFM by the sum of FM and FFM. Log linear models adjusting for age (continuous), race/ethnicity, education, physical activity (dichotomized at the median), hypertension, diabetes, and total calories (continuous). Just 33% of women and 50% of men reported meeting the RDA for protein. Both fat free mass index (FFMI) and fat mass index (FMI) were negatively associated with meeting the RDA for protein (Women: FFMI -1.78 95%CI [-2.24, -1.33], FMI -4.12 95% CI [-4.82, -3.42]; Men: FFMI -1.62 95% CI [-2.32, -0.93] FMI -1.80 95% CI [-2.70, -0.89]). After accounting for confounders, women and men consuming at least 0.8 g/kg/day had a 6.2% (95% CI: 5.0%, 7.4%) and a 3.2% (95% CI 1.1%, 5.3%) higher percent fat free mass, respectively. FFM, FFMI, FM, and FMI were inversely related to meeting the RDA for protein. Meeting the RDA for protein of at least 0.8g/kg/day was associated with a higher percentage of fat free mass among older adults. These results suggest meeting the protein recommendations of at least 0.8 g/kg/day may help to promote lower overall body mass, primarily through loss of fat mass rather than lean mass.

  20. Integration analysis of quantitative proteomics and transcriptomics data identifies potential targets of frizzled-8 protein-related antiproliferative factor in vivo.

    Science.gov (United States)

    Yang, Wei; Kim, Yongsoo; Kim, Taek-Kyun; Keay, Susan K; Kim, Kwang Pyo; Steen, Hanno; Freeman, Michael R; Hwang, Daehee; Kim, Jayoung

    2012-12-01

    What's known on the subject? and What does the study add? Interstitial cystitis (IC) is a prevalent and debilitating pelvic disorder generally accompanied by chronic pain combined with chronic urinating problems. Over one million Americans are affected, especially middle-aged women. However, its aetiology or mechanism remains unclear. No efficient drug has been provided to patients. Several urinary biomarker candidates have been identified for IC; among the most promising is antiproliferative factor (APF), whose biological activity is detectable in urine specimens from >94% of patients with both ulcerative and non-ulcerative IC. The present study identified several important mediators of the effect of APF on bladder cell physiology, suggesting several candidate drug targets against IC. In an attempt to identify potential proteins and genes regulated by APF in vivo, and to possibly expand the APF-regulated network identified by stable isotope labelling by amino acids in cell culture (SILAC), we performed an integration analysis of our own SILAC data and the microarray data of Gamper et al. (2009) BMC Genomics 10: 199. Notably, two of the proteins (i.e. MAPKSP1 and GSPT1) that are down-regulated by APF are involved in the activation of mTORC1, suggesting that the mammalian target of rapamycin (mTOR) pathway is potentially a critical pathway regulated by APF in vivo. Several components of the mTOR pathway are currently being studied as potential therapeutic targets in other diseases. Our analysis suggests that this pathway might also be relevant in the design of diagnostic tools and medications targeting IC. • To enhance our understanding of the interstitial cystitis urine biomarker antiproliferative factor (APF), as well as interstitial cystitis biology more generally at the systems level, we reanalyzed recently published large-scale quantitative proteomics and in vivo transcriptomics data sets using an integration analysis tool that we have developed. • To identify more differentially expressed genes with a lower false discovery rate from a previously published microarray data set, an integrative hypothesis-testing statistical approach was applied. • For validation experiments, expression and phosphorylation levels of select proteins were evaluated by western blotting. • Integration analysis of this transcriptomics data set with our own quantitative proteomics data set identified 10 genes that are potentially regulated by APF in vivo from 4140 differentially expressed genes identified with a false discovery rate of 1%. • Of these, five (i.e. JUP, MAPKSP1, GSPT1, PTGS2/COX-2 and XPOT) were found to be prominent after network modelling of the common genes identified in the proteomics and microarray studies. • This molecular signature reflects the biological processes of cell adhesion, cell proliferation and inflammation, which is consistent with the known physiological effects of APF. • Lastly, we found the mammalian target of rapamycin pathway was down-regulated in response to APF. • This unbiased integration analysis of in vitro quantitative proteomics data with in vivo quantitative transcriptomics data led to the identification of potential downstream mediators of the APF signal transduction pathway. © 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.

  1. A Xanthomonas citri subsp citri hypothetical protein related to virulence contains a non-functional HD domain and is implicated in flagellar motility.

    Science.gov (United States)

    Vieira, F C F; Gonçalves, A M; Mendoza, E F R; Ferreira, R M; Costa, M L M; Balbuena, T S; Sebinelli, H G; Ciancaglini, P; Pizauro Junior, J M; Ferro, J A

    2017-08-31

    Citrus canker, caused by the Gram-negative bacterium Xanthomonas citri subsp citri (Xac), severely affects most economically important citrus varieties worldwide. A previous study showed that disruption of the ORF XAC1201 from the Xac 306 strain by transposon Tn5 decreased bacterium virulence in the Rangpur lime host (Citrus limonia L. Osbeck). However, little is known regarding the possible function of the hypothetical protein XAC1201 and how it affects the virulence of Xac 306. Here, we confirmed that disruption of ORF XAC1201 reduces Xac 306 virulence in two different hosts, delaying the onset of typical symptoms. In silico analysis suggested that XAC1201 interacts with the flagellar proteins FliM and FliL, known to be an important factor for virulence. In fact, motility assays revealed that the XAC1201 mutant has a significant difference in motility compared to the wild-type Xac 306. Also, a 3-D structure model revealed modified cofactor binding sites and suggested that XAC1201 has a non-functional HD domain. This hypothesis was confirmed by enzymatic assays performed in purified, XAC1201 recombinant protein expressed in Escherichia coli, which revealed no significant activities previously associated with HD domains for the tested substrates. Thus, the role of the XAC1201 protein in Xac 306 virulence seems to be related to flagellar motility, although a non-classic role for the HD domain cannot be dismissed.

  2. Isoflurane anesthesia promotes cognitive impairment by inducing expression of β-amyloid protein-related factors in the hippocampus of aged rats.

    Directory of Open Access Journals (Sweden)

    Shuai Zhang

    Full Text Available Isoflurane anesthesia has been shown to be responsible for cognitive impairment in Alzheimer's disease (AD and development of AD in the older age groups. However, the pathogenesis of AD-related cognitive impairments induced by isoflurane anesthesia remains elusive. Thus, this study was designed to investigate the mechanism by which isoflurane anesthesia caused AD-related cognitive impairments. Aged Wistar rats were randomly divided into 6 groups (n = 12, 1 control group (CONT and 5 isoflurane treated (ISO groups (ISO 0, ISO 0.5D, ISO 1D, ISO 3D and ISO 7D. The CONT group inhaled 30% O2 for 2 h without any anesthesia. ISO groups were placed under anesthesia with 3% isoflurane and then exposed to 1.5% isoflurane delivered in 30% O2 for 2 h. Rats in each ISO group were then analyzed immediately (ISO 0 or at various time points (0.5, 1, 3 or 7 day after this exposure. Cognitive function was assessed using the Morris water maze test. Protein levels of amyloid precursor protein (APP, β-site APP cleavage enzyme-1 (BACE-1 and Aβ42 peptide were analyzed in hippocampal samples by Western blot. β-Amyloid (Abeta plaques were detected in hippocampal sections by Congo red staining. Compared with controls, all ISO groups showed increased escape latency and impaired spatial memory. Isoflurane increased APP mRNA expression and APP protein depletion, promoting Aβ42 overproduction, oligomerization and accumulation. However, isoflurane did not affect BACE-1 expression. Abeta plaques were observed only in those ISO groups sacrificed at 3 or 7 d. Our data indicate that aged rats exposed to isoflurane had increased APP mRNA expression and APP protein depletion, with Aβ42 peptide overproduction and oligomerization, resulting in formation of Abeta plaques in the hippocampus. Such effects might have contributed to cognitive impairments, including in spatial memory, observed in these rats after isoflurane anesthesia.

  3. Glucagon-Like Peptide 2 Stimulates Postresection Intestinal Adaptation in Preterm Pigs by Affecting Proteins Related to Protein, Carbohydrate, and Sulphur Metabolism

    DEFF Research Database (Denmark)

    Jiang, Pingping; Vegge, Andreas; Thymann, Thomas

    2017-01-01

    cellular structural proteins, while the added GLP-2 treatment affected proteins involved in protein processing and the metabolism of protein, carbohydrate, and sulphur. CONCLUSION: In the first days following resection, proteins affected by resection plus GLP-2 treatment differed markedly from those...

  4. Proteins Related to the Type I Secretion System Are Associated with Secondary SecA_DEAD Domain Proteins in Some Species of Planctomycetes, Verrucomicrobia, Proteobacteria, Nitrospirae and Chlorobi.

    Directory of Open Access Journals (Sweden)

    Olga K Kamneva

    Full Text Available A number of bacteria belonging to the PVC (Planctomycetes-Verrucomicrobia-Chlamydiae super-phylum contain unusual ribosome-bearing intracellular membranes. The evolutionary origins and functions of these membranes are unknown. Some proteins putatively associated with the presence of intracellular membranes in PVC bacteria contain signal peptides. Signal peptides mark proteins for translocation across the cytoplasmic membrane in prokaryotes, and the membrane of the endoplasmic reticulum in eukaryotes, by highly conserved Sec machinery. This suggests that proteins might be targeted to intracellular membranes in PVC bacteria via the Sec pathway. Here, we show that canonical signal peptides are significantly over-represented in proteins preferentially present in PVC bacteria possessing intracellular membranes, indicating involvement of Sec translocase in their cellular targeting. We also characterized Sec proteins using comparative genomics approaches, focusing on the PVC super-phylum. While we were unable to detect unique changes in Sec proteins conserved among membrane-bearing PVC species, we identified (1 SecA ATPase domain re-arrangements in some Planctomycetes, and (2 secondary SecA_DEAD domain proteins in the genomes of some Planctomycetes, Verrucomicrobia, Proteobacteria, Nitrospirae and Chlorobi. This is the first report of potentially duplicated SecA in Gram-negative bacteria. The phylogenetic distribution of secondary SecA_DEAD domain proteins suggests that the presence of these proteins is not related to the occurrence of PVC endomembranes. Further genomic analysis showed that secondary SecA_DEAD domain proteins are located within genomic neighborhoods that also encode three proteins possessing domains specific for the Type I secretion system.

  5. A mechanism for ParB-dependent waves of ParA, a protein related to DNA segregation during cell division in prokaryotes

    DEFF Research Database (Denmark)

    Hunding, Axel; Gerdes, Kenn; Charbon, Gitte Ebersbach

    2003-01-01

    in an autocatalytic process. We discuss this mechanism in relation to recent models for MinDE oscillations in E.coli and to microtubule degradation in mitosis. The study points to an ancestral role for the presented pattern types in generating bipolarity in prokaryotes and eukaryotes.......Prokaryotic plasmids encode partitioning (par) loci involved in segregation of DNA to daughter cells at cell division. A functional fusion protein consisting of Walker-type ParA ATPase and green fluorescent protein (Gfp) oscillates back and forth within nucleoid regions with a wave period of about...

  6. TATA-binding protein and the retinoblastoma gene product bind to overlapping epitopes on c-Myc and adenovirus E1A protein

    NARCIS (Netherlands)

    Hateboer, G.; Timmers, H.T.M.; Rustgi, A.K.; Billaud, Marc; Veer, L.J. Van 't; Bernards, R.A.

    1993-01-01

    Using a protein binding assay, we show that the amino-teminal 204 amino acids of the c-Myc protein interact di y with a key component of the basal p tdon factor TFID, the TATA box-binding protein (TBP). Essentialy the same region of the c-Myc protein alo binds the product of the retinoblatoma

  7. Disease: H01513 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H01513 Retinoblastoma The retinoblastoma is an eye tumor of childhood that arises ...in the retina and represents the most common intraocular malignancy of infancy and childhood. Tumor formatio

  8. Primitive neuroectodermal tumor of the orbit in a 5-year-old girl with microphthalmia

    DEFF Research Database (Denmark)

    Alyahya, Ghassan Ayish Jabur; Heegaard, Steffen; Fledelius, Hans C.

    2000-01-01

    ophthalmology, primitive neuroectodermal tumor (PNET), Ewing's sarcoma, small round-cell tumors, retinoblastoma, medulloepithelioma, microphthalmia, orbitotomy......ophthalmology, primitive neuroectodermal tumor (PNET), Ewing's sarcoma, small round-cell tumors, retinoblastoma, medulloepithelioma, microphthalmia, orbitotomy...

  9. Differentiation and injury-repair signals modulate the interaction of E2F and pRB proteins with novel target genes in keratinocytes.

    Science.gov (United States)

    Chang, Wing Y; Andrews, Joseph; Carter, David E; Dagnino, Lina

    2006-08-01

    E2F transcription factors are central to epidermal morphogenesis and regeneration after injury. The precise nature of E2F target genes involved in epidermal formation and repair has yet to be determined. Identification of these genes is essential to understand how E2F proteins regulate fundamental aspects of epidermal homeostasis and transformation. We have conducted a genome-wide screen using CpG island microarray analysis to identify novel promoters bound by E2F3 and E2F5 in human keratinocytes. We further characterized several of these genes, and determined that multiple E2F and retinoblastoma (pRb) family proteins associate with them in exponentially proliferating cells. We also assessed the effect on E2F and pRb binding to those genes in response to differentiation induced by bone morphogenetic protein-6 (BMP-6), or to activation of repair mechanisms induced by transforming growth factor-beta (TGF-beta). These studies demonstrate promoter- and cytokine-specific changes in binding profiles of E2F and/or pRb family proteins. For example, E2F1, 3, 4 and p107 were recruited to the N-myc promoter in cells treated with BMP-6, whereas E2F1, 3, 4, 5, p107 and p130 were bound to this promoter in the presence of TGF-beta. Functionally, these different interactions resulted in transcriptional repression by BMP-6 and TGF-beta of the N-myc gene, via mechanisms that involved E2F binding to the promoter and association with pRb-family proteins. Thus, multiple combinations of E2F and pRb family proteins may associate with and transcriptionally regulate a given target promoter in response to differentiation and injury-repair stimuli in epidermal keratinocytes.

  10. The PPARα/p16INK4a Pathway inhibits Vascular Smooth Muscle Cell Proliferation by repressing Cell Cycle-dependent Telomerase Activation

    Science.gov (United States)

    Gizard, Florence; Nomiyama, Takashi; Zhao, Yue; Findeisen, Hannes M.; Heywood, Elizabeth B.; Jones, Karrie L.; Staels, Bart; Bruemmer, Dennis

    2009-01-01

    Peroxisome Proliferator-Activated Receptor (PPAR) α, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARα activation suppresses G1→S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16INK4a (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARα is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARα activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect which was dependent on p16. The inhibition of cell proliferation by PPARα activation was lost in VSMC following TERT overexpression or knock-down, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARα. Finally, we demonstrate that PPARα agonists suppress telomerase activation during the proliferative response following vascular injury indicating that these findings are applicable in vivo. In concert, these results demonstrate that the anti-proliferative effects of PPARα in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade. PMID:18818403

  11. 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?...

  12. Interaction of the heterotrimeric G protein alpha subunit SSG-1 of Sporothrix schenckii with proteins related to stress response and fungal pathogenicity using a yeast two-hybrid assay

    Directory of Open Access Journals (Sweden)

    González-Méndez Ricardo

    2010-12-01

    Full Text Available Abstract Background Important biological processes require selective and orderly protein-protein interactions at every level of the signalling cascades. G proteins are a family of heterotrimeric GTPases that effect eukaryotic signal transduction through the coupling of cell surface receptors to cytoplasmic effector proteins. They have been associated with growth and pathogenicity in many fungi through gene knock-out studies. In Sporothrix schenckii, a pathogenic, dimorphic fungus, we previously identified a pertussis sensitive G alpha subunit, SSG-1. In this work we inquire into its interactions with other proteins. Results Using the yeast two-hybrid technique, we identified protein-protein interactions between SSG-1 and other important cellular proteins. The interactions were corroborated using co-immuneprecipitation. Using these techniques we identified a Fe/Mn superoxide dismutase (SOD, a glyceraldehyde-3-P dehydrogenase (GAPDH and two ion transport proteins, a siderophore-iron transporter belonging to the Major Facilitator Superfamily (MFS and a divalent-cation transporter of the Nramp (natural resistance-associated macrophage protein family as interacting with SSG-1. The cDNA's encoding these proteins were sequenced and bioinformatic macromolecular sequence analyses were used for the correct classification and functional assignment. Conclusions This study constitutes the first report of the interaction of a fungal G alpha inhibitory subunit with SOD, GAPDH, and two metal ion transporters. The identification of such important proteins as partners of a G alpha subunit in this fungus suggests possible mechanisms through which this G protein can affect pathogenicity and survival under conditions of environmental stress or inside the human host. The two ion transporters identified in this work are the first to be reported in S. schenckii and the first time they are identified as interacting with fungal G protein alpha subunits. The association of G protein alpha subunits to transport molecules reinforces the role of G proteins in the response to environmental signals and also highlights the involvement of fungal G protein alpha subunits in nutrient sensing in S. schenckii. These interactions suggest that these permeases could function as transceptors for G proteins in fungi.

  13. Insights into the Molecular Mechanisms of Alzheimer’s and Parkinson’s Diseases with Molecular Simulations: Understanding the Roles of Artificial and Pathological Missense Mutations in Intrinsically Disordered Proteins Related to Pathology

    Directory of Open Access Journals (Sweden)

    Orkid Coskuner-Weber

    2018-01-01

    Full Text Available Amyloid-β and α-synuclein are intrinsically disordered proteins (IDPs, which are at the center of Alzheimer’s and Parkinson’s disease pathologies, respectively. These IDPs are extremely flexible and do not adopt stable structures. Furthermore, both amyloid-β and α-synuclein can form toxic oligomers, amyloid fibrils and other type of aggregates in Alzheimer’s and Parkinson’s diseases. Experimentalists face challenges in investigating the structures and thermodynamic properties of these IDPs in their monomeric and oligomeric forms due to the rapid conformational changes, fast aggregation processes and strong solvent effects. Classical molecular dynamics simulations complement experiments and provide structural information at the atomic level with dynamics without facing the same experimental limitations. Artificial missense mutations are employed experimentally and computationally for providing insights into the structure-function relationships of amyloid-β and α-synuclein in relation to the pathologies of Alzheimer’s and Parkinson’s diseases. Furthermore, there are several natural genetic variations that play a role in the pathogenesis of familial cases of Alzheimer’s and Parkinson’s diseases, which are related to specific genetic defects inherited in dominant or recessive patterns. The present review summarizes the current understanding of monomeric and oligomeric forms of amyloid-β and α-synuclein, as well as the impacts of artificial and pathological missense mutations on the structural ensembles of these IDPs using molecular dynamics simulations. We also emphasize the recent investigations on residual secondary structure formation in dynamic conformational ensembles of amyloid-β and α-synuclein, such as β-structure linked to the oligomerization and fibrillation mechanisms related to the pathologies of Alzheimer’s and Parkinson’s diseases. This information represents an important foundation for the successful and efficient drug design studies.

  14. Translational Hyperactivity as a Target for Prostate Cancer

    National Research Council Canada - National Science Library

    Terrian, David

    2003-01-01

    ... expression for PKCepsilon (PKCs) Molecular and biochemical approaches are being employed to specifically determine how PKCs activity influences reactivation of the translational repressor protein retinoblastoma (Rb...

  15. 2-Methoxy-4-vinylphenol can induce cell cycle arrest by blocking the hyper-phosphorylation of retinoblastoma protein in benzo[a]pyrene-treated NIH3T3 cells

    International Nuclear Information System (INIS)

    Jeong, Jin Boo; Jeong, Hyung Jin

    2010-01-01

    Research highlights: → 2M4VP activated the expression of p21 and p15 protein, and down-regulated the expression of cyclin D1 and cyclin E. → 2M4VP inhibited hyper-phosphorylation of Rb protein. → 2M4VP induced cell cycle arrest from G1 to S. → 2M4VP inhibited hyper-proliferation of the cells in BaP-treated cells. → 2M4VP induces growth arrest of BaP-treated cells by blocking hyper-phosphorylation of Rb via regulating the expression of cell cycle-related proteins. -- Abstract: Benzo[a]pyrene (BaP) is an environment carcinogen that can enhance cell proliferation by disturbing the signal transduction pathways in cell cycle regulation. In this study, the effects of 2M4VP on cell proliferation, cell cycle and cell cycle regulatory proteins were studied in BaP-treated NIH 3T3 cells to establish the molecular mechanisms of 2M4VP as anti-proliferative agents. 2M4VP exerted a dose-dependent inhibitory effect on cell growth correlated with a G1 arrest. Analysis of G1 cell cycle regulators expression revealed 2M4VP increased expression of CDK inhibitor, p21Waf1/Cip1 and p15 INK4b, decreased expression of cyclin D1 and cyclin E, and inhibited kinase activities of CDK4 and CDK2. However, 2M4VP did not affect the expression of CDK4 and CDK2. Also, 2M4VP inhibited the hyper-phosphorylation of Rb induced by BaP. Our results suggest that 2M4VP induce growth arrest of BaP-treated NIH 3T3 cells by blocking the hyper-phosphorylation of Rb via regulating the expression of cell cycle-related proteins.

  16. 2-Methoxy-4-vinylphenol can induce cell cycle arrest by blocking the hyper-phosphorylation of retinoblastoma protein in benzo[a]pyrene-treated NIH3T3 cells

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, Jin Boo [Bioresource Sciences, Andong National University, Andong 760749 (Korea, Republic of); Jeong, Hyung Jin, E-mail: jhj@andong.ac.kr [Bioresource Sciences, Andong National University, Andong 760749 (Korea, Republic of)

    2010-10-01

    Research highlights: {yields} 2M4VP activated the expression of p21 and p15 protein, and down-regulated the expression of cyclin D1 and cyclin E. {yields} 2M4VP inhibited hyper-phosphorylation of Rb protein. {yields} 2M4VP induced cell cycle arrest from G1 to S. {yields} 2M4VP inhibited hyper-proliferation of the cells in BaP-treated cells. {yields} 2M4VP induces growth arrest of BaP-treated cells by blocking hyper-phosphorylation of Rb via regulating the expression of cell cycle-related proteins. -- Abstract: Benzo[a]pyrene (BaP) is an environment carcinogen that can enhance cell proliferation by disturbing the signal transduction pathways in cell cycle regulation. In this study, the effects of 2M4VP on cell proliferation, cell cycle and cell cycle regulatory proteins were studied in BaP-treated NIH 3T3 cells to establish the molecular mechanisms of 2M4VP as anti-proliferative agents. 2M4VP exerted a dose-dependent inhibitory effect on cell growth correlated with a G1 arrest. Analysis of G1 cell cycle regulators expression revealed 2M4VP increased expression of CDK inhibitor, p21Waf1/Cip1 and p15 INK4b, decreased expression of cyclin D1 and cyclin E, and inhibited kinase activities of CDK4 and CDK2. However, 2M4VP did not affect the expression of CDK4 and CDK2. Also, 2M4VP inhibited the hyper-phosphorylation of Rb induced by BaP. Our results suggest that 2M4VP induce growth arrest of BaP-treated NIH 3T3 cells by blocking the hyper-phosphorylation of Rb via regulating the expression of cell cycle-related proteins.

  17. Programa nacional de prevención y consejería genética del retinoblastoma mediante detección de mutaciones en el gen RB.

    Directory of Open Access Journals (Sweden)

    H. Frayle

    2001-07-01

    una la doble mutación inactivante del gen Rb, exclusivamente somática en los esporádicos y germinal más somática en los hereditarios. Esta investigacin tuvo como objetivo caracterizar las mutaciones en el gen Rb mediante secuenciación directa y evaluar su utilidad en la consejería genética.

  18. Reprogramming of the Ovarian Tumor Stroma by Activation of a Biomechanical ECM Switch

    Science.gov (United States)

    2015-07-01

    which includes P130Cas. Phosphorylation of P130Cas within both its SH2 and SH3 domains facilitates protein-protein interactions that can...switch and Erk activation which may collectively promote stromal cell accumulation. While multiple protein kinases including members of the Src...family kinases as well as Abl are thought to contribute to the phosphorylation of P130Cas, the precise molecular mechanism by which cellular interactions

  19. Journal of Biosciences | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Retinoblastoma is the most frequently occurring tumour in the eyes in early childhood. Novel targets that areimportant for the diagnosis or ... In summary,our findings indicate that HOTAIR may play important roles in retinoblastoma progression via Notch pathway.HOTAIR has the potential to enhance the development of ...

  20. Journal of Genetics | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Effective counselling and management of retinoblastoma families using genetic information is presently practised in many parts of the world. We studied histopathological, chromosomal and molecular-genetic data of two retinoblastoma patients from India. The two patients, one with bilateral and the other with unilateral ...

  1. Pattern Of Paediatric Malignancies Seen At The Radiotherapy ...

    African Journals Online (AJOL)

    23 tumour types were seen with retinoblastoma accounting for about 45% of all the patients reviewed. Burkitt\\'s lymphoma accounted for only about 2.5%. Conclusion: Retinoblastoma, nephroblastoma, intracranial malignancies and rhabdomyosarcoma are the tumours most commonly seen at the Radiotherapy Department ...

  2. Cancer genetics education in a low- to middle-income country: evaluation of an interactive workshop for clinicians in Kenya.

    Directory of Open Access Journals (Sweden)

    Jessica A Hill

    Full Text Available Clinical genetic testing is becoming an integral part of medical care for inherited disorders. While genetic testing and counseling are readily available in high-income countries, in low- and middle-income countries like Kenya genetic testing is limited and genetic counseling is virtually non-existent. Genetic testing is likely to become widespread in Kenya within the next decade, yet there has not been a concomitant increase in genetic counseling resources. To address this gap, we designed an interactive workshop for clinicians in Kenya focused on the genetics of the childhood eye cancer retinoblastoma. The objectives were to increase retinoblastoma genetics knowledge, build genetic counseling skills and increase confidence in those skills.The workshop was conducted at the 2013 Kenyan National Retinoblastoma Strategy meeting. It included a retinoblastoma genetics presentation, small group discussion of case studies and genetic counseling role-play. Knowledge was assessed by standardized test, and genetic counseling skills and confidence by questionnaire.Knowledge increased significantly post-workshop, driven by increased knowledge of retinoblastoma causative genetics. One-year post-workshop, participant knowledge had returned to baseline, indicating that knowledge retention requires more frequent reinforcement. Participants reported feeling more confident discussing genetics with patients, and had integrated more genetic counseling into patient interactions.A comprehensive retinoblastoma genetics workshop can increase the knowledge and skills necessary for effective retinoblastoma genetic counseling.

  3. Cancer genetics education in a low- to middle-income country: evaluation of an interactive workshop for clinicians in Kenya.

    Science.gov (United States)

    Hill, Jessica A; Lee, Su Yeon; Njambi, Lucy; Corson, Timothy W; Dimaras, Helen

    2015-01-01

    Clinical genetic testing is becoming an integral part of medical care for inherited disorders. While genetic testing and counseling are readily available in high-income countries, in low- and middle-income countries like Kenya genetic testing is limited and genetic counseling is virtually non-existent. Genetic testing is likely to become widespread in Kenya within the next decade, yet there has not been a concomitant increase in genetic counseling resources. To address this gap, we designed an interactive workshop for clinicians in Kenya focused on the genetics of the childhood eye cancer retinoblastoma. The objectives were to increase retinoblastoma genetics knowledge, build genetic counseling skills and increase confidence in those skills. The workshop was conducted at the 2013 Kenyan National Retinoblastoma Strategy meeting. It included a retinoblastoma genetics presentation, small group discussion of case studies and genetic counseling role-play. Knowledge was assessed by standardized test, and genetic counseling skills and confidence by questionnaire. Knowledge increased significantly post-workshop, driven by increased knowledge of retinoblastoma causative genetics. One-year post-workshop, participant knowledge had returned to baseline, indicating that knowledge retention requires more frequent reinforcement. Participants reported feeling more confident discussing genetics with patients, and had integrated more genetic counseling into patient interactions. A comprehensive retinoblastoma genetics workshop can increase the knowledge and skills necessary for effective retinoblastoma genetic counseling.

  4. Gametophyte differentiation and imprinting control in plants: Crosstalk between RBR and chromatin.

    Science.gov (United States)

    Johnston, Amal J; Gruissem, Wilhelm

    2009-01-01

    The Retinoblastoma (pRb) pathway has been implicated as a convergent regulatory unit in the control of cell cycle and disease. We have shown that a crosstalk between RETINOBLASTOMA RELATED (RBR), the Arabidopsis homologue of pRb, and the genes encoding proteins of the chromatin complexes involved in DNA or histone methylation, controls gametophytic and post-fertilization differentiation events and a subset of imprinting effects. We describe here a plausible model that incorporates several components of the plant Retinoblastoma pathway, thus offering a novel paradigm that merges the traditional cell cycle and the chromatin components in the control of cell differentiation and imprinting.

  5. to view fulltext PDF

    Indian Academy of Sciences (India)

    Prakash

    Mutation of the Rb-coding gene in sporadic cancers is rare. (with the exception of ..... rapid phosphorylation of serine 795 of the retinoblastoma gene product in ... tumor suppressor induces apoptosis protease-activating factor-1 dependent and.

  6. Is advanced paternal age a health risk for the offspring?

    DEFF Research Database (Denmark)

    Andersen, Anne-Marie Nybo; Urhoj, Stine Kjaer

    2017-01-01

    consistently associated with increased paternal age are stillbirths, musculo-skeletal syndromes, cleft palate, acute lymphoblastic leukemia and retinoblastoma, and neurodevelopmental disorders in the autism spectrum and schizophrenia. Finally, we consider the public health impact of the increasing paternal age...

  7. Oncogenic Functions of cdK4 and cdK6

    National Research Council Canada - National Science Library

    Grossel, Martha

    1999-01-01

    .... The retinoblastoma protein (pRb) is one negative regulator of cellular proliferation. Many breast cancers retain functional pRb and therefore must use other mechanisms to alleviate the tumor-suppressive function of pRb...

  8. The Role of RB in the Therapeutic Response of Breast Cancer

    National Research Council Canada - National Science Library

    Bosco, Emily E

    2005-01-01

    The retinoblastoma tumor suppressor protein (RB) participates in the growth regulation of breast cancer cells by controlling G-S phase progression and mediating cell cycle arrest in response to anti-mitogenic signaling...

  9. BRCA1: RB Interaction in Breast Cancer Suppression

    National Research Council Canada - National Science Library

    Fan, Saijun

    2000-01-01

    .... Recent studies suggest that the tumor suppressor activity of BRCAl is due, in part, to physical/functional interactions with other tumor suppressors, including p53 and the retinoblastoma (RB) protein...

  10. BRCA1: RB Interaction in Breast Cancer Suppression

    National Research Council Canada - National Science Library

    Fan, Saijun

    2001-01-01

    .... Recent studies suggest that the tumor suppressor activity of BRCAl is due, in part, to physical/functional interactions with other tumor suppressors, including p53 and the retinoblastoma (RB) protein...

  11. Long non-coding RNA HOTAIR regulates proliferation and invasion ...

    Indian Academy of Sciences (India)

    2016-09-22

    Sep 22, 2016 ... Retinoblastoma (Rb) is an eye cancer that originates from the retina, and the most ..... receptor, and Jagged1, the most common ligand in Notch signalling .... urothelial bladder cancer (UBC) patients can serve as bio- markers ...

  12. Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors

    Science.gov (United States)

    2018-05-15

    Ewing's Sarcoma; Osteosarcoma; Astrocytoma; Atypical Teratoid/Rhabdoid Tumor; Ependymoma; Germ Cell Tumor; Glioma; Medulloblastoma; Rhabdoid Tumor; Retinoblastoma; Clear Cell Sarcoma; Renal Cell Carcinoma; Wilms Tumor; Hepatoblastoma; Neuroblastoma; Rhabdomyosarcoma

  13. US and MRI of pediatric ocular masses with histopathological correlation

    Energy Technology Data Exchange (ETDEWEB)

    Brennan, Rachel C. [St. Jude Children' s Research Hospital, Department of Oncology, Memphis, TN (United States); University of Tennessee Health Sciences Center, College of Medicine, Department of Ophthalmology, Memphis, TN (United States); University of Tennessee Health Sciences Center, College of Medicine, Department of Pediatrics, Memphis, TN (United States); Wilson, Matthew W. [St. Jude Children' s Research Hospital, Departments of Surgery and Pathology, Memphis, TN (United States); University of Tennessee Health Sciences Center, College of Medicine, Department of Ophthalmology, Memphis, TN (United States); Kaste, Sue; McCarville, M.B. [St. Jude Children' s Research Hospital, Department of Radiological Sciences, Memphis, TN (United States); University of Tennessee Health Sciences Center, College of Medicine, Department of Radiology, Memphis, TN (United States); Helton, Kathleen J. [St. Jude Children' s Research Hospital, Department of Radiological Sciences, Memphis, TN (United States)

    2012-06-15

    We review our experience with unusual ocular pathologies, some mimicking retinoblastoma, that were referred to our institution during the past two decades. After presenting the imaging anatomy of the normal eye, we discuss pertinent clinical and pathological features, and illustrate the US and MRI appearance of retinoblastoma, medulloepithelioma, uveal melanoma, persistent fetal vasculature, Coats disease, corneal dermoid, retinal dysplasia and toxocara granuloma. Features useful in discriminating among these entities are emphasized. (orig.)

  14. US and MRI of pediatric ocular masses with histopathological correlation

    International Nuclear Information System (INIS)

    Brennan, Rachel C.; Wilson, Matthew W.; Kaste, Sue; McCarville, M.B.; Helton, Kathleen J.

    2012-01-01

    We review our experience with unusual ocular pathologies, some mimicking retinoblastoma, that were referred to our institution during the past two decades. After presenting the imaging anatomy of the normal eye, we discuss pertinent clinical and pathological features, and illustrate the US and MRI appearance of retinoblastoma, medulloepithelioma, uveal melanoma, persistent fetal vasculature, Coats disease, corneal dermoid, retinal dysplasia and toxocara granuloma. Features useful in discriminating among these entities are emphasized. (orig.)

  15. DNA-based detection of chromosome deletion and amplification: diagnostic and mechanistic significance

    International Nuclear Information System (INIS)

    Latt, S.A.; Lalande, M.; Donlon, T.

    1986-01-01

    This paper describes a few of the many possible examples in which application of a molecular cytogenetic approach can ultimately lead to a new, important understanding about the statics and dynamics of human chromosome structure. In the case of retinoblastoma, cytological observations of deletions and linkage analysis have positioned the retinoblastoma locus to bank 13q14. This locus is grossly deleted in some spontaneous tumors. It is still necessary to locate more precisely and characterize the nature of the retinoblastoma locus, as well as the basis for the heterogeneity in deletions removing one copy of this locus. One is left with the possibility that those deletions that may be observed cytologically reflect but the tip of the iceberg of deletions; detection of others may require molecular probes. A related question is the nature of the DNA sequences at the deletion boundaries and the role they play in promoting these deletions

  16. Lactate dehydrogenase (LDH isoenzymes patterns in ocular tumours

    Directory of Open Access Journals (Sweden)

    Singh Rajendra

    1991-01-01

    Full Text Available Estimation of lactate dehydrogenase (LDH isoenzymes in the serum and aqueous humor was carried out in 15 cases of benign ocular tumour, 15 cases of malignant tumor and 15 normal cases. Cases of both sexes aged between 1 year and 75 years were included. LDH, isoenzymes specially LDH4 and LDH5 are higher and LDH1 and LDH2 lower in sera of patients with malignant tumor specially retinoblastoma as compared to benign tumor cases and control cases. LDH isoenzymes in aqueous humor are significantly higher and show a characteristic pattern in retinoblastoma cases, the concentration was presumably too low in the control, malignant tumor other than retinoblastoma and benign tumor cases as its fractionation was not possible.

  17. Fluorescence angiography in retinal tumours

    International Nuclear Information System (INIS)

    Fuhrmann, M.

    1980-01-01

    On the basis of the available photographic material the results of fluorescein angiography are reported in 4 cases of retinoblastoma and 3 cases of Bourneville's disease. The clinical diagnosis of retinoblastoma was confirmed histologically in all cases since the first eye had been removed for the same reason previously. One child had not yet been treated, and in 3 cases radioactive isotopes were used in the treatment. In the group of phacomatosis the patients had only periodical outpatient examinations. The importance of this angiography in the diagnosis and follow-up of these diseases is stressed. (author)

  18. Fluorescence angiography in retinal tumours

    Energy Technology Data Exchange (ETDEWEB)

    Fuhrmann, M [Staedtisches Klinikum Berlin-Buch (German Democratic Republic)

    1980-01-01

    On the basis of the available photographic material the results of fluorescein angiography are reported in 4 cases of retinoblastoma and 3 cases of Bourneville's disease. The clinical diagnosis of retinoblastoma was confirmed histologically in all cases since the first eye had been removed for the same reason previously. One child had not yet been treated, and in 3 cases radioactive isotopes were used in the treatment. In the group of phacomatosis the patients had only periodical outpatient examinations. The importance of this angiography in the diagnosis and follow-up of these diseases is stressed.

  19. Afican Health Sciences Vol 9 No 4.pmd

    African Journals Online (AJOL)

    Administrator

    A delay in the diagnosis of retinoblastoma is not uncommon particularly in unilateral cases presenting with subtle signs like strabismus or masquerading features such as hyphaema, uveitis or secondary glaucoma 17, 18.In a study by Wirix et al in Belgium, a child was found to have been followed up for strabismus for four.

  20. Coats' disease in Tanzania: first case report and literature review ...

    African Journals Online (AJOL)

    Background: Coats' disease is an exudative retinal detachment with vascular telangiectasis occurring mostly in male children, the age group most affected by retinoblastoma. Objectives: To compare the differential diagnoses of Coats' disease. To establish recommendation to early disease detection. Materials and Methods:

  1. A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F

    DEFF Research Database (Denmark)

    Helin, K; Lees, J A; Vidal, M

    1992-01-01

    The retinoblastoma protein (pRB) plays an important role in the control of cell proliferation, apparently by binding to and regulating cellular transcription factors such as E2F. Here we describe the characterization of a cDNA clone that encodes a protein with properties of E2F. This clone, RBP3...

  2. DIDACTIC COURSES

    African Journals Online (AJOL)

    2016-11-04

    Nov 4, 2016 ... Pan retinal photocoagulation (PRP) for proliferative diabetic retinopathy, sickle cell retinopathy, and central retinal vein occlusion. •. Management of early retinoblastoma. •. Cyclo-photocoagulation which is increasingly being utilized in the overall management of POAG. By Micropulse, it is meant that only a ...

  3. Author Details

    African Journals Online (AJOL)

    Itoua, C. Vol 92, No 4 (2015) - Articles Ophthalmoplegia, Dysphonia and Tetraparesis Due to Guillain-Barre's Syndrome in Pregnant at 14 Weeks of Gestation: Case Report Abstract · Vol 92, No 5 (2015) - Articles Retinoblastoma: Assessing the Level of Knowledge of Tumour By Midwives in Brazzaville Abstract · Vol 92, No 6 ...

  4. Childhood Cancer Genomics (PDQ®)—Health Professional Version

    Science.gov (United States)

    Genomic findings have been useful in the identification of subsets of patients that have distinct biological features and clinical characteristics (such as prognosis) for some pediatric cancers. Learn about the genomic alterations associated with central nervous system, leukemia, lymphoma, liver, sarcoma, neuroblastoma, retinoblastoma, melanoma, kidney, and thyroid cancers in children in this comprehensive summary for clinicians.

  5. E2F1 is crucial for E2F-dependent apoptosis

    DEFF Research Database (Denmark)

    Lazzerini Denchi, Eros; Helin, Kristian

    2005-01-01

    Loss of the retinoblastoma protein, pRB, leads to apoptosis, and several results have suggested that this is dependent on the E2F transcription factors. However, so far, the ability of the different E2F family members to contribute to apoptosis is controversial. Here, we show that ectopic...

  6. 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...

  7. Aberrations of the p53 pathway components p53, MDM2 and CDKN2A appear independent in diffuse large B cell lymphoma

    DEFF Research Database (Denmark)

    Møller, Michael Boe; Ino, Y; Gerdes, A M

    1999-01-01

    The two gene products of the CDKN2A gene, p16 and p19ARF, have recently been linked to each of two major tumour suppressor pathways in human carcinogenesis, the RB1 pathway and the p53 pathway. p16 inhibits the phosphorylation of the retinoblastoma gene product by cyclin D-dependent kinases...

  8. Constitutive Cdk2 activity promotes aneuploidy while altering the spindle assembly and tetraploidy checkpoints

    DEFF Research Database (Denmark)

    Jahn, Stephan C; Corsino, Patrick E; Davis, Bradley J

    2013-01-01

    instability. Expression of these complexes in the MCF10A cell line leads to retinoblastoma protein (Rb) hyperphosphorylation, a subsequent increase in proliferation rate, and increased expression of the spindle assembly checkpoint protein Mad2. This results in a strengthening of the spindle assembly...

  9. All-trans retinoic acid increases oxidative metabolism in mature adipocytes

    DEFF Research Database (Denmark)

    Mercader, Josep; Madsen, Lise; Felipe, Francisco

    2007-01-01

    ), and to an increased expression of proteins favoring fat oxidation (peroxisome proliferator-activated receptor gamma coactivator-1alpha, uncoupling protein 2, fasting-induced adipose factor, enzymes of mitochondrial fatty acid oxidation). These changes paralleled inactivation of the retinoblastoma protein and were...

  10. Deregulation of the RB pathway in human testicular germ cell tumours

    DEFF Research Database (Denmark)

    Bartkova, Jirina; Lukas, Claudia; Sørensen, Claus S

    2003-01-01

    Deregulation of the RB pathway is shared by most human malignancies. Components upstream of the retinoblastoma tumour suppressor (pRB), namely the INK4 family of cyclin-dependent kinase (CDK) inhibitors, the D-type cyclins, their partner kinases CDK4/CDK6, and pRB as their critical substrate...

  11. Growth suppression by transforming growth factor beta 1 of human small-cell lung cancer cell lines is associated with expression of the type II receptor

    DEFF Research Database (Denmark)

    Nørgaard, P; Damstrup, L; Rygaard, K

    1994-01-01

    was observed in two cell lines expressing only type III receptor and in TGF-beta-r negative cell lines. In two cell lines expressing all three receptor types, growth suppression was accompanied by morphological changes. To evaluate the possible involvement of the retinoblastoma protein (pRb) in mediating...

  12. Conditional E2F1 activation in transgenic mice causes testicular atrophy and dysplasia mimicking human CIS

    DEFF Research Database (Denmark)

    Agger, Karl; Santoni-Rugiu, Eric; Holmberg, Christian

    2005-01-01

    E2F1 is a crucial downstream effector of the retinoblastoma protein (pRB) pathway. To address the consequences of short-term increase in E2F1 activity in adult tissues, we generated transgenic mice expressing the human E2F1 protein fused to the oestrogen receptor (ER) ligand-binding domain...

  13. Hvid pupil hos børn kan være tegn på alvorlig øjensygdom

    DEFF Research Database (Denmark)

    Hansen, Michael Stormly; Ostri, Christoffer

    2015-01-01

    A whitish pupillary reflex (leukocoria) indicates abnormal reflection from intraocular pathology. In a child, leukocoria may be a sign of serious and even life-threatening eye disease (retinoblastoma), but the most common cause is congenital cataract. Both diagnoses require immediate referral...

  14. Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex

    DEFF Research Database (Denmark)

    Lukas, C; Sørensen, Claus Storgaard; Kramer, E

    1999-01-01

    In mammalian somatic-cell cycles, progression through the G1-phase restriction point and initiation of DNA replication are controlled by the ability of the retinoblastoma tumour-suppressor protein (pRb) family to regulate the E2F/DP transcription factors. Continuing transcription of E2F target...

  15. Phosphorylation of pRb by cyclin D kinase is necessary for development of cardiac hypertrophy

    DEFF Research Database (Denmark)

    Hinrichsen, Rebecca; Hansen, A.H.; Haunsø, S.

    2008-01-01

    /6-phosphorylated retinoblastoma protein (pRb) during hypertrophy and expression of an unphosphorylatable pRb mutant impaired hypertrophic growth in cardiomyocytes. Transcription factor E2F was activated by hypertrophic elicitors but activation was impaired by pharmacological inhibition of cyclin D-cdk4...

  16. Expression of cell cycle regulating factor mRNA in small cell lung cancer xenografts

    DEFF Research Database (Denmark)

    Krarup, M; Poulsen, H S; Spang-Thomsen, M

    1998-01-01

    and CDK6 when in vitro and in vivo data were compared. Two of the cell lines that express the retinoblastoma (Rb) protein had no sign of a deregulated Rb pathway but further studies at the protein level are necessary to demonstrate whether these two cell lines should have a normal Rb pathway or whether...

  17. Characterization of E2F8, a novel E2F-like cell-cycle regulated repressor of E2F-activated transcription

    DEFF Research Database (Denmark)

    Christensen, Jesper; Cloos, Paul; Toftegaard, Ulla

    2005-01-01

    The E2F family of transcription factors are downstream effectors of the retinoblastoma protein, pRB, pathway and are essential for the timely regulation of genes necessary for cell-cycle progression. Here we describe the characterization of human and murine E2F8, a new member of the E2F family...

  18. High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer

    DEFF Research Database (Denmark)

    Alves, Carla Maria Lourenco; Elias, Daniel; Lyng, Maria B

    2016-01-01

    expression impaired fulvestrant-resistant cell growth and induced apoptosis. Treatment with palbociclib re-sensitized fulvestrant-resistant cells to fulvestrant through alteration of retinoblastoma protein phosphorylation. High CDK6 levels in metastatic samples from two independent cohorts of breast cancer...

  19. Cyclin E-induced S phase without activation of the pRb/E2F pathway

    DEFF Research Database (Denmark)

    Lukas, J; Herzinger, T; Hansen, Klaus

    1997-01-01

    In cells of higher eukaryotes, cyclin D-dependent kinases Cdk4 and Cdk6 and, possibly, cyclin E-dependent Cdk2 positively regulate the G1- to S-phase transition, by phosphorylating the retinoblastoma protein (pRb), thereby releasing E2F transcription factors that control S-phase genes. Here we...

  20. E2F-HDAC complexes negatively regulate the tumor suppressor gene ARHI in breast cancer

    DEFF Research Database (Denmark)

    Lu, Z; Luo, R Z; Peng, H

    2006-01-01

    . While the retinoblastoma protein, pRB, alone had no effect on ARHI promoter activity, repression by E2F1, but not E2F4, was enhanced by the coexpression of pRB. Taken together, our results suggest that E2F1, 4 and their complexes with HDAC play an important role in downregulating the expression...