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Sample records for distinct molecular subtypes

  1. Identification of distinct molecular subtypes of uterine carcinosarcoma.

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    An, Yang; Wang, Haojie; Jie, Jingyao; Tang, Yitai; Zhang, Weijuan; Ji, Shaoping; Guo, Xiangqian

    2017-02-28

    Uterine carcinosarcoma (UCS) is a rare but lethal neoplasm with high metastasis and recurrence rate, and to date, no molecular classification of UCS has been defined to achieve targeted therapies. In this study, we identified two distinct molecular subtypes of UCS with distinct gene expression patterns and clinicopathologic characteristics. Subtype I UCS recapitulates low-grade UCS, in contrast subtype II UCS represents high-grade UCS with higher tumor invasion rate and tumor weight. Interestingly, subtype I UCS is characterized by cell adhesion and apoptosis pathways, whereas genes over-expressed in subtype II UCS are more involved in myogenesis/muscle development. We also proposed certain potential subtype specific therapeutic targets, such as SYK (spleen tyrosine kinase) for subtype I and cell-cycle proteins for subtype II. Our findings provide a better recognition of UCS molecular subtypes and subtype specific oncogenesis mechanisms, and can help develop more specific targeted treatment options for these tumors.

  2. Distinct molecular features of different macroscopic subtypes of colorectal neoplasms.

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    Kenichi Konda

    Full Text Available Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs.We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI] and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers alterations in 158 CRNs including 56 polypoid neoplasms (PNs, 25 granular type laterally spreading tumors (LST-Gs, 48 non-granular type LSTs (LST-NGs, 19 depressed neoplasms (DNs and 10 small flat-elevated neoplasms (S-FNs on the basis of macroscopic appearance.S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs (P<0.001. By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively (P<0.007. We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively (P<0.005. Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05. PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41.We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.

  3. Distinct Molecular Features of Different Macroscopic Subtypes of Colorectal Neoplasms

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    Konda, Kenichi; Konishi, Kazuo; Yamochi, Toshiko; Ito, Yoichi M.; Nozawa, Hisako; Tojo, Masayuki; Shinmura, Kensuke; Kogo, Mari; Katagiri, Atsushi; Kubota, Yutaro; Muramoto, Takashi; Yano, Yuichiro; Kobayashi, Yoshiya; Kihara, Toshihiro; Tagawa, Teppei; Makino, Reiko; Takimoto, Masafumi; Imawari, Michio; Yoshida, Hitoshi

    2014-01-01

    Background Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). Methods We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. Results S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). Conclusion We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal

  4. Distinct molecular subtypes of uterine leiomyosarcoma respond differently to chemotherapy treatment.

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    An, Yang; Wang, Shuzhen; Li, Songlin; Zhang, Lulu; Wang, Dayong; Wang, Haojie; Zhu, Shibai; Zhu, Wan; Li, Yongqiang; Chen, Wenwu; Ji, Shaoping; Guo, Xiangqian

    2017-09-11

    Uterine leiomyosarcoma (ULMS) is an aggressive form of soft tissue tumors. The molecular heterogeneity and pathogenesis of ULMS are not well understood. Expression profiling data were used to determine the possibility and optimal number of ULMS molecular subtypes. Next, clinicopathological characters and molecular pathways were analyzed in each subtype to prospect the clinical applications and progression mechanisms of ULMS. Two distinct molecular subtypes of ULMS were defined based on different gene expression signatures. Subtype I ULMS recapitulated low-grade ULMS, the gene expression pattern of which resembled normal smooth muscle cells, characterized by overexpression of smooth muscle function genes such as LMOD1, SLMAP, MYLK, MYH11. In contrast, subtype II ULMS recapitulated high-grade ULMS with higher tumor weight and invasion rate, and was characterized by overexpression of genes involved in the pathway of epithelial to mesenchymal transition and tumorigenesis, such as CDK6, MAPK13 and HOXA1. We identified two distinct molecular subtypes of ULMS responding differently to chemotherapy treatment. Our findings provide a better understanding of ULMS intrinsic molecular subtypes, and will potentially facilitate the development of subtype-specific diagnosis biomarkers and therapy strategies for these tumors.

  5. Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities.

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    Itakura, Haruka; Achrol, Achal S; Mitchell, Lex A; Loya, Joshua J; Liu, Tiffany; Westbroek, Erick M; Feroze, Abdullah H; Rodriguez, Scott; Echegaray, Sebastian; Azad, Tej D; Yeom, Kristen W; Napel, Sandy; Rubin, Daniel L; Chang, Steven D; Harsh, Griffith R; Gevaert, Olivier

    2015-09-02

    Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic "clusters" emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters--pre-multifocal, spherical, and rim-enhancing, names reflecting their image features--were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM. Copyright © 2015, American Association for the Advancement of Science.

  6. Molecular subtypes of Alzheimer's disease.

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    Di Fede, Giuseppe; Catania, Marcella; Maderna, Emanuela; Ghidoni, Roberta; Benussi, Luisa; Tonoli, Elisa; Giaccone, Giorgio; Moda, Fabio; Paterlini, Anna; Campagnani, Ilaria; Sorrentino, Stefano; Colombo, Laura; Kubis, Adriana; Bistaffa, Edoardo; Ghetti, Bernardino; Tagliavini, Fabrizio

    2018-02-19

    Protein misfolding and aggregation is a central feature of several neurodegenerative disorders including Alzheimer's disease (AD), in which assemblies of amyloid β (Aβ) peptides accumulate in the brain in the form of parenchymal and/or vascular amyloid. A widely accepted concept is that AD is characterized by distinct clinical and neuropathological phenotypes. Recent studies revealed that Aβ assemblies might have structural differences among AD brains and that such pleomorphic assemblies can correlate with distinct disease phenotypes. We found that in both sporadic and inherited forms of AD, amyloid aggregates differ in the biochemical composition of Aβ species. These differences affect the physicochemical properties of Aβ assemblies including aggregation kinetics, resistance to degradation by proteases and seeding ability. Aβ-amyloidosis can be induced and propagated in animal models by inoculation of brain extracts containing aggregated Aβ. We found that brain homogenates from AD patients with different molecular profiles of Aβ are able to induce distinct patterns of Aβ-amyloidosis when injected into mice. Overall these data suggest that the assembly of mixtures of Aβ peptides into different Aβ seeds leads to the formation of distinct subtypes of amyloid having distinctive physicochemical and biological properties which result in the generation of distinct AD molecular subgroups.

  7. The expression pattern of small nucleolar and small Cajal body-specific RNAs characterizes distinct molecular subtypes of multiple myeloma

    International Nuclear Information System (INIS)

    Ronchetti, D; Todoerti, K; Tuana, G; Agnelli, L; Mosca, L; Lionetti, M; Fabris, S; Colapietro, P; Miozzo, M; Ferrarini, M; Tassone, P; Neri, A

    2012-01-01

    Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs (scaRNAs) are non-coding RNAs involved in the maturation of other RNA molecules and generally located in the introns of host genes. It is now emerging that altered sno/scaRNAs expression may have a pathological role in cancer. This study elucidates the patterns of sno/scaRNAs expression in multiple myeloma (MM) by profiling purified malignant plasma cells from 55 MMs, 8 secondary plasma cell leukemias (sPCLs) and 4 normal controls. Overall, a global sno/scaRNAs downregulation was found in MMs and, even more, in sPCLs compared with normal plasma cells. Whereas SCARNA22 resulted the only sno/scaRNA characterizing the translocation/cyclin D4 (TC4) MM, TC2 group displayed a distinct sno/scaRNA signature overexpressing members of SNORD115 and SNORD116 families located in a region finely regulated by an imprinting center at 15q11, which, however, resulted overall hypomethylated in MMs independently of the SNORD115 and SNORD116 expression levels. Finally, integrative analyses with available gene expression and genome-wide data revealed the occurrence of significant sno/scaRNAs/host genes co-expression and the putative influence of allelic imbalances on specific snoRNAs expression. Our data extend the current view of sno/scaRNAs deregulation in cancer and add novel information to the bio-molecular complexity of plasma cell dyscrasias

  8. The endogenous and reactive depression subtypes revisited: integrative animal and human studies implicate multiple distinct molecular mechanisms underlying major depressive disorder.

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    Malki, Karim; Keers, Robert; Tosto, Maria Grazia; Lourdusamy, Anbarasu; Carboni, Lucia; Domenici, Enrico; Uher, Rudolf; McGuffin, Peter; Schalkwyk, Leonard C

    2014-05-07

    distinct changes in gene-expression. However, they also suggest that the molecular signature of 'reactive' depression caused by early stressors differs considerably from that of 'reactive' depression caused by late stressors. A small set of genes was consistently dysregulated across each paradigm and in post-mortem brain tissue of depressed patients suggesting a final common pathway to the disorder. These genes included the VAMP-2 gene, which has previously been associated with Axis-I disorders including MDD, bipolar depression, schizophrenia and with antidepressant treatment response. We also discuss the implications of our findings for disease classification, personalized medicine and case-control studies of MDD.

  9. Molecular Subtyping in Cholera Outbreak, Laos, 2010

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    Sithivong, Noikaseumsy; Morita-Ishihara, Tomoko; Vongdouangchanh, Arounnapha; Phouthavane, Traykhouane; Chomlasak, Khampheng; Sisavath, Lay; Khamphaphongphane, Bouaphanh; Sengkeopraseuth, Bounthanom; Vongprachanh, Phengta; Keosavanh, Onechanh; Southalack, Kongmany; Jiyoung, Lee; Tsuyuoka, Reiko; Ohnishi, Makoto

    2011-01-01

    A cholera outbreak in Laos in July 2010 involved 237 cases, including 4 deaths. Molecular subtyping indicated relatedness between the Vibrio cholerae isolates in this and in a 2007 outbreak, uncovering a clonal group of V. cholerae circulating in the Mekong basin. Our finding suggests the subtyping methods will affect this relatedness. PMID:22099098

  10. Anatomic mapping of molecular subtypes in diffuse glioma.

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    Tang, Qisheng; Lian, Yuxi; Yu, Jinhua; Wang, Yuanyuan; Shi, Zhifeng; Chen, Liang

    2017-09-15

    Tumor location served as an important prognostic factor in glioma patients was considered to postulate molecular features according to cell origin theory. However, anatomic distribution of unique molecular subtypes was not widely investigated. The relationship between molecular phenotype and histological subgroup were also vague based on tumor location. Our group focuses on the study of glioma anatomic location of distinctive molecular subgroups and histology subtypes, and explores the possibility of their consistency based on clinical background. We retrospectively reviewed 143 cases with both molecular information (IDH1/TERT/1p19q) and MRI images diagnosed as cerebral diffuse gliomas. The anatomic distribution was analyzed between distinctive molecular subgroups and its relationship with histological subtypes. The influence of tumor location, molecular stratification and histology diagnosis on survival outcome was investigated as well. Anatomic locations of cerebral diffuse glioma indicate varied clinical outcome. Based on that, it can be stratified into five principal molecular subgroups according to IDH1/TERT/1p19q status. Triple-positive (IDH1 and TERT mutation with 1p19q codeletion) glioma tended to be oligodendroglioma present with much better clinical outcome compared to TERT mutation only group who is glioblastoma inclined (median overall survival 39 months VS 18 months). Five molecular subgroups were demonstrated with distinctive locational distribution. This kind of anatomic feature is consistent with its corresponding histological subtypes. Each molecular subgroup in glioma has unique anatomic location which indicates distinctive clinical outcome. Molecular diagnosis can be served as perfect complementary tool for the precise diagnosis. Integration of histomolecular diagnosis will be much more helpful in routine clinical practice in the future.

  11. Identification of Two Distinct Molecular Subtypes of Non-Invasive Follicular Neoplasm with Papillary-Like Nuclear Features by Digital RNA Counting.

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    Giannini, Riccardo; Ugolini, Clara; Poma, Anello Marcello; Urpì, Maria; Niccoli, Cristina; Elisei, Rossella; Chiarugi, Massimo; Vitti, Paolo; Miccoli, Paolo; Basolo, Fulvio

    2017-10-01

    The follicular variant (FV) of papillary thyroid cancer (PTC) is one of the most common variants of PTC. Clinically, non-infiltrative FVPTC is considered a low-risk variant of PTC, and the non-invasive encapsulated forms of FVPTC represent a group of thyroid tumors with a particularly good prognosis. Consequently, these neoplasms have been very recently reclassified as non-invasive follicular neoplasms with papillary-like nuclear features (NIFTP). From a molecular standpoint, NIFTP appears to be similar to follicular neoplasms. However, only limited data are currently available regarding their gene expression profile. The aim of this study was to identify specific molecular signatures of 26 NIFTPs compared to those of 19 follicular adenomas (FAs) and 18 infiltrative FVPTCs (IFVPTCs). A nanoString custom assay was used to perform mRNA expression analysis. All cases were also genotyped for BRAF, N-, H-, and K-RAS mutations. Samples were grouped on the basis of gene expression profiles by Pearson's correlation and non-negative matrix factorization clustering analysis. Finally, the uncorrelated shrunken centroid machine-learning algorithm was used to classify the samples. The results revealed distinct expression profiles of FAs and IFVPTCs. NIFTP samples can exhibit different expression profiles, more similar to FAs (FA-like) or to IFVPTCs (IFVPTC-like), and these different expression profiles largely depend on the presence of different mutations (RAS or BRAF). In conclusion, although further validation of the model is required by using a larger group of prospective cases, these data reinforce the hypothesis that IFVPTC-like NIFTPs might represent precursors of IFVPTC.

  12. Practical and robust identification of molecular subtypes in colorectal cancer by immunohistochemistry

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    Trinh, Anne; Trumpi, Kari; De Sousa E Melo, Felipe; Wang, Xin; De Jong, Joan H.; Fessler, Evelyn; Kuppen, Peter J K; Reimers, Marlies S.; Swets, Marloes; Koopman, Miriam; Nagtegaal, Iris D.; Jansen, Marnix; Hooijer, Gerrit K J; Offerhaus, George J A; Kranenburg, Onno; Punt, Cornelis J.; Medema, Jan Paul; Markowetz, Florian; Vermeulen, Louis

    2017-01-01

    URPOSE: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer (CRC) with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high quality genome-wide transcriptome data from

  13. Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry

    NARCIS (Netherlands)

    Trinh, A.; Trumpi, K.; Sousa, E.M.F. De; Wang, X.; Jong, J.H.A.L. de; Fessler, E.; Kuppen, P.J.; Reimers, M.S.; Swets, M.; Koopman, M.; Nagtegaal, I.D.; Jansen, M.; Hooijer, G.K.J.; Offerhaus, G.J.; Kranenburg, O.; Punt, C.J.A.; Medema, J.P.; Markowetz, F.; Vermeulen, L.

    2017-01-01

    PURPOSE: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from

  14. Parent stress across molecular subtypes of children with Angelman syndrome.

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    Miodrag, N; Peters, S

    2015-09-01

    Parenting stress has been consistently reported among parents of children with developmental disabilities. However, to date, no studies have investigated the impact of a molecular subtype of Angelman syndrome (AS) on parent stress, despite distinct phenotypic differences among subtypes. Data for 124 families of children with three subtypes of AS: class I and II deletions (n = 99), imprinting centre defects (IC defects; n = 11) and paternal uniparental disomy (UPD; n = 14) were drawn from the AS Rare Diseases Clinical Research Network (RDCRN) database and collected from five research sites across the Unites States. The AS study at the RDCRN gathered health information to understand how the syndrome develops and how to treat it. Parents completed questionnaires on their perceived psychological stress, the severity of children's aberrant behaviour and children's sleep patterns. Children's adaptive functioning and developmental levels were clinically evaluated. Child-related stress reached clinical levels for 40% of parents of children with deletions, 100% for IC defects and 64.3% for UPD. Sleep difficulties were similar and elevated across subtypes. There were no differences between molecular subtypes for overall child and parent-related stress. However, results showed greater isolation and lack of perceived parenting skills for parents of children with UPD compared with deletions. Better overall cognition for children with deletions was significantly related to more child-related stress while their poorer adaptive functioning was associated with more child-related stress. For all three groups, the severity of children's inappropriate behaviour was positively related to different aspects of stress. How parents react to stress depends, in part, on children's AS molecular subtype. Despite falling under the larger umbrella term of AS, it is important to acknowledge the unique aspects associated with children's molecular subtype. Identifying these factors can

  15. Correlation of microarray-based breast cancer molecular subtypes and clinical outcomes: implications for treatment optimization

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    Kao, Kuo-Jang; Chang, Kai-Ming; Hsu, Hui-Chi; Huang, Andrew T

    2011-01-01

    Optimizing treatment through microarray-based molecular subtyping is a promising method to address the problem of heterogeneity in breast cancer; however, current application is restricted to prediction of distant recurrence risk. This study investigated whether breast cancer molecular subtyping according to its global intrinsic biology could be used for treatment customization. Gene expression profiling was conducted on fresh frozen breast cancer tissue collected from 327 patients in conjunction with thoroughly documented clinical data. A method of molecular subtyping based on 783 probe-sets was established and validated. Statistical analysis was performed to correlate molecular subtypes with survival outcome and adjuvant chemotherapy regimens. Heterogeneity of molecular subtypes within groups sharing the same distant recurrence risk predicted by genes of the Oncotype and MammaPrint predictors was studied. We identified six molecular subtypes of breast cancer demonstrating distinctive molecular and clinical characteristics. These six subtypes showed similarities and significant differences from the Perou-Sørlie intrinsic types. Subtype I breast cancer was in concordance with chemosensitive basal-like intrinsic type. Adjuvant chemotherapy of lower intensity with CMF yielded survival outcome similar to those of CAF in this subtype. Subtype IV breast cancer was positive for ER with a full-range expression of HER2, responding poorly to CMF; however, this subtype showed excellent survival when treated with CAF. Reduced expression of a gene associated with methotrexate sensitivity in subtype IV was the likely reason for poor response to methotrexate. All subtype V breast cancer was positive for ER and had excellent long-term survival with hormonal therapy alone following surgery and/or radiation therapy. Adjuvant chemotherapy did not provide any survival benefit in early stages of subtype V patients. Subtype V was consistent with a unique subset of luminal A intrinsic

  16. Molecular subtypes and imaging phenotypes of breast cancer

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    Cho, Nariya [Dept. of Radiology, Seoul National University Hospital, Seoul (Korea, Republic of)

    2016-08-15

    During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2), and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics.

  17. Molecular subtypes and imaging phenotypes of breast cancer

    Directory of Open Access Journals (Sweden)

    Nariya Cho

    2016-10-01

    Full Text Available During the last 15 years, traditional breast cancer classifications based on histopathology have been reorganized into the luminal A, luminal B, human epidermal growth factor receptor 2 (HER2, and basal-like subtypes based on gene expression profiling. Each molecular subtype has shown varying risk for progression, response to treatment, and survival outcomes. Research linking the imaging phenotype with the molecular subtype has revealed that non-calcified, relatively circumscribed masses with posterior acoustic enhancement are common in the basal-like subtype, spiculated masses with a poorly circumscribed margin and posterior acoustic shadowing in the luminal subtype, and pleomorphic calcifications in the HER2-enriched subtype. Understanding the clinical implications of the molecular subtypes and imaging phenotypes could help radiologists guide precision medicine, tailoring medical treatment to patients and their tumor characteristics.

  18. Bevacizumab May Differentially Improve Ovarian Cancer Outcome in Patients with Proliferative and Mesenchymal Molecular Subtypes.

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    Kommoss, Stefan; Winterhoff, Boris; Oberg, Ann L; Konecny, Gottfried E; Wang, Chen; Riska, Shaun M; Fan, Jian-Bing; Maurer, Matthew J; April, Craig; Shridhar, Viji; Kommoss, Friedrich; du Bois, Andreas; Hilpert, Felix; Mahner, Sven; Baumann, Klaus; Schroeder, Willibald; Burges, Alexander; Canzler, Ulrich; Chien, Jeremy; Embleton, Andrew C; Parmar, Mahesh; Kaplan, Richard; Perren, Timothy; Hartmann, Lynn C; Goode, Ellen L; Dowdy, Sean C; Pfisterer, Jacobus

    2017-07-15

    Purpose: Recent progress in understanding the molecular biology of epithelial ovarian cancer has not yet translated into individualized treatment for these women or improvements in their disease outcome. Gene expression has been utilized to identify distinct molecular subtypes, but there have been no reports investigating whether or not molecular subtyping is predictive of response to bevacizumab in ovarian cancer. Experimental Design: DASL gene expression arrays were performed on FFPE tissue from patients enrolled on the ICON7 trial. Patients were stratified into four TCGA molecular subtypes. Associations between molecular subtype and the efficacy of randomly assigned therapy with bevacizumab were assessed. Results: Molecular subtypes were assigned as follows: 122 immunoreactive (34%), 96 proliferative (27%), 73 differentiated (20%), and 68 mesenchymal (19%). In univariate analysis patients with tumors of proliferative subtype obtained the greatest benefit from bevacizumab with a median PFS improvement of 10.1 months [HR, 0.55 (95% CI, 0.34-0.90), P = 0.016]. For the mesenchymal subtype, bevacizumab conferred a nonsignificant improvement in PFS of 8.2 months [HR 0.78 (95% CI, 0.44-1.40), P = 0.41]. Bevacizumab conferred modest improvements in PFS for patients with immunoreactive subtype (3.8 months; P = 0.08) or differentiated subtype (3.7 months; P = 0.61). Multivariate analysis demonstrated significant PFS improvement in proliferative subtype patients only [HR, 0.45 (95% CI, 0.27-0.74), P = 0.0015]. Conclusions: Ovarian carcinoma molecular subtypes with the poorest survival (proliferative and mesenchymal) derive a comparably greater benefit from treatment that includes bevacizumab. Validation of our findings in an independent cohort could enable the use of bevacizumab for those patients most likely to benefit, thereby reducing side effects and healthcare cost. Clin Cancer Res; 23(14); 3794-801. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. Identifying molecular subtypes in human colon cancer using gene expression and DNA methylation microarray data.

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    Ren, Zhonglu; Wang, Wenhui; Li, Jinming

    2016-02-01

    Identifying colon cancer subtypes based on molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications using gene expression data have been attempted before with little concordance between the different studies carried out. In this study we aimed to uncover subtypes of colon cancer that have distinct biological characteristics and identify a set of novel biomarkers which could best reflect the clinical and/or biological characteristics of each subtype. Clustering analysis and discriminant analysis were utilized to discover the subtypes in two different molecular levels on 153 colon cancer samples from The Cancer Genome Atlas (TCGA) Data Portal. At gene expression level, we identified two major subtypes, ECL1 (expression cluster 1) and ECL2 (expression cluster 2) and a list of signature genes. Due to the heterogeneity of colon cancer, the subtype ECL1 can be further subdivided into three nested subclasses, and HOTAIR were found upregulated in subclass 2. At DNA methylation level, we uncovered three major subtypes, MCL1 (methylation cluster 1), MCL2 (methylation cluster 2) and MCL3 (methylation cluster 3). We found only three subtypes of CpG island methylator phenotype (CIMP) in colon cancer instead of the four subtypes in the previous reports, and we found no sufficient evidence to subdivide MCL3 into two distinct subgroups.

  20. Genetic Alterations in the Molecular Subtypes of Bladder Cancer: Illustration in the Cancer Genome Atlas Dataset.

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    Choi, Woonyoung; Ochoa, Andrea; McConkey, David J; Aine, Mattias; Höglund, Mattias; Kim, William Y; Real, Francisco X; Kiltie, Anne E; Milsom, Ian; Dyrskjøt, Lars; Lerner, Seth P

    2017-09-01

    Recent whole genome mRNA expression profiling studies revealed that bladder cancers can be grouped into molecular subtypes, some of which share clinical properties and gene expression patterns with the intrinsic subtypes of breast cancer and the molecular subtypes found in other solid tumors. The molecular subtypes in other solid tumors are enriched with specific mutations and copy number aberrations that are thought to underlie their distinct progression patterns, and biological and clinical properties. The availability of comprehensive genomic data from The Cancer Genome Atlas (TCGA) and other large projects made it possible to correlate the presence of DNA alterations with tumor molecular subtype membership. Our overall goal was to determine whether specific DNA mutations and/or copy number variations are enriched in specific molecular subtypes. We used the complete TCGA RNA-seq dataset and three different published classifiers developed by our groups to assign TCGA's bladder cancers to molecular subtypes, and examined the prevalence of the most common DNA alterations within them. We interpreted the results against the background of what was known from the published literature about the prevalence of these alterations in nonmuscle-invasive and muscle-invasive bladder cancers. The results confirmed that alterations involving RB1 and NFE2L2 were enriched in basal cancers, whereas alterations involving FGFR3 and KDM6A were enriched in luminal tumors. The results further reinforce the conclusion that the molecular subtypes of bladder cancer are distinct disease entities with specific genetic alterations. Our observation showed that some of subtype-enriched mutations and copy number aberrations are clinically actionable, which has direct implications for the clinical management of patients with bladder cancer. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

  1. Molecular Subtyping of Tumors from Patients with Familial Glioma.

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    Ruiz, Vanessa Y; Praska, Corinne E; Armstrong, Georgina; Kollmeyer, Thomas M; Yamada, Seiji; Decker, Paul A; Kosel, Matthew L; Eckel-Passow, Jeanette E; Consortium, The Gliogene; Lachance, Daniel H; Bainbridge, Matthew N; Melin, Beatrice S; Bondy, Melissa L; Jenkins, Robert B

    2017-10-10

    Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on IDH mutation and 1p/19q co-deletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas, and that tumors in the same family should have the same molecular subtype. Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded (FFPE) tumor was obtained for a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation (CNV) data was obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wild type, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q-codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (p=0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (κ=0.59): 3 IDH-mutant non-codeleted, 2 IDH-wild type, and 2 IDH-mutant and 1p/19q-codeleted gliomas. Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight about the distribution of molecular subtypes in FG. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  2. Molecular profiling of thyroid cancer subtypes using large-scale text mining.

    Science.gov (United States)

    Wu, Chengkun; Schwartz, Jean-Marc; Brabant, Georg; Nenadic, Goran

    2014-01-01

    Thyroid cancer is the most common endocrine tumor with a steady increase in incidence. It is classified into multiple histopathological subtypes with potentially distinct molecular mechanisms. Identifying the most relevant genes and biological pathways reported in the thyroid cancer literature is vital for understanding of the disease and developing targeted therapeutics. We developed a large-scale text mining system to generate a molecular profiling of thyroid cancer subtypes. The system first uses a subtype classification method for the thyroid cancer literature, which employs a scoring scheme to assign different subtypes to articles. We evaluated the classification method on a gold standard derived from the PubMed Supplementary Concept annotations, achieving a micro-average F1-score of 85.9% for primary subtypes. We then used the subtype classification results to extract genes and pathways associated with different thyroid cancer subtypes and successfully unveiled important genes and pathways, including some instances that are missing from current manually annotated databases or most recent review articles. Identification of key genes and pathways plays a central role in understanding the molecular biology of thyroid cancer. An integration of subtype context can allow prioritized screening for diagnostic biomarkers and novel molecular targeted therapeutics. Source code used for this study is made freely available online at https://github.com/chengkun-wu/GenesThyCan.

  3. Identifying molecular subtypes in human colon cancer using gene expression and DNA methylation microarray data

    OpenAIRE

    REN, ZHONGLU; WANG, WENHUI; LI, JINMING

    2015-01-01

    Identifying colon cancer subtypes based on molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications using gene expression data have been attempted before with little concordance between the different studies carried out. In this study we aimed to uncover subtypes of colon cancer that have distinct biological characteristics and identify a set of novel biomarkers which could best reflect the clinical and/or biological characteristi...

  4. Expression and function of MutT homolog 1 in distinct subtypes of breast cancer.

    Science.gov (United States)

    Zhang, Xiaohui; Song, Wei; Zhou, Yidong; Mao, Feng; Lin, Yan; Guan, Jinghong; Sun, Qiang

    2017-04-01

    Human MutT homolog 1 (MTH1) detoxifies the oxidized DNA precursor 8-oxo-2'-deoxyguanosine-5'-triphosphate and serves a tumor suppressive role in distinct types of cancer. In the present study, the expression of MTH1 was examined in various subtypes of breast cancer, and the effect of its suppression on breast cancer growth was characterized in vitro and in vivo . MTH1 mRNA and protein levels were assessed using the reverse transcription-quantitative polymerase chain reaction and immunohistochemistry. The effect of MTH1 expression on the proliferation of breast cancer cells was investigated in vitro using Cell Counting Kit-8 and colony formation assays, and in vivo using breast cancer cell line xenografts in mice. The toxicity of the MTH1 inhibitor TH588 was investigated in nude mice. A marked increase in MTH1 protein and mRNA levels was demonstrated in breast cancer tissues compared with the non-cancerous control. However, no apparent differences in MTH1 expression were observed between distinct molecular subtypes of breast cancer. MTH1 overexpression was demonstrated to be independent of patient age, tumor size and lymph node metastasis. Inhibition of MTH1 decreased cancer cell viability and the clonogenic potential of cancer cells in a dose-dependent manner. These results were confirmed by decreased in vivo proliferation of MCF7, MDA-MB-231 and MDA-MB-453 cancer cell lines, representing distinct subtypes of breast cancer. Although inhibition of MTH1 activity decreased xenograft growth in mice, no major adverse effects of TH588 were detected on the basis of blood biochemistry, and liver and kidney function. The results of the present study suggested that MTH1 is overexpressed in the majority of breast cancers, independent of the molecular identity and clinicopathological features of the tumor, including patient age, tumor size and lymph node metastasis. Inhibition of MTH1 activity suppressed the growth of three subtypes of breast cancer, including luminal, basal

  5. Amyloid polymorphisms constitute distinct clouds of conformational variants in different etiological subtypes of Alzheimer's disease.

    Science.gov (United States)

    Rasmussen, Jay; Mahler, Jasmin; Beschorner, Natalie; Kaeser, Stephan A; Häsler, Lisa M; Baumann, Frank; Nyström, Sofie; Portelius, Erik; Blennow, Kaj; Lashley, Tammaryn; Fox, Nick C; Sepulveda-Falla, Diego; Glatzel, Markus; Oblak, Adrian L; Ghetti, Bernardino; Nilsson, K Peter R; Hammarström, Per; Staufenbiel, Matthias; Walker, Lary C; Jucker, Mathias

    2017-12-05

    The molecular architecture of amyloids formed in vivo can be interrogated using luminescent conjugated oligothiophenes (LCOs), a unique class of amyloid dyes. When bound to amyloid, LCOs yield fluorescence emission spectra that reflect the 3D structure of the protein aggregates. Given that synthetic amyloid-β peptide (Aβ) has been shown to adopt distinct structural conformations with different biological activities, we asked whether Aβ can assume structurally and functionally distinct conformations within the brain. To this end, we analyzed the LCO-stained cores of β-amyloid plaques in postmortem tissue sections from frontal, temporal, and occipital neocortices in 40 cases of familial Alzheimer's disease (AD) or sporadic (idiopathic) AD (sAD). The spectral attributes of LCO-bound plaques varied markedly in the brain, but the mean spectral properties of the amyloid cores were generally similar in all three cortical regions of individual patients. Remarkably, the LCO amyloid spectra differed significantly among some of the familial and sAD subtypes, and between typical patients with sAD and those with posterior cortical atrophy AD. Neither the amount of Aβ nor its protease resistance correlated with LCO spectral properties. LCO spectral amyloid phenotypes could be partially conveyed to Aβ plaques induced by experimental transmission in a mouse model. These findings indicate that polymorphic Aβ-amyloid deposits within the brain cluster as clouds of conformational variants in different AD cases. Heterogeneity in the molecular architecture of pathogenic Aβ among individuals and in etiologically distinct subtypes of AD justifies further studies to assess putative links between Aβ conformation and clinical phenotype.

  6. Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

    Science.gov (United States)

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev; Kimbung, Siker; Jönsson, Mats; Bonde, Jesper Hansen; Kannisto, Päivi; Måsbäck, Anna; Malander, Susanne; Nilbert, Mef; Hedenfalk, Ingrid

    2014-01-01

    Objective Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. Methods Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. Results 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. Conclusions These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast

  7. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma

    DEFF Research Database (Denmark)

    Chaisaingmongkol, Jittiporn; Budhu, Anuradha; Dang, Hien

    2017-01-01

    Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are clinically disparate primary liver cancers with etiological and biological heterogeneity. We identified common molecular subtypes linked to similar prognosis among 199 Thai ICC and HCC patients through systems integratio...

  8. Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia

    OpenAIRE

    Qian, Zhijian; Fernald, Anthony A.; Godley, Lucy A.; Larson, Richard A.; Le Beau, Michelle M.

    2002-01-01

    One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34+ hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to ...

  9. Molecular Subtyping of Treponema pallidum subsp. pallidum in Lisbon, Portugal▿

    Science.gov (United States)

    Castro, R.; Prieto, E.; Águas, M. J.; Manata, M. J.; Botas, J.; Martins Pereira, F.

    2009-01-01

    The objectives of this study were to evaluate the reproducibility of a molecular method for the subtyping of Treponema pallidum subsp. pallidum and to discriminate strains of this microorganism from strains from patients with syphilis. We studied 212 specimens from a total of 82 patients with different stages of syphilis (14 primary, 7 secondary and 61 latent syphilis). The specimens were distributed as follows: genital ulcers (n = 9), skin and mucosal lesions (n = 7), blood (n = 82), plasma (n = 82), and ear lobe scrapings (n = 32). The samples were assayed by a PCR technique to amplify a segment of the polymerase gene I (polA). Positive samples were typed on the basis of the analysis of two variable genes, tpr and arp. Sixty-two of the 90 samples positive for polA yielded typeable Treponema pallidum DNA. All skin lesions in which T. pallidum was identified (six of six [100%]) were found to contain enough DNA for typing of the organism. It was also possible to type DNA from 7/9 (77.7%) genital ulcer samples, 13/22 (59.1%) blood samples, 20/32 (62.5%) plasma samples, and 16/21 (76.2%) ear lobe scrapings. The same subtype was identified in all samples from the same patient. Five molecular subtypes (subtypes 10a, 14a, 14c, 14f, and 14g) were identified, with the most frequently found subtype being subtype 14a and the least frequently found subtype being subtype 10a. In conclusion, the subtyping technique used in this study seems to have good reproducibility. To our knowledge, subtype 10a was identified for the first time. Further studies are needed to explain the presence of this subtype in Portugal, namely, its relationship to the Treponema pallidum strains circulating in the African countries where Portuguese is spoken. PMID:19494073

  10. Distinct Subtypes of Apathy Revealed by the Apathy Motivation Index.

    Science.gov (United States)

    Ang, Yuen-Siang; Lockwood, Patricia; Apps, Matthew A J; Muhammed, Kinan; Husain, Masud

    2017-01-01

    Apathy is a debilitating but poorly understood disorder characterized by a reduction in motivation. As well as being associated with several brain disorders, apathy is also prevalent in varying degrees in healthy people. Whilst many tools have been developed to assess levels of apathy in clinical disorders, surprisingly there are no measures of apathy suitable for healthy people. Moreover, although apathy is commonly comorbid with symptoms of depression, anhedonia and fatigue, how and why these symptoms are associated is unclear. Here we developed the Apathy-Motivation Index (AMI), a brief self-report index of apathy and motivation. Using exploratory factor analysis (in a sample of 505 people), and then confirmatory analysis (in a different set of 479 individuals), we identified subtypes of apathy in behavioural, social and emotional domains. Latent profile analyses showed four different profiles of apathy that were associated with varying levels of depression, anhedonia and fatigue. The AMI is a novel and reliable measure of individual differences in apathy and might provide a useful means of probing different mechanisms underlying sub-clinical lack of motivation in otherwise healthy individuals. Moreover, associations between apathy and comorbid states may be reflective of problems in different emotional, social and behavioural domains.

  11. Distinct Subtypes of Apathy Revealed by the Apathy Motivation Index.

    Directory of Open Access Journals (Sweden)

    Yuen-Siang Ang

    Full Text Available Apathy is a debilitating but poorly understood disorder characterized by a reduction in motivation. As well as being associated with several brain disorders, apathy is also prevalent in varying degrees in healthy people. Whilst many tools have been developed to assess levels of apathy in clinical disorders, surprisingly there are no measures of apathy suitable for healthy people. Moreover, although apathy is commonly comorbid with symptoms of depression, anhedonia and fatigue, how and why these symptoms are associated is unclear. Here we developed the Apathy-Motivation Index (AMI, a brief self-report index of apathy and motivation. Using exploratory factor analysis (in a sample of 505 people, and then confirmatory analysis (in a different set of 479 individuals, we identified subtypes of apathy in behavioural, social and emotional domains. Latent profile analyses showed four different profiles of apathy that were associated with varying levels of depression, anhedonia and fatigue. The AMI is a novel and reliable measure of individual differences in apathy and might provide a useful means of probing different mechanisms underlying sub-clinical lack of motivation in otherwise healthy individuals. Moreover, associations between apathy and comorbid states may be reflective of problems in different emotional, social and behavioural domains.

  12. Identification of human immunodeficiency virus subtypes with distinct patterns of sensitivity to serum neutralization.

    OpenAIRE

    Cheng-Mayer, C; Homsy, J; Evans, L A; Levy, J A

    1988-01-01

    The human immunodeficiency virus (HIV) type 1 displays a high degree of genetic variation, especially in the glycoprotein (gp120) domain of the envelope gene. To determine whether this genomic heterogeneity leads to the expression of independent HIV subtypes, 12 sera from HIV type 1 antibody-positive individuals were tested for their ability to neutralize 20 HIV isolates of various origins. Four distinct HIV subtypes with different sensitivity to serum neutralization were identified. These re...

  13. Prediction consistency and clinical presentations of breast cancer molecular subtypes for Han Chinese population

    Directory of Open Access Journals (Sweden)

    Huang Chi-Cheng

    2012-09-01

    Full Text Available Abstract Background Breast cancer is a heterogeneous disease in terms of transcriptional aberrations; moreover, microarray gene expression profiles had defined 5 molecular subtypes based on certain intrinsic genes. This study aimed to evaluate the prediction consistency of breast cancer molecular subtypes from 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50 as well as clinical presentations of each molecualr subtype in Han Chinese population. Methods In all, 169 breast cancer samples (44 from Taiwan and 125 from China of Han Chinese population were gathered, and the gene expression features corresponding to 3 distinct intrinsic gene sets (Sørlie 500, Hu 306 and PAM50 were retrieved for molecular subtype prediction. Results For Sørlie 500 and Hu 306 intrinsic gene set, mean-centring of genes and distance-weighted discrimination (DWD remarkably reduced the number of unclassified cases. Regarding pairwise agreement, the highest predictive consistency was found between Hu 306 and PAM50. In all, 150 and 126 samples were assigned into identical subtypes by both Hu 306 and PAM50 genes, under mean-centring and DWD. Luminal B tended to show a higher nuclear grade and have more HER2 over-expression status than luminal A did. No basal-like breast tumours were ER positive, and most HER2-enriched breast tumours showed HER2 over-expression, whereas, only two-thirds of ER negativity/HER2 over-expression tumros were predicted as HER2-enriched molecular subtype. For 44 Taiwanese breast cancers with survival data, a better prognosis of luminal A than luminal B subtype in ER-postive breast cancers and a better prognosis of basal-like than HER2-enriched subtype in ER-negative breast cancers was observed. Conclusions We suggest that the intrinsic signature Hu 306 or PAM50 be used for breast cancers in the Han Chinese population during molecular subtyping. For the prognostic value and decision making based on intrinsic subtypes, further prospective

  14. Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value.

    Directory of Open Access Journals (Sweden)

    Laetitia Marisa

    Full Text Available Colon cancer (CC pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses.Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype-like, normal-like, serrated CC phenotype-like, and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II-III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after

  15. Advances of Molecular Subtype and Targeted Therapy of Lung Cancer

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    Lan SHAO

    2012-09-01

    Full Text Available The discovery of multiple molecular mechanisms underlying the development, progression, and prognosis of lung cancer, has created new opportunities for targeted therapy. Each subtype is associated with molecular tests that define the subtype and drugs that may have potential therapeutic effect on lung cancer. In 2004, mutations in the epidermal growth factor receptor (epidermal growth factor receptor, EGFR gene were discovered in non-small cell lung cancers (NSCLC, especially in adenocarcinomas. And they are strongly associated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs. Moreover, in 2007 the existence of the echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK fusion gene was discovered in NSCLC, and the same as EGFR-TKIs, ALK inhibitors are being found to be highly effective in lung cancers. At present, multiple molecular subtype of lung cancer and relevant targeted drugs are undering study. Here, we review the remarkable progress in molecular subtype of lung cancer and the related targeted therapy.

  16. Molecular subtypes of glioblastoma are relevant to lower grade glioma.

    Directory of Open Access Journals (Sweden)

    Xiaowei Guan

    Full Text Available Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas.Gene expression array, single nucleotide polymorphism (SNP array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson. Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP was assigned using prediction models by Fine et al.Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs.GBM gene-expression and methylation based subtypes are relevant for GII/III s and associate with overall survival differences. A better understanding of the association between these subtypes and GII/IIIs could further knowledge regarding prognosis and mechanisms of glioma progression.

  17. Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev

    2014-01-01

    OBJECTIVE: Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities...... with the well-established intrinsic molecular subtypes of breast cancer. METHODS: Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published...... expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal...

  18. Classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy.

    Science.gov (United States)

    Longo, Caterina; Lallas, Aimilios; Kyrgidis, Athanassios; Rabinovitz, Harold; Moscarella, Elvira; Ciardo, Silvana; Zalaudek, Iris; Oliviero, Margaret; Losi, Amanda; Gonzalez, Salvador; Guitera, Pascale; Piana, Simonetta; Argenziano, Giuseppe; Pellacani, Giovanni

    2014-10-01

    The current guidelines for the management of basal cell carcinoma (BCC) suggest a different therapeutic approach according to histopathologic subtype. Although dermatoscopic and confocal criteria of BCC have been investigated, no specific studies were performed to evaluate the distinct reflectance confocal microscopy (RCM) aspects of BCC subtypes. To define the specific dermatoscopic and confocal criteria for delineating different BCC subtypes. Dermatoscopic and confocal images of histopathologically confirmed BCCs were retrospectively evaluated for the presence of predefined criteria. Frequencies of dermatoscopic and confocal parameters are provided. Univariate and adjusted odds ratios were calculated. Discriminant analyses were performed to define the independent confocal criteria for distinct BCC subtypes. Eighty-eight BCCs were included. Dermatoscopically, superficial BCCs (n=44) were primarily typified by the presence of fine telangiectasia, multiple erosions, leaf-like structures, and revealed cords connected to the epidermis and epidermal streaming upon RCM. Nodular BCCs (n=22) featured the classic dermatoscopic features and well outlined large basaloid islands upon RCM. Infiltrative BCCs (n=22) featured structureless, shiny red areas, fine telangiectasia, and arborizing vessels on dermatoscopy and dark silhouettes upon RCM. The retrospective design. Dermatoscopy and confocal microscopy can reliably classify different BCC subtypes. Copyright © 2014 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  19. Distinct subtype distribution and somatic mutation spectrum of lymphomas in East Asia.

    Science.gov (United States)

    Ren, Weicheng; Li, Wei; Ye, Xiaofei; Liu, Hui; Pan-Hammarström, Qiang

    2017-07-01

    Here, we give an updated overview of the subtype distribution of lymphomas in East Asia and also present the genome sequencing data on two major subtypes of these tumors. The distribution of lymphoma types/subtypes among East Asian countries is very similar, with a lower proportion of B-cell malignancies and a higher proportion of T/natural killer (NK)-cell lymphomas as compared to Western populations. Extranodal NK/T-cell lymphoma is more frequently observed in East Asia, whereas follicular lymphoma and chronic lymphocytic leukemia, are proportionally lower. The incidence rate of lymphoma subtypes in Asians living in the US was generally intermediate to the general rate in US and Asia, suggesting that both genetic and environmental factors may underlie the geographical variations observed.Key cancer driver mutations have been identified in Asian patients with diffuse large B-cell lymphoma or extranodal NK/T-cell lymphoma through genome sequencing. A distinct somatic mutation profile has also been observed in Chinese diffuse large B-cell lymphoma patients. The incidence and distribution of lymphoma subtypes differed significantly between patients from East Asia and Western countries, suggesting subtype-specific etiologic mechanisms. Further studies on the mechanism underlying these geographical variations may give new insights into our understanding of lymphomagenesis.

  20. Breast Cancer Molecular Subtypes Among Moroccan Women

    Directory of Open Access Journals (Sweden)

    Wissal Mahir

    2016-12-01

    Full Text Available Introduction: Breast cancer remains despite the therapeutic progress, the leading cause of death by cancer among women. It represents a group of very heterogeneous clinical, histopathological and molecular diseases. Molecular heterogeneity has been demonstrated by genomic analysis, even for similar histology cancers. Four subgroups of breast carcinomas are distinguished: Luminal A, Luminal B, HER2 over expression and Basal - like. The Immuno-histo-chemical analysis useip (estrogen receptors RE, the PR (progesterone receptors, the ((Human Epidermal Growth Factor Receptor-2, the Ki67 (proliferation marker HER2, CK5/6 has shown a subdivision into subgroups similar to those found by genomic analysis. These subgroups are different from the point of view of clinical course and response to adjuvant treatment.Objectives: The aim of this work is to study the molecular profile of the breast cancers by immunostaining on Moroccan series to a classification with a prognostic value allowing a treatment tailored to each group of patients. Furthermore, the molecular subgroups were correlated to other clinical and histological factors.Material and methods: It is a prospective study of the laboratory of Anatomy and Pathologic cytology of the children's Hospital, the service I of the maternity hospital in Rabat and in cooperation with the United Nations Centre of pathological anatomy. To do this, 88 cases of breast cancer together were diagnosed between January 1, 2010 and December 31, 2014, taking a period of five years. All tissue samples made subject study of Immuno-histo-chemistry with the following markers: RE, PR, HER2 and Ki67. Only negative triple cases (HR and HER2 negative benefited from an additional marking with CK5/6 and EGFR to set the basal profile.Results: Series of 88 cases of mammary carcinomas observed on operating parts, ranged in age between 28 and 84 years old, with an average of 51 ± 12, 8. Carcinoma infiltrating non-specific (DOCTORS was

  1. Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry.

    Science.gov (United States)

    Trinh, Anne; Trumpi, Kari; De Sousa E Melo, Felipe; Wang, Xin; de Jong, Joan H; Fessler, Evelyn; Kuppen, Peter J K; Reimers, Marlies S; Swets, Marloes; Koopman, Miriam; Nagtegaal, Iris D; Jansen, Marnix; Hooijer, Gerrit K J; Offerhaus, George J A; Kranenburg, Onno; Punt, Cornelis J; Medema, Jan Paul; Markowetz, Florian; Vermeulen, Louis

    2017-01-15

    Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study. Tissue microarrays from 1,076 patients with colorectal cancer from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1, and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semiquantitative pathologist scoring of the cores as input and applied to three independent clinical cohorts. This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular colorectal cancer subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild-type metastatic cancers of the canonical epithelial-like subtypes. This study shows that a practical and robust immunohistochemical assay can be employed to identify molecular colorectal cancer subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of colorectal cancer samples, both in the format of an automated image analysis pipeline to score tumor core staining, and as a classifier based on semiquantitative pathology scoring. Clin Cancer Res; 23(2); 387-98. ©2016 AACR. ©2016 American Association for Cancer Research.

  2. Interaction Pattern of Arg 62 in the A-Pocket of Differentially Disease-Associated HLA-B27 Subtypes Suggests Distinct TCR Binding Modes

    Science.gov (United States)

    Cauli, Alberto; Mathieu, Alessandro; Tedeschi, Valentina; Caristi, Silvana; Sorrentino, Rosa; Böckmann, Rainer A.; Fiorillo, Maria Teresa

    2012-01-01

    The single amino acid replacement Asp116His distinguishes the two subtypes HLA-B*2705 and HLA-B*2709 which are, respectively, associated and non-associated with Ankylosing Spondylitis, an autoimmune chronic inflammatory disease. The reason for this differential association is so far poorly understood and might be related to subtype-specific HLA:peptide conformations as well as to subtype/peptide-dependent dynamical properties on the nanoscale. Here, we combine functional experiments with extensive molecular dynamics simulations to investigate the molecular dynamics and function of the conserved Arg62 of the α1-helix for both B27 subtypes in complex with the self-peptides pVIPR (RRKWRRWHL) and TIS (RRLPIFSRL), and the viral peptides pLMP2 (RRRWRRLTV) and NPflu (SRYWAIRTR). Simulations of HLA:peptide systems suggest that peptide-stabilizing interactions of the Arg62 residue observed in crystal structures are metastable for both B27 subtypes under physiological conditions, rendering this arginine solvent-exposed and, probably, a key residue for TCR interaction more than peptide-binding. This view is supported by functional experiments with conservative (R62K) and non-conservative (R62A) B*2705 and B*2709 mutants that showed an overall reduction in their capability to present peptides to CD8+ T cells. Moreover, major subtype-dependent differences in the peptide recognition suggest distinct TCR binding modes for the B*2705 versus the B*2709 subtype. PMID:22403718

  3. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior

    International Nuclear Information System (INIS)

    Perez Villamil, Beatriz; Alfonso, Rosario; Caldes, Trinidad; Martin Sanchez, Fernando; Diaz Rubio, Eduardo; Romera Lopez, Alejandro; Hernandez Prieto, Susana; Lopez Campos, Guillermo; Calles, Antonio; Lopez Asenjo, Jose Antonio; Sanz Ortega, Julian; Fernandez Perez, Cristina; Sastre, Javier

    2012-01-01

    Colon cancer patients with the same stage show diverse clinical behavior due to tumor heterogeneity. We aimed to discover distinct classes of tumors based on microarray expression patterns, to analyze whether the molecular classification correlated with the histopathological stages or other clinical parameters and to study differences in the survival. Hierarchical clustering was performed for class discovery in 88 colon tumors (stages I to IV). Pathways analysis and correlations between clinical parameters and our classification were analyzed. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the main subtype was generated using the 3-Nearest-Neighbor method. Coincidences with other prognostic predictors were assesed. Hierarchical clustering identified four robust tumor subtypes with biologically and clinically distinct behavior. Stromal components (p < 0.001), nuclear β-catenin (p = 0.021), mucinous histology (p = 0.001), microsatellite-instability (p = 0.039) and BRAF mutations (p < 0.001) were associated to this classification but it was independent of Dukes stages (p = 0.646). Molecular subtypes were established from stage I. High-stroma-subtype showed increased levels of genes and altered pathways distinctive of tumour-associated-stroma and components of the extracellular matrix in contrast to Low-stroma-subtype. Mucinous-subtype was reflected by the increased expression of trefoil factors and mucins as well as by a higher proportion of MSI and BRAF mutations. Tumor subtypes were validated using an external set of 78 patients. A 167 gene signature associated to the Low-stroma-subtype distinguished low risk patients from high risk patients in the external cohort (Dukes B and C:HR = 8.56(2.53-29.01); Dukes B,C and D:HR = 1.87(1.07-3.25)). Eight different reported survival gene signatures segregated our tumors into two groups the Low-stroma-subtype and the other tumor subtypes. We have identified novel

  4. Breast cancer molecular subtype classifier that incorporates MRI features.

    Science.gov (United States)

    Sutton, Elizabeth J; Dashevsky, Brittany Z; Oh, Jung Hun; Veeraraghavan, Harini; Apte, Aditya P; Thakur, Sunitha B; Morris, Elizabeth A; Deasy, Joseph O

    2016-07-01

    To use features extracted from magnetic resonance (MR) images and a machine-learning method to assist in differentiating breast cancer molecular subtypes. This retrospective Health Insurance Portability and Accountability Act (HIPAA)-compliant study received Institutional Review Board (IRB) approval. We identified 178 breast cancer patients between 2006-2011 with: 1) ERPR + (n = 95, 53.4%), ERPR-/HER2 + (n = 35, 19.6%), or triple negative (TN, n = 48, 27.0%) invasive ductal carcinoma (IDC), and 2) preoperative breast MRI at 1.5T or 3.0T. Shape, texture, and histogram-based features were extracted from each tumor contoured on pre- and three postcontrast MR images using in-house software. Clinical and pathologic features were also collected. Machine-learning-based (support vector machines) models were used to identify significant imaging features and to build models that predict IDC subtype. Leave-one-out cross-validation (LOOCV) was used to avoid model overfitting. Statistical significance was determined using the Kruskal-Wallis test. Each support vector machine fit in the LOOCV process generated a model with varying features. Eleven out of the top 20 ranked features were significantly different between IDC subtypes with P machine-learning-based predictive model using features extracted from MRI that can distinguish IDC subtypes with significant predictive power. J. Magn. Reson. Imaging 2016;44:122-129. © 2016 Wiley Periodicals, Inc.

  5. Right Versus Left Colon Cancer Biology: Integrating the Consensus Molecular Subtypes.

    Science.gov (United States)

    Lee, Michael S; Menter, David G; Kopetz, Scott

    2017-03-01

    Although clinical management of colon cancer generally has not accounted for the primary tumor site, left-sided and right-sided colon cancers harbor different clinical and biologic characteristics. Right-sided colon cancers are more likely to have genome-wide hypermethylation via the CpG island methylator phenotype (CIMP), hypermutated state via microsatellite instability, and BRAF mutation. There are also differential exposures to potential carcinogenic toxins and microbiota in the right and left colon. Gene expression analyses further shed light on distinct biologic subtypes of colorectal cancers (CRCs), with 4 consensus molecular subtypes (CMSs) identified. Importantly, these subtypes are differentially distributed between right- and left-sided CRCs, with greater proportions of the "microsatellite unstable/immune" CMS1 and the "metabolic" CMS3 subtypes found in right-sided colon cancers. This review summarizes important biologic distinctions between right- and left-sided CRCs that likely impact prognosis and may predict for differential responses to biologic therapy. Given the inferior prognosis of stage III-IV right-sided CRCs and emerging data suggesting that anti-epidermal growth factor receptor antibody therapy is associated with worse survival in right-sided stage IV CRCs compared with left-sided cancers, these biologic differences between right- and left-sided CRCs provide critical context and may provide opportunities to personalize therapy. Copyright © 2017 by the National Comprehensive Cancer Network.

  6. The melanomas: a synthesis of epidemiological, clinical, histopathological, genetic, and biological aspects, supporting distinct subtypes, causal pathways, and cells of origin

    Science.gov (United States)

    Whiteman, David C.; Pavan, William J; Bastian, Boris C.

    2012-01-01

    Summary Converging lines of evidence from varied scientific disciplines suggest that cutaneous melanomas comprise biologically distinct subtypes that arise through multiple causal pathways. Understanding the respective relationships of each subtype with etiologic factors such as UV radiation and constitutional factors is the first necessary step toward developing refined prevention strategies for the specific forms of melanoma. Furthermore, classifying this disease precisely into biologically distinct subtypes is the key to developing mechanism- based treatments, as highlighted by recent discoveries. In this review, we outline the historical developments that underpin our understanding of melanoma heterogeneity, and we do this from the perspectives of clinical presentation, histopathology, epidemiology, molecular genetics, and developmental biology. We integrate the evidence from these separate trajectories to catalog the emerging major categories of melanomas and conclude with important unanswered questions relating to the development of melanoma and its cells of origin. PMID:21707960

  7. Molecular epidemiology of salmonid alphavirus (SAV subtype 3 in Norway

    Directory of Open Access Journals (Sweden)

    Jansen Mona D

    2010-08-01

    by other researchers. Larger scale, full length sequence analyses should be instigated to allow further phylogenetic and molecular epidemiology investigations of SAV subtype 3.

  8. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features.

    Directory of Open Access Journals (Sweden)

    Marcel Kool

    Full Text Available BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements in cure rates, prediction of disease outcome remains a major challenge and survivors suffer from serious therapy-related side-effects. Recent data showed that patients with WNT-activated tumors have a favorable prognosis, suggesting that these patients could be treated less intensively, thereby reducing the side-effects. This illustrates the potential benefits of a robust classification of medulloblastoma patients and a detailed knowledge of associated biological mechanisms. METHODS AND FINDINGS: To get a better insight into the molecular biology of medulloblastoma we established mRNA expression profiles of 62 medulloblastomas and analyzed 52 of them also by comparative genomic hybridization (CGH arrays. Five molecular subtypes were identified, characterized by WNT signaling (A; 9 cases, SHH signaling (B; 15 cases, expression of neuronal differentiation genes (C and D; 16 and 11 cases, respectively or photoreceptor genes (D and E; both 11 cases. Mutations in beta-catenin were identified in all 9 type A tumors, but not in any other tumor. PTCH1 mutations were exclusively identified in type B tumors. CGH analysis identified several fully or partly subtype-specific chromosomal aberrations. Monosomy of chromosome 6 occurred only in type A tumors, loss of 9q mostly occurred in type B tumors, whereas chromosome 17 aberrations, most common in medulloblastoma, were strongly associated with type C or D tumors. Loss of the inactivated X-chromosome was highly specific for female cases of type C, D and E tumors. Gene expression levels faithfully reflected the chromosomal copy number changes. Clinicopathological features significantly different between the 5 subtypes included metastatic disease and age at diagnosis and histology. Metastatic disease at diagnosis was significantly associated with subtypes C and D and most strongly with subtype E

  9. Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance.

    Science.gov (United States)

    Ziol, Marianne; Poté, Nicolas; Amaddeo, Giuliana; Laurent, Alexis; Nault, Jean-Charles; Oberti, Frédéric; Costentin, Charlotte; Michalak, Sophie; Bouattour, Mohamed; Francoz, Claire; Pageaux, Georges Philippe; Ramos, Jeanne; Decaens, Thomas; Luciani, Alain; Guiu, Boris; Vilgrain, Valérie; Aubé, Christophe; Derman, Jonathan; Charpy, Cécile; Zucman-Rossi, Jessica; Barget, Nathalie; Seror, Olivier; Ganne-Carrié, Nathalie; Paradis, Valérie; Calderaro, Julien

    2017-12-27

    We recently identified a novel histological subtype of hepatocellular carcinoma, designated as "macrotrabecular-massive" (MTM-HCC) and associated with specific molecular features. In order to assess the clinical relevance of this novel variant, we aimed to investigate its prognostic value in two large series of patients with HCC treated either by surgical resection or radiofrequency ablation (RFA). We retrospectively included 237 HCC surgical samples and 284 HCC liver biopsies from patients treated by surgical resection and RFA, respectively. Histological slides were reviewed by pathologists specialized in liver disease, and the MTM-HCC subtype was defined by the presence of a predominant (>50%) macrotrabecular architecture (more than 6 cells thick). The main clinical and biological features were recorded at baseline. Clinical endpoints were early and overall recurrence. The MTM-HCC subtype was identified in 12% of the whole cohort (16% of surgically resected samples, 8.5% of liver biopsy samples). It was associated at baseline with known poor prognostic factors (tumor size, AFP level, satellite nodules and vascular invasion). Multivariate analysis showed that MTM-HCC subtype was an independent predictor of early and overall recurrence (surgical series: OR 3.03 (1.38-6.65), p=0.006 and 2.76 (1.63-4.67), pvalue was retained even after patients stratification according to common clinical, biological and pathological features of aggressiveness. No other baseline parameter was independently associated to recurrence in the RFA series. The MTM-HCC subtype, reliably observed in 12% of patients eligible for a curative treatment, represents an aggressive form of HCC that may require more specific therapeutic strategies. This article is protected by copyright. All rights reserved. © 2017 by the American Association for the Study of Liver Diseases.

  10. MRI and pathological features of different molecular subtypes of breast cancers

    International Nuclear Information System (INIS)

    Yu Yang; Huo Tianlong; Lai Yunyao; Hong Nan

    2014-01-01

    subtypes (P<0.01). Luminal breast cancer consisted of various histologic types, 32.6% (47/144) of which were mixed type. The majority of the other two molecular subtypes were invasive ductal carcinoma. Furthermore,invasive ductal carcinomas with different molecular subtypes showed different histologic grades (Hc=30.014, P<0.01). Basal-like breast cancer was more likely associated with a higher grade of malignancy. Conclusions: Different molecular subtypes of breast showed distinct MRI features and pathologic characteristics. MRI might be a useful tool for preoperative prediction of molecular subtypes of breast cancer. (authors)

  11. Cerebrospinal fluid markers in the differentiation of molecular subtypes of sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Gmitterová, K; Heinemann, U; Krasnianski, A; Gawinecka, J; Zerr, I

    2016-06-01

    Cerebrospinal fluid (CSF) analysis supports the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) when applied within an adequate clinical context. A diagnostic potential has been attributed to CSF proteins such as 14-3-3, but also tau protein, phosphorylated tau (181P) (p-tau) protein, amyloid β1-42 , S100B and neuron-specific enolase (NSE). There has been only limited information available about the contribution of CSF analysis in the differentiation of various molecular sCJD subtypes. The CSF levels of the aforementioned proteins from 73 sCJD patients with distinct molecular subtypes were determined. Differences in tau values were significant amongst the homozygous patients (MM and VV genotype) compared to the heterozygous group (P = 0.07 and P = 0.02 respectively). Significantly higher CSF tau levels (P = 0.003) and NSE (P = 0.02) but lower p-tau/tau ratio (P = 0.01) were observed in MM1 compared to MM2 patients. The p-tau/tau ratio enabled the differentiation of MV genotype with higher levels in PrP(sc) type 2 (P = 0.04). Elevation of S100B (P disease duration and clinical stage influenced the test sensitivity in all proteins. Cerebrospinal fluid protein levels might be useful in the pre-mortem differentiation of molecular sCJD subtypes when the codon 129 genotype is known. © 2016 EAN.

  12. Can the dissociative PTSD subtype be identified across two distinct trauma samples meeting caseness for PTSD?

    Science.gov (United States)

    Hansen, Maj; Műllerová, Jana; Elklit, Ask; Armour, Cherie

    2016-08-01

    For over a century, the occurrence of dissociative symptoms in connection to traumatic exposure has been acknowledged in the scientific literature. Recently, the importance of dissociation has also been recognized in the long-term traumatic response within the DSM-5 nomenclature. Several studies have confirmed the existence of the dissociative posttraumatic stress disorder (PTSD) subtype. However, there is a lack of studies investigating latent profiles of PTSD solely in victims with PTSD. This study investigates the possible presence of PTSD subtypes using latent class analysis (LCA) across two distinct trauma samples meeting caseness for DSM-5 PTSD based on self-reports (N = 787). Moreover, we assessed if a number of risk factors resulted in an increased probability of membership in a dissociative compared with a non-dissociative PTSD class. The results of LCA revealed a two-class solution with two highly symptomatic classes: a dissociative class and a non-dissociative class across both samples. Increased emotion-focused coping increased the probability of individuals being grouped into the dissociative class across both samples. Social support reduced the probability of individuals being grouped into the dissociative class but only in the victims of motor vehicle accidents (MVAs) suffering from whiplash. The results are discussed in light of their clinical implications and suggest that the dissociative subtype can be identified in victims of incest and victims of MVA suffering from whiplash meeting caseness for DSM-5 PTSD.

  13. Breast Conservation Therapy: The Influence of Molecular Subtype and Margins

    International Nuclear Information System (INIS)

    Demirci, Senem; Broadwater, Gloria; Marks, Lawrence B.; Clough, Robert; Prosnitz, Leonard R.

    2012-01-01

    Purpose: To evaluate treatment results and prognostic factors, especially margin status and molecular subtype, in early-stage breast cancer patients treated with breast conservation therapy (BCT). Methods and Materials: The records of 1,058 Stage I or II breast cancer patients treated with BCT (surgical excision plus radiotherapy) at Duke University Medical Center, Durham, North Carolina, from 1985–2005 were retrospectively reviewed. Conventional receptor analyses were used as surrogate markers for molecular subtype classification (luminal A, luminal B, Her2 positive, and basal like). Actuarial estimates of overall survival (OS), cause-specific survival (CSS), failure-free survival, and locoregional control (LRC) were computed by use of Kaplan-Meier plots. We analyzed prognostic variables for significance using Cox proportional hazards univariate and multivariate analysis. The study was approved by the Duke University Medical Center Institutional Review Board. Results: The median age of the patients was 56 years (range, 18–89 years). Of the patients, 80% had T1 disease and 66% N0 disease pathologically. With a median follow-up of 9.8 years, an in-breast recurrence developed in 53 patients and 10 patients had nodal failure. For all patients, the 10-year CSS rate was 94%; LRC rate, 94%; and failure-free survival rate, 88%. Luminal A patients had a CSS rate of 95% and LRC rate of 99%. Basal-type patients appeared to do worse, with regard to both CSS rate (74%) and LRC rate (76%), but the numbers were small and the difference was not statistically significant. LRC rates of patients with negative margins (widely negative, close, and extent of margin not known) were virtually identical (93%, 96%, and 94%, respectively). Those with positive margins appeared to fare slightly worse based on LRC rate (88%), but again, the numbers were small and the difference was not statistically significant. Conclusions: BCT remains the treatment of choice for early-stage breast cancer

  14. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

    Science.gov (United States)

    Farshidfar, Farshad; Zheng, Siyuan; Gingras, Marie-Claude; Newton, Yulia; Shih, Juliann; Robertson, A Gordon; Hinoue, Toshinori; Hoadley, Katherine A; Gibb, Ewan A; Roszik, Jason; Covington, Kyle R; Wu, Chia-Chin; Shinbrot, Eve; Stransky, Nicolas; Hegde, Apurva; Yang, Ju Dong; Reznik, Ed; Sadeghi, Sara; Pedamallu, Chandra Sekhar; Ojesina, Akinyemi I; Hess, Julian M; Auman, J Todd; Rhie, Suhn K; Bowlby, Reanne; Borad, Mitesh J; Zhu, Andrew X; Stuart, Josh M; Sander, Chris; Akbani, Rehan; Cherniack, Andrew D; Deshpande, Vikram; Mounajjed, Taofic; Foo, Wai Chin; Torbenson, Michael S; Kleiner, David E; Laird, Peter W; Wheeler, David A; McRee, Autumn J; Bathe, Oliver F; Andersen, Jesper B; Bardeesy, Nabeel; Roberts, Lewis R; Kwong, Lawrence N

    2017-03-14

    Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  15. Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles

    Directory of Open Access Journals (Sweden)

    Farshad Farshidfar

    2017-03-01

    Full Text Available Cholangiocarcinoma (CCA is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.

  16. hisBreast cancer Molecular subtypes and their clinicopathological ...

    African Journals Online (AJOL)

    Introduction Breast cancer is a heterogeneous disease with varying clinical outcomes in histologically similar tumors. Micro arrays gene profiling has identified several breast cancer subtypes which include luminal A, Luminal B, Basal, and Her2 subtype. These subtypes show variable prognosis and response to therapy.

  17. Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia.

    Science.gov (United States)

    Qian, Zhijian; Fernald, Anthony A; Godley, Lucy A; Larson, Richard A; Le Beau, Michelle M

    2002-11-12

    One of the most serious consequences of cytotoxic cancer therapy is the development of therapy-related acute myeloid leukemia (t-AML), a neoplastic disorder arising from a multipotential hematopoietic stem cell. To gain insights into the molecular basis of this disease, we performed gene expression profiling of CD34(+) hematopoietic progenitor cells from t-AML patients. Our analysis revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern. Common to each of the subgroups are gene expression patterns typical of arrested differentiation in early progenitor cells. Leukemias with a -5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2), checkpoints (BUB1), or growth (MYC), and loss of expression of the gene encoding IFN consensus sequence-binding protein (ICSBP). A second subgroup of t-AML is characterized by down-regulation of transcription factors involved in early hematopoiesis (TAL1, GATA1, and EKLF) and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3) and cell survival (BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of selectively expressed genes that can be exploited for the development of urgently needed targeted therapies.

  18. Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization.

    Science.gov (United States)

    Gorden, Brandi H; Kim, Jong-Hyuk; Sarver, Aaron L; Frantz, Aric M; Breen, Matthew; Lindblad-Toh, Kerstin; O'Brien, Timothy D; Sharkey, Leslie C; Modiano, Jaime F; Dickerson, Erin B

    2014-04-01

    Canine hemangiosarcomas have been ascribed to an endothelial origin based on histologic appearance; however, recent findings suggest that these tumors may arise instead from hematopoietic progenitor cells. To clarify this ontogenetic dilemma, we used genome-wide expression profiling of primary hemangiosarcomas and identified three distinct tumor subtypes associated with angiogenesis (group 1), inflammation (group 2), and adipogenesis (group 3). Based on these findings, we hypothesized that a common progenitor may differentiate into the three tumor subtypes observed in our gene profiling experiment. To investigate this possibility, we cultured hemangiosarcoma cell lines under normal and sphere-forming culture conditions to enrich for tumor cell progenitors. Cells from sphere-forming cultures displayed a robust self-renewal capacity and exhibited genotypic, phenotypic, and functional properties consistent with each of the three molecular subtypes seen in primary tumors, including expression of endothelial progenitor cell (CD133 and CD34) and endothelial cell (CD105, CD146, and αvβ3 integrin) markers, expression of early hematopoietic (CD133, CD117, and CD34) and myeloid (CD115 and CD14) differentiation markers in parallel with increased phagocytic capacity, and acquisition of adipogenic potential. Collectively, these results suggest that canine hemangiosarcomas arise from multipotent progenitors that differentiate into distinct subtypes. Improved understanding of the mechanisms that determine the molecular and phenotypic differentiation of tumor cells in vivo could change paradigms regarding the origin and progression of endothelial sarcomas. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  19. Cerebrospinal fluid tau levels are a marker for molecular subtype in sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Karch, André; Hermann, Peter; Ponto, Claudia; Schmitz, Matthias; Arora, Amandeep; Zafar, Saima; Llorens, Franc; Müller-Heine, Annika; Zerr, Inga

    2015-05-01

    The molecular subtype of sporadic Creutzfeldt-Jakob disease (sCJD) is an important prognostic marker for patient survival. However, subtype determination is not possible during lifetime. Because the rate of disease progression is associated with the molecular subtype, this study aimed at investigating if total tau, a marker of neuronal death, allows premortem diagnosis of molecular subtype when codon 129 genotype is known. Two hundred ninety-six sCJD patients were tested for their cerebrospinal fluid total tau level at the time of diagnosis and were investigated for their sCJD subtype postmortem. There was a significant association between tau levels and the prion protein type in patients with codon 129 MM (p disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer.

    Science.gov (United States)

    Michaut, Magali; Chin, Suet-Feung; Majewski, Ian; Severson, Tesa M; Bismeijer, Tycho; de Koning, Leanne; Peeters, Justine K; Schouten, Philip C; Rueda, Oscar M; Bosma, Astrid J; Tarrant, Finbarr; Fan, Yue; He, Beilei; Xue, Zheng; Mittempergher, Lorenza; Kluin, Roelof J C; Heijmans, Jeroen; Snel, Mireille; Pereira, Bernard; Schlicker, Andreas; Provenzano, Elena; Ali, Hamid Raza; Gaber, Alexander; O'Hurley, Gillian; Lehn, Sophie; Muris, Jettie J F; Wesseling, Jelle; Kay, Elaine; Sammut, Stephen John; Bardwell, Helen A; Barbet, Aurélie S; Bard, Floriane; Lecerf, Caroline; O'Connor, Darran P; Vis, Daniël J; Benes, Cyril H; McDermott, Ultan; Garnett, Mathew J; Simon, Iris M; Jirström, Karin; Dubois, Thierry; Linn, Sabine C; Gallagher, William M; Wessels, Lodewyk F A; Caldas, Carlos; Bernards, Rene

    2016-01-05

    Invasive lobular carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype after invasive ductal carcinoma (IDC), accounting for around 10% of all breast cancers. The molecular processes that drive the development of ILC are still largely unknown. We have performed a comprehensive genomic, transcriptomic and proteomic analysis of a large ILC patient cohort and present here an integrated molecular portrait of ILC. Mutations in CDH1 and in the PI3K pathway are the most frequent molecular alterations in ILC. We identified two main subtypes of ILCs: (i) an immune related subtype with mRNA up-regulation of PD-L1, PD-1 and CTLA-4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone related subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using the somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization may help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies.

  1. A Comparative Analysis of Biomarker Expression and Molecular Subtypes of Pure Ductal Carcinoma In Situ and Invasive Breast Carcinoma by Image Analysis: Relationship of the Subtypes with Histologic Grade, Ki67, p53 Overexpression, and DNA Ploidy

    Directory of Open Access Journals (Sweden)

    Venetia R. Sarode

    2011-01-01

    Full Text Available There is a paucity of data regarding molecular subtypes of pure ductal carcinoma in situ (pDCIS. We evaluated the expression of ER, PR, HER2, Ki67, and p53 and DNA ploidy in 118 pDCIS and 100 invasive breast carcinomas (IBCAs by routine IHC and classified them according to molecular subtypes. Quantification of biomarkers and DNA ploidy was performed by image analysis. Expression of ER, PR, and high ki67 was more frequent in pDCIS compared to IBCA. High-grade tumors had lower ER and PR expression, high Ki67, overexpression of HER2 and p53, and DNA aneuploidy. Luminal A and HER2 subtypes were more common in pDCIS, and triple negative was more prevalent in IBCA. In both groups, HER2 and triple negative subtypes were characterized by high ki67, overexpression of p53, and DNA aneuploidy compared to luminal subtypes. Molecular subtypes of IBCA are distinct from those of pDCIS. Invasion is characterized by change in phenotype in some tumors.

  2. Distinct Physiological Maturation of Parvalbumin-Positive Neuron Subtypes in Mouse Prefrontal Cortex.

    Science.gov (United States)

    Miyamae, Takeaki; Chen, Kehui; Lewis, David A; Gonzalez-Burgos, Guillermo

    2017-05-10

    Parvalbumin-positive (PV + ) neurons control the timing of pyramidal cell output in cortical neuron networks. In the prefrontal cortex (PFC), PV + neuron activity is involved in cognitive function, suggesting that PV + neuron maturation is critical for cognitive development. The two major PV + neuron subtypes found in the PFC, chandelier cells (ChCs) and basket cells (BCs), are thought to play different roles in cortical circuits, but the trajectories of their physiological maturation have not been compared. Using two separate mouse lines, we found that in the mature PFC, both ChCs and BCs are abundant in superficial layer 2, but only BCs are present in deeper laminar locations. This distinctive laminar distribution was observed by postnatal day 12 (P12), when we first identified ChCs by the presence of axon cartridges. Electrophysiology analysis of excitatory synapse development, starting at P12, showed that excitatory drive remains low throughout development in ChCs, but increases rapidly before puberty in BCs, with an earlier time course in deeper-layer BCs. Consistent with a role of excitatory synaptic drive in the maturation of PV + neuron firing properties, the fast-spiking phenotype showed different maturation trajectories between ChCs and BCs, and between superficial versus deep-layer BCs. ChC and BC maturation was nearly completed, via different trajectories, before the onset of puberty. These findings suggest that ChC and BC maturation may contribute differentially to the emergence of cognitive function, primarily during prepubertal development. SIGNIFICANCE STATEMENT Parvalbumin-positive (PV + ) neurons tightly control pyramidal cell output. Thus PV + neuron maturation in the prefrontal cortex (PFC) is crucial for cognitive development. However, the relative physiological maturation of the two major subtypes of PV + neurons, chandelier cells (ChCs) and basket cells (BCs), has not been determined. We assessed the maturation of ChCs and BCs in different

  3. Rosacea Subtypes Visually and Optically Distinct When Viewed with Parallel-Polarized Imaging Technique.

    Science.gov (United States)

    Kwon, In Hyuk; Choi, Jae Eun; Seo, Soo Hong; Kye, Young Chul; Ahn, Hyo Hyun

    2017-04-01

    Parallel-polarized light (PPL) photography evaluates skin characteristics by analyzing light reflections from the skin surface. The aim of this study was to determine the significance of quantitative analysis of PPL images in rosacea patients, and to provide a new objective evaluation method for use in clinical research and practice. A total of 49 rosacea patients were enrolled. PPL images using green and white light emitting diodes (LEDs) were taken of the lesion and an adjacent normal area. The values from the PPL images were converted to CIELAB coordinates: L * corresponding to the brightness, a * to the red and green intensities, and b * to the yellow and blue intensities. A standard grading system showed negative correlations with L * (r=-0.67862, p =0.0108) and b * (r=-0.67862, p =0.0108), and a positive correlation with a * (r=0.64194, p =0.0180) with the green LEDs for papulopustular rosacea (PPR) types. The xerosis severity scale showed a positive correlation with L * (r=0.36709, p =0.0276) and a negative correlation with b * (r=-0.33068, p =0.0489) with the white LEDs for erythematotelangiectatic rosacea (ETR) types. In the ETR types, there was brighter lesional and normal skin with white LEDs and a higher score on the xerosis severity scale than the PPR types. This technique using PPL images is applicable to the quantitative and objective assessment of rosacea in clinical settings. In addition, the two main subtypes of ETR and PPR are distinct entities visually and optically.

  4. Molecular subtyping of cancer: current status and moving toward clinical applications.

    Science.gov (United States)

    Zhao, Lan; Lee, Victor H F; Ng, Michael K; Yan, Hong; Bijlsma, Maarten F

    2018-04-12

    Cancer is a collection of genetic diseases, with large phenotypic differences and genetic heterogeneity between different types of cancers and even within the same cancer type. Recent advances in genome-wide profiling provide an opportunity to investigate global molecular changes during the development and progression of cancer. Meanwhile, numerous statistical and machine learning algorithms have been designed for the processing and interpretation of high-throughput molecular data. Molecular subtyping studies have allowed the allocation of cancer into homogeneous groups that are considered to harbor similar molecular and clinical characteristics. Furthermore, this has helped researchers to identify both actionable targets for drug design as well as biomarkers for response prediction. In this review, we introduce five frequently applied techniques for generating molecular data, which are microarray, RNA sequencing, quantitative polymerase chain reaction, NanoString and tissue microarray. Commonly used molecular data for cancer subtyping and clinical applications are discussed. Next, we summarize a workflow for molecular subtyping of cancer, including data preprocessing, cluster analysis, supervised classification and subtype characterizations. Finally, we identify and describe four major challenges in the molecular subtyping of cancer that may preclude clinical implementation. We suggest that standardized methods should be established to help identify intrinsic subgroup signatures and build robust classifiers that pave the way toward stratified treatment of cancer patients.

  5. Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers

    Directory of Open Access Journals (Sweden)

    Xinxin Peng

    2018-04-01

    Full Text Available Summary: Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility. : Peng et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to characterize tumor subtypes based on the expression of seven metabolic pathways. They find metabolic expression subtypes are associated with patient survivals and suggest the therapeutic and predictive relevance of subtype-related master regulators. Keywords: The Cancer Genome Atlas, tumor subtypes, prognostic markers, somatic drivers, master regulator, therapeutic targets, drug sensitivity, carbohydrate metabolism

  6. Distinct subtypes of genomic PTEN deletion size influence the landscape of aneuploidy and outcome in prostate cancer.

    Science.gov (United States)

    Vidotto, Thiago; Tiezzi, Daniel Guimarães; Squire, Jeremy A

    2018-01-01

    Inactivation of the PTEN tumor suppressor gene by deletion occurs in 20-30% of prostate cancer tumors and loss strongly correlates with a worse outcome. PTEN loss of function not only leads to activation of the PI3K/AKT pathway, but is also thought to affect genome stability and increase levels of tumor aneuploidy. We performed an in silico integrative genomic and transcriptomic analysis of 491 TCGA prostate cancer tumors. These data were used to map the genomic sizes of PTEN gene deletions and to characterize levels of instability and patterns of aneuploidy acquisition. PTEN homozygous deletions had a significant increase in aneuploidy compared to PTEN tumors without an apparent deletion, and hemizygous deletions showed an intermediate aneuploidy profile. A supervised clustering of somatic copy number alterations (SCNA) demonstrated that the size of PTEN deletions was not random, but comprised five distinct subtypes: (1) "Small Interstitial" (70 bp-789Kb); (2) "Large Interstitial" (1-7 MB); (3) "Large Proximal" (3-65 MB); (4) "Large Terminal" (8-64 MB), and (5) "Extensive" (71-132 MB). Many of the deleted fragments in each subtype were flanked by low copy repetitive (LCR) sequences. SCNAs such as gain at 3q21.1-3q29 and deletions at 8p, RB1 , TP53 and TMPRSS2-ERG were variably present in all subtypes. Other SCNAs appeared to be recurrent in some deletion subtypes, but absent from others. To determine how the aneuploidy influenced global levels of gene expression, we performed a comparative transcriptome analysis. One deletion subtype (Large Interstitial) was characterized by gene expression changes associated with angiogenesis and cell adhesion, structure, and metabolism. Logistic regression demonstrated that this deletion subtype was associated with a high Gleason score (HR = 2.386; 95% C.I. 1.245-4.572), extraprostatic extension (HR = 2.423, 95% C.I. 1.157-5.075), and metastasis (HR = 7.135; 95% C.I. 1.540-33.044). Univariate and multivariate

  7. MR Imaging Findings in Molecular Subtypes of Breast Cancer According to BIRADS System.

    Science.gov (United States)

    Navarro Vilar, Lidia; Alandete Germán, Salvador Pascual; Medina García, Rosana; Blanc García, Esther; Camarasa Lillo, Natalia; Vilar Samper, José

    2017-07-01

    To evaluate magnetic resonance imaging (MRI) findings, according to Breast Imaging-Reporting and Data System (BI-RADS), and to relate them with molecular subtypes of breast cancer. The MRI findings were reviewed retrospectively in 201 women diagnosed of invasive breast cancer confirmed by surgery and were compared with the molecular subtypes. Following the BI-RADS, MRI findings included disease type, size, enhancement, morphology and contrast kinetics. In mass-like lesion types were studied shape, margin and enhancement, and in nonmass-like lesion types, distribution modifiers and internal enhancement. Chi-squared analysis showed significant association (p < 0.01) between molecular subtypes and lesion type on MRI and histologic grade. Shape, margin and mass enhancement (p < 0.05) also showed significant association among molecular subtypes. Triple negative were more frequently unifocal and mass-like lesion, high histologic grade, round shape, smooth margin, and rim enhancement. Luminal-A were more frequently low grade, mass-like lesion, irregular shape and spiculated or irregular margin. Luminal-B were more frequently moderate-low grade, mass-like lesion, nonirregular shape and spiculated margin. HER-2-enriched were more frequently moderate grade, nonmass-like lesion and multicentric lesions were more present than in other subtypes. There are significantly different MRI features, according to BI-RADS, between the molecular subtypes breast cancer. © 2017 Wiley Periodicals, Inc.

  8. Molecular Subtypes of Indonesian Breast Carcinomas - Lack of Association with Patient Age and Tumor Size

    Science.gov (United States)

    Rahmawati, Yeni; Setyawati, Yunita; Widodo, Irianiwati; Ghozali, Ahmad; Purnomosari, Dewajani

    2018-01-27

    Objective: Breast carcinoma (BC) is a heterogeneous disease that exhibits variation in biological behaviour, prognosis and response to therapy. Molecular classification is generally into Luminal A, Luminal B, HER2+ and triple negative/basal-like, depending on receptor characteristics. Clinical factors that determined the BC prognosis are age and tumor size. Since information on molecular subtypes of Indonesian BCs is limited, the present study was conducted, with attention to subtypes in relation to age and tumor size. Methods: A retrospective cross-sectional study of 247 paraffin-embedded samples of invasive BC from Dr. Sardjito General Hospital Yogyakarta in the year 2012- 2015 was performed. Immunohistochemical staining using anti- ER, PR, HER2, Ki-67 and CK 5/6 antibodies was applied to classify molecular subtypes. Associations with age and tumor size were analyzed using the Chi Square Test. Results: The Luminal A was the most common subtype of Indonesian BC (41.3%), followed by triple negative (25.5%), HER2 (19.4%) and luminal B (13.8%). Among the triple negative lesions, the basal-like subtype was more frequent than the non basal-like (58.8 % vs 41.2%). Luminal B accounted for the highest percentage of younger age cases (age (> 50 years old) patients. Triple negative/basal-like were commonly large in size. Age (p = 0.080) and tumor size (p = 0.462) were not significantly associated with molecular subtypes of BC. Conclusion: The most common molecular subtype of Indonesian BC is luminal A, followed by triple-negative, HER2+ and luminal B. The majority of triple-negative lesions are basal-like. There are no association between age and tumor size with molecular subtypes of Indonesian BCs. Creative Commons Attribution License

  9. Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets.

    Science.gov (United States)

    Agarwal, Rahul; Narayan, Jitendra; Bhattacharyya, Amitava; Saraswat, Mayank; Tomar, Anil Kumar

    2017-10-01

    A very low 5-year survival rate among hepatocellular carcinoma (HCC) patients is mainly due to lack of early stage diagnosis, distant metastasis and high risk of postoperative recurrence. Hence ascertaining novel biomarkers for early diagnosis and patient specific therapeutics is crucial and urgent. Here, we have performed a comprehensive analysis of the expression data of 423 HCC patients (373 tumors and 50 controls) downloaded from The Cancer Genome Atlas (TCGA) followed by pathway enrichment by gene ontology annotations, subtype classification and overall survival analysis. The differential gene expression analysis using non-parametric Wilcoxon test revealed a total of 479 up-regulated and 91 down-regulated genes in HCC compared to controls. The list of top differentially expressed genes mainly consists of tumor/cancer associated genes, such as AFP, THBS4, LCN2, GPC3, NUF2, etc. The genes over-expressed in HCC were mainly associated with cell cycle pathways. In total, 59 kinases associated genes were found over-expressed in HCC, including TTK, MELK, BUB1, NEK2, BUB1B, AURKB, PLK1, CDK1, PKMYT1, PBK, etc. Overall four distinct HCC subtypes were predicted using consensus clustering method. Each subtype was unique in terms of gene expression, pathway enrichment and median survival. Conclusively, this study has exposed a number of interesting genes which can be exploited in future as potential markers of HCC, diagnostic as well as prognostic and subtype classification may guide for improved and specific therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  10. Right Sided Colon Cancer as a Distinct Histopathological Subtype with Reduced Prognosis.

    Science.gov (United States)

    Nitsche, Ulrich; Stögbauer, Fabian; Späth, Christoph; Haller, Bernhard; Wilhelm, Dirk; Friess, Helmut; Bader, Franz G

    2016-01-01

    Recent data suggest that tumors of the right and left colon should be distinguished as they differ in clinical and molecular characteristics. A total of 1,319 patients who underwent surgical resection for colon cancer (CC) were investigated. Tumors between the ileocecal valve and the hepatic flexure were classified as right CC (RCC), tumors between the splenic flexure and the rectum as left CC (LCC). RCC revealed a higher cause-specific mortality risk (hazard ratio 1.36, 95% CI 1.10-1.68, p = 0.005) and lower 5-year cause-specific (RCC 64.9%, 95% CI 60.4-69.4, LCC 70.7%, 95% CI 67.2-74.2, p = 0.032) and disease-free (RCC 56.0%, 95% CI 51.5-60.5, LCC 59.9%, 95% CI 56.2-63.6, p = 0.025) survival rates. RCCs were more often microsatellite instable (RCC 37.2%, LCC 13.0%, p clinical, histopathological and molecular genetic features and can be considered as distinct entities. The reduced prognosis of RCC may be caused by higher rates of microsatellite instability, KRAS and BRAF mutations. © 2016 S. Karger AG, Basel.

  11. Portraying the Expression Landscapes of B-CellLymphoma-Intuitive Detection of Outlier Samples and of Molecular Subtypes

    Directory of Open Access Journals (Sweden)

    Lydia Hopp

    2013-12-01

    Full Text Available We present an analytic framework based on Self-Organizing Map (SOM machine learning to study large scale patient data sets. The potency of the approach is demonstrated in a case study using gene expression data of more than 200 mature aggressive B-cell lymphoma patients. The method portrays each sample with individual resolution, characterizes the subtypes, disentangles the expression patterns into distinct modules, extracts their functional context using enrichment techniques and enables investigation of the similarity relations between the samples. The method also allows to detect and to correct outliers caused by contaminations. Based on our analysis, we propose a refined classification of B-cell Lymphoma into four molecular subtypes which are characterized by differential functional and clinical characteristics.

  12. Molecular subtyping of breast cancer improves identification of both high and low risk patients

    DEFF Research Database (Denmark)

    Rossing, Maria; Østrup, Olga; Majewski, Wiktor W.

    2018-01-01

    was performed on a consecutive and unselected series of 524 tumors from women with primary breast cancer (n = 508). Tumors were classified by the 256 gene expression signature (CIT) and compared to conventional immunohistochemistry (IHC) procedures. Results: More than 99% of tumors were eligible for molecular......Background: Transcriptome analysis enables classification of breast tumors into molecular subtypes that correlate with prognosis and effect of therapy. We evaluated the clinical benefits of molecular subtyping compared to our current diagnostic practice. Materials and methods: Molecular subtyping...... classification and final reports were available prior to the multidisciplinary conference. Using a prognostic standard mortality rate index (PSMRi) developed by the Danish Breast Cancer Group (DBCG) 39 patients were assigned with an intermediate risk and among these 16 (41%) were furthermore diagnosed...

  13. Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location.

    Science.gov (United States)

    Faisal, Farzana A; Sundi, Debasish; Tosoian, Jeffrey J; Choeurng, Voleak; Alshalalfa, Mohammed; Ross, Ashley E; Klein, Eric; Den, Robert; Dicker, Adam; Erho, Nicholas; Davicioni, Elai; Lotan, Tamara L; Schaeffer, Edward M

    2016-07-01

    Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, pRacial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling. This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships. Copyright © 2015. Published by Elsevier B.V.

  14. Association Between Imaging Characteristics and Different Molecular Subtypes of Breast Cancer.

    Science.gov (United States)

    Wu, Mingxiang; Ma, Jie

    2017-04-01

    Breast cancer can be divided into four major molecular subtypes based on the expression of hormone receptor (estrogen receptor and progesterone receptor), human epidermal growth factor receptor 2, HER2 status, and molecular proliferation rate (Ki67). In this study, we sought to investigate the association between breast cancer subtype and radiological findings in the Chinese population. Medical records of 300 consecutive invasive breast cancer patients were reviewed from the database: the Breast Imaging Reporting and Data System. The imaging characteristics of the lesions were evaluated. The molecular subtypes of breast cancer were classified into four types: luminal A, luminal B, HER2 overexpressed (HER2), and basal-like breast cancer (BLBC). Univariate and multivariate logistic regression analyses were performed to assess the association between the subtype (dependent variable) and mammography or 15 magnetic resonance imaging (MRI) indicators (independent variables). Luminal A and B subtypes were commonly associated with "clustered calcification distribution," "nipple invasion," or "skin invasion" (P cancers showed association with persistent enhancement in the delayed phase on MRI and "clustered calcification distribution" on mammography (P breast tumor, which are potentially useful tools in the diagnosis and subtyping of breast cancer. Copyright © 2017 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.

  15. Breast cancer in Ethiopia: evidence for geographic difference in the distribution of molecular subtypes in Africa.

    Science.gov (United States)

    Hadgu, Endale; Seifu, Daniel; Tigneh, Wondemagegnhu; Bokretsion, Yonas; Bekele, Abebe; Abebe, Markos; Sollie, Thomas; Merajver, Sofia D; Karlsson, Christina; Karlsson, Mats G

    2018-02-14

    Breast cancer is a heterogeneous disease with several morphological and molecular subtypes. Widely accepted molecular classification system uses assessment of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and proliferation marker Ki67. Few studies have been conducted on the incidence and molecular types of breast cancer in Sub-Saharan Africa. Previous studies mainly from Western and Central Africa, showed breast cancer to occur at younger ages and to present with aggressive features, such as high-grade, advanced stage and triple-negative phenotype (negative for ER, PR and HER2). Limited data from East Africa including Ethiopia however shows hormone receptor negative tumors to account for a lower proportion of all breast cancers than has been reported from elsewhere in Africa. In this study from Tikur Anbessa Specialized Hospital, 114 breast cancer patients diagnosed between 2012 and 2015 were enrolled. ER, PR, Ki67 and HER2 receptor status were assessed using immunohistochemistry from tissue microarrays. FISH was used for assessment of gene amplification in all equivocal tumor samples and for confirmation in HER2-enriched cases. The distribution of molecular subtypes was: Luminal A: 40%; Luminal B: 26%; HER2-enriched: 10%; TNBC: 23%. ER were positive in 65% of all tumors and 43% the cases were positive for PR. There was statistically significant difference in median age at diagnosis between the molecular subtypes (P molecular subtypes in different age ranges with Luminal B subtype being more common at younger ages (median = 36) and Luminal A subtype more prevalent at older ages (median = 42). There were no statistically significant differences in tumor grade, histology, and stage between the molecular subtypes of breast cancer. The present study detected Luminal A breast cancer to be the most common subtype and reveals a relatively low rate of hormone receptor negative and TNBC. Our findings and

  16. Beta-Sulfonamido Functionalized Aspartate Analogs as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype-Selectivity Profiles Arising from Subtle Structural Differences

    DEFF Research Database (Denmark)

    Hansen, Jacob Christian; Bjørn-Yoshimoto, Walden Emil; Bisballe, Niels

    2016-01-01

    EAAT inhibitors displaying IC50 values ∼1 μM at all three subtypes, this elaborate structure-activity relationship also identified analogues exhibiting distinct preferences or selectivities for specific transporter subtypes. Introduction of two fluorine atoms on the phenyl ring yielded analogue 4y...

  17. Relationships Between MRI Breast Imaging-Reporting and Data System (BI-RADS) Lexicon Descriptors and Breast Cancer Molecular Subtypes: Internal Enhancement is Associated with Luminal B Subtype.

    Science.gov (United States)

    Grimm, Lars J; Zhang, Jing; Baker, Jay A; Soo, Mary S; Johnson, Karen S; Mazurowski, Maciej A

    2017-09-01

    The aim of this study was to determine the associations between breast MRI findings using the Breast Imaging-Reporting and Data System (BI-RADS) lexicon descriptors and breast cancer molecular subtypes. In this retrospective, IRB-approved, single institution study MRIs from 278 women with breast cancer were reviewed by one of six fellowship-trained breast imagers. Readers reported BI-RADS descriptors for breast masses (shape, margin, internal enhancement) and non-mass enhancement (distribution, internal enhancement). Pathology reports were reviewed for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Surrogates were used to categorize tumors by molecular subtype: ER/PR+, HER2- (luminal A); ER/PR+, HER2+ (luminal B); ER/PR-, HER2+ (HER2); ER/PR/HER2- (basal). A univariate logistic regression model was developed to identify associations between BI-RADS descriptors and molecular subtypes. Internal enhancement for mass and non-mass enhancement was combined for analysis. There was an association between mass shape and basal subtype (p = 0.039), which was more frequently round (17.1%) than other subtypes (range: 0-8.3%). In addition, there was an association between mass margin and HER2 subtype (p = 0.040), as HER2 cancers more frequently had a smooth margin (33.3%) than other subtypes (range: 4.2-17.1%). Finally, there was an association between internal enhancement and luminal B subtype (p = 0.003), with no cases of luminal B cancer demonstrating homogeneous internal enhancement versus a range of 10.9-23.5% for other subtypes. There are associations between breast cancer molecular subtypes and lesion appearance on MRI using the BI-RADS lexicon. © 2017 Wiley Periodicals, Inc.

  18. Metastatic Organotropism: An Intrinsic Property of Breast Cancer Molecular Subtypes.

    Science.gov (United States)

    Wei, Shi; Siegal, Gene P

    2017-03-01

    It has long been known that some cancers have the propensity to metastasize to certain organs thus creating a nonrandom distribution of sites for distant relapse, a phenomenon known as "metastatic organotropism." Some of these examples include ovary primary to abdominal cavity, prostate primary to bone, and pancreas primary to liver. In contrast, other tumor types, such as mammary and renal cell carcinoma, can relapse in multiple organs although approximately half of advanced breast cancers metastasize to bone. On the other hand gene expression profiling studies have identified various breast cancer classes with prognostic significance. Recent studies have revealed that breast cancer subtypes differ not only in primary tumor characteristics but also in their metastatic behavior. In particular, the luminal tumors are remarkable for their significant bone-seeking phenotype; the HER2 subtype demonstrates a significant liver-homing characteristic; whereas so-called triple-negative breast cancers predispose to lung metastases. These findings suggest that this knowledge could potentially be utilized in the development of effective disease surveillance strategies in the pursuit of precision medicine, thus necessitating further investigation.

  19. Characterization of a novel mutation in the von Willebrand factor propeptide in a distinct subtype of recessive von Willebrand disease

    DEFF Research Database (Denmark)

    Lanke, Elsa; Kristoffersson, Ann-Charlotte; Philips, Malou

    2008-01-01

    , caused by a 1709G>C transition in exon 14 of the VWF gene coding for the propeptide. Three asymptomatic relatives were found to be heterozygous. In-vitro mutagenesis and expression in COS-7 cells confirmed the detrimental effect of the mutation on VWF multimerization. Our findings show that the C570S...... species which underlines its critical role. This variant constitutes a distinct subtype of recessive 2A VWD with the exclusive presence of the dimeric form of VWF in plasma Udgivelsesdato: 2008/8...

  20. Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma

    International Nuclear Information System (INIS)

    Janky, Rekin’s; Binda, Maria Mercedes; Allemeersch, Joke; Van den broeck, Anke; Govaere, Olivier; Swinnen, Johannes V.; Roskams, Tania; Aerts, Stein; Topal, Baki

    2016-01-01

    Pancreatic cancer is poorly characterized at genetic and non-genetic levels. The current study evaluates in a large cohort of patients the prognostic relevance of molecular subtypes and key transcription factors in pancreatic ductal adenocarcinoma (PDAC). We performed gene expression analysis of whole-tumor tissue obtained from 118 surgically resected PDAC and 13 histologically normal pancreatic tissue samples. Cox regression models were used to study the effect on survival of molecular subtypes and 16 clinicopathological prognostic factors. In order to better understand the biology of PDAC we used iRegulon to identify transcription factors (TFs) as master regulators of PDAC and its subtypes. We confirmed the PDAssign gene signature as classifier of PDAC in molecular subtypes with prognostic relevance. We found molecular subtypes, but not clinicopathological factors, as independent predictors of survival. Regulatory network analysis predicted that HNF1A/B are among thousand TFs the top enriched master regulators of the genes expressed in the normal pancreatic tissue compared to the PDAC regulatory network. On immunohistochemistry staining of PDAC samples, we observed low expression of HNF1B in well differentiated towards no expression in poorly differentiated PDAC samples. We predicted IRF/STAT, AP-1, and ETS-family members as key transcription factors in gene signatures downstream of mutated KRAS. PDAC can be classified in molecular subtypes that independently predict survival. HNF1A/B seem to be good candidates as master regulators of pancreatic differentiation, which at the protein level loses its expression in malignant ductal cells of the pancreas, suggesting its putative role as tumor suppressor in pancreatic cancer. The study was registered at ClinicalTrials.gov under the number NCT01116791 (May 3, 2010). The online version of this article (doi:10.1186/s12885-016-2540-6) contains supplementary material, which is available to authorized users

  1. Population dynamics and rates of molecular evolution of a recently emerged paramyxovirus, avian metapneumovirus subtype C.

    Science.gov (United States)

    Padhi, Abinash; Poss, Mary

    2009-02-01

    We report the existence of two distinct sublineages of avian metapneumovirus (MPV) subtype C, a virus which has caused serious economic loss in commercial turkey farms in the United States. This subtype is closely related to human MPV, infects multiple avian species, and is globally distributed. The evolutionary rates of this virus are estimated to be 1.3 x 10(-3) to 7 x 10(-3) substitutions per site per year, and coalescent estimates place its emergence between 1991 and 1996. The four genes examined show a concordant demographic pattern which is characterized by a rapid increase in population size followed by stable population grown until the present.

  2. Distinct classical and molecular cytogenetics of Astyanax marionae ...

    Indian Academy of Sciences (India)

    DIOVANI PISCOR

    2017-08-24

    Aug 24, 2017 ... DOI 10.1007/s12041-017-0813-8. RESEARCH ARTICLE. Distinct classical and molecular cytogenetics of Astyanax marionae ... 1Laboratório de Citogenética, Departamento de Biologia, Instituto de Biociências, Universidade Estadual Paulista 'Júlio de Mesquita Filho' (UNESP), Av. 24A, 1515, 13506-900, ...

  3. High-resolution molecular epidemiology and evolutionary history of HIV-1 subtypes in Albania.

    Directory of Open Access Journals (Sweden)

    Marco Salemi

    2008-01-01

    Full Text Available HIV-1 epidemic in Western Europe is largely due to subtype B. Little is known about the HIV-1 in Eastern Europe, but a few studies have shown that non-B subtypes are quite common. In Albania, where a recent study estimated a ten-fold increase of AIDS incidence during the last six years, subtype A and B account for 90% of the know infections.We investigated the demographic history of HIV-1 subtype A and B in Albania by using a statistical framework based on coalescent theory and phylogeography. High-resolution phylogenetic and molecular clock analysis showed a limited introduction to the Balkan country of subtype A during the late 1980s followed by an epidemic outburst in the early 1990 s. In contrast, subtype B was apparently introduced multiple times between the mid-1970s and mid-1980s. Both subtypes are growing exponentially, although the HIV-1A epidemic displays a faster growth rate, and a significantly higher basic reproductive number R(0. HIV-1A gene flow occurs primarily from the capital Tirane, in the center of the country, to the periphery, while HIV-1B flow is characterized by a balanced exchange between center and periphery. Finally, we calculated that the actual number of infections in Albania is at least two orders of magnitude higher than previously thought.Our analysis demonstrates the power of recently developed computational tools to investigate molecular epidemiology of pathogens, and emphasize the complex factors involved in the establishment of HIV-1 epidemics. We suggest that a significant correlation exists between HIV-1 exponential spread and the socio-political changes occurred during the Balkan wars. The fast growth of a relatively new non-B epidemic in the Balkans may have significant consequences for the evolution of HIV-1 epidemiology in neighboring countries in Eastern and Western Europe.

  4. Functional and Developmental Identification of a Molecular Subtype of Brain Serotonergic Neuron Specialized to Regulate Breathing Dynamics

    Directory of Open Access Journals (Sweden)

    Rachael D. Brust

    2014-12-01

    Full Text Available Serotonergic neurons modulate behavioral and physiological responses from aggression and anxiety to breathing and thermoregulation. Disorders involving serotonin (5HT dysregulation are commensurately heterogeneous and numerous. We hypothesized that this breadth in functionality derives in part from a developmentally determined substructure of distinct subtypes of 5HT neurons each specialized to modulate specific behaviors. By manipulating developmentally defined subgroups one by one chemogenetically, we find that the Egr2-Pet1 subgroup is specialized to drive increased ventilation in response to carbon dioxide elevation and acidosis. Furthermore, this subtype exhibits intrinsic chemosensitivity and modality-specific projections—increasing firing during hypercapnic acidosis and selectively projecting to respiratory chemosensory but not motor centers, respectively. These findings show that serotonergic regulation of the respiratory chemoreflex is mediated by a specialized molecular subtype of 5HT neuron harboring unique physiological, biophysical, and hodological properties specified developmentally and demonstrate that the serotonergic system contains specialized modules contributing to its collective functional breadth.

  5. Association between {sup 18}F-FDG uptake and molecular subtype of breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Kitajima, Kazuhiro; Fukushima, Kazuhito; Igarashi, Yoko; Katsuura, Takayuki; Maruyama, Kaoru [Hyogo College of Medicine, Department of Nuclear Medicine and PET center, Nishinomiya, Hyogo (Japan); Miyoshi, Yasuo; Nishimukai, Arisa [Hyogo College of Medicine, Department of Breast and Endocrine Surgery, Nishinomiya, Hyogo (Japan); Hirota, Seiichi [Hyogo College of Medicine, Department of Surgical Pathology, Nishinomiya, Hyogo (Japan); Hirota, Shozo [Hyogo College of Medicine, Department of Radiology, Nishinomiya, Hyogo (Japan)

    2015-08-15

    To determine whether {sup 18}F-FDG uptake in breast cancer correlates with immunohistochemically defined subtype and is able to predict molecular subtypes. This retrospective study involved 306 patients with 308 mass-type invasive breast cancers (mean size 2.65 cm, range 1.0-15.0 cm) who underwent {sup 18}F-FDG PET/CT before therapy. The correlations between primary tumour {sup 18}F-FDG uptake on PET/CT, expressed as SUVmax, and clinicopathological findings and molecular subtype, i.e. luminal A, luminal B (HER2-negative), luminal B (HER2-positive), HER2-positive and triple-negative, were analysed. The predictors of these subtypes were investigated. The mean SUVmax of the 308 tumours was 5.33 ± 3.63 (range 1.15-19.01). Among the subtypes of the 308 tumours, 87 (28.2 %) were luminal A, 111 (36.0 %) were luminal B (HER2-negative), 31 (10.1 %) were luminal B (HER2-positive), 26 (8.4 %) were HER2-positive and 53 (17.2 %) were triple-negative, and the corresponding mean SUVmax were 3.41 ± 2.07 (range 1.18-14.30), 5.17 ± 3.52 (range 1.35-19.01), 6.57 ± 3.84 (range 1.42-15.58), 7.55 ± 3.63 (range 2.30-13.60) and 6.97 ± 4.17 (range 1.15-16.06), respectively. A cut-off value of 3.60 yielded 70.1 % sensitivity and 66.1 % specificity with an area under the receiver operating characteristics curve (AUC) of 0.734 for predicting that a tumour was of the luminal A subtype. A cut-off value of 6.75 yielded 65.4 % sensitivity and 75.2 % specificity with an AUC of 0.704 for predicting a HER2-positive subtype. SUVmax, a metabolic semiquantitative parameter, shows a significant correlation with the molecular subtype of breast cancer, and is useful for predicting the luminal A or HER2-positive subtype. (orig.)

  6. Molecular signatures define alopecia areata subtypes and transcriptional biomarkers

    Directory of Open Access Journals (Sweden)

    Ali Jabbari

    2016-05-01

    Full Text Available Alopecia areata (AA is an autoimmune disease typified by nonscarring hair loss with a variable clinical course. In this study, we conducted whole genome gene expression analysis of 96 human scalp skin biopsy specimens from AA or normal control subjects. Based on gene expression profiling, samples formed distinct clusters based on the presence or absence of disease as well as disease phenotype (patchy disease compared with alopecia totalis or universalis. Differential gene expression analysis allowed us to robustly demonstrate graded immune activity in samples of increasing phenotypic severity and generate a quantitative gene expression scoring system that classified samples based on interferon and cytotoxic T lymphocyte immune signatures critical for disease pathogenesis.

  7. Distinct Neural Signatures Detected for ADHD Subtypes After Controlling for Micro-Movements in Resting State Functional Connectivity MRI Data

    Directory of Open Access Journals (Sweden)

    Damien eFair

    2013-02-01

    Full Text Available In recent years, there has been growing enthusiasm that functional MRI could achieve clinical utility for a broad range of neuropsychiatric disorders. However, several barriers remain. For example, the acquisition of large-scale datasets capable of clarifying the marked heterogeneity that exists in psychiatric illnesses will need to be realized. In addition, there continues to be a need for the development of image processing and analysis methods capable of separating signal from artifact. As a prototypical hyperkinetic disorder, and movement related artifact being a significant confound in functional imaging studies, ADHD offers a unique challenge. As part of the ADHD-200 Global Competition and this special edition of Frontiers, the ADHD-200 Consortium demonstrates the utility of an aggregate dataset pooled across five institutions in addressing these challenges. The work aimed to A examine the impact of emerging techniques for controlling for micro-movements, and B provide novel insights into the neural correlates of ADHD subtypes. Using SVM based MVPA we show that functional connectivity patterns in individuals are capable of differentiating the two most prominent ADHD subtypes. The application of graph-theory revealed that the Combined (ADHD-C and Inattentive (ADHD-I subtypes demonstrated some overlapping (particularly sensorimotor systems, but unique patterns of atypical connectivity. For ADHD-C, atypical connectivity was prominent in midline default network components, as well as insular cortex; in contrast, the ADHD-I group exhibited atypical patterns within the dlPFC regions and cerebellum. Systematic motion-related artifact was noted, and highlighted the need for stringent motion correction. Findings reported were robust to the specific motion correction strategy employed. These data suggest that rs-fcMRI data can be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical

  8. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy.

    Science.gov (United States)

    Seiler, Roland; Ashab, Hussam Al Deen; Erho, Nicholas; van Rhijn, Bas W G; Winters, Brian; Douglas, James; Van Kessel, Kim E; Fransen van de Putte, Elisabeth E; Sommerlad, Matthew; Wang, Natalie Q; Choeurng, Voleak; Gibb, Ewan A; Palmer-Aronsten, Beatrix; Lam, Lucia L; Buerki, Christine; Davicioni, Elai; Sjödahl, Gottfrid; Kardos, Jordan; Hoadley, Katherine A; Lerner, Seth P; McConkey, David J; Choi, Woonyoung; Kim, William Y; Kiss, Bernhard; Thalmann, George N; Todenhöfer, Tilman; Crabb, Simon J; North, Scott; Zwarthoff, Ellen C; Boormans, Joost L; Wright, Jonathan; Dall'Era, Marc; van der Heijden, Michiel S; Black, Peter C

    2017-10-01

    An early report on the molecular subtyping of muscle-invasive bladder cancer (MIBC) by gene expression suggested that response to neoadjuvant chemotherapy (NAC) varies by subtype. To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC. Whole transcriptome profiling was performed on pre-NAC transurethral resection specimens from 343 patients with MIBC. Samples were classified according to four published molecular subtyping methods. We developed a single-sample genomic subtyping classifier (GSC) to predict consensus subtypes (claudin-low, basal, luminal-infiltrated and luminal) with highest clinical impact in the context of NAC. Overall survival (OS) according to subtype was analyzed and compared with OS in 476 non-NAC cases (published datasets). Gene expression analysis was used to assign subtypes. Receiver-operating characteristics were used to determine the accuracy of GSC. The effect of GSC on survival was estimated by Cox proportional hazard regression models. The models generated subtype calls in expected ratios with high concordance across subtyping methods. GSC was able to predict four consensus molecular subtypes with high accuracy (73%), and clinical significance of the predicted consensus subtypes could be validated in independent NAC and non-NAC datasets. Luminal tumors had the best OS with and without NAC. Claudin-low tumors were associated with poor OS irrespective of treatment regimen. Basal tumors showed the most improvement in OS with NAC compared with surgery alone. The main limitations of our study are its retrospective design and comparison across datasets. Molecular subtyping may have an impact on patient benefit to NAC. If validated in additional studies, our results suggest that patients with basal tumors should be prioritized for NAC. We discovered the first single-sample classifier to subtype MIBC, which may be suitable for integration into routine clinical practice. Different molecular

  9. Molecular subtypes and phenotypic expression of Beckwith-Wiedemann syndrome.

    Science.gov (United States)

    Cooper, Wendy N; Luharia, Anita; Evans, Gail A; Raza, Hussain; Haire, Antonita C; Grundy, Richard; Bowdin, Sarah C; Riccio, Andrea; Sebastio, Gianfranco; Bliek, Jet; Schofield, Paul N; Reik, Wolf; Macdonald, Fiona; Maher, Eamonn R

    2005-09-01

    Beckwith-Wiedemann Syndrome (BWS) results from mutations or epigenetic events involving imprinted genes at 11p15.5. Most BWS cases are sporadic and uniparental disomy (UPD) or putative imprinting errors predominate in this group. Sporadic cases with putative imprinting defects may be subdivided into (a) those with loss of imprinting (LOI) of IGF2 and H19 hypermethylation and silencing due to a defect in a distal 11p15.5 imprinting control element (IC1) and (b) those with loss of methylation at KvDMR1, LOI of KCNQ1OT1 (LIT1) and variable LOI of IGF2 in whom there is a defect at a more proximal imprinting control element (IC2). We investigated genotype/epigenotype-phenotype correlations in 200 cases with a confirmed molecular genetic diagnosis of BWS (16 with CDKN1C mutations, 116 with imprinting centre 2 defects, 14 with imprinting centre 1 defects and 54 with UPD). Hemihypertrophy was strongly associated with UPD (Pmanagement and surveillance of BWS children such that screening for Wilms' tumour and hepatoblastoma can be focused on those at highest risk.

  10. Multiple distinct subtypes of GABAergic neurons in mouse visual cortex identified by triple immunostaining

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    Yuri Gonchar

    2008-03-01

    Full Text Available The majority of cortical interneurons use GABA (gamma amino butyric acid as inhibitory neurotransmitter. GABAergic neurons are morphologically, connectionally, electrically and chemically heterogeneous. In rat cerebral cortex three distinct groups of GABAergic interneurons have been identifi ed by the expression of parvalbumin (PV, calretinin (CR and somatostatin (SOM. Recent studies in mouse cerebral cortex have revealed a different organization in which the CR and SOM populations are partially overlapping. Because CR and SOM neurons derive from different progenitors located in different embryonic structures, the coexpression of CR + SOM suggests that the chemical differentiation of interneurons is regulated postmitotically. Here, we have taken an important fi rst step towards understanding this process by triple immunostaining mouse visual cortex with a panel of antibodies, which has been used extensively for classifying developing interneurons. We have found at least 13 distinct groups of GABAergic neurons which include PV, CR, SOM, CCK (cholecystokinin, CR + SOM, CR + NPY (neuropeptide Y, CR + VIP (vasointestinal polypeptide, SOM + NPY, SOM + VIP, VIP + ChAT (choline acetyltransferase, CCK + NPY, CR + SOM + NPY and CR + SOM + VIP expressing cells. Triple immunostaining with PV, CR and SOM antibodies during postnatal development further showed that PV is never colocalized with CR and SOM. Importantly, expression of SOM and CR + SOM developed after the percentage of CR cells that do not express SOM has reached the mature level, suggesting that the chemical differentiation of SOM and CR + SOM neurons is a postnatal event, which may be controlled by transcriptional regulation.

  11. Integration of gene expression and DNA-methylation profiles improves molecular subtype classification in acute myeloid leukemia.

    Science.gov (United States)

    Taskesen, Erdogan; Babaei, Sepideh; Reinders, Marcel M J; de Ridder, Jeroen

    2015-01-01

    Acute Myeloid Leukemia (AML) is characterized by various cytogenetic and molecular abnormalities. Detection of these abnormalities is important in the risk-classification of patients but requires laborious experimentation. Various studies showed that gene expression profiles (GEP), and the gene signatures derived from GEP, can be used for the prediction of subtypes in AML. Similarly, successful prediction was also achieved by exploiting DNA-methylation profiles (DMP). There are, however, no studies that compared classification accuracy and performance between GEP and DMP, neither are there studies that integrated both types of data to determine whether predictive power can be improved. Here, we used 344 well-characterized AML samples for which both gene expression and DNA-methylation profiles are available. We created three different classification strategies including early, late and no integration of these datasets and used them to predict AML subtypes using a logistic regression model with Lasso regularization. We illustrate that both gene expression and DNA-methylation profiles contain distinct patterns that contribute to discriminating AML subtypes and that an integration strategy can exploit these patterns to achieve synergy between both data types. We show that concatenation of features from both data sets, i.e. early integration, improves the predictive power compared to classifiers trained on GEP or DMP alone. A more sophisticated strategy, i.e. the late integration strategy, employs a two-layer classifier which outperforms the early integration strategy. We demonstrate that prediction of known cytogenetic and molecular abnormalities in AML can be further improved by integrating GEP and DMP profiles.

  12. Ki-67 as a prognostic marker according to breast cancer molecular subtype

    OpenAIRE

    Soliman, Nahed A.; Yussif, Shaimaa M.

    2016-01-01

    Objective: Ki-67 plays an important function in cell division, but its exact role is still unknown. Moreover, few works regarding its overall function were published. The present study evaluated the clinical significance of Ki-67 index as a prognostic marker and predictor of recurrence in different molecular subtypes of breast cancer. The relationship of Ki-67 index with different clinicopathological factors was also analyzed. Methods: Ki-67 index was measured in 107 cases of primary breast c...

  13. New insights into the metastatic behavior after breast cancer surgery, according to well-established clinicopathological variables and molecular subtypes.

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    Oreste Claudio Buonomo

    Full Text Available Despite advances in treatment, up to 30% of patients with early breast cancer (BC experience distant disease relapse. However, a comprehensive understanding of tumor spread and site-specific recurrence patterns remains lacking. This retrospective case-control study included 103 consecutive patients with metastatic BC admitted to our institution (2000-2013. Cases were matched according to age, tumor biology, and clinicopathological features to 221 patients with non-metastatic BC (control group. The median follow-up period among the 324 eligible patients was 7.3 years. While relatively low values for sensitivity (71% and specificity (56% were found for axillary lymph node (ALN involvement as an indicator of risk and pattern of distant relapse, nodal status remained the most powerful predictor of metastases (OR: 3.294; CL: 1.9-5.5. Rates of dissemination and metastatic efficiency differed according to molecular subtype. HER2-positive subtypes showed a stronger association with systemic spread (OR: 2.127; CL: 1.2-3.8 than other subgroups. Classification as Luminal or Non-Luminal showed an increased risk of lung and distant nodal recurrence, and a decreased risk in bone metastases in the Non-Luminal group (OR: 2.9, 3.345, and 0.2, respectively. Tumors with HER2 overexpression had a significantly high risk for distant relapse (OR: 2.127 compared with HER2-negative tumors and also showed higher central nervous system (CNS and lung metastatic potential (OR: 5.6 and 2.65, respectively and low risk of bone disease progression (OR: 0.294. Furthermore, we found significant associations between biological profiles and sites of recurrence. A new process of clinical/diagnostic staging, including molecular subtypes, could better predict the likelihood of distant relapses and their anatomical location. Recognition and appreciation of clinically distinct molecular subtypes may assist in evaluation of the probability of distant relapses and their sites. Our

  14. A distinct subtype of ``metatropic dysplasia variant`` characterised by advanced carpal skeletal age and subluxation of the radial heads

    Energy Technology Data Exchange (ETDEWEB)

    Nishimura, G. [Department of Radiology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu Shimotsuga-gun, Tochigi-ken 321-02 (Japan); Satoh, Masato [Department of Orthopedics, Saitama Children`s Medical Center, Saitama (Japan); Aihara, Toshinori [Department of Radiology, Saitama Children`s Medical Center, Saitama (Japan); Aida, Noriko [Department of Radiology, Kanagawa Children`s Medical Center, Yokohama (Japan); Yamamoto, Takehisa [Department of Pediatrics, Osaka University School of Medicine, Osaka (Japan); Ozono, Keiichi [Department of Environmental Medicine, Osaka Medical Center and Institute for Maternal and Child Health, Osaka (Japan)

    1998-02-01

    Background. ``Metatropic dysplasia variants`` are a group of bone dysplasias whose skeletal abnormalities are similar to, but milder than, those of classical metatropic dysplasia. The genetic and phenotypic heterogeneity has not been thoroughly elucidated. Objective. The objective was to designate a distinct subtype of these metatropic dysplasia variants. Materials and methods. The subjects were four Japanese patients, two sporadic cases and two siblings, who all had identical skeletal changes. The radiological features in these patients were compared with those of previously reported metatropic dysplasia variants. Results. Moderate platyspondyly with pear-shaped and/or anterior-tongued vertebral bodies, halberd pelvis, and dumbbell deformity of the tubular bones were regarded as hallmarks of metatropic dysplasia variants. The peculiar skeletal change in our patients was advanced carpal skeletal age in childhood, unlike most patients reported as metatropic dysplasia variants who manifest delayed carpal ossification. Another hallmark was congenital dislocation of the radial heads. A description of a patient with similar skeletal changes was found in the literature. Conclusion. These patients are considered to represent a distinct subgroup of metatropic dysplasia variants. It remains unknown whether the present siblings represent an autosomal recessive trait or an autosomal dominant trait with germinal mosaicism related to increased paternal age. (orig.) With 3 figs., 10 refs.

  15. Virus Infection Triggers MAVS Polymers of Distinct Molecular Weight

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    Natalia Zamorano Cuervo

    2018-01-01

    Full Text Available The mitochondrial antiviral signaling (MAVS adaptor protein is a central signaling hub required for cells to mount an antiviral response following virus sensing by retinoic acid-inducible gene I (RIG-I-like receptors. MAVS localizes in the membrane of mitochondria and peroxisomes and in mitochondrial-associated endoplasmic reticulum membranes. Structural and functional studies have revealed that MAVS activity relies on the formation of functional high molecular weight prion-like aggregates. The formation of protein aggregates typically relies on a dynamic transition between oligomerization and aggregation states. The existence of intermediate state(s of MAVS polymers, other than aggregates, has not yet been documented. Here, we used a combination of non-reducing SDS-PAGE and semi-denaturing detergent agarose gel electrophoresis (SDD-AGE to resolve whole cell extract preparations to distinguish MAVS polymerization states. While SDD-AGE analysis of whole cell extracts revealed the formation of previously described high molecular weight prion-like aggregates upon constitutively active RIG-I ectopic expression and virus infection, non-reducing SDS-PAGE allowed us to demonstrate the induction of lower molecular weight oligomers. Cleavage of MAVS using the NS3/4A protease revealed that anchoring to intracellular membranes is required for the appropriate polymerization into active high molecular weight aggregates. Altogether, our data suggest that RIG-I-dependent MAVS activation involves the coexistence of MAVS polymers with distinct molecular weights.

  16. Social cognitive impairments and negative symptoms in schizophrenia: are there subtypes with distinct functional correlates?

    Science.gov (United States)

    Bell, Morris D; Corbera, Silvia; Johannesen, Jason K; Fiszdon, Joanna M; Wexler, Bruce E

    2013-01-01

    Social cognitive impairments and negative symptoms are core features of schizophrenia closely associated with impaired community functioning. However, little is known about whether these are independent dimensions of illness and if so, whether individuals with schizophrenia can be meaningfully classified based on these dimensions (SANS) and potentially differentially treated. Five social cognitive measures plus Scale for the Assessment of Negative Symptoms (SANS) and Positive and Negative Syndrome Scale (PANSS) scores in a sample of 77 outpatients produced 2 distinct factors--a social cognitive factor and a negative symptom factor. Factor scores were used in a cluster analysis, which yielded 3 well-defined groupings--a high negative symptom group (HN) and 2 low negative symptom groups, 1 with higher social cognition (HSC) and 1 with low social cognition (LSC). To make these findings more practicable for research and clinical settings, a rule of thumb for categorizing using only the Mayer-Salovey-Caruso Emotional Intelligence Test and PANSS negative component was created and produced 84.4% agreement with the original cluster groups. An additional 63 subjects were added to cross validate the rule of thumb. When samples were combined (N = 140), the HSC group had significantly better quality of life and Global Assessment of Functioning (GAF) scores, higher rates of marriage and more hospitalizations. The LSC group had worse criminal and substance abuse histories. With 2 common assessment instruments, people with schizophrenia can be classified into 3 subgroups that have different barriers to community integration and could potentially benefit from different treatments.

  17. Lineage Reprogramming of Astroglial Cells from Different Origins into Distinct Neuronal Subtypes

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    Malek Chouchane

    2017-07-01

    Full Text Available Astroglial cells isolated from the rodent postnatal cerebral cortex are particularly susceptible to lineage reprogramming into neurons. However, it remains unknown whether other astroglial populations retain the same potential. Likewise, little is known about the fate of induced neurons (iNs in vivo. In this study we addressed these questions using two different astroglial populations isolated from the postnatal brain reprogrammed either with Neurogenin-2 (Neurog2 or Achaete scute homolog-1 (Ascl1. We show that cerebellum (CerebAstro and cerebral cortex astroglia (CtxAstro generates iNs with distinctive neurochemical and morphological properties. Both astroglial populations contribute iNs to the olfactory bulb following transplantation in the postnatal and adult mouse subventricular zone. However, only CtxAstro transfected with Neurog2 differentiate into pyramidal-like iNs after transplantation in the postnatal cerebral cortex. Altogether, our data indicate that the origin of the astroglial population and transcription factors used for reprogramming, as well as the region of integration, affect the fate of iNs.

  18. Molecular subtypes of metastatic colorectal cancer are associated with patient response to irinotecan-based therapies.

    Science.gov (United States)

    Del Rio, M; Mollevi, C; Bibeau, F; Vie, N; Selves, J; Emile, J-F; Roger, P; Gongora, C; Robert, J; Tubiana-Mathieu, N; Ychou, M; Martineau, P

    2017-05-01

    Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first-line therapy. We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed. We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P=0.003), but not to FOLFOX (P=0.911) and FOLFIRI + Bevacizumab (P=0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months). Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some patients. This however remains to be confirmed in a large prospective clinical trial. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. 15-prostaglandin dehydrogenase expression alone or in combination with ACSM1 defines a subgroup of the apocrine molecular subtype of breast carcinoma

    DEFF Research Database (Denmark)

    Celis, J.E.; Gromov, P.; Cabezon, T.

    2008-01-01

    , papillary, medullary, metaplastic, and apocrine breast carcinomas. Molecular profiling technologies, on the other hand, subdivide breast tumors into five subtypes, basal-like, luminal A, luminal B, normal breast tissue-like, and ERBB2-positive, that have different prognostic characteristics. An additional......Established histopathological criteria divide invasive breast carcinomas into defined groups. Ductal of no specific type and lobular are the two major subtypes accounting for around 75 and 15% of all cases, respectively. The remaining 10% include rarer types such as tubular, cribriform, mucinous...... subclass termed "molecular apocrine" has recently been described, but these lesions did not exhibit all the histopathological features of classical invasive apocrine carcinomas (IACs). IACs make up 0.5-3% of the invasive ductal carcinomas, and despite the fact that they are morphologically distinct from...

  20. Molecular epizootiology of recurrent low pathogenic avian influenza by H9N2 subtype virus in Korea.

    Science.gov (United States)

    Kwon, Hyuk-Joon; Cho, Sun-Hee; Kim, Min-Chul; Ahn, Young-Jin; Kim, Sun-Joong

    2006-08-01

    The first outbreak of low pathogenic avian influenza (LPAI), H9N2 virus subtype, in 1996 prompted an eradication response, but LPAI returned to Korea in 1999. The relationship between the first and the recurrent viruses is unclear. To determine the molecular epizootiology of recurrent LPAI, we performed phylogenetic analysis with partial nucleotide sequences of four gene segments (HA, NA, NP and PB2) from eight chicken-origin H9N2 viruses. The recurrent H9N2 viruses showed higher nucleotide similarity in haemagglutinin and neuraminidase genes to the 1996 Korean isolates than other Eurasian viruses, and formed a distinct cluster with the early Korean isolates and some isolates from migratory and domestic ducks in Japan and China. Phylogenetic analysis with internal genes showed that some Korean isolates formed a cluster with other subtypes, such as H5N1, H6N1, and H6N2 in China and Taiwan. These results suggest that the recurrent viruses are progeny of the early Korean H9N2 isolates, but further studies are required to explain their phylogenetic relatedness to viruses in China.

  1. BI-RADS 3-5 microcalcifications can preoperatively predict breast cancer HER2 and Luminal a molecular subtype.

    Science.gov (United States)

    Cen, DongZhi; Xu, Li; Li, Ningna; Chen, Zhiguang; Wang, Lu; Zhou, Shuqin; Xu, Biao; Liu, Chun Ling; Liu, Zaiyi; Luo, Tingting

    2017-02-21

    To investigate associations between breast cancer molecular subtype and the patterns of mammographically detected calcifications. Identified were 93 (19.1%) Luminal A, 242 (49.9%) Luminal B, 108 (22.2%) HER2 and 42 (8.7%) basal subtypes. In univariate analysis, the clinicopathological parameters and BI-RADS 3-5 microcalcifications, which consisted 9 selected features was significantly associated with breast cancer molecular subtype (all P 2 cm in range (OR: 1.878, 95% CI: 1.150 to 3.067) and calcification > 0.5 mm in diameter (OR:2.206, 95% CI: 1.235 to 3.323) was independently predictive of HER2 subtype. The model showed good discrimination for predicting HER2 subtype, with a C-index of 0.704. In addition, multivariate analysis showed that calcification morphology (amorphour or coarse heterogenous calcifications OR: 2.847, 95% CI: 1.526 to 5.312) was independently predictive of Luminal A subtype. The model showed good discrimination for predicting Luminal A subtype, with a C-index of 0.74. And we demonstrated that amorphour or coarse heterogenous calcifications were associated with a higher incidence of Luminal A subtype than pleomorphic or fine linear or branching calcifications. There was no significant difference between breast cancer subtypes (Luminal B vs. other; Basal vs. other) and the patterns of mammographically detected calcifications. Mammographic images of 485 female patients were included. The correlation between mammographic imaging features and breast cancer subtype was analyzed using Chi-square test, univariate and binary logistic regression analysis. This study shows that BI-RADS 3-5 microcalcifications can be conveniently used to facilitate the preoperative prediction of HER2 and Luminal A molecular subtype in patients with infiltrating ductal carcinoma.

  2. Molecular-based tumour subtypes of canine mammary carcinomas assessed by immunohistochemistry

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    Sarli Giuseppe

    2010-01-01

    Full Text Available Abstract Background Human breast cancer is classified by gene expression profile into subtypes consisting of two hormone (oestrogen and/or progesterone receptor-positive types (luminal-like A and luminal-like B and three hormone receptor-negative types [human epidermal growth factor receptor 2-expressing, basal-like, and unclassified ("normal-like"]. Immunohistochemical surrogate panels are also proposed to potentially identify the molecular-based groups. The present study aimed to apply an immunohistochemical panel (anti-ER, -PR, -ERB-B2, -CK 5/6 and -CK14 in a series of canine malignant mammary tumours to verify the molecular-based classification, its correlation with invasion and grade, and its use as a prognostic aid in veterinary practice. Results Thirty-five tumours with luminal pattern (ER+ and PR+ were subgrouped into 13 A type and 22 B type, if ERB-B2 positive or negative. Most luminal-like A and basal-like tumours were grade 1 carcinomas, while the percentage of luminal B tumours was higher in grades 2 and 3 (Pearson Chi-square P = 0.009. No difference in the percentage of molecular subtypes was found between simple and complex/mixed carcinomas (Pearson Chi-square P = 0.47. No significant results were obtained by survival analysis, even if basal-like tumours had a more favourable prognosis than luminal-like lesions. Conclusion The panel of antibodies identified only three tumour groups (luminal-like A and B, and basal-like in the dog. Even though canine mammary tumours may be a model of human breast cancer, the existence of the same carcinoma molecular subtypes in women awaits confirmation. Canine mammary carcinomas show high molecular heterogeneity, which would benefit from a classification based on molecular differences. Stage and grade showed independent associations with survival in the multivariate regression, while molecular subtype grouping and histological type did not show associations. This suggests that caution should be

  3. Dietary Patterns and Risk of Colorectal Cancer: Analysis by Tumor Location and Molecular Subtypes.

    Science.gov (United States)

    Mehta, Raaj S; Song, Mingyang; Nishihara, Reiko; Drew, David A; Wu, Kana; Qian, Zhi Rong; Fung, Teresa T; Hamada, Tsuyoshi; Masugi, Yohei; da Silva, Annacarolina; Shi, Yan; Li, Wanwan; Gu, Mancang; Willett, Walter C; Fuchs, Charles S; Giovannucci, Edward L; Ogino, Shuji; Chan, Andrew T

    2017-06-01

    Western and prudent dietary patterns have been associated with higher and lower risks of colorectal cancer (CRC), respectively. However, little is known about the associations between dietary patterns and specific anatomic subsites or molecular subtypes of CRC. We used multivariable Cox proportional hazards models to examine the associations between Western and prudent dietary patterns and CRC risk in the Health Professionals Follow-up Study and Nurses' Health Study. After up to 32 years of follow-up of 137,217 men and women, we documented 3260 cases of CRC. Among individuals from whom subsite data were available, we observed 1264 proximal colon, 866 distal colon, and 670 rectal tumors. Western diet was associated with an increased incidence of CRC (P trend pattern, we observed a RR of 0.86 for overall CRC (95% CI, 0.77-0.95; P trend  = .01), with similar trends at anatomic subsites. However, the trend appeared stronger among men than women. Among 1285 cases (39%) with tissue available for molecular profiling, Western diet appeared to be more strongly associated with some CRC molecular subtypes (no mutations in KRAS [KRAS wildtype] or BRAF [BRAF wildtype], no or a low CpG island methylator phenotype, and microsatellite stability), although formal tests for heterogeneity did not produce statistically significant results. Western dietary patterns are associated with an increased risk of CRC, particularly distal colon and rectal tumors. Western dietary patterns also appear more strongly associated with tumors that are KRAS wildtype, BRAF wildtype, have no or a low CpG island methylator phenotype, and microsatellite stability. In contrast, prudent dietary patterns are associated with a lower risk of CRC that does not vary according to anatomic subsite or molecular subtype. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  4. Structural brain alterations associated with schizophrenia preceded by conduct disorder: a common and distinct subtype of schizophrenia?

    Science.gov (United States)

    Schiffer, Boris; Leygraf, Norbert; Müller, Bernhard W; Scherbaum, Norbert; Forsting, Michael; Wiltfang, Jens; Gizewski, Elke R; Hodgins, Sheilagh

    2013-09-01

    Conduct disorder (CD) prior to age 15 is a precursor of schizophrenia in a minority of cases and is associated with violent behavior through adulthood, after taking account of substance misuse. The present study used structural magnetic imaging to examine gray matter (GM) volumes among 27 men with schizophrenia preceded by CD (SZ+CD), 23 men with schizophrenia but without CD (SZ-CD), 27 men with CD only (CD), and 25 healthy (H) men. The groups with schizophrenia were similar in terms of age of onset and duration of illness, levels of psychotic symptoms, and medication. The 2 groups with CD were similar as to number of CD symptoms, lifelong aggressive behavior, and number of criminal convictions. Men with SZ+CD, relative to those with SZ-CD, displayed (1) increased GM volumes in the hypothalamus, the left putamen, the right cuneus/precuneus, and the right inferior parietal cortex after controlling for age, alcohol, and drug misuse and (2) decreased GM volumes in the inferior frontal region. Men with SZ+CD (relative to the SZ-CD group) and CD (relative to the H group) displayed increased GM volumes of the hypothalamus and the inferior and superior parietal lobes, which were not associated with substance misuse. Aggressive behavior, both prior to age 15 and lifetime tendency, was positively correlated with the GM volume of the hypothalamus. Thus, among males, SZ+CD represents a distinct subtype of schizophrenia. Although differences in behavior emerge in childhood and remain stable through adulthood, further research is needed to determine whether the differences in GM volumes result from abnormal neural development distinct from that of other males developing schizophrenia.

  5. Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer.

    Science.gov (United States)

    Dunne, Philip D; McArt, Darragh G; Bradley, Conor A; O'Reilly, Paul G; Barrett, Helen L; Cummins, Robert; O'Grady, Tony; Arthur, Ken; Loughrey, Maurice B; Allen, Wendy L; McDade, Simon S; Waugh, David J; Hamilton, Peter W; Longley, Daniel B; Kay, Elaine W; Johnston, Patrick G; Lawler, Mark; Salto-Tellez, Manuel; Van Schaeybroeck, Sandra

    2016-08-15

    A number of independent gene expression profiling studies have identified transcriptional subtypes in colorectal cancer with potential diagnostic utility, culminating in publication of a colorectal cancer Consensus Molecular Subtype classification. The worst prognostic subtype has been defined by genes associated with stem-like biology. Recently, it has been shown that the majority of genes associated with this poor prognostic group are stromal derived. We investigated the potential for tumor misclassification into multiple diagnostic subgroups based on tumoral region sampled. We performed multiregion tissue RNA extraction/transcriptomic analysis using colorectal-specific arrays on invasive front, central tumor, and lymph node regions selected from tissue samples from 25 colorectal cancer patients. We identified a consensus 30-gene list, which represents the intratumoral heterogeneity within a cohort of primary colorectal cancer tumors. Using a series of online datasets, we showed that this gene list displays prognostic potential HR = 2.914 (confidence interval 0.9286-9.162) in stage II/III colorectal cancer patients, but in addition, we demonstrated that these genes are stromal derived, challenging the assumption that poor prognosis tumors with stem-like biology have undergone a widespread epithelial-mesenchymal transition. Most importantly, we showed that patients can be simultaneously classified into multiple diagnostically relevant subgroups based purely on the tumoral region analyzed. Gene expression profiles derived from the nonmalignant stromal region can influence assignment of colorectal cancer transcriptional subtypes, questioning the current molecular classification dogma and highlighting the need to consider pathology sampling region and degree of stromal infiltration when employing transcription-based classifiers to underpin clinical decision making in colorectal cancer. Clin Cancer Res; 22(16); 4095-104. ©2016 AACRSee related commentary by Morris and

  6. Antimicrobial resistance profiling and molecular subtyping of Campylobacter spp. from processed turkey

    Directory of Open Access Journals (Sweden)

    Sherwood Julie S

    2009-09-01

    Ciprofloxacin and erythromycin resistance in Campylobacter recovered from processed turkey occurred more frequently among C. coli than C. jejuni. Fla-PFGE types were associated with a particular species, antimicrobial resistance profiles, and a specific plant. Molecular subtyping in this study provided more information about the relationships among antimicrobial-resistant Campylobacter at the processing level.

  7. Distinct Splice Variants and Pathway Enrichment in the Cell Line Models of Aggressive Human Breast Cancer Subtypes

    Science.gov (United States)

    Menon, Rajasree; Im, Hogune; Zhang, Emma (Yue); Wu, Shiaw-Lin; Chen, Rui; Snyder, Michael; Hancock, William S.; Omenn, Gilbert S.

    2013-01-01

    This study was conducted as a part of the Chromosome-Centric Human Proteome Project (C-HPP) of the Human Proteome Organization. The United States team of C-HPP is focused on characterizing the protein-coding genes in chromosome 17. Despite its small size, chromosome 17 is rich in protein-coding genes, it contains many cancer-associated genes, including BRCA1, ERBB2 (Her2/neu), and TP53. The goal of this study was to examine the splice variants expressed in three ERBB2 expressed breast cancer cell line models of hormone receptor negative breast cancers by integrating RNA-Seq and proteomic mass spectrometry data. The cell-lines represent distinct phenotypic variations subtype: SKBR3 (ERBB2+ (over-expression)/ ER−/PR−; adenocarcinoma), SUM190 (ERBB2+ (over-expression)/ER−/PR−; inflammatory breast cancer) and SUM149 (ERBB2 (low expression) ER−/PR −; inflammatory breast cancer). We identified more than one splice variant for 1167 genes expressed in at least one of the three cancer cell lines. We found multiple variants of genes that are in the signaling pathways downstream of ERBB2 along with variants specific to one cancer cell line compared to the other two cancer cell lines and to normal mammary cells. The overall transcript profiles based on read counts indicated more similarities between SKBR3 and SUM190. The top-ranking Gene Ontology and BioCarta pathways for the cell-line specific variants pointed to distinct key mechanisms including: amino sugar metabolism, caspase activity, and endocytosis in SKBR3; different aspects of metabolism, especially of lipids in SUM190; cell- to-cell adhesion, integrin and ERK1/ERK2 signaling, and translational control in SUM149. The analyses indicated an enrichment in the electron transport chain processes in the ERBB2 over-expressed cell line models; and an association of nucleotide binding, RNA splicing and translation processes with the IBC models, SUM190 and SUM149. Detailed experimental studies on the distinct

  8. [Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer. Its relation with molecular subtypes].

    Science.gov (United States)

    Ruano, R; Ramos, M; García-Talavera, J R; Ramos, T; Rosero, A S; González-Orus, J M; Sancho, M

    2014-01-01

    To evaluate the influence of the molecular subtype (MS) in the Sentinel Node Biopsy (SNB) technique after neoadjuvant chemotherapy (NAC) in women with locally advanced breast cancer (BC) and a complete axillary response (CR). A prospective study involving 70 patients with BC treated with NAC was carried out. An axillary lymph node dissection was performed in the first 48 patients (validation group: VG), and in case of micro- or macrometastases in the therapeutic application phase (therapy group:TG). Classified according to MS: 14 luminal A; 16 luminal B HER2-, 13 luminal B HER2+, 10HER2+ non-luminal, 17 triple-negative. SNB was carried out in 98.6% of the cases, with only one false negative result in the VG (FN=2%). Molecular subtype did not affect SN detection. Despite the existence of axillary CR, statistically significant differences were found in the proportion of macrometastasis (16.7% vs. 35.7%, p=0.043) on comparing the pre-NAC cN0 and cN+. Breast tumor response to NAC varied among the different MS, this being lowest in luminal A (21.5%) and highest in non-luminal HER2+ group (80%). HER2+ and triple-negative were the groups with the best axillary histological response both when there was prior clinical involvement and when there was not. Molecular subtype is a predictive factor of the degree of tumor response to NAC in breast cancer. However, it does not affect SNB detection and efficiency. SNB can also be used safely in women with prior node involvement as long as a complete clinical and radiological assessment is made of the node response to NAC. Copyright © 2014 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

  9. Molecular Subtyping of Salmonella Typhimurium with Multiplex Oligonucleotide Ligation-PCR (MOL-PCR).

    Science.gov (United States)

    Wuyts, Véronique; Mattheus, Wesley; Roosens, Nancy H C; Marchal, Kathleen; Bertrand, Sophie; De Keersmaecker, Sigrid C J

    2017-01-01

    A multiplex oligonucleotide ligation-PCR (MOL-PCR) assay is a valuable high-throughput technique for the detection of bacteria and viruses, for characterization of pathogens and for diagnosis of genetic diseases, as it allows one to combine different types of molecular markers in a high-throughput multiplex assay. A MOL-PCR assay starts with a multiplex oligonucleotide ligation reaction for detection of the molecular marker, followed by a singleplex PCR for signal amplification and analysis of the MOL-PCR products on a Luminex platform. This last step occurs through a liquid bead suspension array in which the MOL-PCR products are hybridized to MagPlex-TAG beads.In this chapter, we describe the complete procedure for a MOL-PCR assay for subtyping of Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) and its monophasic variant S. 1,4[5],12:i:- from DNA isolation through heat lysis up to data interpretation through a Gödel Prime Product. The subtyping assay consists of 50 discriminative molecular markers and two internal positive control markers divided over three MOL-PCR assays.

  10. Sporadic early-onset colorectal cancer is a specific sub-type of cancer: a morphological, molecular and genetics study.

    Directory of Open Access Journals (Sweden)

    Sylvain Kirzin

    Full Text Available Sporadic early onset colorectal carcinoma (EOCRC which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve identification of distinct sub-types of colorectal cancers (CRC with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45-60 years were excluded to help define "young" and "old" groups. Thirty-nine cases of sporadic EOCRC (patients ≤ 45 years with microsatellite stable tumors were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013. Genetic studies also showed the absence of BRAF mutations (p = 0.022 and the methylator phenotype (p = 0.005 in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01. This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the

  11. Characterisation of adipocyte-derived extracellular vesicle subtypes identifies distinct protein and lipid signatures for large and small extracellular vesicles.

    Science.gov (United States)

    Durcin, Maëva; Fleury, Audrey; Taillebois, Emiliane; Hilairet, Grégory; Krupova, Zuzana; Henry, Céline; Truchet, Sandrine; Trötzmüller, Martin; Köfeler, Harald; Mabilleau, Guillaume; Hue, Olivier; Andriantsitohaina, Ramaroson; Martin, Patrice; Le Lay, Soazig

    2017-01-01

    Extracellular vesicles (EVs) are biological vectors that can modulate the metabolism of target cells by conveying signalling proteins and genomic material. The level of EVs in plasma is significantly increased in cardiometabolic diseases associated with obesity, suggesting their possible participation in the development of metabolic dysfunction. With regard to the poor definition of adipocyte-derived EVs, the purpose of this study was to characterise both qualitatively and quantitatively EVs subpopulations secreted by fat cells. Adipocyte-derived EVs were isolated by differential centrifugation of conditioned media collected from 3T3-L1 adipocytes cultured for 24 h in serum-free conditions. Based on morphological and biochemical properties, as well as quantification of secreted EVs, we distinguished two subpopulations of adipocyte-derived EVs, namely small extracellular vesicles (sEVs) and large extracellular vesicles (lEVs). Proteomic analyses revealed that lEVs and sEVs exhibit specific protein signatures, allowing us not only to define novel markers of each population, but also to predict their biological functions. Despite similar phospholipid patterns, the comparative lipidomic analysis performed on these EV subclasses revealed a specific cholesterol enrichment of the sEV population, whereas lEVs were characterised by high amounts of externalised phosphatidylserine. Enhanced secretion of lEVs and sEVs is achievable following exposure to different biological stimuli related to the chronic low-grade inflammation state associated with obesity. Finally, we demonstrate the ability of primary murine adipocytes to secrete sEVs and lEVs, which display physical and biological characteristics similar to those described for 3T3-L1. Our study provides additional information and elements to define EV subtypes based on the characterisation of adipocyte-derived EV populations. It also underscores the need to distinguish EV subpopulations, through a combination of multiple

  12. Molecular subtypes of breast cancer emerging in young women in Taiwan: evidence for more than just westernization as a reason for the disease in Asia.

    Science.gov (United States)

    Lin, Ching-Hung; Liau, Jau-Yu; Lu, Yen-Shen; Huang, Chiun-Sheng; Lee, Wei-Chung; Kuo, Kuan-Ting; Shen, Ying-Chun; Kuo, Sung-Hsin; Lan, Chieh; Liu, Jacqueline Ming; Kuo, Wun-Hon; Chang, King-Jen; Cheng, Ann-Lii

    2009-06-01

    In the past two decades, the incidence of breast cancer in young Taiwanese females has been rapidly increasing, approaching the risk level of western countries. As a first step to investigate the possible etiology, we examined the molecular subtypes of female breast cancer in Taiwan. This study included 1,028 consecutive patients with breast cancer diagnosed in National Taiwan University Hospital between 2004 and 2006. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2, cytokeratin 5/6, and epidermal growth factor receptor expression and/or gene amplification were analyzed. Younger (cancer patients had a higher prevalence of luminal A (67% versus 57%; P 50 years) patients. The higher prevalence of luminal A subtype was mainly attributed to a higher ER (75% versus 63%; P cancer patients in Taiwan are characterized by a high prevalence of luminal A subtype and low prevalence of histologic grade 3 tumor and/or basal-like subtype. These features are distinct from young breast cancer patients in western countries.

  13. Calretinin expression as a reliable prognostic marker in different molecular subtypes of breast carcinoma

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    Mayada Saad Farrag

    2017-01-01

    Full Text Available Background: Calretinin (CR, a known mesothelial marker, is expressed in both epithelial and mesenchymal malignancies including breast cancer. Aims: We aimed to measure the frequency of CR expression in correlation with other clinicopathological parameters of different molecular subtypes of invasive breast carcinoma and to study its prognostic implications in this common cancer.Study Design: Tissue microarrays were constructed from 225 tissue samples of breast carcinoma cases. Subjects and Methods: Immunostaining for CR in addition to estrogen receptors, progesterone receptors, human epidermal growth factor receptor 2 (HER2, epidermal growth factor receptor, CK5/6, and Ki-67 for molecular subtyping. Statistical Analysis Used: Chi-square and Fisher's exact tests were done using SPSS 18.0 software (IBM Inc.. Survival data were analyzed using Kaplan–Meier test, Log-rank test, and Cox proportional hazard models. Results: Cases of invasive breast carcinomas with different grades were classified into 84 luminal A, 45 luminal B, 27 HER2 positive, 40 basal-like, and 29 unclassified. High CR expression was associated with tumors of high grade (P < 0.0001, high locoregional recurrence (P = 0.005, hormonal receptors negative, and high Ki-67 indices. They frequently display a basal-like phenotype (70%, P < 0.0001, HER2 (59.3%, and luminal B (33.3% tumors compared to luminal A (9.5% and unclassified subtypes (17.2%. Moreover, it is associated with poor overall patient survival (P = 0.034, but it does not affect disease-free survival. Conclusions: Calretinin could be a reliable predictor marker of adverse prognosis in breast cancer.

  14. Local and Regional Breast Cancer Recurrences: Salvage Therapy Options in the New Era of Molecular Subtypes

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    Yazid Belkacemi

    2018-04-01

    Full Text Available Isolated local or regional recurrence of breast cancer (BC leads to an increased risk of metastases and decreased survival. Ipsilateral breast recurrence can occur at the initial tumor bed or in another quadrant of the breast. Depending on tumor patterns and molecular subtypes, the risk and time to onset of metastatic recurrence differs. HER2-positive and triple-negative (TNG BC have a risk of locoregional relapse between six and eight times than luminal A. Thus, the management of local and locoregional relapses must take into account the prognostic factors for metastatic disease development. It is important to personalize the overall management, including or not systemic treatment according to the metastatic risk. All isolated recurrence cases should be treated with curative intent. Complete surgical resection is recommended whenever possible. Patients who did not receive postoperative irradiation during their initial management should receive full-dose radiotherapy to the chest wall and to the regional lymph nodes if appropriate. Overall, total mastectomy is the “gold standard” among patients who were previously treated by conservative surgery followed by radiation therapy. In terms of systemic therapy, the benefits of additional treatments are not conclusively proven in cases of isolated recurrence. The beneficial role of chemotherapy has been reported in at least one randomized trial, while endocrine therapy and anti-HER2 are common practice. This review will discuss salvage treatment options of local and locoregional recurrences in the new era of BC molecular subtypes.

  15. Conventional and molecular methods used in the detection and subtyping of Yersinia enterocolitica in food.

    Science.gov (United States)

    Petsios, Stefanos; Fredriksson-Ahomaa, Maria; Sakkas, Hercules; Papadopoulou, Chrissanthy

    2016-11-21

    Yersinia enterocolitica is an important foodborne pathogen, but the prevalence in food is underestimated due to drawbacks in the detection methods. Problems arise from the low concentration of pathogenic strains present in food samples, similarities with other Enterobacteriaceae and Y. enterocolitica-like species and the heterogeneity of Y. enterocolitica as it comprises both pathogenic and non-pathogenic isolates. New rapid, cost-effective and more sensitive culture media and molecular techniques have been developed to overcome the drawbacks of conventional culture methods. Recent molecular subtyping methods have been applied to Y. enterocolitica strains to track infection sources and to investigate phylogenetic relationships between different Yersinia strains. Further application of modern subtyping tools such as WGS in a variety of bioserotypes, and comparison with other members of the genus will help to better understanding of the virulence determinants of pathogenic Y. enterocolitica, its mechanisms to cope in the host environments, and can contribute to the development of more specific detection and typing strategies.

  16. Subtype-Specific Genes that Characterize Subpopulations of Callosal Projection Neurons in Mouse Identify Molecularly Homologous Populations in Macaque Cortex.

    Science.gov (United States)

    Fame, Ryann M; Dehay, Colette; Kennedy, Henry; Macklis, Jeffrey D

    2017-03-01

    Callosal projection neurons (CPN) interconnect the neocortical hemispheres via the corpus callosum and are implicated in associative integration of multimodal information. CPN have undergone differential evolutionary elaboration, leading to increased diversity of cortical neurons-and more extensive and varied connections in neocortical gray and white matter-in primates compared with rodents. In mouse, distinct sets of genes are enriched in discrete subpopulations of CPN, indicating the molecular diversity of rodent CPN. Elements of rodent CPN functional and organizational diversity might thus be present in the further elaborated primate cortex. We address the hypothesis that genes controlling mouse CPN subtype diversity might reflect molecular patterns shared among mammals that arose prior to the divergence of rodents and primates. We find that, while early expression of the examined CPN-enriched genes, and postmigratory expression of these CPN-enriched genes in deep layers are highly conserved (e.g., Ptn, Nnmt, Cited2, Dkk3), in contrast, the examined genes expressed by superficial layer CPN show more variable levels of conservation (e.g., EphA3, Chn2). These results suggest that there has been evolutionarily differential retraction and elaboration of superficial layer CPN subpopulations between mouse and macaque, with independent derivation of novel populations in primates. Together, these data inform future studies regarding CPN subpopulations that are unique to primates and rodents, and indicate putative evolutionary relationships. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  17. Cognitive and familial risk evidence converged: A data-driven identification of distinct and homogeneous subtypes within the heterogeneous sample of reading disabled children.

    Science.gov (United States)

    Willems, Gonny; Jansma, Bernadette; Blomert, Leo; Vaessen, Anniek

    2016-01-01

    The evident degree of heterogeneity observed in reading disabled children has puzzled reading researchers for decades. Recent advances in the genetic underpinnings of reading disability have indicated that the heritable, familial risk for dyslexia is a major risk factor. The present data-driven, classification attempt aims to revisit the possibility of identifying distinct cognitive deficit profiles in a large sample of second to fourth grade reading disabled children. In this sample, we investigated whether genetic and environmental risk factors are able to distinguish between poor reader subtypes. In this profile, we included reading-related measures of phonemic awareness, letter-speech sound processing and rapid naming, known as candidate vulnerability markers associated with dyslexia and familial risk for dyslexia, as well as general cognitive abilities (non-verbal IQ and vocabulary). Clustering was based on a 200 multi-start K-means approach. Results revealed four emerging subtypes of which the first subtype showed no cognitive deficits underlying their poor reading skills (Reading-only impaired poor readers). The other three subtypes shared a core phonological deficit (PA) with a variable and discriminative expression across the other underlying vulnerability markers. More specific, type 2 showed low to poor performance across all reading-related and general cognitive abilities (general poor readers), type 3 showed a specific letter-speech sound mapping deficit next to a PA deficit (PA-LS specific poor readers) and type 4 showed a specific rapid naming deficit complementing their phonological weakness (PA-RAN specific poor readers). The first three poor reader profiles were more characterized by variable environmental risk factor, while the fourth, PA-RAN poor reader subtype showed a significantly strong familial risk for dyslexia. Overall, when we zoom in on the heterogeneous phenomenon of reading disability, unique and distinct cognitive subtypes can be

  18. TCGA researchers identify 4 subtypes of stomach cancer

    Science.gov (United States)

    Stomach cancers fall into four distinct molecular subtypes, researchers with The Cancer Genome Atlas (TCGA) Network have found. Scientists report that this discovery could change how researchers think about developing treatments for stomach cancer, also c

  19. Molecular identification, cloning and characterization of transmitted/founder HIV-1 subtype A, D and A/D infectious molecular clones.

    Science.gov (United States)

    Baalwa, Joshua; Wang, Shuyi; Parrish, Nicholas F; Decker, Julie M; Keele, Brandon F; Learn, Gerald H; Yue, Ling; Ruzagira, Eugene; Ssemwanga, Deogratius; Kamali, Anatoli; Amornkul, Pauli N; Price, Matt A; Kappes, John C; Karita, Etienne; Kaleebu, Pontiano; Sanders, Eduard; Gilmour, Jill; Allen, Susan; Hunter, Eric; Montefiori, David C; Haynes, Barton F; Cormier, Emmanuel; Hahn, Beatrice H; Shaw, George M

    2013-02-05

    We report the molecular identification, cloning and initial biological characterization of 12 full-length HIV-1 subtype A, D and A/D recombinant transmitted/founder (T/F) genomes. T/F genomes contained intact canonical open reading frames and all T/F viruses were replication competent in primary human T-cells, although subtype D virus replication was more efficient (pHIV IgG (pHIV-1 clones available for pathogenesis and vaccine research and extends their representation to include subtypes A, B, C and D. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Molecular identification, cloning and characterization of transmitted/founder HIV-1 subtype A, D and A/D infectious molecular clones

    OpenAIRE

    Baalwa, Joshua; Wang, Shuyi; Parrish, Nicholas; Decker, Julie M.; Keele, Brandon F.; Learn, Gerald H.; Yue, Ling; Ruzagira, Eugene; Ssemwanga, Deogratius; Kamali, Anatoli; Amornkul, Pauli N.; Price, Matt A.; Kappes, John C.; Karita, Etienne; Kaleebu, Pontiano

    2012-01-01

    We report the molecular identification, cloning and initial biological characterization of 12 full-length HIV-1 subtype A, D and A/D recombinant transmitted/founder (T/F) genomes. T/F genomes contained intact canonical open reading frames and all T/F viruses were replication competent in primary human T-cells, although subtype D virus replication was more efficient (p

  1. First Identification and Molecular Characterization of Avian metapneumovirus Subtype B from Chickens in Greece.

    Science.gov (United States)

    Tucciarone, Claudia Maria; Andreopoulou, Marianna; Franzo, Giovanni; Prentza, Zoi; Chaligiannis, Ilias; Cecchinato, Mattia

    2017-09-01

    Avian metapneumovirus (aMPV) is considered a major pathogen for turkeys but its impact on chicken production is still partially neglected, even though it is fully acknowledged as a primary pathogen in chickens as well. The lack of structured diagnostic surveys does not allow a pervasive understanding of aMPV epidemiology. Being that aMPV is almost an everyday challenge for farmers and veterinarians, a more accurate report of its presence should be detailed, posing the basis for a deep and global epidemiologic analysis. With these premises, the present work aims to report the first detection and molecular characterization of aMPV subtype B field strains from unvaccinated chickens in Greece. The Greek strains appear to be phylogenetically related among each other and with other recent Mediterranean strains while being distant from the currently applied vaccines, thus stressing once more the necessity to evaluate aMPV diffusion and evolution.

  2. Population Dynamics and Rates of Molecular Evolution of a Recently Emerged Paramyxovirus, Avian Metapneumovirus Subtype C▿ †

    OpenAIRE

    Padhi, Abinash; Poss, Mary

    2008-01-01

    We report the existence of two distinct sublineages of avian metapneumovirus (MPV) subtype C, a virus which has caused serious economic loss in commercial turkey farms in the United States. This subtype is closely related to human MPV, infects multiple avian species, and is globally distributed. The evolutionary rates of this virus are estimated to be 1.3 × 10−3 to 7 × 10−3 substitutions per site per year, and coalescent estimates place its emergence between 1991 and 1996. The four genes exam...

  3. Population Dynamics and Rates of Molecular Evolution of a Recently Emerged Paramyxovirus, Avian Metapneumovirus Subtype C▿ †

    Science.gov (United States)

    Padhi, Abinash; Poss, Mary

    2009-01-01

    We report the existence of two distinct sublineages of avian metapneumovirus (MPV) subtype C, a virus which has caused serious economic loss in commercial turkey farms in the United States. This subtype is closely related to human MPV, infects multiple avian species, and is globally distributed. The evolutionary rates of this virus are estimated to be 1.3 × 10−3 to 7 × 10−3 substitutions per site per year, and coalescent estimates place its emergence between 1991 and 1996. The four genes examined show a concordant demographic pattern which is characterized by a rapid increase in population size followed by stable population grown until the present. PMID:19052092

  4. Identifying the mesenchymal molecular subtype of glioblastoma using quantitative volumetric analysis of anatomic magnetic resonance images

    Science.gov (United States)

    Naeini, Kourosh M.; Pope, Whitney B.; Cloughesy, Timothy F.; Harris, Robert J.; Lai, Albert; Eskin, Ascia; Chowdhury, Reshmi; Phillips, Heidi S.; Nghiemphu, Phioanh L.; Behbahanian, Yalda; Ellingson, Benjamin M.

    2013-01-01

    Background Subtypes of glioblastoma multiforme (GBM) based on genetic and molecular alterations are thought to cause alterations in anatomic MRI owing to downstream biological changes, such as edema production, blood–brain barrier breakdown, and necrosis. The purpose of the current study was to identify a potential relationship between imaging features and the mesenchymal (MES) GBM subtype, which has the worst patient prognosis. Methods MRIs from 46 patients with histologically confirmed GBM were retrospectively analyzed. The volume of contrast enhancement, regions of central necrosis, and hyperintensity of T2/fluid attenuated inversion recovery (FLAIR) were measured. Additionally, the ratio of T2/FLAIR hyperintense volume to the volume of contrast enhancement and necrosis was calculated. Results The volume of contrast enhancement, volume of central necrosis, combined volume of contrast enhancement and central necrosis, and the ratio of T2/FLAIR to contrast enhancement and necrosis were significantly different in MES compared with non-MES GBM (Mann–Whitney, P < .05). Receiver-operator characteristics indicated that these 4 metrics were all significant predictors of the MES phenotype. The volume ratio of T2 hyperintensity to contrast enhancement and central necrosis was significantly lower in MES vs non-MES GBM (P < .0001), was a significant predictor of the MES phenotype (area under the curve = 0.93, P < .001), and could be used to stratify short- and long-term overall survival (log-rank, P = .0064 using cutoff of 3.0). These trends were also present when excluding isocitrate dehydrogenase 1 mutant tumors and incorporating covariates such as age and KPS score. Conclusions Results suggest that volume ratio may be a simple, cost-effective, and noninvasive biomarker for quickly identifying MES GBM. PMID:23444259

  5. Differential Immune Microenvironments and Response to Immune Checkpoint Blockade among Molecular Subtypes of Murine Medulloblastoma.

    Science.gov (United States)

    Pham, Christina D; Flores, Catherine; Yang, Changlin; Pinheiro, Elaine M; Yearley, Jennifer H; Sayour, Elias J; Pei, Yanxin; Moore, Colin; McLendon, Roger E; Huang, Jianping; Sampson, John H; Wechsler-Reya, Robert; Mitchell, Duane A

    2016-02-01

    Despite significant strides in the identification and characterization of potential therapeutic targets for medulloblastoma, the role of the immune system and its interplay with the tumor microenvironment within these tumors are poorly understood. To address this, we adapted two syngeneic animal models of human Sonic Hedgehog (SHH)-driven and group 3 medulloblastoma for preclinical evaluation in immunocompetent C57BL/6 mice. Multicolor flow cytometric analyses were used to phenotype and characterize immune infiltrating cells within established cerebellar tumors. We observed significantly higher percentages of dendritic cells, infiltrating lymphocytes, myeloid-derived suppressor cells, and tumor-associated macrophages in murine SHH model tumors compared with group 3 tumors. However, murine group 3 tumors had higher percentages of CD8(+) PD-1(+) T cells within the CD3 population. PD-1 blockade conferred superior antitumor efficacy in animals bearing intracranial group 3 tumors compared with SHH group tumors, indicating that immunologic differences within the tumor microenvironment can be leveraged as potential targets to mediate antitumor efficacy. Further analysis of anti-PD-1 monoclonal antibody localization revealed binding to PD-1(+) peripheral T cells, but not tumor infiltrating lymphocytes within the brain tumor microenvironment. Peripheral PD-1 blockade additionally resulted in a marked increase in CD3(+) T cells within the tumor microenvironment. This is the first immunologic characterization of preclinical models of molecular subtypes of medulloblastoma and demonstration that response to immune checkpoint blockade differs across subtype classification. Our findings also suggest that effective anti-PD-1 blockade does not require that systemically administered antibodies penetrate the brain tumor microenvironment. ©2015 American Association for Cancer Research.

  6. Molecular mechanism of ligand recognition by NR3 subtype glutamate receptors

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    Yao, Yongneng; Harrison, Chris B.; Freddolino, Peter L.; Schulten, Klaus; Mayer, Mark L. (UIUC); (NIH)

    2008-10-27

    NR3 subtype glutamate receptors have a unique developmental expression profile, but are the least well-characterized members of the NMDA receptor gene family, which have key roles in synaptic plasticity and brain development. Using ligand binding assays, crystallographic analysis, and all atom MD simulations, we investigate mechanisms underlying the binding by NR3A and NR3B of glycine and D-serine, which are candidate neurotransmitters for NMDA receptors containing NR3 subunits. The ligand binding domains of both NR3 subunits adopt a similar extent of domain closure as found in the corresponding NR1 complexes, but have a unique loop 1 structure distinct from that in all other glutamate receptor ion channels. Within their ligand binding pockets, NR3A and NR3B have strikingly different hydrogen bonding networks and solvent structures from those found in NR1, and fail to undergo a conformational rearrangement observed in NR1 upon binding the partial agonist ACPC. MD simulations revealed numerous interdomain contacts, which stabilize the agonist-bound closed-cleft conformation, and a novel twisting motion for the loop 1 helix that is unique in NR3 subunits.

  7. Predictive value of breast cancer molecular subtypes in Chinese patients with four or more positive nodes after postmastectomy radiotherapy.

    Science.gov (United States)

    Wu, San-Gang; He, Zhen-Yu; Li, Qun; Li, Feng-Yan; Lin, Qin; Lin, Huan-Xin; Guan, Xun-Xing

    2012-10-01

    The molecular subtypes of breast cancer based on status of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) expression are associated with markedly different clinical outcomes. We retrospectively analyzed 774 breast cancer patients with four or more positive nodes, who underwent mastectomy between March 1999 and December 2007. Treatment with postmastectomy radiotherapy (PMRT) reduced the rates of locoregional recurrence-free survival (LRFS; 6.7% vs. 26.6%), distant metastasis-free survival (DMFS; 26.9% vs. 50.0%), and mortality (24.4% vs. 45.3%) for luminal-A subtypes (ER+ or PR+, Her2-) and reduced LRFS (12.1% vs. 27.5%) for the luminal-B subtype (ER+ or PR+, Her2+) compared with patients not receiving PMRT. However, PMRT did not affect the endpoints for the Her2-enriched or basal subtypes. Thus, understanding the differences in patterns of relapse between the different subtypes of breast cancer may enable targeted adjuvant therapy and improved surveillance decisions. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    C.E. Henry

    2017-06-01

    Full Text Available OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178. Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.

  9. Invasive lobular breast cancer: the prognostic impact of histopathological grade, E-cadherin and molecular subtypes.

    Science.gov (United States)

    Engstrøm, Monica J; Opdahl, Signe; Vatten, Lars J; Haugen, Olav A; Bofin, Anna M

    2015-02-01

    The aim of this study was to compare breast cancer specific survival (BCSS) for invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) and, further, to evaluate critically the prognostic value of histopathological grading of ILC and examine E-cadherin as a prognostic marker in ILC. The study comprised 116 lobular and 611 ductal breast carcinomas occurring between 1961 and 2008. All cases had been classified previously according to histopathological type and grade, stained for oestrogen receptor (ER), progesterone receptor (PR), antigen Ki67 (Ki67), epithelial growth factor receptor (EGFR), cytokeratin 5 (CK5) and human epidermal growth factor receptor 2 (HER2) and classified into molecular subtypes. For the present study, immunohistochemical staining for E-cadherin was performed. The Kaplan-Meier method and Cox proportional hazards models were used in the analyses. Grade 2 tumours comprised 85.3% of the lobular tumours and 51.9% of the ductal tumours. BCSS in ILC grade 2 was comparable to that of IDC grade 3. E-cadherin-negative ILC had a poorer prognosis compared to E-cadherin positive ILC and to IDC regardless of E-cadherin status. The implication of histopathological grading may differ in ILC compared to IDC. E-cadherin may be useful in prognostication in ILC and thereby influence the determination of treatment strategies for this group of women. © 2014 The Authors. Histopathology published by John Wiley & Sons Ltd.

  10. Baseline blood immunological profiling differentiates between Her2– breast cancer molecular subtypes: implications for immunomediated mechanisms of treatment response

    Directory of Open Access Journals (Sweden)

    Tudoran O

    2015-11-01

    Full Text Available Oana Tudoran,1,2,* Oana Virtic,2,* Loredana Balacescu,1,2 Carmen Lisencu,3 Bogdan Fetica,4 Claudia Gherman,1 Ovidiu Balacescu,1 Ioana Berindan-Neagoe1,2,5 1Department of Functional Genomics and Experimental Pathology, The Oncology Institute “Prof Dr Ion Chiricuţă”, 2Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 3Department of Radiotherapy I, 4Department of Pathology, The Oncology Institute “Prof Dr Ion Chiricuţă”, 5Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania *These authors contributed equally to this work Purpose: Breast cancer patients’ response to treatment is highly dependent on the primary tumor molecular features, with triple-negative breast tumors having the worst prognosis of all subtypes. According to the molecular features, tumors stimulate the microenvironment to induce distinct immune responses, baseline immune activation being associated with higher likelihood of pathologic response. In this study, we investigated the deconvolution of the immunological status of triple-negative tumors in comparison with luminal tumors and the association with patients’ clinicopathological characteristics.Patients and methods: Gene expression of 84 inflammatory molecules and their receptors were analyzed in 40 peripheral blood samples from patients with Her2- primary breast cancer tumors. We studied the association of triple-negative phenotype with age, clinical stage, tumor size, lymph nodes, and menopausal status.Results: We observed that more patients with estrogen (ER/progesterone (PR-negative tumors had grade III, while more patients with ER/PR-positive tumors had grade II tumors. Gene expression analysis revealed a panel of 14 genes to have differential expression between the two groups: several interleukins: IL13, IL16, IL17C and IL17F, IL1A, IL3; interleukin receptors: IL10RB, IL5RA; chemokines: CXCL13 and CCL

  11. BMI, reproductive factors, and breast cancer molecular subtypes: A case-control study and meta-analysis

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    Hui Li

    2017-04-01

    Full Text Available Background: The effects of body mass index (BMI and reproductive factors may vary among breast cancer molecular subtypes, evidence of which is lacking in East Asia. Methods: From 2002 to 2010, 1256 breast cancer patients and 1416 healthy women were recruited. Anthropometric and reproductive factors were collected from medical charts. Breast cancer subtype was defined by ER, PR, and HER2 status. Polytomous logistic regression was used to evaluate associations between risk factors and breast cancer subtypes, with subgroup analysis by menopausal status. A metaanalysis of relevant published studies in East Asia was also performed. Results: In our case-control study, late menarche was negatively associated with luminal tumor risk (Ptrend = 0.03. Higher BMI was associated with risk of both luminal and triple-negative tumors (Ptrend<0.001. Late age at first live birth was associated with a 1.41- to 2.08-fold increased risk of all subtypes, while late menopause increased risk by 2.62–5.56 times. Heterogeneity of these associations was not detected for different menopausal statuses. The meta-analysis revealed a positive dose-response relationship between BMI and risk of both luminal and ER-PR- subtypes (Ptrend<0.05. Early menarche and nulliparity increased luminal tumor risk by 1.39 and 1.26 times, respectively. Non-breastfeeding also increased the risk of all subtypes. Conclusions: For East Asian women, overweight, late menopause, and lack of breastfeeding appear to increase risk of both luminal and ER–PR– tumors. Early menarche and nulliparity mainly impacted luminal tumor risk. These associations were not impacted by menopausal status.

  12. Molecular subtyping of Treponema pallidum during a local syphilis epidemic in men who have sex with men in Melbourne, Australia.

    Science.gov (United States)

    Azzato, Francesca; Ryan, Norbert; Fyfe, Janet; Leslie, David E

    2012-06-01

    Treponema pallidum is the causative agent of syphilis, a sexually transmitted infection of significant public health importance. Since 2000 there has been a marked increase in the number of cases of syphilis infections notified in Victoria, Australia, with the majority of cases occurring in men who have sex with men (MSM) and the highest incidence being in HIV-infected MSM. The molecular subtyping method described by Pillay et al. (A. Pillay et al., Sex. Transm. Dis. 25:408-414, 1998) has been used in this study to determine the diversity of T. pallidum subtypes circulating locally and to look for any relationship between T. pallidum subtypes and HIV status over a 6-year period (2004 to 2009). Treponema pallidum DNA was detected in 303 patient specimens (n = 3,652), and full subtyping profiles were obtained from 90 of these (from 88 patients). A total of 11 T. pallidum subtypes were identified: types 14e (28, 31.1%), 14d (15, 16.7%), 14k (13, 14.4%), 14p (12, 13.3%), 14i (7, 7.8%) 14b (6, 6.7%), 14l (5, 5.6%), and 12i, 13b, 13i, and 13e (1 each, 1.1%). This study showed a similar level of variation among circulating T. pallidum strains compared with that in other studies using the same methodology. A different mix of strains and different predominating strains have been found at each geographical study location, with type 14e emerging as the predominant local strain in Victoria. There was no detectable trend between T. pallidum subtypes and the specimen collection site or stage of syphilis (where known), nor was there any relationship between particular strains and HIV status.

  13. Molecular epidemiology and biological properties of avian influenza viruses of subtype H5N1 and H9N2

    OpenAIRE

    Parvin, Rokshana

    2015-01-01

    Rokshana Parvin Molecular epidemiology and biological properties of avian influenza viruses of subtype H5N1 and H9N2 Institute of Virology Submitted in November 2014 Pages 106, Figures 7, Table 1, References 339, Publications 4 Keywords: Avian Influenza Virus, H5N1, H9N2, Reassortment, Mutation, Replication and Growth kinetics Introduction Avian influenza viruses (AIVs) are the major cause of significant disease outbreaks with high morbidity and mortality worldwide in ...

  14. Molecular identification of a rare subtype of Cryptosporidium hominis in infants in China.

    Science.gov (United States)

    Zhu, Huili; Zhao, Jinfeng; Wang, Rongjun; Zhang, Longxian

    2012-01-01

    Two Cryptosporidium isolates from separate infants suffering from diarrhea were obtained from a hospital in Zhengzhou, China and were genotyped by PCR amplification and sequence analysis of the small-subunit ribosomal RNA (rRNA) (SSU rRNA), 70-kDa heat shock protein (HSP70), and actin genes. Further subtyping was performed by PCR amplification and sequence analysis of the 60-kDa glycoprotein (gp60) gene. Both the isolates were identified as Cryptosporidium hominis subtype IdA21, a rare subtype previously found only in a human immunodeficiency virus-infected child in South Africa and another child in Jordan.

  15. Molecular identification of a rare subtype of Cryptosporidium hominis in infants in China.

    Directory of Open Access Journals (Sweden)

    Huili Zhu

    Full Text Available Two Cryptosporidium isolates from separate infants suffering from diarrhea were obtained from a hospital in Zhengzhou, China and were genotyped by PCR amplification and sequence analysis of the small-subunit ribosomal RNA (rRNA (SSU rRNA, 70-kDa heat shock protein (HSP70, and actin genes. Further subtyping was performed by PCR amplification and sequence analysis of the 60-kDa glycoprotein (gp60 gene. Both the isolates were identified as Cryptosporidium hominis subtype IdA21, a rare subtype previously found only in a human immunodeficiency virus-infected child in South Africa and another child in Jordan.

  16. Molecular cloning and pharmacology of functionally distinct isoforms of the human histamine H(3) receptor

    DEFF Research Database (Denmark)

    Wellendorph, Petrine; Goodman, M W; Burstein, E S

    2002-01-01

    The pharmacology of histamine H(3) receptors suggests the presence of distinct receptor isoforms or subtypes. We herein describe multiple, functionally distinct, alternatively spliced isoforms of the human H(3) receptor. Combinatorial splicing at three different sites creates at least six distinct...... receptor isoforms, of which isoforms 1, 2, and 4, encode functional proteins. Detailed pharmacology on isoforms 1 (unspliced receptor), and 2 (which has an 80 amino acid deletion within the third intracellular loop of the protein) revealed that both isoforms displayed robust responses to a series of known...... revealed a rank order of potency at both isoforms of clobenpropit>iodophenpropit>thioperamide, and these drugs are fivefold less potent at isoform 2 than isoform 1. To further explore the pharmacology of H(3) receptor function, we screened 150 clinically relevant neuropsychiatric drugs for H(3) receptor...

  17. Exhaled air molecular profiling in relation to inflammatory subtype and activity in COPD

    NARCIS (Netherlands)

    Fens, N.; de Nijs, S. B.; Peters, S.; Dekker, T.; Knobel, H. H.; Vink, T. J.; Willard, N. P.; Zwinderman, A. H.; Krouwels, F. H.; Janssen, H.-G.; Lutter, R.; Sterk, P. J.

    2011-01-01

    Eosinophilic inflammation in chronic obstructive pulmonary disease (COPD) is predictive for responses to inhaled steroids. We hypothesised that the inflammatory subtype in mild and moderate COPD can be assessed by exhaled breath metabolomics. Exhaled compounds were analysed using gas chromatography

  18. Distribution of molecular breast cancer subtypes among Algerian women and correlation with clinical and tumor characteristics: a population-based study.

    Science.gov (United States)

    Cherbal, Farid; Gaceb, Hadjer; Mehemmai, Chiraz; Saiah, Insaf; Bakour, Rabah; Rouis, Abdelhalim Ould; Boualga, Kada; Benbrahim, Wassila; Mahfouf, Hassen

    2015-01-01

    Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. Molecular classification of breast cancer is an important factor for prognosis and clinical outcome. There are limited data regarding molecular breast cancer subtypes among Algerian women. The objective of the present study was to analyze the proportion and distribution of molecular subtypes and to determine their associations with some clinical and tumor characteristics: age at diagnosis, menopausal status, histological type and histological grade. The study population included 3014 female breast cancers. We analyzed breast cancers from cancer registries of academic medical oncology service of public hospital of Rouiba, anticancer center of Blida, and anticancer center of Batna. Breast cancers were diagnosed between 2008 and 2013. Molecular subtype classification was done based on immunohistochemical surrogates for ER (Estrogen receptor), PR (Progesterone receptor) and HER2 (human epidermal growth factor receptor-2) status obtained from medical records for 3014 breast cancer patients. Breast cancer subtypes definitions were as follow: Luminal A (ER+ and/or PR+, HER2-), Luminal B (ER+ and/or PR+, HER2+), TNBC (ER-, PR - , HER2-), HER2+ (ER-, PR-, HER2+). Molecular subtypes were correlated with the clinicopathological characteristics of the tumors. The mean age at diagnosis cancer was 48.5 years. Proportions of the luminal A, TNBC, luminal B and HER2+ breast cancer subtypes were 50.59%, 20.80%, 19.67% and 8.92%, respectively. We noted a significant difference in the distribution of age at diagnosis among the four cancer subtypes (P= 0.004). Luminal A, Luminal B, TNBC and HER2+ subtypes were significantly different by premenopausal and postmenopausal status (P= 0.01). Invasive Ductal Carcinoma was the most common histological type in all breast cancer subtypes. Tumors with histological grade 2 and 3 were more common in patients for the four breast cancer subtypes. For

  19. Surgery time interval and molecular subtype may influence Ki67 change after core needle biopsy in breast cancer patients.

    Science.gov (United States)

    Chen, Xiaosong; Zhu, Siji; Fei, Xiaochun; Garfield, David H; Wu, Jiayi; Huang, Ou; Li, Yafen; Zhu, Li; He, Jianrong; Chen, Weiguo; Jin, Xiaolong; Shen, Kunwei

    2015-10-30

    To investigate the accuracy of core needle biopsy (CNB) in evaluating breast cancer estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 status and to identify factors which might be associated with Ki67 value change after CNB. A retrospective study was carried out on 276 patients with paired CNB and surgically removed samples (SRS). Clinico-pathological factors as well as the surgery time interval (STI) between CNB and surgery were analyzed to determine whether there were factors associated with Ki67 value change after CNB. Five tumor subtypes were classified as follows: Luminal A, Luminal B-HER2-, Luminal B-HER2+, Triple Negative (TN), and HER2+. Ki67 value change was calculated as SRS minus CNB. Mean STI after CNB was 4.5 (1-37) days. Good agreement was achieved for ER, PR, and HER2 evaluation between CNB and SRS. However, Ki67 expression level was significantly higher in SRS compared with CNB samples: 29.1 % vs. 26.2 % (P Ki67 change after CNB. Luminal A tumors experienced more Ki67 elevation than Luminal B-HER2- diseases (6.2 % vs -0.1 %, P = 0.014). Patients with longer STI after CNB had a higher Ki67 increase: -1.1 % within 1-2 days, 2.1 % with 3-4 days, and 5.6 % more than 4 days, respectively (P = 0.007). For TN and HER2+ tumors, the Ki67 change was apt to be 0 with STI ≤ 4 days, while a >7 % Ki67 increase was noticed in patients with STI ≥ 5 days. CNB was accurate in evaluating ER, PR, HER2, and molecular subtype status. Ki67 value significantly increased after CNB, which was associated with STI and molecular subtype. Further translational research needs to consider Ki67 changes following CNB among different breast cancer molecular subtypes.

  20. Alcohol consumption and distinct molecular pathways to colorectal cancer.

    Science.gov (United States)

    Bongaerts, Brenda W C; de Goeij, Anton F P M; de Vogel, Stefan; van den Brandt, Piet A; Goldbohm, R Alexandra; Weijenberg, Matty P

    2007-03-01

    High alcohol consumption is related to colorectal cancer (CRC). Our objective was to study associations between alcohol consumption and risk of CRC according to characteristics of aetiological pathways: the chromosomal instability (CIN) and the microsatellite instability (MIN) pathway. We classified CIN+ tumours (tumours with either a truncating APC mutation, an activating K-ras mutation or overexpression of p53), MIN+ tumours (tumours lacking hMLH1 expression) and CIN- /MIN- tumours (tumours without these defects). In the Netherlands Cohort Study on diet and cancer, 120852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer at baseline (1986). Case-cohort analyses were conducted using 573 CRC cases with complete data after 7 x 3 years of follow-up, excluding the first 2 x 3 years. Adjusted incidence rate ratios (RR) and 95 % confidence intervals (CI) were estimated. Compared with abstaining, alcohol consumption of >or=30 g/d was positively associated with the risk of CRC irrespective of genetic or molecular aberrations present, although statistical significance was not reached (RR 1 x 35 (95 % CI 0 x 9-2 x 0) for the CIN+ tumours, RR 1 x 59 (95 % CI 0 x 4-5 x 8) for the MIN+ tumours and RR 1.15 (95 % CI 0 x 5-2 x 7) for the CIN- /MIN- tumours). Beer, wine and liquor consumption were, independent of their alcoholic content, not consistently associated with the risk of CRC within the defined subgroups. In conclusion, our results indicate that a daily alcohol consumption of >or=30 g is associated with an increase in risk of CRC, independent of the presence or absence of the studied characteristics of different aetiological pathways.

  1. Different Achilles Tendon Pathologies Show Distinct Histological and Molecular Characteristics

    Directory of Open Access Journals (Sweden)

    Franka Klatte-Schulz

    2018-01-01

    Full Text Available Reasons for the development of chronic tendon pathologies are still under debate and more basic knowledge is needed about the different diseases. The aim of the present study was therefore to characterize different acute and chronic Achilles tendon disorders. Achilles tendon samples from patients with chronic tendinopathy (n = 7, chronic ruptures (n = 6, acute ruptures (n = 13, and intact tendons (n = 4 were analyzed. The histological score investigating pathological changes was significantly increased in tendinopathy and chronic ruptures compared to acute ruptures. Inflammatory infiltration was detected by immunohistochemistry in all tendon pathology groups, but was significantly lower in tendinopathy compared to chronic ruptures. Quantitative real-time PCR (qRT-PCR analysis revealed significantly altered expression of genes related to collagens and matrix modeling/remodeling (matrix metalloproteinases, tissue inhibitors of metalloproteinases in tendinopathy and chronic ruptures compared to intact tendons and/or acute ruptures. In all three tendon pathology groups markers of inflammation (interleukin (IL 1β, tumor necrosis factor α, IL6, IL10, IL33, soluble ST2, transforming growth factor β1, cyclooxygenase 2, inflammatory cells (cluster of differentaition (CD 3, CD68, CD80, CD206, fat metabolism (fatty acid binding protein 4, peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, adiponectin, and innervation (protein gene product 9.5, growth associated protein 43, macrophage migration inhibitory factor were detectable, but only in acute ruptures significantly regulated compared to intact tendons. The study gives an insight into structural and molecular changes of pathological processes in tendons and might be used to identify targets for future therapy of tendon pathologies.

  2. Intrinsic subtypes and tumor grades in breast cancer are associated with distinct 3-D power Doppler sonographic vascular features

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Yeun-Chung [Department of Medical Imaging, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10041, Taiwan, ROC (China); Huang, Yao-Sian [Department of Computer Science and Information Engineering, National Taiwan University, Taipei 10617, Taiwan, ROC (China); Huang, Chiun-Sheng [Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 10041, Taiwan, ROC (China); Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan, ROC (China); Chen, Jeon-Hor [Center for Functional Onco-Imaging and Department of Radiological Science, University of California Irvine, California, CA 92868 (United States); Department of Radiology, E-Da Hospital and I-Shou University, Kaohsiung 82445, Taiwan, ROC (China); Chang, Ruey-Feng, E-mail: rfchang@csie.ntu.edu.tw [Department of Computer Science and Information Engineering, National Taiwan University, Taipei 10617, Taiwan, ROC (China); Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei 10617, Taiwan, ROC (China)

    2014-08-15

    Purpose: This study aimed to investigate the three-dimensional (3-D) power Doppler ultrasonographic (PDUS) vascular features of breast carcinoma according to intrinsic subtypes, nodal stage, and tumor grade. Materials and methods: Total 115 receiving mastectomy breast carcinomas (mean size, 2.5 cm; range, 0.7–6.5 cm), including 102 invasive ductal carcinomas (IDC), 10 ductal carcinomas in situ (DCIS), and 3 invasive lobular carcinomas (ILC) diagnosed after mastectomy, were used in this retrospective study. Sixty IDC had nodal status and histopathologic tumor grades available for analysis. Vascular features, including number of vascular trees (NV), longest path length (LPL), total vessel length (TVL), number of bifurcations (NB), distance metric (DM), inflection count metric (ICM), vessel diameter (VD), and vessel-to-volume ratio (VVR) were extracted using 3-D thinning method. The Mann–Whitney U test, Student's t-test, one-way ANOVA, and Kruskal–Wallis test were performed as appropriate. Results: There was no significant difference of vascular features among IDC, DCIS and ILC. Except VD, vascular features in luminal type were significantly lower compared to HER2-enriched or triple negative types (p < 0.05). Compared to ER+ (estrogen receptor positive) tumors, all features in ER− (estrogen receptor negative) tumors were significantly higher (p < 0.01). Despite some significantly higher vascular features in high grade IDC compared to low and intermediate grade, there was no significant correlation between vascular features and nodal stages. Conclusion: Differences in 3-D PDUS vascular features among intrinsic types of IDC are attributed to their ER status. Vascular features extracted by 3-D PDUS correlate with tumor grades but not nodal stage in IDC.

  3. 16S rRNA partial gene sequencing for the differentiation and molecular subtyping of Listeria species.

    Science.gov (United States)

    Hellberg, Rosalee S; Martin, Keely G; Keys, Ashley L; Haney, Christopher J; Shen, Yuelian; Smiley, R Derike

    2013-12-01

    Use of 16S rRNA partial gene sequencing within the regulatory workflow could greatly reduce the time and labor needed for confirmation and subtyping of Listeria monocytogenes. The goal of this study was to build a 16S rRNA partial gene reference library for Listeria spp. and investigate the potential for 16S rRNA molecular subtyping. A total of 86 isolates of Listeria representing L. innocua, L. seeligeri, L. welshimeri, and L. monocytogenes were obtained for use in building the custom library. Seven non-Listeria species and three additional strains of Listeria were obtained for use in exclusivity and food spiking tests. Isolates were sequenced for the partial 16S rRNA gene using the MicroSeq ID 500 Bacterial Identification Kit (Applied Biosystems). High-quality sequences were obtained for 84 of the custom library isolates and 23 unique 16S sequence types were discovered for use in molecular subtyping. All of the exclusivity strains were negative for Listeria and the three Listeria strains used in food spiking were consistently recovered and correctly identified at the species level. The spiking results also allowed for differentiation beyond the species level, as 87% of replicates for one strain and 100% of replicates for the other two strains consistently matched the same 16S type. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Sensitivity to PI3K and AKT inhibitors is mediated by divergent molecular mechanisms in subtypes of DLBCL.

    Science.gov (United States)

    Erdmann, Tabea; Klener, Pavel; Lynch, James T; Grau, Michael; Vočková, Petra; Molinsky, Jan; Tuskova, Diana; Hudson, Kevin; Polanska, Urszula M; Grondine, Michael; Mayo, Michele; Dai, Beiying; Pfeifer, Matthias; Erdmann, Kristian; Schwammbach, Daniela; Zapukhlyak, Myroslav; Staiger, Annette M; Ott, German; Berdel, Wolfgang E; Davies, Barry R; Cruzalegui, Francisco; Trneny, Marek; Lenz, Peter; Barry, Simon T; Lenz, Georg

    2017-07-20

    Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton's tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors. © 2017 by The American Society of Hematology.

  5. Assessing the genetic architecture of epithelial ovarian cancer histological subtypes

    DEFF Research Database (Denmark)

    Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C

    2016-01-01

    Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent...... studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian...

  6. Computational approach to radiogenomics of breast cancer: Luminal A and luminal B molecular subtypes are associated with imaging features on routine breast MRI extracted using computer vision algorithms.

    Science.gov (United States)

    Grimm, Lars J; Zhang, Jing; Mazurowski, Maciej A

    2015-10-01

    To identify associations between semiautomatically extracted MRI features and breast cancer molecular subtypes. We analyzed routine clinical pre-operative breast MRIs from 275 breast cancer patients at a single institution in this retrospective, Institutional Review Board-approved study. Six fellowship-trained breast imagers reviewed the MRIs and annotated the cancers. Computer vision algorithms were then used to extract 56 imaging features from the cancers including morphologic, texture, and dynamic features. Surrogate markers (estrogen receptor [ER], progesterone receptor [PR], human epidermal growth factor receptor-2 [HER2]) were used to categorize tumors by molecular subtype: ER/PR+, HER2- (luminal A); ER/PR+, HER2+ (luminal B); ER/PR-, HER2+ (HER2); ER/PR/HER2- (basal). A multivariate analysis was used to determine associations between the imaging features and molecular subtype. The imaging features were associated with both luminal A (P = 0.0007) and luminal B (P = 0.0063) molecular subtypes. No association was found for either HER2 (P = 0.2465) or basal (P = 0.1014) molecular subtype and the imaging features. A P-value of 0.0125 (0.05/4) was considered significant. Luminal A and luminal B molecular subtype breast cancer are associated with semiautomatically extracted features from routine contrast enhanced breast MRI. © 2015 Wiley Periodicals, Inc.

  7. CALTECH CORE-COLLAPSE PROJECT (CCCP) OBSERVATIONS OF TYPE II SUPERNOVAE: EVIDENCE FOR THREE DISTINCT PHOTOMETRIC SUBTYPES

    International Nuclear Information System (INIS)

    Arcavi, Iair; Gal-Yam, Avishay; Yaron, Ofer; Cenko, S. Bradley; Becker, Adam B.; Fox, Derek B.; Leonard, Douglas C.; Moon, Dae-Sik; Sand, David J.; Soderberg, Alicia M.; Kiewe, Michael; Scheps, Raphael; Birenbaum, Gali; Chamudot, Daniel; Zhou, Jonathan

    2012-01-01

    We present R-band light curves of Type II supernovae (SNe) from the Caltech Core-Collapse Project (CCCP). With the exception of interacting (Type IIn) SNe and rare events with long rise times, we find that most light curve shapes belong to one of three apparently distinct classes: plateau, slowly declining, and rapidly declining events. The last class is composed solely of Type IIb SNe which present similar light curve shapes to those of SNe Ib, suggesting, perhaps, similar progenitor channels. We do not find any intermediate light curves, implying that these subclasses are unlikely to reflect variance of continuous parameters, but rather might result from physically distinct progenitor systems, strengthening the suggestion of a binary origin for at least some stripped SNe. We find a large plateau luminosity range for SNe IIP, while the plateau lengths seem rather uniform at approximately 100 days. As analysis of additional CCCP data goes on and larger samples are collected, demographic studies of core-collapse SNe will likely continue to provide new constraints on progenitor scenarios.

  8. Characterization of KIR intermediate promoters reveals four promoter types associated with distinct expression patterns of KIR subtypes.

    Science.gov (United States)

    Li, H; Wright, P W; McCullen, M; Anderson, S K

    2016-01-01

    The human killer cell immunoglobulin-like receptor (KIR) genes contain multiple promoters that control the process of gene activation and variegated expression of KIR on natural killer (NK) and T cells. Specific subfamilies of KIR genes have differences in the timing and tissue specificity of expression: however, previous studies of the proximal KIR promoters have not shown significant differences in activity between differentially expressed KIR gene subsets. The recent identification of an intermediate KIR promoter (ProI) associated with KIR2DL1 expression suggested a central role for this element in KIR expression. The current study identifies ProI elements in all of the KIR genes, revealing four classes of ProI that correspond with four distinct expression phenotypes of KIR subgroups: KIR2DL2/S2/L3 that are expressed early in reconstituting NK after transplant; KIR2DL4 that is expressed by CD56-bright NK in a non-variegated manner; KIR3DL3 that is not expressed by circulating NK cells; and the remaining KIR that are expressed by subsets of CD56-dim NK. The four classes of ProI are structurally diverse and display distinct functional properties. Altogether, these results indicate that KIR ProI elements contribute to the tissue/cell-type specificity of KIR transcription and cooperate with the probabilistic proximal promoter to control KIR expression.

  9. Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia

    NARCIS (Netherlands)

    Balgobind, Brian V.; Van den Heuvel-Eibrink, Marry M.; De Menezes, Renee X.; Reinhardt, Dirk; Hollink, Iris H. I. M.; Arentsen-Peters, Susan T. J. C. M.; van Wering, Elisabeth R.; Kaspers, Gertjan J. L.; Cloos, Jacqueline; de Bont, Evelien S. J. M.; Cayuela, Jean-Michel; Baruchel, Andre; Meyer, Claus; Marschalek, Rolf; Trka, Jan; Stary, Jan; Beverloo, H. Berna; Pieters, Rob; Zwaan, C. Michel; den Boer, Monique L.

    Background Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity. Design and Methods We examined the

  10. Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia

    NARCIS (Netherlands)

    B.V. Balgobind (Brian); M.M. van den Heuvel-Eibrink (Marry); R.X. de Menezes (Renee); D. Reinhardt (Dirk); I.H.I.M. Hollink (Iris); S.T.C.J.M. Arentsen-Peters (Susan); E.R. van Wering (Elisabeth); G.J. Kaspers (Gertjan); J. Cloos (Jacqueline); E.S.J.M. de Bont (Eveline); J.M. Cayuela (Jean Michel); A. Baruchel (André); C. Meyer (Claus); R. Marschalek (Rolf); J. Trka (Jan); J. Stary (Jan); H.B. Beverloo (Berna); R. Pieters (Rob); C.M. Zwaan (Christian Michel); M.L. den Boer (Monique)

    2011-01-01

    textabstractBackground Pediatric acute myeloid leukemia is a heterogeneous disease characterized by non-random genetic aberrations related to outcome. The genetic subtype is currently detected by different diagnostic procedures which differ in success rate and/or specificity. Design and Methods We

  11. Deep sequencing of RNA from three different extracellular vesicle (EV subtypes released from the human LIM1863 colon cancer cell line uncovers distinct miRNA-enrichment signatures.

    Directory of Open Access Journals (Sweden)

    Hong Ji

    Full Text Available Secreted microRNAs (miRNAs enclosed within extracellular vesicles (EVs play a pivotal role in intercellular communication by regulating recipient cell gene expression and affecting target cell function. Here, we report the isolation of three distinct EV subtypes from the human colon carcinoma cell line LIM1863--shed microvesicles (sMVs and two exosome populations (immunoaffinity isolated A33-exosomes and EpCAM-exosomes. Deep sequencing of miRNA libraries prepared from parental LIM1863 cells/derived EV subtype RNA yielded 254 miRNA identifications, of which 63 are selectively enriched in the EVs--miR-19a/b-3p, miR-378a/c/d, and miR-577 and members of the let-7 and miR-8 families being the most prominent. Let-7a-3p*, let-7f-1-3p*, miR-451a, miR-574-5p*, miR-4454 and miR-7641 are common to all EV subtypes, and 6 miRNAs (miR-320a/b/c/d, miR-221-3p, and miR-200c-3p discern LIM1863 exosomes from sMVs; miR-98-5p was selectively represented only in sMVs. Notably, A33-Exos contained the largest number (32 of exclusively-enriched miRNAs; 14 of these miRNAs have not been reported in the context of CRC tissue/biofluid analyses and warrant further examination as potential diagnostic markers of CRC. Surprisingly, miRNA passenger strands (star miRNAs for miR-3613-3p*, -362-3p*, -625-3p*, -6842-3p* were the dominant strand in A33-Exos, the converse to that observed in parental cells. This finding suggests miRNA biogenesis may be interlinked with endosomal/exosomal processing.

  12. Associations between body mass index and molecular subtypes as well as other clinical characteristics of breast cancer in Chinese women

    Directory of Open Access Journals (Sweden)

    Chen FY

    2013-03-01

    Full Text Available Fei-Yu Chen, Hui-Ying Ou, Shou-Man Wang, Yu-Hui Wu, Guo-Jiao Yan, Li-Li Tang Department of Breast Surgery, Xiangya Hospital, Central South University, Changsha City, Hunan Province, People's Republic of China Background: Several studies have shown a positive association between body mass index (BMI and the development of hormone receptor-positive breast cancer in postmenopausal women; however, the associations between BMI groups and molecular subtypes have yet to be well defined in premenopausal breast cancer patients. Methods: A total of 2465 female breast cancer patients diagnosed at our institution were recruited for this study. Clinicopathologic information (including age, body height and weight, as well as tumor subtypes and stages was collected; analyses of these characteristics and the associations between them were performed. Results: A total of 1951 cases were included in the study. The mean age was 47.3 years, the majority of patients were of normal weight, premenopausal, had stage 2 cancer, and did not present with positive nodes. The prevalence of the luminal A, luminal B, human epidermal growth factor receptor 2+, and triple-negative subtypes were 57.8%, 11.6%, 6.1%, and 24.5%, respectively. There were significant differences in the clinicopathologic features among BMI groups in premenopausal patients. The case-only odds ratio (OR analysis revealed that normal weight patients tended to have luminal B cancer (OR = 1.4, P = 0.206, and overweight and obese patients tended to have triple-negative cancer in premenopausal patients (OR = 2.8, OR = 3.7, respectively; P < 0.001. Conclusion: In Chinese women, breast cancer came with these characteristics: young mean age (premenopause, luminal A subtype, and the majority of them were within a normal weight range. In premenopausal patients, underweight patients tended to have luminal A, lower human epidermal growth factor receptor 2+ expression, stage 1 and no positive node cancer. However

  13. Magnetic resonance imaging in breast cancer treated with neoadjuvant chemotherapy: radiologic-pathologic correlation of the response and disease-free survival depending on molecular subtype.

    Science.gov (United States)

    Cruz Ciria, S; Jiménez Aragón, F; García Mur, C; Esteban Cuesta, H; Gros Bañeres, B

    2014-01-01

    To evaluate the radiologic and pathologic responses to neoadjuvant chemotherapy and their correlation in the molecular subtypes of breast cancer and to analyze their impact in disease-free survival. We included 205 patients with breast cancer treated with neoadjuvant chemotherapy. We evaluated the radiologic response by comparing MRI images acquired before and after chemotherapy. The pathologic response was classified on the Miller and Payne scale. For each subtype (HER2+, TN, luminal A, luminal B HER2-, and luminal B HER2+), we used the χ(2) test, Student's t-test, ANOVA, and Kendall's Tau-b to evaluate the radiologic response and the pathologic response, the radiologic-pathologic correlation, and the disease-free survival. The subtypes HER2+ (62.1%) and TN (45.2%) had higher rates of complete radiologic response. The pathologic response was 65.5% in the HER2+ subtype, 38.1% in the TN subtype, 2.6% in the luminal A subtype, 8.2% in the luminal B HER2- subtype, and 31% in the luminal B HER2+ subtype. The rate of radiologic-pathologic correlation was significant in all subtypes, higher in TN and HER2 (Tau-b coefficients 0.805 and 0.717, respectively). Disease-free survival was higher in HER2+ (91.9±3.3 months) and lower in TN (69.5±6.3 months), with significant differences between the cases with poor and good radiologic responses (P=.040). Survival was greater in cases with good radiologic response, except in cases with luminal A subtype. MRI can be a useful tool that provides information about the evolution of breast cancer treated with neoadjuvant chemotherapy, which varies with the immunohistochemical subtype. Copyright © 2012 SERAM. Published by Elsevier Espana. All rights reserved.

  14. Molecular characterization of Cryptosporidium parvum and Cryptosporidium hominis GP60 subtypes worldwide

    Directory of Open Access Journals (Sweden)

    Catalina Avendaño V

    2017-09-01

    Full Text Available Cryptosporidium is a zoonotic parasite very important in animal health as well as in public health. It is because this is one of the main causes of diarrhea in children, calves, lambs and other variety of youth mammalians in a lot of countries. The globalization has enabled the exchange of biological material in different regions worldwide, encouraging the spread of diseases and exposure to these biological agents to different environmental conditions, inducing adaptation through genetic changes. Based in the polymorphism of the gene for GP60, this review intended to present the distribution of Cryptosporidium parvum and Cryptosporidium hominis in humans and calves worldwide. The subtype that affects cattle more frequently corresponds to IIaA15G2R; while the subtype most frequently isolated from human samples is IaA19G2.

  15. RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families

    DEFF Research Database (Denmark)

    Larsen, Martin J; Thomassen, Mads; Tan, Qihua

    2014-01-01

    and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. CONCLUSIONS: Our finding indicates involvement of hereditary factors in non-BRCA1/2 breast cancer families in which family members may carry genetic susceptibility not just to breast...... cancer but to a particular subtype of breast cancer. This is the first study to provide a biological link between breast cancers from family members of high-risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly......BACKGROUND: In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar...

  16. Molecular identification of Blastocystis sp. subtypes in water samples collected from Black sea, Turkey.

    Science.gov (United States)

    Koloren, Zeynep; Gulabi, Berivan Basak; Karanis, Panagiotis

    2018-04-01

    The aim of this study was to identify the subtypes of Blastocystis sp. and complete a phylogenetic analysis of 268 water samples that were collected from the Samsun, Amasya and Sinop Provinces of the Black Sea in Turkey, between the years 2011 and 2014. Blastocystis sp. was investigated in 48 uncultured sea water samples that were collected from 4 sites within the Sinop Province. A total of 100 river water samples were collected from 37 sites in the Samsun Province and 120 river water samples were collected from 10 sampling sites within the Amasya Province. The small subunit (SSU) rDNA gene Polymerase chain reaction (PCR) were performed for the detection of Blastocytis sp. and the PCR-positive samples were sequenced. Subsequently, the (SSU) rDNA sequences were aligned by Bioedit and phylogenetic trees were constructed for Blastocystis with reference to the genotypes from GenBank. Blastocystis sp. were found in 3 out of the 75 (4%) river water samples that were collected from the Samsun Province. Six of the 120 (5%) river water samples and 1 out of the 48 (2%) seawater samples were positive for Blastocystis in the Amasya and Sinop Provinces. There were two different subtypes (ST; 1 and 3) found from sequencing all of the samples from the investigated sites. Two and one PCR products were found to be positive for ST1 and ST3 from the different samples collected within the Samsun Province. Two and 4 PCR products from the Amasya Province were ST1 and ST3, respectively and only one sample from the Sinop Province was found to be positive for ST1. This is the first report to identify and report the occurrence of Blastocystis subtypes within the Black Sea of Turkey. Copyright © 2018 Elsevier B.V. All rights reserved.

  17. CCR 20th Anniversary Commentary: The Development of Breast Cancer Molecular Subtyping.

    Science.gov (United States)

    Nielsen, Torsten O; Perou, Charles M

    2015-04-15

    In the August 15, 2004, issue of Clinical Cancer Research, Nielsen and colleagues demonstrated how a cancer subtype identified by gene expression profiling could be validated using a widely accessible technology (immunohistochemistry). This opened the door to large-scale studies of archival cohorts and clinical trials, which allowed detailed clinical understanding of a new genomic discovery. Clin Cancer Res; 21(8); 1779-81. ©2015 AACR. See related article by Nielsen et al., Clin Cancer Res 2004;10(16) Aug 15, 2004;5367-74. ©2015 American Association for Cancer Research.

  18. Aspirin and NSAID use in association with molecular subtypes of prostate cancer defined by TMPRSS2:ERG fusion status.

    Science.gov (United States)

    Wright, J L; Chéry, L; Holt, S; Lin, D W; Luedeke, M; Rinckleb, A E; Maier, C; Stanford, J L

    2016-03-01

    The TMPRSS2:ERG (T2E) gene fusion is the most common rearrangement in prostate cancer (PCa). It is unknown if these molecular subtypes have a different etiology. We evaluated aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in association with T2E fusion status. Subjects were from a population-based case-control study of PCa. T2E fusion status for prostatectomy cases (n=346) was determined by fluorescence in situ hybridization. Medication use was determined from questionnaires. Logistic regression, controlling for age, race, PCa family history and PSA screening, was used to evaluate the association of T2E fusion status according to medication use. T2E fusion was present in 171 (49%) cases, with younger cases more likely to be fusion positive (Paspirin use was associated with a 37% risk reduction of T2E-positive tumors (adjusted odds ratio (OR) 0.63, 95% confidence interval 0.43-0.93). Aspirin use was not associated with T2E negative PCa (adjusted OR 0.99, 0.69-1.42). There were no associations between PCa fusion status and use of nonaspirin NSAIDs or acetaminophen. Aspirin was associated with a significant reduction in the relative risk of T2E fusion positive, but not T2E negative, PCa. As inflammation and androgen pathways are implicated in prostate carcinogenesis, additional studies of anti-inflammatory medications in relation to these PCa subtypes are warranted.

  19. E-cadherin expression phenotypes associated with molecular subtypes in invasive non-lobular breast cancer: evidence from a retrospective study and meta-analysis.

    Science.gov (United States)

    Liu, Jiang-Bo; Feng, Chen-Yi; Deng, Miao; Ge, Dong-Feng; Liu, De-Chun; Mi, Jian-Qiang; Feng, Xiao-Shan

    2017-08-01

    This retrospective study and meta-analysis was designed to explore the relationship between E-cadherin (E-cad) expression and the molecular subtypes of invasive non-lobular breast cancer, especially in early-stage invasive ductal carcinoma (IDC). A total of 156 post-operative cases of early-stage IDCs were retrospectively collected for the immunohistochemistry (IHC) detection of E-cad expression. The association of E-cad expression with molecular subtypes of early-stage IDCs was analyzed. A literature search was conducted in March 2016 to retrieve publications on E-cad expression in association with molecular subtypes of invasive non-lobular breast cancer, and a meta-analysis was performed to estimate the relational statistics. E-cad was expressed in 82.7% (129/156) of early-stage IDCs. E-cad expression was closely associated with the molecular types of early-stage IDCs (P cancer (TNBC) than in other molecular subtypes (TNBC vs. luminal A: RR = 3.45, 95% CI = 2.79-4.26; TNBC vs. luminal B: RR = 2.41, 95% CI = 1.49-3.90; TNBC vs. HER2-enriched: RR = 1.95, 95% CI = 1.24-3.07). Early-stage IDCs or invasive non-lobular breast cancers with the TNBC molecular phenotype have a higher risk for the loss of E-cad expression than do tumors with non-TNBC molecular phenotypes, suggesting that E-cad expression phenotypes were closely related to molecular subtypes and further studies are needed to clarify the underlying mechanism.

  20. Molecular Epidemiology of Blastocystis in Lebanon and Correlation between Subtype 1 and Gastrointestinal Symptoms

    Science.gov (United States)

    El Safadi, Dima; Meloni, Dionigia; Poirier, Philippe; Osman, Marwan; Cian, Amandine; Gaayeb, Lobna; Wawrzyniak, Ivan; Delbac, Frederic; El Alaoui, Hicham; Delhaes, Laurence; Dei-Cas, Eduardo; Mallat, Hassan; Dabboussi, Fouad; Hamze, Monzer; Viscogliosi, Eric

    2013-01-01

    Blastocystis is the most common eukaryotic parasite in the intestinal tract of humans. Because of its potential impact in public health, we acquired the first data concerning the prevalence of this parasite and the frequency of the Blastocystis subtypes (STs) in the Lebanese population. In this study, fecal samples from 220 Lebanese symptomatic and asymptomatic patients were collected and a total of 42 patients (19%) were identified as positive for this parasite by direct-light microscopy of smears. Among these, 36 Blastocystis isolates were genotyped using partial small subunit ribosomal RNA gene sequencing. The ST distribution in the present Lebanese population was as follows: ST3 (33.3%), ST2 (33.3%), ST1 (30.6%), and ST4 (2.8%). These data were compared with those available in other Middle Eastern and neighboring countries. Finally, ST1 was significantly more prevalent among symptomatic patients of this Lebanese population. PMID:23458955

  1. Molecular epidemiology of HIV-1 subtype A in former Soviet Union countries.

    Science.gov (United States)

    Aibekova, Lazzat; Foley, Brian; Hortelano, Gonzalo; Raees, Muhammad; Abdraimov, Sabit; Toichuev, Rakhmanbek; Ali, Syed

    2018-01-01

    While in other parts of the world it is on decline, incidence of HIV infection continues to rise in the former Soviet Union (FSU) countries. The present study was conducted to investigate the patterns and modes of HIV transmission in FSU countries. We performed phylogenetic analysis of publicly available 2705 HIV-1 subtype A pol sequences from thirteen FSU countries: Armenia, Azerbaijan, Belarus, Estonia, Georgia, Kazakhstan, Kyrgyzstan, Latvia, Lithuania, Moldova, Russia, Ukraine and Uzbekistan. Our analysis showed that the clusters from FSU countries were intermixed, indicating a possible role of transmigration in HIV transmission. Injection drug use was found to be the most frequent mode of transmission, while the clusters from PWID and heterosexual transmission were intermixed, indicating bridging of HIV infection across populations. To control the expanding HIV epidemic in this region, harm reduction strategies should be focused on three modes of transmission, namely, cross-border migration, injection drug use and heterosexual.

  2. Molecular determinants of subtype-selective efficacies of cytisine and the novel compound NS3861 at heteromeric nicotinic acetylcholine receptors

    DEFF Research Database (Denmark)

    Harpsøe, Kasper; Hald, Helle; Timmermann, Daniel B

    2013-01-01

    Deciphering which specific agonist-receptor interactions affect efficacy levels is of high importance, because this will ultimately aid in designing selective drugs. The novel compound NS3861 and cytisine are agonists of nicotinic acetylcholine receptors (nAChRs) and both bind with high affinity...... electrophysiological measurements of efficacy levels at heteromeric combinations of a3- and a4-, with ß2- and ß4-subunits, and various chimeric constructs thereof. Compared with cytisine, which selectively activates receptors containing ß4- but not ß2-subunits, NS3861 displays the opposite ß-subunit preference...... and a complete lack of activation at a4-containing receptors. The maximal efficacy of NS3861 appeared solely dependent on the nature of the ligand-binding domain, whereas efficacy of cytisine was additionally affected by the nature of the ß-subunit transmembrane domain. Molecular docking to nAChR subtype...

  3. Association of Screening and Treatment With Breast Cancer Mortality by Molecular Subtype in US Women, 2000-2012.

    Science.gov (United States)

    Plevritis, Sylvia K; Munoz, Diego; Kurian, Allison W; Stout, Natasha K; Alagoz, Oguzhan; Near, Aimee M; Lee, Sandra J; van den Broek, Jeroen J; Huang, Xuelin; Schechter, Clyde B; Sprague, Brian L; Song, Juhee; de Koning, Harry J; Trentham-Dietz, Amy; van Ravesteyn, Nicolien T; Gangnon, Ronald; Chandler, Young; Li, Yisheng; Xu, Cong; Ergun, Mehmet Ali; Huang, Hui; Berry, Donald A; Mandelblatt, Jeanne S

    2018-01-09

    Given recent advances in screening mammography and adjuvant therapy (treatment), quantifying their separate and combined effects on US breast cancer mortality reductions by molecular subtype could guide future decisions to reduce disease burden. To evaluate the contributions associated with screening and treatment to breast cancer mortality reductions by molecular subtype based on estrogen-receptor (ER) and human epidermal growth factor receptor 2 (ERBB2, formerly HER2 or HER2/neu). Six Cancer Intervention and Surveillance Network (CISNET) models simulated US breast cancer mortality from 2000 to 2012 using national data on plain-film and digital mammography patterns and performance, dissemination and efficacy of ER/ERBB2-specific treatment, and competing mortality. Multiple US birth cohorts were simulated. Screening mammography and treatment. The models compared age-adjusted, overall, and ER/ERBB2-specific breast cancer mortality rates from 2000 to 2012 for women aged 30 to 79 years relative to the estimated mortality rate in the absence of screening and treatment (baseline rate); mortality reductions were apportioned to screening and treatment. In 2000, the estimated reduction in overall breast cancer mortality rate was 37% (model range, 27%-42%) relative to the estimated baseline rate in 2000 of 64 deaths (model range, 56-73) per 100 000 women: 44% (model range, 35%-60%) of this reduction was associated with screening and 56% (model range, 40%-65%) with treatment. In 2012, the estimated reduction in overall breast cancer mortality rate was 49% (model range, 39%-58%) relative to the estimated baseline rate in 2012 of 63 deaths (model range, 54-73) per 100 000 women: 37% (model range, 26%-51%) of this reduction was associated with screening and 63% (model range, 49%-74%) with treatment. Of the 63% associated with treatment, 31% (model range, 22%-37%) was associated with chemotherapy, 27% (model range, 18%-36%) with hormone therapy, and 4% (model range, 1

  4. Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules

    DEFF Research Database (Denmark)

    van Weering, Jan R.T.; Sessions, Richard B.; Traer, Colin J.

    2012-01-01

    Sorting nexins (SNXs) are regulators of endosomal sorting. For the SNX-BAR subgroup, a Bin/Amphiphysin/Rvs (BAR) domain is vital for formation/stabilization of tubular subdomains that mediate cargo recycling. Here, by analysing the in vitro membrane remodelling properties of all 12 human SNX......-loop' interactions. Overall, the restricted and selective nature of these interactions provide a molecular explanation for how distinct SNX-BAR-decorated tubules are nucleated from the same endosomal vacuole, as observed in living cells. Our data provide insight into the molecular mechanism that generates...

  5. The Convergent Evolution of Blue Iris Pigmentation in Primates Took Distinct Molecular Paths

    OpenAIRE

    Meyer, Wynn K; Zhang, Sidi; Hayakawa, Sachiko; Imai, Hiroo; Przeworski, Molly

    2013-01-01

    How many distinct molecular paths lead to the same phenotype? One approach to this question has been to examine the genetic basis of convergent traits, which likely evolved repeatedly under a shared selective pressure. We investigated the convergent phenotype of blue iris pigmentation, which has arisen independently in four primate lineages: humans, blue-eyed black lemurs, Japanese macaques, and spider monkeys. Characterizing the phenotype across these species, we found that the variation wit...

  6. Latent memory facilitates relearning through molecular signaling mechanisms that are distinct from original learning.

    Science.gov (United States)

    Menges, Steven A; Riepe, Joshua R; Philips, Gary T

    2015-09-01

    A highly conserved feature of memory is that it can exist in a latent, non-expressed state which is revealed during subsequent learning by its ability to significantly facilitate (savings) or inhibit (latent inhibition) subsequent memory formation. Despite the ubiquitous nature of latent memory, the mechanistic nature of the latent memory trace and its ability to influence subsequent learning remains unclear. The model organism Aplysia californica provides the unique opportunity to make strong links between behavior and underlying cellular and molecular mechanisms. Using Aplysia, we have studied the mechanisms of savings due to latent memory for a prior, forgotten experience. We previously reported savings in the induction of three distinct temporal domains of memory: short-term (10min), intermediate-term (2h) and long-term (24h). Here we report that savings memory formation utilizes molecular signaling pathways that are distinct from original learning: whereas the induction of both original intermediate- and long-term memory in naïve animals requires mitogen activated protein kinase (MAPK) activation and ongoing protein synthesis, 2h savings memory is not disrupted by inhibitors of MAPK or protein synthesis, and 24h savings memory is not dependent on MAPK activation. Collectively, these findings reveal that during forgetting, latent memory for the original experience can facilitate relearning through molecular signaling mechanisms that are distinct from original learning. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Molecular cloning and functional characterization of eleven subtypes of interferon-α in Amur tigers (Panthera tigris altaica).

    Science.gov (United States)

    Zhao, Hongjing; Ma, Jian; Wang, Yu; Liu, Juanjuan; Shao, Yizhi; Li, Jinglun; Jiang, Guangshun; Xing, Mingwei

    2017-12-01

    Interferon has a broad-spectrum of antiviral effects and represents an ideal choice for the development of antiviral drugs. Nonetheless, information about alpha interferon (IFN-α) is vacant in Amur tiger (Panthera tigris altaica), an endangered species and indigenous to northeast Asia. Herein, 11 PtIFN-αs genes, which encoded proteins of 164-165 amino acids, were amplified. Afterwards, expression and purification were conducted in Escherichia coli. In physicochemical analysis, PtIFN-αs were shown to be highly sensitive to trypsin and remained stable despite changes in pH and temperature. In feline kidney cells (F81)/vesicular stomatitis virus (VSV)/canine distemper virus (CDV)/avian influenza virus (AIV) systems, PtIFN-αs were demonstrated to have distinct antiviral activities, some of them (PtIFN-α and PtIFN-α9) inhibited viral transcription levels more effectively than the other subtypes including Felis catus IFN-α, an effective therapeutic agent used for viral infections clinically. Additionally, PtIFN-α and PtIFN-α9 can up-regulate the transcription and expression of p53, a tumor suppressor factor, which could promote apoptosis of virus-infected cells. In conclusion, we cloned and expressed 11 subtypes of PtIFN-α for the first time. Furthermore, PtIFN-α and PtIFN-α9 were likely to be more efficient against both chronic viral infections and neoplastic diseases that affect the Amur tiger population. It will be of significant importance for further studies to protect this endangered species. Copyright © 2017. Published by Elsevier Ltd.

  8. Molecular Subtyping and Source Attribution of Campylobacter Isolated from Food Animals.

    Science.gov (United States)

    Tyson, Gregory H; Tate, Heather P; Abbott, Jason; Tran, Thu-Thuy; Kabera, Claudine; Crarey, Emily; Young, Shenia; McDermott, Patrick F; Sprague, Grisselle; Campbell, Mark; Adeyemo, Oyewole; Browne-Silva, Johnette; Myers, Michael; Thitaram, Sutawee; Zhao, Shaohua

    2016-11-01

    Campylobacter spp. commonly cause gastrointestinal illness in humans. Poultry meats have long been considered the predominant source of these infections, but few in-depth Campylobacter source attribution studies have been completed. We analyzed more than 1,300 Campylobacter isolates recovered from a number of animal and food sources, including dairy and beef cattle, pigs, poultry, and retail poultry meat, and compared them with Campylobacter isolates recovered from human clinical samples. Each isolate was subtyped using pulsed-field gel electrophoresis (PFGE) with SmaI and queried against the Centers for Disease Control and Prevention PulseNet database to identify human isolates with indistinguishable patterns. Half (49.5%) of the PFGE patterns from poultry animal and retail meat isolates were indistinguishable from patterns of at least one human isolate. Among the isolates from beef and dairy cows, 56.6 and 65.0%, respectively, of their PFGE patterns were indistinguishable from those of human isolates. Only a small portion of the PFGE patterns of Campylobacter isolated from pigs (9.5%) were found to have PFGE patterns in common with human isolates. These data imply that cattle may be larger contributors to Campylobacter infections than previously recognized and help further our understanding of potential sources of human campylobacteriosis.

  9. How many molecular subtypes? Implications of the unique tumor principle in personalized medicine.

    Science.gov (United States)

    Ogino, Shuji; Fuchs, Charles S; Giovannucci, Edward

    2012-07-01

    Cancers are complex multifactorial diseases. For centuries, conventional organ-based classification system (i.e., breast cancer, lung cancer, colon cancer, colorectal cancer, prostate cancer, lymphoma, leukemia, and so on) has been utilized. Recently, molecular diagnostics has become an essential component in clinical decision-making. However, tumor evolution and behavior cannot accurately be predicted, despite numerous research studies reporting promising tumor biomarkers. To advance molecular diagnostics, a better understanding of intratumor and intertumor heterogeneity is essential. Tumor cells interact with the extracellular matrix and host non-neoplastic cells in the tumor microenvironment, which is influenced by genomic variation, hormones, and dietary, lifestyle and environmental exposures, implicated by molecular pathological epidemiology. Essentially, each tumor possesses its own unique characteristics in terms of molecular make-up, tumor microenvironment and interactomes within and between neoplastic and host cells. Starting from the unique tumor concept and paradigm, we can better classify tumors by molecular methods, and move closer toward personalized cancer medicine and prevention.

  10. Superficial spreading and nodular melanoma are distinct biological entities: a challenge to the linear progression model.

    Science.gov (United States)

    Greenwald, Holly S; Friedman, Erica B; Osman, Iman

    2012-02-01

    The classification of melanoma subtypes into prognostically relevant and therapeutically insightful categories has been a challenge since the first description of melanoma in the 1800s. One limitation has been the assumption that the two most common histological subtypes of melanoma, superficial spreading and nodular, evolve according to a linear model of progression, as malignant melanocytes spread radially and then invade vertically. However, recent clinical, pathological, and molecular data indicate that these two histological subtypes might evolve as distinct entities. Here, we review the published data that support distinct molecular characterization of superficial spreading and nodular melanoma, the clinical significance of this distinction including prognostic relevance and the therapeutic implications.

  11. Molecular characterization of HCV in a Swedish county over 8 years (2002–2009 reveals distinct transmission patterns

    Directory of Open Access Journals (Sweden)

    Josefine Ederth

    2016-02-01

    Full Text Available Background: Hepatitis C virus (HCV is a major public health concern and data on its molecular epidemiology in Sweden is scarce. We carried out an 8-year population-based study of newly diagnosed HCV cases in one of Sweden's centrally situated counties, Södermanland (D-county. The aim was to characterize the HCV strains circulating, analyze their genetic relatedness to detect networks, and in combination with demographic data learn more about transmission. Methods: Molecular analyses of serum samples from 91% (N=557 of all newly notified cases in D-county, 2002–2009, were performed. Phylogenetic analysis (NS5B gene, 300 bp was linked to demographic data from the national surveillance database, SmiNet, to characterize D-county transmission clusters. The linear-by-linear association test (LBL was used to analyze trends over time. Results: The most prevalent subtypes were 1a (38% and 3a (34%. Subtype 1a was most prevalent among cases transmitted via sexual contact, via contaminated blood, or blood products, while subtype 3a was most prevalent among people who inject drugs (PWIDs. Phylogenetic analysis revealed that the subtype 3a sequences formed more and larger transmission clusters (50% of the sequences clustered, while the 1a sequences formed smaller clusters (19% of the sequences clustered, possibly suggesting different epidemics. Conclusion: We found different transmission patterns in D-county which may, from a public health perspective, have implications for how to control virus infections by targeted interventions.

  12. Molecular Characterization of Subtype H11N9 Avian Influenza Virus Isolated from Shorebirds in Brazil.

    Directory of Open Access Journals (Sweden)

    Renata Hurtado

    Full Text Available Migratory aquatic birds play an important role in the maintenance and spread of avian influenza viruses (AIV. Many species of aquatic migratory birds tend to use similar migration routes, also known as flyways, which serve as important circuits for the dissemination of AIV. In recent years there has been extensive surveillance of the virus in aquatic birds in the Northern Hemisphere; however in contrast only a few studies have been attempted to detect AIV in wild birds in South America. There are major flyways connecting South America to Central and North America, whereas avian migration routes between South America and the remaining continents are uncommon. As a result, it has been hypothesized that South American AIV strains would be most closely related to the strains from North America than to those from other regions in the world. We characterized the full genome of three AIV subtype H11N9 isolates obtained from ruddy turnstones (Arenaria interpres on the Amazon coast of Brazil. For all gene segments, all three strains consistently clustered together within evolutionary lineages of AIV that had been previously described from aquatic birds in North America. In particular, the H11N9 isolates were remarkably closely related to AIV strains from shorebirds sampled at the Delaware Bay region, on the Northeastern coast of the USA, more than 5000 km away from where the isolates were retrieved. Additionally, there was also evidence of genetic similarity to AIV strains from ducks and teals from interior USA and Canada. These findings corroborate that migratory flyways of aquatic birds play an important role in determining the genetic structure of AIV in the Western hemisphere, with a strong epidemiological connectivity between North and South America.

  13. Molecular Subtyping and Antibiotic Resistance of Campylobacter Species Isolated from Chicken Livers in Beijing, China

    Directory of Open Access Journals (Sweden)

    Xiayang Liu

    2016-11-01

    Full Text Available The incidence of Campylobacter outbreaks caused by contaminated chicken livers has recently increased. We aimed to investigate where contamination occurs, and the drug resistance and genetic characteristics of Campylobacter from chicken livers sold in Beijing, China. The bacteria were isolated from 103 raw chicken livers bought from the retail market in two districts of Beijing. The E-test, Multilocus Sequence Typing (MLST and pulsed-field gel electrophoresis techniques (PFGE were used to study the antibiotic susceptibility and genetic sub-typing of the obtained isolates. A total of 42 Campylobacter isolates (30 C. jejuni and 12 C. coli were obtained from 38 samples of the 103 samples tested (37%, 38/103. The rates of resistance against the tested antibiotics were as follows: erythromycin (2.38%, 1/42, azithromycin (4.76%, 2/42, streptomycin (4.76%, 2/40, gentamicin (40.47%, 17/42, chloramphenicol (11.90%, 5/42, ampicillin (23.81%, 10/42, nalidixic acid (92.85%, 39/42, ciprofloxacin (90.48%, 38/40, doxycycline (78.57%, 33/42, and tetracycline (83.33%, 35/42. The isolates were obtained both from the interior and exterior of the liver samples. Seven sequence types were identified among the 42 isolates; 23 PFGE patterns were found among 32 of the 42 isolates. Different PFGE patterns were identified in isolates from the interior and exterior of the same sample. In conclusion, both the interior and exterior of chicken livers can be contaminated with Campylobacter. They may therefore be a major food source of human campylobacteriosis in Beijing.

  14. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma | Center for Cancer Research

    Science.gov (United States)

    About the Cover:  The Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) Consortium (depicted as a tiger) emerges from foliage, representing molecular, clinical, and epidemiological studies from teams in the United States, Thailand, and Japan, to generate a multilayered genomic and genetic liver cancer data ecosystem (represented by the tiger’s tail).

  15. Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype

    Directory of Open Access Journals (Sweden)

    K. Brennan

    2017-03-01

    Further distinguishing features of this ‘CIMP-Atypical’ subtype include an antiviral gene expression profile associated with pro-inflammatory M1 macrophages and CD8+ T cell infiltration, CASP8 mutations, and a well-differentiated state corresponding to normal SOX2 copy number and SOX2OT hypermethylation. We developed a gene expression classifier for the CIMP-Atypical subtype that could classify atypical disease features in two independent patient cohorts, demonstrating the reproducibility of this subtype. Taken together, these findings provide unprecedented evidence that atypical HNSCC is molecularly distinct, and postulates the CIMP-Atypical subtype as a distinct clinical entity that may be caused by chronic inflammation.

  16. Clinicopathological characteristics of patients of certain molecular subtypes and elevated postoperative cancer antigen 15.3 levels and its correlation with menopausal status

    Directory of Open Access Journals (Sweden)

    Soumi Saha

    2016-01-01

    Full Text Available Context: It is well established that breast cancer subtypes differ in their outcome and treatment response. Aim: To observe tumor characteristics of different molecular subgroup and patients with postoperative (PO raised cancer antigen 15.3 (CA 15.3 group and variation of tumor nature between pre- and post-menopausal breast cancer patients. Materials and Methods: Blood samples and tumor blocks were collected from 95 nonmetastatic female breast cancer patients. Immunohistochemical stains for estrogen receptors (ER, progesterone receptor (PR, and HER2/Neu were used to classify molecular subtypes. CA 15.3 level was detected by ELISA. Significance levels were ascertained by Pearson Chi-square test. Results: Prevalence of luminal A tumor with grade 3 was high. Triple negative and ER positive (ER+ types showed tumors with high grade and high lymph node (LN metastasis. More nodal involvement was noticed in patients with PO raised CA 15.3. In addition, premenopausal patients with triple-negative and ER+ subtypes exhibited more aggressive tumors which were characterized by high grade and large numbers of LN metastasis. Conclusion: Clinicopathological characteristics of certain molecular subtypes and influence of menopausal status on it can predict disease recurrence or overall survival of breast cancer patients.

  17. The Src, Syk, and Tec family kinases: distinct types of molecular switches.

    Science.gov (United States)

    Bradshaw, J Michael

    2010-08-01

    The Src, Syk, and Tec family kinases are three of the most well characterized tyrosine kinase families found in the human genome. Members of these kinase families function downstream of antigen and F(c) receptors in hematopoietic cells and transduce signals leading to calcium mobilization, altered gene expression, cytokine production, and cell proliferation. Over the last several years, structural and biochemical studies have begun to uncover the molecular mechanisms regulating activation of these kinases. It appears that each kinase family functions as a distinct type of molecular switch. This review discusses the activation of the Src, Syk, and Tec kinases from the perspective of structure, phosphorylation, allosteric regulation, and kinetics. The multiple factors that regulate the Src, Syk, and Tec families illustrate the important role played by each of these kinases in immune cell signaling.

  18. Molecular epidemiological analysis of Mycoplasma bovis isolates from the United Kingdom shows two genetically distinct clusters

    DEFF Research Database (Denmark)

    McAuliffe, Laura; Kokotovic, Branko; Ayling, Roger D.

    2004-01-01

    polymorphism (AFLP), and random amplified polymorphic DNA (RAPD) analysis. In addition, the influence of variable surface protein (Vsp) profiles on the profiles generated with molecular typing techniques was studied. Both AFLP and RAPD separated the isolates into two distinct groups, but PFGE showed less......Mycoplasma bovis is an important veterinary pathogen causing pneumonia, arthritis, and mastitis in infected cattle. We investigated the genetic diversity of 53 isolates collected in the United Kingdom between 1996 and 2002 with pulsed-field gel electrophoresis (PFGE), amplified fragment length...... congruence with the other techniques. There was no clear relationship between the geographic origin or year of isolation of the isolates and the profiles produced. No correlation between Vsp profiles and any of the molecular typing techniques was observed. We propose that RAPD and AFLP provide valuable tools...

  19. Distinct cellular and molecular environments support aging-related DNA methylation changes in the substantia nigra.

    Science.gov (United States)

    Fasolino, Maria; Liu, Shuo; Wang, Yinsheng; Zhou, Zhaolan

    2017-01-01

    We aimed to couple brain region-specific changes in global DNA methylation over aging to underlying cellular and molecular environments. We measured two major forms of DNA methylation and analyzed Dnmt, Tet and metabolite levels in the striatum and substantia nigra (SN) over aging in healthy male mice. The ratio of 5-hydroxymethylcytosine to 5-methylcytosine increases over aging in the SN, and 5-hydroxymethylcytosine increases preferentially in dopaminergic neurons. Additionally, this age-dependent alteration in methylation correlates with a reduction in the ratio of α-ketoglutarate to succinate in the SN. Distinct cellular and molecular environments correlate with aging-associated methylation changes in the SN, implicating this epigenetic mechanism in the susceptibility of this brain region to age-related cell loss.

  20. Observation of a distinct surface molecular orientation in films of a high mobility conjugated polymer.

    Science.gov (United States)

    Schuettfort, Torben; Thomsen, Lars; McNeill, Christopher R

    2013-01-23

    The molecular orientation and microstructure of films of the high-mobility semiconducting polymer poly(N,N-bis-2-octyldodecylnaphthalene-1,4,5,8-bis-dicarboximide-2,6-diyl-alt-5,5-2,2-bithiophene) (P(NDI2OD-T2)) are probed using a combination of grazing-incidence wide-angle X-ray scattering (GIWAXS) and near-edge X-ray absorption fine-structure (NEXAFS) spectroscopy. In particular a novel approach is used whereby the bulk molecular orientation and surface molecular orientation are simultaneously measured on the same sample using NEXAFS spectroscopy in an angle-resolved transmission experiment. Furthermore, the acquisition of bulk-sensitive NEXAFS data enables a direct comparison of the information provided by GIWAXS and NEXAFS. By comparison of the bulk-sensitive and surface-sensitive NEXAFS data, a distinctly different molecular orientation is observed at the surface of the film compared to the bulk. While a more "face-on" orientation of the conjugated backbone is observed in the bulk of the film, consistent with the lamella orientation observed by GIWAXS, a more "edge-on" orientation is observed at the surface of the film with surface-sensitive NEXAFS spectroscopy. This distinct edge-on surface orientation explains the high in-plane mobility that is achieved in top-gate P(NDI2OD-T2) field-effect transistors (FETs), while the bulk face-on texture explains the high out-of-plane mobilities that are observed in time-of-flight and diode measurements. These results also stress that GIWAXS lacks the surface sensitivity required to probe the microstructure of the accumulation layer that supports charge transport in organic FETs and hence may not necessarily be appropriate for correlating film microstructure and FET charge transport.

  1. Molecular Subtyping and Surveillance of Resistance Genes In Treponema pallidum DNA From Patients With Secondary and Latent Syphilis in Hunan, China.

    Science.gov (United States)

    Xiao, Yongjian; Liu, Shuangquan; Liu, Zhuoran; Xie, Yafeng; Jiang, Chuanhao; Xu, Man; Zhao, Feijun; Zeng, TieBing; Yu, Jian; Wu, Yimou

    2016-05-01

    Over the past decade, the incidence of syphilis and widespread macrolide resistance in its etiological agent, Treponema pallidum subsp. pallidum, have become a major health concern across countries, including China. Regional trends in subtypes and antibiotic resistance can be monitored effectively by molecular surveillance programs. In this study, whole blood samples were used to assess circulating T. pallidum strains collected from various regions of Hunan, China, between 2013 and 2015. Traditional polymerase chain reaction, targeting polA, tpp47, bmp, and tp0319 genes, was used as preliminary screening assay. About 455 polymerase chain reaction-positive specimens were obtained from 2253 whole blood samples of patients with secondary or latent syphilis. Molecular subtyping was performed using a Centers for Disease Control and Prevention-based typing method combined with an analysis of the variable region of tp0548 gene. Resistance to macrolides was analyzed by examining point mutations in 23S rRNA, and the presence of the G1058C point mutation within 16S rRNA associated with decreased susceptibility to doxycycline was assessed. Circulating T. pallidum strains were resolved into 32 subtypes, among which subtype 14d/f was predominant. A2059G mutation in 23S rRNA, and the G1058C mutation in 16S rRNA was absent, but the prevalence of A2058G mutation in 23S rRNA was 97.5%. We found that it is possible to use whole blood to evaluate molecular subtypes and monitor antibiotic resistance in circulating T. pallidum strains, especially when chancres are absent. High frequency of macrolide-resistant T. pallidum indicates that macrolide antibiotics, such as azithromycin, should be avoided as a treatment option for syphilis in Hunan, China.

  2. Diffusion-weighted imaging features of breast tumours and the surrounding stroma reflect intrinsic heterogeneous characteristics of molecular subtypes in breast cancer

    KAUST Repository

    Fan, Ming

    2017-12-16

    Breast cancer heterogeneity is the main obstacle preventing the identification of patients with breast cancer with poor prognoses and treatment responses; however, such heterogeneity has not been well characterized. The purpose of this retrospective study was to reveal heterogeneous patterns in the apparent diffusion coefficient (ADC) signals in tumours and the surrounding stroma to predict molecular subtypes of breast cancer. A dataset of 126 patients with breast cancer, who underwent preoperative diffusion-weighted imaging (DWI) on a 3.0-T image system, was collected. Breast images were segmented into regions comprising the tumour and surrounding stromal shells in which features that reflect heterogeneous ADC signal distribution were extracted. For each region, imaging features were computed, including the mean, minimum, variance, interquartile range (IQR), range, skewness, kurtosis and entropy of ADC values. Univariate and stepwise multivariate logistic regression modelling was performed to identify the magnetic resonance imaging features that optimally discriminate luminal A, luminal B, human epidermal growth factor 2 (HER2)-enriched and basal-like molecular subtypes. The performance of the predictive models was evaluated using the area under the receiver operating characteristic curve (AUC). Univariate logistic regression analysis showed that the skewness in the tumour boundary achieved an AUC of 0.718 for discrimination between luminal A and non-luminal A tumours, whereas the IQR of the ADC value in the tumour boundary had an AUC of 0.703 for classification of the HER2-enriched subtype. Imaging features in the tumour boundary and the proximal peritumoral stroma corresponded to a higher overall prediction performance than those in other regions. A multivariate logistic regression model combining features in all the regions achieved an overall AUC of 0.800 for the classification of the four tumour subtypes. These findings suggest that features in the tumour

  3. Molecular characterization of HIV-1 subtype C gp-120 regions potentially involved in virus adaptive mechanisms.

    Directory of Open Access Journals (Sweden)

    Alessandra Cenci

    Full Text Available The role of variable regions of HIV-1 gp120 in immune escape of HIV has been investigated. However, there is scant information on how conserved gp120 regions contribute to virus escaping. Here we have studied how molecular sequence characteristics of conserved C3, C4 and V3 regions of clade C HIV-1 gp120 that are involved in HIV entry and are target of the immune response, are modulated during the disease course. We found an increase of "shifting" putative N-glycosylation sites (PNGSs in the α2 helix (in C3 and in C4 and an increase of sites under positive selection pressure in the α2 helix during the chronic stage of disease. These sites are close to CD4 and to co-receptor binding sites. We also found a negative correlation between electric charges of C3 and V4 during the late stage of disease counteracted by a positive correlation of electric charges of α2 helix and V5 during the same stage. These data allow us to hypothesize possible mechanisms of virus escape involving constant and variable regions of gp120. In particular, new mutations, including new PNGSs occurring near the CD4 and CCR5 binding sites could potentially affect receptor binding affinity and shield the virus from the immune response.

  4. Molecular epidemiology of HIV type 1 in Chile: differential geographic and transmission route distribution of B and F subtypes.

    Science.gov (United States)

    Rios, M; Fernandez, J; Jaramillo, P; Paredes, V; Sanchez, J L; Laguna-Torres, V A; Carr, J K; Ramirez, E

    2005-10-01

    We examined the genetic makeup of 221 HIV-1 strains from Chilean persons living with HIV/AIDS by HMA and DNA sequencing of the env gene: 143 cases were infected by sexual contact with an already-infected partner, 76 were infected by mother-to-child transmission, and 2 were transfusion related. We found env HIV-1 subtype B in 202 cases (91.4%) and subtype F in 19 cases (8.6%). Subtype B strains were found throughout the country whereas subtype F viruses were predominantly found in cases from the metropolitan/central to the northern regions of Chile (p Chile by separate heterosexual transmission events from other nearby countries in the Southern Cone whereas B subtype strains have continued to persist predominantly among MSM.

  5. Detection by reverse transcriptase-polymerase chain reaction and molecular characterization of subtype B avian metapneumovirus isolated in Brazil.

    Science.gov (United States)

    Chacón, Jorge Luis; Brandão, Paulo E; Buim, Marcos; Villarreal, Laura; Ferreira, Antonio J Piantino

    2007-10-01

    Subtype B avian metapneumovirus (aMPV) was isolated and detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in Brazilian commercial laying chicken flocks with no history of vaccination against aMPV and presenting respiratory signs and decreased egg production. RT-PCR results from samples from three affected flocks revealed that the three isolates were subtype B. Partial sequence analysis of the G glycoprotein gene confirmed that the samples belonged to subtype B and were not of the vaccine type. Comparison of nucleotide and amino acid sequences of the G gene of the three Brazilian aMPV samples with subtype B isolates from other countries revealed 95.1% to 96.1% identity. Nucleotide sequences showed 100% identity among the Brazilian subtype B samples and 95.6% identity with the subtype B vaccine strain used in Brazil. This work describes the circulation of subtype B aMPV in Brazil and discusses its importance in terms of disease epidemiology.

  6. Prognostic Value of Molecular Subtypes, Ki67 Expression and Impact of Postmastectomy Radiation Therapy in Breast Cancer Patients With Negative Lymph Nodes After Mastectomy

    Energy Technology Data Exchange (ETDEWEB)

    Selz, Jessica, E-mail: chaumontjessica@yahoo.fr [Department of Radiation Oncology, Institut Curie, Hopital Rene Huguenin, Saint Cloud (France); Stevens, Denise; Jouanneau, Ludivine [Department of Medical Statistics, Institut Curie, Hopital Rene Huguenin, Saint Cloud (France); Labib, Alain [Department of Radiation Oncology, Institut Curie, Hopital Rene Huguenin, Saint Cloud (France); Le Scodan, Romuald [Department of Radiation Oncology, Centre Hospitalier Prive Saint Gregoire, Saint Gregoire (France)

    2012-12-01

    Purpose: To determine whether Ki67 expression and breast cancer subtypes could predict locoregional recurrence (LRR) and influence the postmastectomy radiotherapy (PMRT) decision in breast cancer (BC) patients with pathologic negative lymph nodes (pN0) after modified radical mastectomy (MRM). Methods and Materials: A total of 699 BC patients with pN0 status after MRM, treated between 2001 and 2008, were identified from a prospective database in a single institution. Tumors were classified by intrinsic molecular subtype as luminal A or B, HER2+, and triple-negative (TN) using estrogen, progesterone, and HER2 receptors. Multivariate Cox analysis was used to determine the risk of LRR associated with intrinsic subtypes and Ki67 expression, adjusting for known prognostic factors. Results: At a median follow-up of 56 months, 17 patients developed LRR. Five-year LRR-free survival and overall survival in the entire population were 97%, and 94.7%, respectively, with no difference between the PMRT (n=191) and no-PMRT (n=508) subgroups. No constructed subtype was associated with an increased risk of LRR. Ki67 >20% was the only independent prognostic factor associated with increased LRR (hazard ratio, 4.18; 95% CI, 1.11-15.77; P<.0215). However, PMRT was not associated with better locoregional control in patients with proliferative tumors. Conclusions: Ki67 expression but not molecular subtypes are predictors of locoregional recurrence in breast cancer patients with negative lymph nodes after MRM. The benefit of adjuvant RT in patients with proliferative tumors should be further investigated in prospective studies.

  7. Molecular detection of HIV-1 subtype B, CRF01_AE, CRF33_01B, and newly emerging recombinant lineages in Malaysia.

    Science.gov (United States)

    Chook, Jack Bee; Ong, Lai Yee; Takebe, Yutaka; Chan, Kok Gan; Choo, Martin; Kamarulzaman, Adeeba; Tee, Kok Keng

    2015-03-01

    A molecular genotyping assay for human immunodeficiency virus type 1 (HIV-1) circulating in Southeast Asia is difficult to design because of the high level of genetic diversity. We developed a multiplex real-time polymerase chain reaction (PCR) assay to detect subtype B, CRF01_AE, CRF33_01B, and three newly described circulating recombinant forms, (CRFs) (CRF53_01B, CRF54_01B, and CRF58_01B). A total of 785 reference genomes were used for subtype-specific primers and TaqMan probes design targeting the gag, pol, and env genes. The performance of this assay was compared and evaluated with direct sequencing and phylogenetic analysis. A total of 180 HIV-infected subjects from Kuala Lumpur, Malaysia were screened and 171 samples were successfully genotyped, in agreement with the phylogenetic data. The HIV-1 genotype distribution was as follows: subtype B (16.7%); CRF01_AE (52.8%); CRF33_01B (24.4%); CRF53_01B (1.1%); CRF54_01B (0.6%); and CRF01_AE/B unique recombinant forms (4.4%). The overall accuracy of the genotyping assay was over 95.0%, in which the sensitivities for subtype B, CRF01_AE, and CRF33_01B detection were 100%, 100%, and 97.7%, respectively. The specificity of genotyping was 100%, inter-subtype specificities were > 95% and the limit of detection of 10(3) copies/mL for plasma. The newly developed real-time PCR assay offers a rapid and cost-effective alternative for large-scale molecular epidemiological surveillance for HIV-1. © The American Society of Tropical Medicine and Hygiene.

  8. [Use of molecular subtyping methods to investigate two nosocomial outbreaks due to Salmonella Livingstone in Sfax hospital, Tunisia].

    Science.gov (United States)

    Ktari, S; Mahjoubi, F; Jaoua, S; Karray, A; Marty, N; Ben Redjeb, S; Hammami, A

    2006-07-01

    The aim of the study was to investigate two nosocomial outbreaks due to Salmonella Livingstone in a pediatric ward in Sfax hospital using molecular typing techniques. We included 84 strains of S. Livingstone isolated from patients hospitalized in a pediatric ward between November 1999 through August 2002 in addition to one environmental sample. Three epidemiological unrelated strains of S. Livingstone were also tested. The molecular typing techniques were: plasmid analysis, enterobacterial repetitive intergenic consensus (ERIC-PCR), random amplification of polymorphic DNA (RAPD-PCR) and pulsed field gel electrophoresis (PFGE). The plasmid analysis and the ERIC-PCR generated a similar profile for outbreak isolates including the environmental sample while the epidemiologically unrelated strains demonstrated distinct patterns. The RAPD-PCR applied on 20 strains showed three patterns but one profile was predominating. All the strains isolate of S. Livingstone, except the veterinary strain, could not be typed by PFGE. Using the molecular typing techniques, we showed that these two outbreaks in the pediatric ward were due to the clonal spread of a single strain of S. Livingstone. The identification of the source of contamination and the improvement of hygiene conditions are required.

  9. Comprehensive profiling of DNA methylation in colorectal cancer reveals subgroups with distinct clinicopathological and molecular features

    International Nuclear Information System (INIS)

    Ang, Pei Woon; Soong, Richie; Loh, Marie; Liem, Natalia; Lim, Pei Li; Grieu, Fabienne; Vaithilingam, Aparna; Platell, Cameron; Yong, Wei Peng; Iacopetta, Barry

    2010-01-01

    Most previous studies of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been conducted on a relatively small numbers of CpG sites. In the present study we performed comprehensive DNA methylation profiling of CRC with the aim of characterizing CIMP subgroups. DNA methylation at 1,505 CpG sites in 807 cancer-related genes was evaluated using the Illumina GoldenGate ® methylation array in 28 normal colonic mucosa and 91 consecutive CRC samples. Methylation data was analyzed using unsupervised hierarchical clustering. CIMP subgroups were compared for various clinicopathological and molecular features including patient age, tumor site, microsatellite instability (MSI), methylation at a consensus panel of CpG islands and mutations in BRAF and KRAS. A total of 202 CpG sites were differentially methylated between tumor and normal tissue. Unsupervised hierarchical clustering of methylation data from these sites revealed the existence of three CRC subgroups referred to as CIMP-low (CIMP-L, 21% of cases), CIMP-mid (CIMP-M, 14%) and CIMP-high (CIMP-H, 65%). In comparison to CIMP-L tumors, CIMP-H tumors were more often located in the proximal colon and showed more frequent mutation of KRAS and BRAF (P < 0.001). Comprehensive DNA methylation profiling identified three CRC subgroups with distinctive clinicopathological and molecular features. This study suggests that both KRAS and BRAF mutations are involved with the CIMP-H pathway of CRC rather than with distinct CIMP subgroups

  10. Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore

    Energy Technology Data Exchange (ETDEWEB)

    Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radi, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer (UCB); (UCSD)

    2008-07-28

    Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 {angstrom} in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids.

  11. Monosodium Urate Crystals Generate Nuclease-Resistant Neutrophil Extracellular Traps via a Distinct Molecular Pathway.

    Science.gov (United States)

    Chatfield, Simon M; Grebe, Kathrin; Whitehead, Lachlan W; Rogers, Kelly L; Nebl, Thomas; Murphy, James M; Wicks, Ian P

    2018-03-01

    Neutrophil extracellular traps (NETs) and the cell death associated with it (NETosis) have been implicated in numerous diseases. Mechanistic studies of NETosis have typically relied on nonphysiological stimuli, such as PMA. The human disease of gout is caused by monosodium urate (MSU) crystals. We observed that DNA consistent with NETs is present in fluid from acutely inflamed joints of gout patients. NETs also coat the crystals found in uninflamed tophi of chronic gout patients. We developed a quantitative, live cell imaging assay, which measures the key features of NETosis, namely, cell death and chromatin decondensation. We show that MSU and other physiologically relevant crystals induce NETosis through a molecular pathway that is distinct from PMA and Candida hyphae. Crystals interact with lysosomes to induce NADPH oxidase-independent cell death, with postmortem chromatin decondensation mediated by neutrophil elastase. The resulting MSU-induced NETs are enriched for actin and are resistant to serum and DNase degradation. These findings demonstrate a distinct physiological NETosis pathway in response to MSU crystals, which coats MSU crystals in DNA that persists in tissues as gouty tophi. Copyright © 2018 by The American Association of Immunologists, Inc.

  12. Functional and molecular evidence for Kv7 channel subtypes in human detrusor from patients with and without bladder outflow obstruction.

    Directory of Open Access Journals (Sweden)

    Julie Svalø

    Full Text Available The aim of the study was to investigate whether Kv7 channels and their ancillary β-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT-qPCR and myography, respectively. We found mRNA expression of KCNQ1, KCNQ3-KCNQ5 and KCNE1-5 in the human urinary bladder from patients with normal bladder function (n = 7 and in patients with bladder outflow obstruction (n = 3. Interestingly, a 3.4-fold up-regulation of KCNQ1 was observed in the latter. The Kv7 channel subtype selective modulators, ML277 (activator of Kv7.1 channels, 10 μM and ML213 (activator of Kv7.2, Kv7.4, Kv7.4/7.5 and Kv7.5 channels, 10 μM, reduced the tone of 1 μM carbachol pre-constricted bladder strips. XE991 (blocker of Kv7.1-7.5 channels, 10 μM had opposing effects as it increased contractions achieved with 20 mM KPSS. Furthermore, we investigated if there is interplay between Kv7 channels and β-adrenoceptors. Using cumulative additions of isoprenaline (β-adrenoceptor agonist and forskolin (adenylyl cyclase activator in combination with the Kv7 channel activator and blocker, retigabine and XE991, we did not find interplay between Kv7 channels and β-adrenoceptors in the human urinary bladder. The performed gene expression analysis combined with the organ bath studies imply that compounds that activate Kv7 channels could be useful for treatment of overactive bladder syndrome.

  13. Ovarian carcinoma subtypes are different diseases: implications for biomarker studies.

    Directory of Open Access Journals (Sweden)

    Martin Köbel

    2008-12-01

    Full Text Available BACKGROUND: Although it has long been appreciated that ovarian carcinoma subtypes (serous, clear cell, endometrioid, and mucinous are associated with different natural histories, most ovarian carcinoma biomarker studies and current treatment protocols for women with this disease are not subtype specific. With the emergence of high-throughput molecular techniques, distinct pathogenetic pathways have been identified in these subtypes. We examined variation in biomarker expression rates between subtypes, and how this influences correlations between biomarker expression and stage at diagnosis or prognosis. METHODS AND FINDINGS: In this retrospective study we assessed the protein expression of 21 candidate tissue-based biomarkers (CA125, CRABP-II, EpCam, ER, F-Spondin, HE4, IGF2, K-Cadherin, Ki-67, KISS1, Matriptase, Mesothelin, MIF, MMP7, p21, p53, PAX8, PR, SLPI, TROP2, WT1 in a population-based cohort of 500 ovarian carcinomas that was collected over the period from 1984 to 2000. The expression of 20 of the 21 biomarkers differs significantly between subtypes, but does not vary across stage within each subtype. Survival analyses show that nine of the 21 biomarkers are prognostic indicators in the entire cohort but when analyzed by subtype only three remain prognostic indicators in the high-grade serous and none in the clear cell subtype. For example, tumor proliferation, as assessed by Ki-67 staining, varies markedly between different subtypes and is an unfavourable prognostic marker in the entire cohort (risk ratio [RR] 1.7, 95% confidence interval [CI] 1.2%-2.4% but is not of prognostic significance within any subtype. Prognostic associations can even show an inverse correlation within the entire cohort, when compared to a specific subtype. For example, WT1 is more frequently expressed in high-grade serous carcinomas, an aggressive subtype, and is an unfavourable prognostic marker within the entire cohort of ovarian carcinomas (RR 1.7, 95% CI 1

  14. Muscarinic acetylcholine receptor subtypes: localization and structure/function

    DEFF Research Database (Denmark)

    Brann, M R; Ellis, J; Jørgensen, H

    1993-01-01

    Based on the sequence of the five cloned muscarinic receptor subtypes (m1-m5), subtype selective antibody and cDNA probes have been prepared. Use of these probes has demonstrated that each of the five subtypes has a markedly distinct distribution within the brain and among peripheral tissues....... The distributions of these subtypes and their potential physiological roles are discussed. By use of molecular genetic manipulation of cloned muscarinic receptor cDNAs, the regions of muscarinic receptors that specify G-protein coupling and ligand binding have been defined in several recent studies. Overall......, these studies have shown that amino acids within the third cytoplasmic loop of the receptors define their selectivities for different G-proteins and that multiple discontinuous epitopes contribute to their selectivities for different ligands. The residues that contribute to ligand binding and G-protein coupling...

  15. Highly distinct chromosomal structures in cowpea (Vigna unguiculata), as revealed by molecular cytogenetic analysis.

    Science.gov (United States)

    Iwata-Otsubo, Aiko; Lin, Jer-Young; Gill, Navdeep; Jackson, Scott A

    2016-05-01

    Cowpea (Vigna unguiculata (L.) Walp) is an important legume, particularly in developing countries. However, little is known about its genome or chromosome structure. We used molecular cytogenetics to characterize the structure of pachytene chromosomes to advance our knowledge of chromosome and genome organization of cowpea. Our data showed that cowpea has highly distinct chromosomal structures that are cytologically visible as brightly DAPI-stained heterochromatic regions. Analysis of the repetitive fraction of the cowpea genome present at centromeric and pericentromeric regions confirmed that two retrotransposons are major components of pericentromeric regions and that a 455-bp tandem repeat is found at seven out of 11 centromere pairs in cowpea. These repeats likely evolved after the divergence of cowpea from common bean and form chromosomal structure unique to cowpea. The integration of cowpea genetic and physical chromosome maps reveals potential regions of suppressed recombination due to condensed heterochromatin and a lack of pairing in a few chromosomal termini. This study provides fundamental knowledge on cowpea chromosome structure and molecular cytogenetics tools for further chromosome studies.

  16. Distinct molecular components for thalamic- and cortical-dependent plasticity in the lateral amygdala.

    Science.gov (United States)

    Mirante, Osvaldo; Brandalise, Federico; Bohacek, Johannes; Mansuy, Isabelle M

    2014-01-01

    N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) in the lateral nucleus of the amygdala (LA) is a form of synaptic plasticity thought to be a cellular substrate for the extinction of fear memory. The LA receives converging inputs from the sensory thalamus and neocortex that are weakened following fear extinction. Combining field and patch-clamp electrophysiological recordings in mice, we show that paired-pulse low-frequency stimulation can induce a robust LTD at thalamic and cortical inputs to LA, and we identify different underlying molecular components at these pathways. We show that while LTD depends on NMDARs and activation of the protein phosphatases PP2B and PP1 at both pathways, it requires NR2B-containing NMDARs at the thalamic pathway, but NR2C/D-containing NMDARs at the cortical pathway. LTD appears to be induced post-synaptically at the thalamic input but presynaptically at the cortical input, since post-synaptic calcium chelation and NMDAR blockade prevent thalamic but not cortical LTD. These results highlight distinct molecular features of LTD in LA that may be relevant for traumatic memory and its erasure, and for pathologies such as post-traumatic stress disorder (PTSD).

  17. Distinct molecular components for thalamic- and cortical-dependent plasticity in the lateral amygdala

    Directory of Open Access Journals (Sweden)

    Osvaldo eMirante

    2014-07-01

    Full Text Available N-methyl-D-aspartate receptor (NMDAR-dependent long-term depression (LTD in the lateral nucleus of the amygdala (LA is a form of synaptic plasticity thought to be a cellular substrate for the extinction of fear memory. The LA receives converging inputs from the sensory thalamus and neocortex that are weakened following fear extinction. Combining field and patch-clamp electrophysiological recordings in mice, we show that a paired-pulse low-frequency stimulation can induce a robust LTD at thalamic and cortical inputs to LA, and we identify different underlying molecular components at these pathways. We show that while LTD depends on NMDARs and activation of the protein phosphatases PP2B and PP1 at both pathways, it requires NR2B-containing NMDARs at the thalamic pathway, but NR2C/D-containing NMDARs at the cortical pathway. LTD appears to be induced postsynaptically at the thalamic input but presynaptically at the cortical input, since postsynaptic calcium chelation and NMDAR blockade prevent thalamic but not cortical LTD. These results highlight distinct molecular features of LTD in LA that may be relevant for traumatic memory and its erasure, and for pathologies such as post-traumatic stress disorder (PTSD.

  18. Molecular signatures of lymph node status by intrinsic subtype: gene expression analysis of primary breast tumors from patients with and without metastatic lymph nodes.

    Science.gov (United States)

    Shriver, Craig D; Hueman, Matthew T; Ellsworth, Rachel E

    2014-12-31

    Identification of a gene expression signature in primary breast tumors that could classify patients by lymph node status would allow patients to avoid the morbidities of surgical disruption of the lymph nodes. Attempts to identify such a signature have, to date, been unsuccessful. Because breast tumor subtypes have unique molecular characteristics and different sites of metastasis, molecular signatures for lymph node involvement may vary by subtype. Gene expression data was generated from HG U133A 2.0 arrays for 135 node positive and 210 node negative primary breast tumors. Intrinsic subtype was assigned using the BreastPRS. Differential gene expression analysis was performed using one-way ANOVA using lymph node status as the variable with a False-discovery rate basal-like (27%), HER2-enriched (14%) luminal B (7%) and normal-like (1%). Basal-like and luminal A tumors were less likely to have metastatic lymph nodes (35% and 37%, respectively) compared to luminal B or HER2-enriched (52% and 51%, respectively). No differentially expressed genes associated with lymph node status were detected when all tumors were considered together or within each subtype. Gene expression patterns from the primary tumor are not able to stratify patients by lymph node status. Although the primary breast tumor may influence tumor cell dissemination, once metastatic cells enter the lymphatics, it is likely that characteristics of the lymph node microenvironment, such as establishment of a pre-metastatic niche and release of pro-survival factors, determine which cells are able to colonize. The inability to utilize molecular profiles from the primary tumor to determine lymph node status suggest that other avenues of investigation, such as how systemic factors including diminished immune response or genetic susceptibility contribute to metastasis, may be critical in the development of tools for non-surgical assessment of lymph node status with a corresponding reduction in downstream sequelae

  19. PAM50 Breast Cancer Subtyping by RT-qPCR and Concordance with Standard Clinical Molecular Markers

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    Bastien Roy RL

    2012-10-01

    Full Text Available Abstract Background Many methodologies have been used in research to identify the “intrinsic” subtypes of breast cancer commonly known as Luminal A, Luminal B, HER2-Enriched (HER2-E and Basal-like. The PAM50 gene set is often used for gene expression-based subtyping; however, surrogate subtyping using panels of immunohistochemical (IHC markers are still widely used clinically. Discrepancies between these methods may lead to different treatment decisions. Methods We used the PAM50 RT-qPCR assay to expression profile 814 tumors from the GEICAM/9906 phase III clinical trial that enrolled women with locally advanced primary invasive breast cancer. All samples were scored at a single site by IHC for estrogen receptor (ER, progesterone receptor (PR, and Her2/neu (HER2 protein expression. Equivocal HER2 cases were confirmed by chromogenic in situ hybridization (CISH. Single gene scores by IHC/CISH were compared with RT-qPCR continuous gene expression values and “intrinsic” subtype assignment by the PAM50. High, medium, and low expression for ESR1, PGR, ERBB2, and proliferation were selected using quartile cut-points from the continuous RT-qPCR data across the PAM50 subtype assignments. Results ESR1, PGR, and ERBB2 gene expression had high agreement with established binary IHC cut-points (area under the curve (AUC ≥ 0.9. Estrogen receptor positivity by IHC was strongly associated with Luminal (A and B subtypes (92%, but only 75% of ER negative tumors were classified into the HER2-E and Basal-like subtypes. Luminal A tumors more frequently expressed PR than Luminal B (94% vs 74% and Luminal A tumors were less likely to have high proliferation (11% vs 77%. Seventy-seven percent (30/39 of ER-/HER2+ tumors by IHC were classified as the HER2-E subtype. Triple negative tumors were mainly comprised of Basal-like (57% and HER2-E (30% subtypes. Single gene scoring for ESR1, PGR, and ERBB2 was more prognostic than the corresponding IHC markers as

  20. Luminal B tumors are the most frequent molecular subtype in breast cancer of North African women: an immunohistochemical profile study from Morocco

    Directory of Open Access Journals (Sweden)

    El Fatemi Hinde

    2012-12-01

    Full Text Available Abstract Background Breast cancer may be classified into luminal A, luminal B, HER2+/ER-, basal-like and normal-like subtypes based on gene expression profiling or immunohistochemical (IHC characteristics. The aim of our study is to show the molecular profile characteristic of breast cancer in the North African population of Morocco. This work showed preliminary results and correlations with clinicopathological and histological parameters. Three hundred and ninety primary breast carcinomas tumor tissues were immunostained for ER, PR, HER2, CK5/6, CK8/18 and Ki67 using paraffin tissue. Methods We reviewed 390 cases of breast cancer diagnosed on January 2008 to December 2011 at the Department of pathology, Hassan II teaching hospital, Fez, Morocco. Age, size tumor, metastatic profile, node involvement profile, histological type and immunohistochemical profile were studied. Results The average age was 46 years; our patients were diagnosed late with a high average tumor size. Luminal B subtype was more prevalent (41.8%, followed by luminal A (30.5%, basal-like (13, 6%, Her2-overexpressing (9, 2%, and unclassified subtype (4.9%. Conclusion This study showed that molecular classification and biological profile may be different according to geographical distribution, to encourage further studies to know the genomic profile of tumors and the environment. Virtual slide http://www.diagnosticpathology.diagnomx.eu/vs/1675272504826544

  1. Pathological Gambling Subtypes

    Science.gov (United States)

    Vachon, David D.; Bagby, R. Michael

    2009-01-01

    Although pathological gambling (PG) is regarded in the 4th edition of the "Diagnostic and Statistical Manual of Mental Disorders" (American Psychiatric Association, 1994) as a unitary diagnostic construct, it is likely composed of distinct subtypes. In the current report, the authors used cluster analyses of personality traits with a…

  2. Radiomics Strategy for Molecular Subtype Stratification of Lower-Grade Glioma: Detecting IDH and TP53 Mutations Based on Multimodal MRI.

    Science.gov (United States)

    Zhang, Xi; Tian, Qiang; Wang, Liang; Liu, Yang; Li, Baojuan; Liang, Zhengrong; Gao, Peng; Zheng, Kaizhong; Zhao, Bofeng; Lu, Hongbing

    2018-02-02

    Noninvasive detection of isocitrate dehydrogenase (IDH) and TP53 mutations are meaningful for molecular stratification of lower-grade gliomas (LrGG). To explore potential MRI features reflecting IDH and TP53 mutations of LrGG, and propose a radiomics strategy for detecting them. Retrospective, radiomics. A total of 103 LrGG patients were separated into development (n = 73) and validation (n = 30) cohorts. T 1 -weighted (before and after contrast-enhanced), T 2 -weighted, and fluid-attenuation inversion recovery images from 1.5T (n = 37) or 3T (n = 66) scanners. After data preprocessing, high-throughput features were derived from patients' volumes of interests of different sequences. The support vector machine-based recursive feature elimination (SVM-RFE) was adopted to find the optimal features for IDH and TP53 mutation detection. SVM models were trained and tested on development and validation cohort. The commonly used metric was used for assessing the efficiency. One-way analysis of variance (ANOVA), chi-square, or Fisher's exact test were applied on clinical characteristics to confirm whether significant differences exist between three molecular subtypes decided by IDH and TP53 status. Intraclass correlation coefficients were calculated to assess the robustness of the radiomics features. The constituent ratio of histopathologic subtypes was significantly different among three molecular subtypes (P = 0.017). SVM models for detecting IDH and TP53 mutation were established using 12 and 22 optimal features selected by SVM-RFE. The accuracies and area under the curves for IDH and TP53 mutations on the development cohort were 84.9%, 0.830, and 92.0%, 0.949, while on the validation cohort were 80.0%, 0.792, and 85.0%, 0.869, respectively. Furthermore, the stratified accuracies of three subtypes were 72.8%, 71.9%, and 70%, respectively. Using a radiomics approach integrating SVM model and multimodal MRI features, molecular subtype stratification of

  3. Triple-negative breast cancer: the importance of molecular and histologic subtyping, and recognition of low-grade variants.

    Science.gov (United States)

    Pareja, Fresia; Geyer, Felipe C; Marchiò, Caterina; Burke, Kathleen A; Weigelt, Britta; Reis-Filho, Jorge S

    2016-01-01

    Triple-negative breast cancers (TNBCs), defined by lack of expression of estrogen receptor, progesterone receptor and HER2, account for 12-17% of breast cancers and are clinically perceived as a discrete breast cancer subgroup. Nonetheless, TNBC has been shown to constitute a vastly heterogeneous disease encompassing a wide spectrum of entities with marked genetic, transcriptional, histological and clinical differences. Although most TNBCs are high-grade tumors, there are well-characterized low-grade TNBCs that have an indolent clinical course, whose natural history, molecular features and optimal therapy vastly differ from those of high-grade TNBCs. Secretory and adenoid cystic carcinomas are two histologic types of TNBCs underpinned by specific fusion genes; these tumors have an indolent clinical behavior and lack all of the cardinal molecular features of high-grade triple-negative disease. Recent studies of rare entities, including lesions once believed to constitute mere benign breast disease (e.g., microglandular adenosis), have resulted in the identification of potential precursors of TNBC and suggested the existence of a family of low-grade triple-negative lesions that, despite having low-grade morphology and indolent clinical behavior, have been shown to harbor the complex genomic landscape of common forms of TNBC, and may progress to high-grade disease. In this review, we describe the heterogeneity of TNBC and focus on the histologic and molecular features of low-grade forms of TNBC. Germane to addressing the challenges posed by the so-called triple-negative disease is the realization that TNBC is merely a descriptive term, and that low-grade types of TNBC may be driven by distinct sets of genetic alterations.

  4. Molecular Expression and Pharmacological Evidence for a Functional Role of Kv7 Channel Subtypes in Guinea Pig Urinary Bladder Smooth Muscle

    Science.gov (United States)

    Afeli, Serge A. Y.; Malysz, John; Petkov, Georgi V.

    2013-01-01

    Voltage-gated Kv7 (KCNQ) channels are emerging as essential regulators of smooth muscle excitability and contractility. However, their physiological role in detrusor smooth muscle (DSM) remains to be elucidated. Here, we explored the molecular expression and function of Kv7 channel subtypes in guinea pig DSM by RT-PCR, qRT-PCR, immunohistochemistry, electrophysiology, and isometric tension recordings. In whole DSM tissue, mRNAs for all Kv7 channel subtypes were detected in a rank order: Kv7.1~Kv7.2Kv7.3~Kv7.5Kv7.4. In contrast, freshly-isolated DSM cells showed mRNA expression of: Kv7.1~Kv7.2Kv7.5Kv7.3~Kv7.4. Immunohistochemical confocal microscopy analyses of DSM, conducted by using co-labeling of Kv7 channel subtype-specific antibodies and α-smooth muscle actin, detected protein expression for all Kv7 channel subtypes, except for the Kv7.4, in DSM cells. L-364373 (R-L3), a Kv7.1 channel activator, and retigabine, a Kv7.2-7.5 channel activator, inhibited spontaneous phasic contractions and the 10-Hz electrical field stimulation (EFS)-induced contractions of DSM isolated strips. Linopiridine and XE991, two pan-Kv7 (effective at Kv7.1-Kv7.5 subtypes) channel inhibitors, had opposite effects increasing DSM spontaneous phasic and 10 Hz EFS-induced contractions. EFS-induced DSM contractions generated by a wide range of stimulation frequencies were decreased by L-364373 (10 µM) or retigabine (10 µM), and increased by XE991 (10 µM). Retigabine (10 µM) induced hyperpolarization and inhibited spontaneous action potentials in freshly-isolated DSM cells. In summary, Kv7 channel subtypes are expressed at mRNA and protein levels in guinea pig DSM cells. Their pharmacological modulation can control DSM contractility and excitability; therefore, Kv7 channel subtypes provide potential novel therapeutic targets for urinary bladder dysfunction. PMID:24073284

  5. Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore

    Science.gov (United States)

    Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radić, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer

    2008-01-01

    Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 Å in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids. PMID:18477694

  6. Molecular Evolution of Two Distinct dmrt1 Promoters for Germ and Somatic Cells in Vertebrate Gonads.

    Science.gov (United States)

    Mawaribuchi, Shuuji; Musashijima, Masato; Wada, Mikako; Izutsu, Yumi; Kurakata, Erina; Park, Min Kyun; Takamatsu, Nobuhiko; Ito, Michihiko

    2017-03-01

    The transcription factor DMRT1 has important functions in two distinct processes, somatic-cell masculinization and germ-cell development in mammals. However, it is unknown whether the functions are conserved during evolution, and what mechanism underlies its expression in the two cell lineages. Our analysis of the Xenopus laevis and Silurana tropicalis dmrt1 genes indicated the presence of two distinct promoters: one upstream of the noncoding first exon (ncEx1), and one within the first intron. In contrast, only the ncEx1-upstream promoter was detected in the dmrt1 gene of the agnathan sand lamprey, which expressed dmrt1 exclusively in the germ cells. In X. laevis, the ncEx1- and exon 2-upstream promoters were predominantly used for germ-cell and somatic-cell transcription, respectively. Importantly, knockdown of the ncEx1-containing transcript led to reduced germ-cell numbers in X. laevis gonads. Intriguingly, two genetically female individuals carrying the knockdown construct developed testicles. Analysis of the reptilian leopard gecko dmrt1 revealed the absence of ncEx1. We propose that dmrt1 regulated germ-cell development in the vertebrate ancestor, then acquired another promoter in its first intron to regulate somatic-cell masculinization during gnathostome evolution. In the common ancestor of reptiles and mammals, only one promoter got function for both the two cell lineages, accompanied with the loss of ncEx1. In addition, we found a conserved noncoding sequence (CNS) in the dmrt1 5'-flanking regions only among amniote species, and two CNSs in the introns among most vertebrates except for agnathans. Finally, we discuss relationships between these CNSs and the promoters of dmrt1 during vertebrate evolution. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  7. Drought Tolerance in Pinus halepensis Seed Sources As Identified by Distinctive Physiological and Molecular Markers

    Directory of Open Access Journals (Sweden)

    Khaled Taïbi

    2017-07-01

    Full Text Available Drought is one of the main constraints determining forest species growth, survival and productivity, and therefore one of the main limitations for reforestation or afforestation. The aim of this study is to characterize the drought response at the physiological and molecular level of different Pinus halepensis (common name Aleppo pine seed sources, previously characterized in field trials as drought-sensitive or drought-tolerant. This approach aims to identify different traits capable of predicting the ability of formerly uncharacterized seedlings to cope with drought stress. Gas-exchange, water potential, photosynthetic pigments, soluble sugars, free amino acids, glutathione and proteomic analyses were carried out on control and drought-stressed seedlings in greenhouse conditions. Gas-exchange determinations were also assessed in field-planted seedlings in order to validate the greenhouse experimental conditions. Drought-tolerant seed sources presented higher values of photosynthetic rates, water use efficiency, photosynthetic pigments and soluble carbohydrates concentrations. We observed the same pattern of variation of photosynthesis rate and maximal efficiency of PSII in field. Interestingly drought-tolerant seed sources exhibited increased levels of glutathione, methionine and cysteine. The proteomic profile of drought tolerant seedlings identified two heat shock proteins and an enzyme related to methionine biosynthesis that were not present in drought sensitive seedlings, pointing to the synthesis of sulfur amino acids as a limiting factor for drought tolerance in Pinus halepensis. Our results established physiological and molecular traits useful as distinctive markers to predict drought tolerance in Pinus halepensis provenances that could be reliably used in reforestation programs in drought prone areas.

  8. Diverse developmental disorders from The One Ring: distinct molecular pathways underlie the cohesinopathies

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    Julia eHorsfield

    2012-09-01

    Full Text Available The multi-subunit protein complex, cohesin, is responsible for sister chromatid cohesion during cell division. The interaction of cohesin with DNA is controlled by a number of additional regulatory proteins. Mutations in cohesin, or its regulators, cause a spectrum of human developmental syndromes known as the ‘cohesinopathies’. Cohesinopathy disorders include Cornelia de Lange Syndrome and Roberts Syndrome. The discovery of novel roles for chromatid cohesion proteins in regulating gene expression led to the idea that cohesinopathies are caused by dysregulation of multiple genes downstream of mutations in cohesion proteins. Consistent with this idea, Drosophila, mouse and zebrafish cohesinopathy models all show altered expression of developmental genes. However, there appears to be incomplete overlap among dysregulated genes downstream of mutations in different components of the cohesion apparatus. This is surprising because mutations in all cohesion proteins would be predicted to affect cohesin’s roles in cell division and gene expression in similar ways. Here we review the differences and similarities between genetic pathways downstream of components of the cohesion apparatus, and discuss how such differences might arise, and contribute to the spectrum of cohesinopathy disorders. We propose that mutations in different elements of the cohesion apparatus have distinct developmental outcomes that can be explained by sometimes subtly different molecular effects.

  9. Classification of alpha 1-adrenoceptor subtypes

    NARCIS (Netherlands)

    Michel, M. C.; Kenny, B.; Schwinn, D. A.

    1995-01-01

    Two alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) have been detected in various tissues by pharmacological techniques, and three distinct cDNAs encoding alpha 1-adrenoceptor subtypes have been cloned. The profile of an increasing number of subtype-selective compounds at cloned and endogenous

  10. Ibuprofen and Diclofenac Restrict Migration and Proliferation of Human Glioma Cells by Distinct Molecular Mechanisms

    Science.gov (United States)

    Leidgens, Verena; Seliger, Corinna; Jachnik, Birgit; Welz, Tobias; Leukel, Petra; Vollmann-Zwerenz, Arabel; Bogdahn, Ulrich; Kreutz, Marina; Grauer, Oliver M.; Hau, Peter

    2015-01-01

    Background Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. For glioma, research has generally focused on diclofenac; however data on other NSAIDs, such as ibuprofen, is limited. Therefore, we performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells. Methods Glioma cell lines were treated with ibuprofen or diclofenac to investigate functional effects on proliferation and cell motility. Cell cycle, extracellular lactate levels, lactate dehydrogenase-A (LDH-A) expression and activity, as well as inhibition of the Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathway, were determined. Specific effects of diclofenac and ibuprofen on STAT-3 were investigated by comparing their effects with those of the specific STAT-3 inhibitor STATTIC. Results Ibuprofen treatment led to a stronger inhibition of cell growth and migration than treatment with diclofenac. Proliferation was affected by cell cycle arrest at different checkpoints by both agents. In addition, diclofenac, but not ibuprofen, decreased lactate levels in all concentrations used. Both decreased STAT-3 phosphorylation; however, diclofenac led to decreased c-myc expression and subsequent reduction in LDH-A activity, whereas treatment with ibuprofen in higher doses induced c-myc expression and less LDH-A alteration. Conclusions This study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct. We postulate that ibuprofen may inhibit tumor cells also by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of STAT-3 signaling and downstream modulation of glycolysis. PMID:26485029

  11. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Directory of Open Access Journals (Sweden)

    Miller Dianne M

    2008-01-01

    Full Text Available Background Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH, and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. Methods A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Results Eighteen (37% of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5, clear cell (n = 4, or low grade serous (n = 2 carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. Conclusion High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic, BRCA1 loss (epigenetic, and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  12. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    International Nuclear Information System (INIS)

    Press, Joshua Z; Smith, Margaret; Spellman, Paul T; Wang, Yuker; Miller, Dianne M; Horsman, Doug; Faham, Malek; Gilks, C Blake; Gray, Joe; Huntsman, David G; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E; Blood, Katherine A

    2008-01-01

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumours were high-grade serous or undifferentiated type. None of the endometrioid (n = 5), clear cell (n = 4), or low grade serous (n = 2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumours with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways

  13. Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities

    Energy Technology Data Exchange (ETDEWEB)

    Gilks, C. Blake; Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Wang, Yuker; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G.

    2008-05-02

    Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/2 in ovarian cancers. The mechanism of BRCA1/2 loss is a potential method of subclassifying high grade serous carcinomas. A consecutive series of 49 ovarian cancers was assessed for mutations status of BRCA1 and BRCA2, LOH at the BRCA1 and BRCA2 loci, methylation of the BRCA1 promoter, BRCA1, BRCA2, PTEN, and PIK3CA transcript levels, PIK3CA gene copy number, and BRCA1, p21, p53, and WT-1 immunohistochemistry. Eighteen (37%) of the ovarian carcinomas had germline or somatic BRCA1 mutations, or epigenetic loss of BRCA1. All of these tumors were high-grade serous or undifferentiated type. None of the endometrioid (n=5), clear cell (n=4), or low grade serous (n=2) carcinomas showed loss of BRCA1, whereas 47% of the 38 high-grade serous or undifferentiated carcinomas had loss of BRCA1. It was possible to distinguish high grade serous carcinomas with BRCA1 mutations from those with epigenetic BRCA1 loss: tumors with BRCA1 mutations typically had decreased PTEN mRNA levels while those with epigenetic loss of BRCA1 had copy number gain of PIK3CA. Overexpression of p53 with loss of p21 expression occurred significantly more frequently in high grade serous carcinomas with epigenetic loss of BRCA1, compared to high grade serous tumors without loss of BRCA1. High grade serous carcinomas can be subclassified into three groups: BRCA1 loss (genetic), BRCA1 loss (epigenetic), and no BRCA1 loss. Tumors in these groups show distinct molecular alterations involving the PI3K/AKT and p53 pathways.

  14. Molecular surveillance of Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi by genotyping and subtyping parasites in wastewater.

    Directory of Open Access Journals (Sweden)

    Na Li

    Full Text Available BACKGROUND: Despite their wide occurrence, cryptosporidiosis and giardiasis are considered neglected diseases by the World Health Organization. The epidemiology of these diseases and microsporidiosis in humans in developing countries is poorly understood. The high concentration of pathogens in raw sewage makes the characterization of the transmission of these pathogens simple through the genotype and subtype analysis of a small number of samples. METHODOLOGY/PRINCIPAL FINDINGS: The distribution of genotypes and subtypes of Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi in 386 samples of combined sewer systems from Shanghai, Nanjing and Wuhan and the sewer system in Qingdao in China was determined using PCR-sequencing tools. Eimeria spp. were also genotyped to assess the contribution of domestic animals to Cryptosporidium spp., G. duodenalis, and E. bieneusi in wastewater. The high occurrence of Cryptosporidium spp. (56.2%, G. duodenalis (82.6%, E. bieneusi (87.6%, and Eimeria/Cyclospora (80.3% made the source attribution possible. As expected, several human-pathogenic species/genotypes, including Cryptosporidium hominis, Cryptosporidium meleagridis, G. duodenalis sub-assemblage A-II, and E. bieneusi genotype D, were the dominant parasites in wastewater. In addition to humans, the common presence of Cryptosporidium spp. and Eimeria spp. from rodents indicated that rodents might have contributed to the occurrence of E. bieneusi genotype D in samples. Likewise, the finding of Eimeria spp. and Cryptosporidium baileyi from birds indicated that C. meleagridis might be of both human and bird origins. CONCLUSIONS/SIGNIFICANCE: The distribution of Cryptosporidium species, G. duodenalis genotypes and subtypes, and E. bieneusi genotypes in urban wastewater indicates that anthroponotic transmission appeared to be important in epidemiology of cryptosporidiosis, giardiasis, and microsporidiosis in the study areas. The finding of

  15. BMP signalling differentially regulates distinct haematopoietic stem cell types

    NARCIS (Netherlands)

    M. Crisan (Mihaela); P. Solaimani Kartalaei (Parham); C.S. Vink (Chris); T. Yamada-Inagawa (Tomoko); K. Bollerot (Karine); W.F.J. van IJcken (Wilfred); R. Van Der Linden (Reinier); S.C. de Sousa Lopes (Susana Chuva); R. Monteiro (Rui); C.L. Mummery (Christine); E.A. Dzierzak (Elaine)

    2015-01-01

    textabstractAdult haematopoiesis is the outcome of distinct haematopoietic stem cell (HSC) subtypes with self-renewable repopulating ability, but with different haematopoietic cell lineage outputs. The molecular basis for this heterogeneity is largely unknown. BMP signalling regulates HSCs as they

  16. MEDULLOBLASTOMA EXOME SEQUENCING UNCOVERS SUBTYPE-SPECIFIC SOMATIC MUTATIONS

    OpenAIRE

    Pugh, Trevor J.; Weeraratne, Shyamal Dilhan; Archer, Tenley C.; Pomeranz Krummel, Daniel A.; Auclair, Daniel; Bochicchio, James; Carneiro, Mauricio O.; Carter, Scott L.; Cibulskis, Kristian; Erlich, Rachel L.; Greulich, Heidi; Lawrence, Michael S.; Lennon, Niall J.; McKenna, Aaron; Meldrim, James

    2012-01-01

    Medulloblastomas are the most common malignant brain tumors in children 1 . Identifying and understanding the genetic events that drive these tumors is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma based on transcriptional and copy number profiles 2?5 . Here, we utilized whole exome hybrid capture and deep sequencing to identify somatic mutations across t...

  17. The Prion Protein Preference of Sporadic Creutzfeldt-Jakob Disease Subtypes*

    Science.gov (United States)

    Klemm, Helen M. J.; Welton, Jeremy M.; Masters, Colin L.; Klug, Genevieve M.; Boyd, Alison; Hill, Andrew F.; Collins, Steven J.; Lawson, Victoria A.

    2012-01-01

    Sporadic Creutzfeldt-Jakob disease (CJD) is the most prevalent manifestation of the transmissible spongiform encephalopathies or prion diseases affecting humans. The disease encompasses a spectrum of clinical phenotypes that have been correlated with molecular subtypes that are characterized by the molecular mass of the protease-resistant fragment of the disease-related conformation of the prion protein and a polymorphism at codon 129 of the gene encoding the prion protein. A cell-free assay of prion protein misfolding was used to investigate the ability of these sporadic CJD molecular subtypes to propagate using brain-derived sources of the cellular prion protein (PrPC). This study confirmed the presence of three distinct sporadic CJD molecular subtypes with PrPC substrate requirements that reflected their codon 129 associations in vivo. However, the ability of a sporadic CJD molecular subtype to use a specific PrPC substrate was not determined solely by codon 129 as the efficiency of prion propagation was also influenced by the composition of the brain tissue from which the PrPC substrate was sourced, thus indicating that nuances in PrPC or additional factors may determine sporadic CJD subtype. The results of this study will aid in the design of diagnostic assays that can detect prion disease across the diversity of sporadic CJD subtypes. PMID:22930754

  18. Distinct APC Subtypes Drive Spatially Segregated CD4+ and CD8+ T-Cell Effector Activity during Skin Infection with HSV-1

    Science.gov (United States)

    Macleod, Bethany L.; Bedoui, Sammy; Hor, Jyh Liang; Mueller, Scott N.; Russell, Tiffany A.; Hollett, Natasha A.; Heath, William R.; Tscharke, David C.

    2014-01-01

    Efficient infection control requires potent T-cell responses at sites of pathogen replication. However, the regulation of T-cell effector function in situ remains poorly understood. Here, we show key differences in the regulation of effector activity between CD4+ and CD8+ T-cells during skin infection with HSV-1. IFN-γ-producing CD4+ T cells disseminated widely throughout the skin and draining lymph nodes (LN), clearly exceeding the epithelial distribution of infectious virus. By contrast, IFN-γ-producing CD8+ T cells were only found within the infected epidermal layer of the skin and associated hair follicles. Mechanistically, while various subsets of lymphoid- and skin-derived dendritic cells (DC) elicited IFN-γ production by CD4+ T cells, CD8+ T cells responded exclusively to infected epidermal cells directly presenting viral antigen. Notably, uninfected cross-presenting DCs from both skin and LNs failed to trigger IFN-γ production by CD8+ T-cells. Thus, we describe a previously unappreciated complexity in the regulation of CD4+ and CD8+ T-cell effector activity that is subset-specific, microanatomically distinct and involves largely non-overlapping types of antigen-presenting cells (APC). PMID:25121482

  19. Distribution of Vascular Patterns in Different Subtypes of Renal Cell Carcinoma. A Morphometric Study in Two Distinct Types of Blood Vessels.

    Science.gov (United States)

    Ruiz-Saurí, Amparo; García-Bustos, V; Granero, E; Cuesta, S; Sales, M A; Marcos, V; Llombart-Bosch, A

    2017-07-01

    To analyze the presence of mature and immature vessels as a prognostic factor in patients with renal cell carcinoma and propose a classification of renal cancer tumor blood vessels according to morphometric parameters. Tissue samples were obtained from 121 renal cell carcinoma patients who underwent radical nephrectomy. Staining with CD31 and CD34 was used to differentiate between immature (CD31+) and mature (CD34+) blood vessels. We quantified the microvascular density, microvascular area and different morphometric parameters: maximum diameter, minimum diameter, major axis, minor axis, perimeter, radius ratio and roundness. We found that the microvascular density was higher in CD31+ than CD34+ vessels, but CD34+ vessels were larger than CD31+ vessels, as well as being strongly correlated with the ISUP tumor grade. We also identified four vascular patterns: pseudoacinar, fascicular, reticular and diffuse. Pseudoacinar and fascicular patterns were more frequent in clear cell renal cell carcinoma (37.62 and 35.64% respectively), followed by reticular pattern (21.78%), while in chromophobe tumors the reticular pattern predominated (90%). The isolated pattern was present in all papillary tumors (100%). In healthy renal tissue, the pseudoacinar and isolated patterns were differentially found in the renal cortex and medulla respectively. We defined four distinct vascular patterns significantly related with the ISUP tumor grade in renal cell carcinomas. Further studies in larger series are needed in order to validate these results. Analysis of both mature and immature vessels (CD34+ and CD31+) provides additional information when evaluating microvascular density.

  20. Impact of molecular subtype on locoregional recurrence in mastectomy patients with T1-T2 breast cancer and 1-3 positive lymph nodes.

    Science.gov (United States)

    Moo, Tracy-Ann; McMillan, Robert; Lee, Michele; Stempel, Michelle; Ho, Alice; Patil, Sujata; El-Tamer, Mahmoud

    2014-05-01

    Postmastectomy radiation (PMRT) in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs) is controversial. Impact of molecular subtype (MST) on locoregional recurrence (LRR) and PMRT benefit is uncertain. We examined the association between MST and LRR, recurrence-free survival (RFS), and overall survival (OS), in T1-T2 tumors with 1-3 positive ALNs. From an institutional database, we identified mastectomy patients with 1-3 positive ALNs between 1995 and 2006. Patients who received neoadjuvant chemotherapy, had T3-T4 tumors, or ≥4 positive ALNs were excluded. MST was defined as: hormone receptor (HR)+/HER2-(luminal A/B), HR+/HER2+(luminal HER2), HR-/HER2+(HER2), and HR-/HER2-(basal). Kaplan-Meier method and Cox regression analysis were used to examine association between MST and LRR, RFS, and OS. This study included 884 patients (700 no PMRT, 141 PMRT): 72.8 % luminal A/B, 7.8 % luminal HER2, 6.8 % HER2, and 12.6 % basal. Median follow-up was 6.3 years; 39 LRRs occurred. Luminal A/B subtype had the smallest tumors (p = 0.03), lowest intraductal component (p = 0.01), histologic grade (p basal and HER2 subtype had the lowest RFS (p = 0.0002) and OS (p nodes who did not receive PMRT, MST was not an independent predictor of LRR and may not be useful in selecting PMRT candidates in that group.

  1. Molecular subtyping of Treponema pallidum and associated factors of serofast status in early syphilis patients: Identified novel genotype and cytokine marker.

    Science.gov (United States)

    Zhang, Rui-Li; Wang, Qian-Qiu; Zhang, Jin-Ping; Yang, Li-Jia

    2017-01-01

    Serofast, a persistent nontreponemal serological response observed in early syphilis patients after conventional treatment, remains a concern of clinicians and syphilis patients. No consensus has been established, however, that defines an effective treatment strategy and clarifies the pathogenesis. In this study, 517 patients with early syphilis were enrolled and treated. Twelve months after treatment, 79.3% (410/517) of patients achieved serological cure, 20.1% (104/517) were serofast, and 0.6% (3/517) were serological failures. Multivariate analysis demonstrated that older age (>40 years) and lower baseline RPR titer (≤ 1:8) were associated with serofast status. We also identified 21 T. pallidum molecular subtypes among early syphilis patients and detected a new subtype, 14i/a. We found that the proportion of 14i/a type in serofast patients was significantly higher than that in patients with serological cure, predicting an increasing risk of serofast status. Levels of chemerin were higher in the serum of serofast cases than serological cure cases, potentially indicating a novel cytokine marker for serofast in early syphilis patients after therapy. We hope that these results contribute to improve guidelines for the management of syphilis patients who experience serofast.

  2. Cysteine- rich secretory protein 3 (CRISP3), ERG and PTEN define a molecular subtype of prostate cancer with implication to patients' prognosis.

    Science.gov (United States)

    Al Bashir, Samir; Alshalalfa, Mohammed; Hegazy, Samar A; Dolph, Michael; Donnelly, Bryan; Bismar, Tarek A

    2014-03-07

    Cysteine- rich secretory protein 3 (CRISP3) prognostic significance in prostate cancer (PCA) has generated mixed result. Herein, we investigated and independently validated CRISP3 expression in relation to ERG and PTEN genomic aberrations and clinical outcome. CRISP3 protein expression was examined by immunohistochemistry using a cohort of patients with localized PCA (n = 215) and castration resistant PCA (CRPC) (n = 46). The Memorial Sloan Kettering (MSKCC) and Swedish cohorts were used for prognostic validation. Results showed, CRISP3 protein intensity to be significantly associated with neoplastic epithelium, being highest in CRPC vs. benign prostate tissue (p protein expression levels. CRISP3 mRNA expression was related to biochemical recurrence in the MSKCC (p = 0.038) and lethal disease in the Swedish cohort (p = 0.0086) and retained its prognostic value in the subgroup of patients with GS 6 & 7. Furthermore, CRISP3 protein and mRNA expression was significantly associated with positive ERG status and with PTEN deletions. Functional biology analysis documented phenylalanine metabolism as the most significant pathway governing high CRISP3 and ERG expression in this subtype of PCA. In conclusion, the combined status of CRISP3, ERG and PTEN define a molecular subtype of PCA with poorest and lethal outcome. Assessing their combined value may be of added value in stratifying patients into different prognostic groups and identify those with poorest clinical outcome.

  3. Early and long-standing rheumatoid arthritis: distinct molecular signatures identified by gene-expression profiling in synovia

    Science.gov (United States)

    Lequerré, Thierry; Bansard, Carine; Vittecoq, Olivier; Derambure, Céline; Hiron, Martine; Daveau, Maryvonne; Tron, François; Ayral, Xavier; Biga, Norman; Auquit-Auckbur, Isabelle; Chiocchia, Gilles; Le Loët, Xavier; Salier, Jean-Philippe

    2009-01-01

    Introduction Rheumatoid arthritis (RA) is a heterogeneous disease and its underlying molecular mechanisms are still poorly understood. Because previous microarray studies have only focused on long-standing (LS) RA compared to osteoarthritis, we aimed to compare the molecular profiles of early and LS RA versus control synovia. Methods Synovial biopsies were obtained by arthroscopy from 15 patients (4 early untreated RA, 4 treated LS RA and 7 controls, who had traumatic or mechanical lesions). Extracted mRNAs were used for large-scale gene-expression profiling. The different gene-expression combinations identified by comparison of profiles of early, LS RA and healthy synovia were linked to the biological processes involved in each situation. Results Three combinations of 719, 116 and 52 transcripts discriminated, respectively, early from LS RA, and early or LS RA from healthy synovia. We identified several gene clusters and distinct molecular signatures specifically expressed during early or LS RA, thereby suggesting the involvement of different pathophysiological mechanisms during the course of RA. Conclusions Early and LS RA have distinct molecular signatures with different biological processes participating at different times during the course of the disease. These results suggest that better knowledge of the main biological processes involved at a given RA stage might help to choose the most appropriate treatment. PMID:19563633

  4. Subtypes of depression in cancer patients : An empirically driven approach

    NARCIS (Netherlands)

    Zhu, Lei; Ranchor, Adelita V; van der Lee, Marije; Garssen, Bert; Sanderman, Robbert; Schroevers, Maya J

    PURPOSE: This study aimed to (1) identify subgroups of cancer patients with distinct subtypes of depression before the start of psychological care, (2) examine whether socio-demographic and medical characteristics distinguished these subtypes, and (3) examine whether people with distinct subtypes

  5. Subtypes of depression in cancer patients: an empirically driven approach

    NARCIS (Netherlands)

    Zhu, Lei; Ranchor, A.V.; van der Lee, Marije; Garssen, Bert; Sanderman, Robbert; Schroevers, Maya J.

    2016-01-01

    Purpose This study aimed to (1) identify subgroups of cancer patients with distinct subtypes of depression before the start of psychological care, (2) examine whether socio-demographic and medical characteristics distinguished these subtypes, and (3) examine whether people with distinct subtypes

  6. Systems Biology Methods for Alzheimer's Disease Research Toward Molecular Signatures, Subtypes, and Stages and Precision Medicine: Application in Cohort Studies and Trials.

    Science.gov (United States)

    Castrillo, Juan I; Lista, Simone; Hampel, Harald; Ritchie, Craig W

    2018-01-01

    Alzheimer's disease (AD) is a complex multifactorial disease, involving a combination of genomic, interactome, and environmental factors, with essential participation of (a) intrinsic genomic susceptibility and (b) a constant dynamic interplay between impaired pathways and central homeostatic networks of nerve cells. The proper investigation of the complexity of AD requires new holistic systems-level approaches, at both the experimental and computational level. Systems biology methods offer the potential to unveil new fundamental insights, basic mechanisms, and networks and their interplay. These may lead to the characterization of mechanism-based molecular signatures, and AD hallmarks at the earliest molecular and cellular levels (and beyond), for characterization of AD subtypes and stages, toward targeted interventions according to the evolving precision medicine paradigm. In this work, an update on advanced systems biology methods and strategies for holistic studies of multifactorial diseases-particularly AD-is presented. This includes next-generation genomics, neuroimaging and multi-omics methods, experimental and computational approaches, relevant disease models, and latest genome editing and single-cell technologies. Their progressive incorporation into basic research, cohort studies, and trials is beginning to provide novel insights into AD essential mechanisms, molecular signatures, and markers toward mechanism-based classification and staging, and tailored interventions. Selected methods which can be applied in cohort studies and trials, with the European Prevention of Alzheimer's Dementia (EPAD) project as a reference example, are presented and discussed.

  7. The Molecular Epidemiology and Evolution of Murray Valley Encephalitis Virus: Recent Emergence of Distinct Sub-lineages of the Dominant Genotype 1.

    Directory of Open Access Journals (Sweden)

    David T Williams

    2015-11-01

    Full Text Available Recent increased activity of the mosquito-borne Murray Valley encephalitis virus (MVEV in Australia has renewed concerns regarding its potential to spread and cause disease.To better understand the genetic relationships between earlier and more recent circulating strains, patterns of virus movement, as well as the molecular basis of MVEV evolution, complete pre-membrane (prM and Envelope (Env genes were sequenced from sixty-six MVEV strains from different regions of the Australasian region, isolated over a sixty year period (1951-2011. Phylogenetic analyses indicated that, of the four recognized genotypes, only G1 and G2 are contemporary. G1 viruses were dominant over the sampling period and found across the known geographic range of MVEV. Two distinct sub-lineages of G1 were observed (1A and 1B. Although G1B strains have been isolated from across mainland Australia, Australian G1A strains have not been detected outside northwest Australia. Similarly, G2 is comprised of only Western Australian isolates from mosquitoes, suggesting G1B and G2 viruses have geographic or ecological restrictions. No evidence of recombination was found and a single amino acid substitution in the Env protein (S332G was found to be under positive selection, while several others were found to be under directional evolution. Evolutionary analyses indicated that extant genotypes of MVEV began to diverge from a common ancestor approximately 200 years ago. G2 was the first genotype to diverge, followed by G3 and G4, and finally G1, from which subtypes G1A and G1B diverged between 1964 and 1994.The results of this study provides new insights into the genetic diversity and evolution of MVEV. The demonstration of co-circulation of all contemporary genetic lineages of MVEV in northwestern Australia, supports the contention that this region is the enzootic focus for this virus.

  8. Integration of gene expression and DNA-methylation profiles improves molecular subtype classification in acute myeloid leukemia

    NARCIS (Netherlands)

    Taskesen, E.; Babaei, S.; Reinders, M.J.M.; De Ridder, J.

    2015-01-01

    Background Acute Myeloid Leukemia (AML) is characterized by various cytogenetic and molecular abnormalities. Detection of these abnormalities is important in the risk-classification of patients but requires laborious experimentation. Various studies showed that gene expression profiles (GEP), and

  9. Molecular epidemiology of Neisseria gonorrhoeae in Amsterdam, The Netherlands, shows distinct heterosexual and homosexual networks

    NARCIS (Netherlands)

    Kolader, Marion-Eliëtte; Dukers, Nicole H. T. M.; van der Bij, Akke K.; Dierdorp, Mirjam; Fennema, Johan S. A.; Coutinho, Roel A.; Bruisten, Sylvia M.

    2006-01-01

    Molecular typing, added to epidemiological data, can better identify transmission patterns of gonorrhea in Western countries, where the incidence has recently been rising. From September 2002 to September 2003, patients with a laboratory-confirmed diagnosis of gonorrhea at the Clinic for Sexually

  10. Molecular epidemiology of Neisseria gonorrhoeae in Amsterdam, The Netherlands, shows distinct heterosexual and homosexual networks.

    NARCIS (Netherlands)

    Kolader, Marion-Eliëtte; Dukers, Nicole H T M; Bij, Akke K van der; Dierdorp, Mirjam; Fennema, Johan S A; Coutinho, Roel A; Bruisten, Sylvia M

    2006-01-01

    Molecular typing, added to epidemiological data, can better identify transmission patterns of gonorrhea in Western countries, where the incidence has recently been rising. From September 2002 to September 2003, patients with a laboratory-confirmed diagnosis of gonorrhea at the Clinic for Sexually

  11. The speciation and subtyping of campylobacter isolates from sewage plants and waste water from a connected poultry abattoir using molecular techniques.

    Science.gov (United States)

    Koenraad, P. M.; Ayling, R.; Hazeleger, W. C.; Rombouts, F. M.; Newell, D. G.

    1995-01-01

    In this study the distribution of phenotypes of campylobacter strains in sewage and surface waters was investigated by subtyping and by speciation of isolates from various aquatic environments. These environments included two municipal sewage plants (SPA and SPB) and waste water from a poultry abattoir (WWA). Both the sewage plants SPA and SPB collected domestic and industrial waste, and SPA received drain water from WWA. SPB received no waste water from any meat-processing plant. The isolates were speciated by PCR and subtyped by PCR/RFLP based on the flagellin PCR products. From all three reservoirs, no Campylobacter lari was isolated, and approximately 80% of the isolates could be identified as C. jejuni and the rest belonged to the C. coli species. The PCR/RFLP typing technique has a high discrimination level and was reproducible between two separate laboratories. The 182 isolates tested yielded 22 distinct Dde I profiles. The results indicate that strains with profiles found in poultry are also detectable in waste water presumed to be solely from domestic and human sources. In addition some strains were unique to the known poultry-related sources, suggesting that avian-specific strains, non-pathogenic to man, may exist in the environment. In contrast some strains were unique to human waste indicating the potential importance of non-poultry sources of infection. No seasonality was observed in the profile distribution. So, at least in the Netherlands, it is unlikely that infections caused by contaminated surface waters contribute to the seasonality of human campylobacteriosis. Images Fig. 1 PMID:8557080

  12. Holistic systems biology approaches to molecular mechanisms of human helper T cell differentiation to functionally distinct subsets.

    Science.gov (United States)

    Chen, Z; Lönnberg, T; Lahesmaa, R

    2013-08-01

    Current knowledge of helper T cell differentiation largely relies on data generated from mouse studies. To develop therapeutical strategies combating human diseases, understanding the molecular mechanisms how human naïve T cells differentiate to functionally distinct T helper (Th) subsets as well as studies on human differentiated Th cell subsets is particularly valuable. Systems biology approaches provide a holistic view of the processes of T helper differentiation, enable discovery of new factors and pathways involved and generation of new hypotheses to be tested to improve our understanding of human Th cell differentiation and immune-mediated diseases. Here, we summarize studies where high-throughput systems biology approaches have been exploited to human primary T cells. These studies reveal new factors and signalling pathways influencing T cell differentiation towards distinct subsets, important for immune regulation. Such information provides new insights into T cell biology and into targeting immune system for therapeutic interventions. © 2013 John Wiley & Sons Ltd.

  13. Classifications within Molecular Subtypes Enables Identification of BRCA1/BRCA2 Mutation Carriers by RNA Tumor Profiling

    Science.gov (United States)

    Larsen, Martin J.; Kruse, Torben A.; Tan, Qihua; Lænkholm, Anne-Vibeke; Bak, Martin; Lykkesfeldt, Anne E.; Sørensen, Kristina P.; Hansen, Thomas v. O.; Ejlertsen, Bent; Gerdes, Anne-Marie; Thomassen, Mads

    2013-01-01

    Pathogenic germline mutations in BRCA1 or BRCA2 are detected in less than one third of families with a strong history of breast cancer. It is therefore expected that mutations still remain undetected by currently used screening methods. In addition, a growing number of BRCA1/2 sequence variants of unclear pathogen significance are found in the families, constituting an increasing clinical challenge. New methods are therefore needed to improve the detection rate and aid the interpretation of the clinically uncertain variants. In this study we analyzed a series of 33 BRCA1, 22 BRCA2, and 128 sporadic tumors by RNA profiling to investigate the classification potential of RNA profiles to predict BRCA1/2 mutation status. We found that breast tumors from BRCA1 and BRCA2 mutation carriers display characteristic RNA expression patterns, allowing them to be distinguished from sporadic tumors. The majority of BRCA1 tumors were basal-like while BRCA2 tumors were mainly luminal B. Using RNA profiles, we were able to distinguish BRCA1 tumors from sporadic tumors among basal-like tumors with 83% accuracy and BRCA2 from sporadic tumors among luminal B tumors with 89% accuracy. Furthermore, subtype-specific BRCA1/2 gene signatures were successfully validated in two independent data sets with high accuracies. Although additional validation studies are required, indication of BRCA1/2 involvement (“BRCAness”) by RNA profiling could potentially be valuable as a tool for distinguishing pathogenic mutations from benign variants, for identification of undetected mutation carriers, and for selecting patients sensitive to new therapeutics such as PARP inhibitors. PMID:23704984

  14. Associations and indications of Ki67 expression with clinicopathological parameters and molecular subtypes in invasive breast cancer: A population-based study.

    Science.gov (United States)

    Sun, Jinzhong; Chen, Chuang; Wei, Wen; Zheng, Hongmei; Yuan, Jingping; Tu, Y I; Yao, Feng; Wang, Lijun; Yao, Xiaoli; Li, Juanjuan; Li, Yan; Sun, Shengrong

    2015-09-01

    Ki67 has potential prognostic and predictive values for breast cancer patients, and has become an important biomarker in routine clinical practice. The aims of the present study were to investigate the distribution of Ki67 expression and its correlation with other clinicopathological parameters in central China. In total, 1,259 patients with newly-diagnosed invasive breast cancer were included in the present study. The clinical information was obtained from the electronic medical records. The expression levels of Ki67, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) were detected by immunohistochemical analysis. The associations between Ki67 scores and other prognostic factors were evaluated as continuous and categorical variables. The mean value of the Ki67 scores of all patients was 31%. In total, ~36% (456/1,259) of the patients demonstrated a low expression of Ki67. A statistically significant correlation was identified between the mean Ki67 scores and the lymph node status, tumor grade, ER, PR and HER2 status, and clinical stage or molecular subtypes (all PKi67 was categorized into high (>14%) and low (≤14%) level groups, the χ 2 test was used to verify these results. The Ki67 scores demonstrated no statistically significant differences between the HER2-positive (non-luminal) and three negative subtypes, with the exception of patients with a tumor size of >2 cm (P=0.02). In conclusion, the results revealed the presence of significant correlations between Ki67 and other clinicopathological parameters.

  15. Distinct roles of molecular chaperones HSP90α and HSP90β in the biogenesis of KCNQ4 channels.

    Directory of Open Access Journals (Sweden)

    Yanhong Gao

    Full Text Available Loss-of-function mutations in the KCNQ4 channel cause DFNA2, a subtype of autosomal dominant non-syndromic deafness that is characterized by progressive sensorineural hearing loss. Previous studies have demonstrated that the majority of the pathogenic KCNQ4 mutations lead to trafficking deficiency and loss of KCNQ4 currents. Over the last two decades, various strategies have been developed to rescue trafficking deficiency of pathogenic mutants; the most exciting advances have been made by manipulating activities of molecular chaperones involved in the biogenesis and quality control of the target protein. However, such strategies have not been established for KCNQ4 mutants and little is known about the molecular chaperones governing the KCNQ4 biogenesis. To identify KCNQ4-associated molecular chaperones, a proteomic approach was used in this study. As a result, two major molecular chaperones, HSP70 and HSP90, were identified and then confirmed by reciprocal co-immunoprecipitation assays, suggesting that the HSP90 chaperone pathway might be involved in the KCNQ4 biogenesis. Manipulating chaperone expression further revealed that two different isoforms of HSP90, the inducible HSP90α and the constitutive HSP90β, had opposite effects on the cellular level of the KCNQ4 channel; that HSP40, HSP70, and HOP, three key components of the HSP90 chaperone pathway, were crucial in facilitating KCNQ4 biogenesis. In contrast, CHIP, a major E3 ubiquitin ligase, had an opposite effect. Collectively, our data suggest that HSP90α and HSP90β play key roles in controlling KCNQ4 homeostasis via the HSP40-HSP70-HOP-HSP90 chaperone pathway and the ubiquitin-proteasome pathway. Most importantly, we found that over-expression of HSP90β significantly improved cell surface expression of the trafficking-deficient, pathogenic KCNQ4 mutants L274H and W276S. KCNQ4 surface expression was restored by HSP90β in cells mimicking heterozygous conditions of the DFNA2 patients

  16. Molecular portrait of breast cancer in China reveals comprehensive transcriptomic likeness to Caucasian breast cancer and low prevalence of luminal A subtype

    International Nuclear Information System (INIS)

    Huang, Xiaoyan; Dugo, Matteo; Callari, Maurizio; Sandri, Marco; De Cecco, Loris; Valeri, Barbara; Carcangiu, Maria Luisa; Xue, Jingyan; Bi, Rui; Veneroni, Silvia; Daidone, Maria Grazia; Ménard, Sylvie; Tagliabue, Elda; Shao, Zhimin; Wu, Jiong; Orlandi, Rosaria

    2015-01-01

    The recent dramatic increase in breast cancer incidence across China with progressive urbanization and economic development has signaled the urgent need for molecular and clinical detailing of breast cancer in the Chinese population. Our analyses of a unique transethnic collection of breast cancer frozen specimens from Shanghai Fudan Cancer Center (Chinese Han) profiled simultaneously with an analogous Caucasian Italian series revealed consistent transcriptomic data lacking in batch effects. The prevalence of Luminal A subtype was significantly lower in Chinese series, impacting the overall prevalence of estrogen receptor (ER)-positive disease in a large cohort of Chinese/Caucasian patients. Unsupervised and supervised comparison of gene and microRNA (miRNA) profiles of Chinese and Caucasian samples revealed extensive similarity in the comprehensive taxonomy of transcriptional elements regulating breast cancer biology. Partition of gene expression data using gene lists relevant to breast cancer as “intrinsic” and “extracellular matrix” genes identified Chinese and Caucasian subgroups with equivalent global gene and miRNA profiles. These findings indicate that in the Chinese and Caucasian groups, breast neoplasia and the surrounding stromal characteristics undergo the same differentiation and molecular processes. Transcriptional similarity across transethnic cohorts may simplify translational medicine approaches and clinical management of breast cancer patients worldwide

  17. Therapy related-chronic myelomonocytic leukemia (CMML): Molecular, cytogenetic, and clinical distinctions from de novo CMML.

    Science.gov (United States)

    Patnaik, Mrinal M; Vallapureddy, Rangit; Yalniz, Fevzi F; Hanson, Curtis A; Ketterling, Rhett P; Lasho, Terra L; Finke, Christy; Al-Kali, Aref; Gangat, Naseema; Tefferi, Ayalew

    2018-01-01

    Therapy related myeloid neoplasms (t-MN) including therapy related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML) are associated with aggressive disease biologies and poor outcomes. In this large (n = 497) and informative (inclusive of molecular and cytogenetic information) chronic myelomonocytic leukemia (CMML) patient cohort, we demonstrate key biological insights and an independent prognostic impact for t-CMML. T-CMML was diagnosed in 9% of patients and occurred approximately 7 years after exposure to prior chemotherapy and/or radiation therapy. In comparison to de novo CMML, t-CMML patients had higher LDH levels, higher frequency of karyotypic abnormalities and had higher risk cytogenetic stratification. There were no differences in the distribution of gene mutations and unlike t-MDS/AML, balanced chromosomal translocations, abnormalities of chromosome 11q23 (1%) and Tp53 mutations (<2%) were uncommon. Molecularly integrated CMML prognostic models were not effective in risk stratifying t-CMML patients and responses to hypomethylating agents were dismal with no complete responses. Median overall (OS) and leukemia free survival (LFS) was shorter for t-CMML in comparison to d-CMML (Median OS 10.9 vs 26 months and median LFS 50 vs 127 months) and t-CMML independently and adversely impacted OS (P = .0001 HR 2.1 95% CI 1.4-3.0). This prognostic impact was retained in the context of the Mayo Molecular Model (P = .001, HR 2.4, 95% CI 1.5-3.7) and the GFM prognostic model (P < .0001, HR 2.15, 95% CI 1.5-3.7). In summary, we highlight the unique genetics and independent prognostic impact of t-CMML, warranting its inclusion as a separate entity in the classification schema for both CMML and t-MN. © 2017 Wiley Periodicals, Inc.

  18. Distinct Subfamilies of Odorant Binding Proteins in Locust (Orthoptera, Acrididae: Molecular Evolution, Structural Variation, and Sensilla-Specific Expression

    Directory of Open Access Journals (Sweden)

    Xingcong Jiang

    2017-09-01

    Full Text Available Odorant binding proteins (OBPs play an important role in insect olfaction, facilitating transportation of odorant molecules in the sensillum lymph. While most of the researches are concentrated on Lepidopteran and Dipteran species, our knowledge about Orthopteran species is still very limited. In this study, we have investigated OBPs of the desert locust Schistocerca gregaria, a representative Orthopteran species. We have identified 14 transcripts from a S. gregaria antennal transcriptome encoding SgreOBPs, and recapitulated the phylogenetic relationship of SgreOBPs together with OBPs from three other locust species. Two conserved subfamilies of classic OBPs have been identified, named I-A and II-A, exhibiting both common and subfamily-specific amino acid motifs. Distinct evolutionary features were observed for subfamily I-A and II-A OBPs. Surface topology and interior cavity were elucidated for OBP members from the two subfamilies. Antennal topographic expression revealed distinct sensilla- and cellular- specific expression patterns for SgreOBPs from subfamily I-A and II-A. These findings give first insight into the repertoire of locust OBPs with respect to their molecular and evolutionary features as well as their expression in the antenna, which may serve as an initial step to unravel specific roles of distinct OBP subfamilies in locust olfaction.

  19. MicroRNAs sequencing unveils distinct molecular subgroups of plasmablastic lymphoma.

    Science.gov (United States)

    Ambrosio, Maria Raffaella; Mundo, Lucia; Gazaneo, Sara; Picciolini, Matteo; Vara, Prasad Satya; Sayed, Shaheen; Ginori, Alessandro; Lo Bello, Giuseppe; Del Porro, Leonardo; Navari, Mohsen; Ascani, Stefano; Yonis, Amhed; Leoncini, Lorenzo; Piccaluga, Pier Paolo; Lazzi, Stefano

    2017-12-08

    Plasmablastic lymphoma (PBL) is an aggressive lymphoma, often arising in the context of immunodeficiency and associated with Epstein-Barr virus (EBV) infection. The most frequently detected genetic alteration is the deregulation of MYC gene through the translocation - t(8;14)(q24;q32). The diagnosis of PBL is often challenging because it has an overlap in morphology, immunophenotype, cytogenetics and virus association with other lymphomas and plasma cell neoplasms; further, its molecular basis remains elusive. In the present study we aimed to better define the possible contribution of EBV infection as well as miRNA deregulation in PBL pathogenesis. We studied 23 cases of PBL, 19 Burkitt lymphomas (BL), and 17 extra-medullary plasmacytoma (EMPC). We used qPCR and immunohistochemistry to assess EBV latency patterns, while micro-RNA (miRNA) profiling was performed by next generation sequencing (Illumina) and validated by qPCR. Our analysis revealed a non-canonical EBV latency program with the partial expression of some proteins characterizing latency II and the activation of an abortive lytic cycle. Moreover, we identified miRNA signatures discriminating PBL from BL and EMPC. Interestingly, based on the miRNA profile, PBL appeared constituted by two discrete subgroups more similar to either BL or EMPC, respectively. This pattern was confirmed in an independent set of cases studied by qPCR and corresponded to different clinico-pathological features in the two groups, including HIV infection, MYC rearrangement and disease localization. In conclusion, we uncovered for the first time 1) an atypical EBV latency program in PBL; 2) a miRNA signature distinguishing PBL from the closest malignant counterparts; 3) the molecular basis of PBL heterogeneity.

  20. Cartography of Pathway Signal Perturbations Identifies Distinct Molecular Pathomechanisms in Malignant and Chronic Lung Diseases.

    Science.gov (United States)

    Arakelyan, Arsen; Nersisyan, Lilit; Petrek, Martin; Löffler-Wirth, Henry; Binder, Hans

    2016-01-01

    Lung diseases are described by a wide variety of developmental mechanisms and clinical manifestations. Accurate classification and diagnosis of lung diseases are the bases for development of effective treatments. While extensive studies are conducted toward characterization of various lung diseases at molecular level, no systematic approach has been developed so far. Here we have applied a methodology for pathway-centered mining of high throughput gene expression data to describe a wide range of lung diseases in the light of shared and specific pathway activity profiles. We have applied an algorithm combining a Pathway Signal Flow (PSF) algorithm for estimation of pathway activity deregulation states in lung diseases and malignancies, and a Self Organizing Maps algorithm for classification and clustering of the pathway activity profiles. The analysis results allowed clearly distinguish between cancer and non-cancer lung diseases. Lung cancers were characterized by pathways implicated in cell proliferation, metabolism, while non-malignant lung diseases were characterized by deregulations in pathways involved in immune/inflammatory response and fibrotic tissue remodeling. In contrast to lung malignancies, chronic lung diseases had relatively heterogeneous pathway deregulation profiles. We identified three groups of interstitial lung diseases and showed that the development of characteristic pathological processes, such as fibrosis, can be initiated by deregulations in different signaling pathways. In conclusion, this paper describes the pathobiology of lung diseases from systems viewpoint using pathway centered high-dimensional data mining approach. Our results contribute largely to current understanding of pathological events in lung cancers and non-malignant lung diseases. Moreover, this paper provides new insight into molecular mechanisms of a number of interstitial lung diseases that have been studied to a lesser extent.

  1. Correlation of molecular subtypes of invasive ductal carcinoma of breast with glucose metabolism in FDG PET/CT: Based on the recommendations of the St. Gallen Consenesus Meeting 2013

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Sang Kyun [Dept. of Nuclear Medicine, Haeundae Paik Hospital, University of Inje College of Medicine, Busan (Korea, Republic of); Lee, Sun Seong; Park, Yun Soo; Park, Ji Sun; Kim, Tae Hyun; Yoon, Hye Kyoung; Ahn, Hyo Jung; Lee, Seok Mo [Busan Paik Hospital, University of Inje College of Medicine, Busan (Korea, Republic of)

    2017-03-15

    This study aimed to investigate the relationship between the SUVmax of primary breast cancer lesions and the molecular subtypes based on the recommendations of the St. Gallen consensus meeting 2013. Clinical records of patients who underwent F-18 FDG PET/CT for initial staging of invasive ductal carcinoma (IDC) of the breast were reviewed. A total of 183 patients were included. SUV{sub max} was correlated with the molecular subtypes defined by the St. Gallen Consensus Meeting 2013, i.e., luminal A-like (LA), luminal B-like HER2 negative (LBHER2-), luminal B-like HER2 positive (LBHER2+), HER2 positive (HER2+), and triple negative (TN), and with the clinicohistopathologic characteristics. The molecular subtype was LA in 38 patients, LBHER2- in 72, LBHER2+ in 21, HER2+ in 30, and TN in 22. The mean SUV{sub max} in the LA, LBHER2-, LBHER2+, HER2+, and TN groups were 4.5 ± 2.3, 7.2 ± 4.9, 7.2 ± 4.3, 10.2 ± 5.5, and 8.8 ± 7.1, respectively. Although SUV{sub max} differed significantly among these subtypes (p < 0.001), the values showed a wide overlap. Optimal cut-off SUV{sub max} to differentiate LA from LBHER2-, LBHER2+, HER2+ and TN were 5.9, 5.8, 7.5, and 10.2 respectively, with area under curve (AUC) of 0.648, 0.709, 0.833, and 0.697 respectively. The cut-off value of 5.9 yielded the highest accuracy for differentiation between the LA and non-LA subtypes, with sensitivity, specificity, and AUC of 79.4 %, 57.9 %, and 0.704 respectively. The SUV{sub max} showed a significant correlation with the molecular subtype. Although SUV{sub max} measurements could be used along with immunohistochemical analysis for differentiating between molecular subtypes, its application to individual patients may be limited due to the wide overlaps in SUV{sub max}.

  2. Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt-Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes.

    Science.gov (United States)

    Faucheux, B A; Morain, E; Diouron, V; Brandel, J-P; Salomon, D; Sazdovitch, V; Privat, N; Laplanche, J-L; Hauw, J-J; Haïk, S

    2011-08-01

    Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease-related prion protein (PrP(Sc) ) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrP(Sc) deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt-Jakob disease (sCJD; n=100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrP(Sc) molecular types. The numerical density of neurones was estimated with a computer-assisted image analysis system and the accumulation of PrP(Sc) deposits was scored. The scores of PrP(Sc) immunoreactive deposits of the punctate type (synaptic type) were correlated with neurone counts - the higher the score the higher the neuronal loss - in all sCJD subtypes. Large 5- to 50-µm-wide deposits (focal type) were found in sCJD-MV2 and sCJD-VV2 subtypes, and occasionally in a few cases of the other studied groups. By contrast, the highest scores for 5- to 50-µm-wide deposits observed in sCJD-MV2 subtype were not associated with higher neuronal loss. In addition, these scores were inversely correlated with neuronal counts in the sCJD-VV2 subtype. These results support a putative pathogenic role for small PrP(Sc) deposits common to the various sCJD subtypes. Furthermore, the observation of a lower loss of neurones associated with PrP(Sc) type-2 large deposits is consistent with a possible 'protective' role of aggregated deposits in both sCJD-MV2 and sCJD-VV2 subtypes. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

  3. Functional and Molecular Evidence for Kv7 Channel Subtypes in Human Detrusor from Patients with and without Bladder Outflow Obstruction

    DEFF Research Database (Denmark)

    Svalø, Julie; Sheykhzade, Majid; Nordling, Jørgen

    2015-01-01

    The aim of the study was to investigate whether Kv7 channels and their ancillary β-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT-qPCR and myography, respectively. We found mRNA expressi...... between Kv7 channels and β-adrenoceptors in the human urinary bladder. The performed gene expression analysis combined with the organ bath studies imply that compounds that activate Kv7 channels could be useful for treatment of overactive bladder syndrome.......The aim of the study was to investigate whether Kv7 channels and their ancillary β-subunits, KCNE, are functionally expressed in the human urinary bladder. Kv7 channels were examined at the molecular level and by functional studies using RT-qPCR and myography, respectively. We found mRNA expression...... (activator of Kv7.1 channels, 10 μM) and ML213 (activator of Kv7.2, Kv7.4, Kv7.4/7.5 and Kv7.5 channels, 10 μM), reduced the tone of 1 μM carbachol pre-constricted bladder strips. XE991 (blocker of Kv7.1-7.5 channels, 10 μM) had opposing effects as it increased contractions achieved with 20 mM KPSS...

  4. Unraveling the distinctive features of hemorrhagic and non-hemorrhagic snake venom metalloproteinases using molecular simulations

    Science.gov (United States)

    de Souza, Raoni Almeida; Díaz, Natalia; Nagem, Ronaldo Alves Pinto; Ferreira, Rafaela Salgado; Suárez, Dimas

    2016-01-01

    Snake venom metalloproteinases are important toxins that play fundamental roles during envenomation. They share a structurally similar catalytic domain, but with diverse hemorrhagic capabilities. To understand the structural basis for this difference, we build and compare two dynamical models, one for the hemorrhagic atroxlysin-I from Bothrops atrox and the other for the non-hemorraghic leucurolysin-a from Bothrops leucurus. The analysis of the extended molecular dynamics simulations shows some changes in the local structure, flexibility and surface determinants that can contribute to explain the different hemorrhagic activity of the two enzymes. In agreement with previous results, the long Ω-loop (from residue 149 to 177) has a larger mobility in the hemorrhagic protein. In addition, we find some potentially-relevant differences at the base of the S1' pocket, what may be interesting for the structure-based design of new anti-venom agents. However, the sharpest differences in the computational models of atroxlysin-I and leucurolysin-a are observed in the surface electrostatic potential around the active site region, suggesting thus that the hemorrhagic versus non-hemorrhagic activity is probably determined by protein surface determinants.

  5. Molecular Phylogeny and Morphological Distinctions of Two Popular Bivalves, Ctenoides scaber and Ctenoides mitis

    Directory of Open Access Journals (Sweden)

    Lindsey F. Dougherty

    2017-01-01

    Full Text Available One of the most well-known species in the bivalve family Limidae (d’Orbigny, 1846 is the brightly colored Ctenoides scaber (Born, 1778, commonly known as the rough file clam or flame scallop. Distinguishing this bivalve from its close relative, C. mitis (Lamarck, 1807, can be difficult using only morphological features and has led to much taxonomic confusion throughout the literature. In this study, morphological characters were compared to a molecular phylogeny constructed using three genes (COI, 28S, and H3 in order to differentiate C. scaber and C. mitis. The phylogeny recovered two well-supported clades that differ significantly in shell rib numbers, but not tentacle colors. The two species were then placed in a larger phylogenetic context of the Limidae family, which revealed the need for further systematic revision across genera. As these bivalves are popular in aquaria, cannot be tank-raised, and have been overcollected in the past, proper species identification is important for assessing sustainable collection practices.

  6. Molecular distinction amongst varieties of Mulberry using RAPD and DAMD profiles

    Directory of Open Access Journals (Sweden)

    Ranade Shirish

    2001-12-01

    Full Text Available Abstract Background Mulberry trees are the most important host for rearing mulberry silkworms in sericulture. Improved varieties of mulberry tree have been developed through traditional breeding procedures. Not much work, however, has been carried out on the molecular characterization of these varieties. Random Amplified Polymorphic DNA (RAPD and Directed Amplification of Minisatellite DNA (DAMD methods based on Polymerase Chain Reaction are important tools to analyze genetic diversity of mulberries. These have been used to determine variation amongst nine varieties of Morus spp. maintained at Banthra Research Station of National Botanical Research Institute, Lucknow. Results and Discussion The varieties were analyzed using 23 arbitrary sequence decamer primers for RAPD, and 3 minisatellite core sequence primers for DAMD reactions. The RAPD and DAMD band data, (a total of 200 bands, were used to determine the pair wise distances according to Jaccard's algorithm. From these distance values Neighbour Joining (NJ analyses were carried out separately for the RAPD and the DAMD data. The triploid varieties were found to be most similar to each other using RAPD analysis, while the varieties S13 and S34 were more similar using DAMD analysis. Nearly 85% of the RAPD bands and 91% of the DAMD bands were polymorphic across the nine varieties. Conclusions The mulberry varieties could be distinguished by their RAPD and DAMD profiles. As many as five RAPD primers and one DAMD primer generated profiles that can together differentiate all the nine varieties in terms of unique bands.

  7. Development of mesenchymal subtype gene signature for clinical application in gastric cancer.

    Science.gov (United States)

    Lee, Jeeyun; Cristescu, Razvan; Kim, Kyoung-Mee; Kim, Kyung; Kim, Seung Tae; Park, Se Hoon; Kang, Won Ki

    2017-09-12

    Previously, in the Asian Cancer Research Group (ACRG) project, we defined four distinct molecular subtypes in gastric cancer (GC). Mesenchymal (microsatellite stable with epithelial-to-mesenchymal transition phenotype, MSS/EMT) tumors showed the worst prognosis among all the subtypes. To develop a gene signature for predicting mesenchymal subtype GC, we conducted gene expression profiling using a NanoString assay in 70 ACRG specimens. The gene signature was validated in an independent set obtained from the prospective Adjuvant chemoRadioTherapy In Stomach Tumor (ARTIST) trial. The association between the mesenchymal subtype and survival was investigated. After cross-platform concordance test performed in 70 ACRG specimens, a 71-gene MSS/EMT signature was obtained. In the validation set, the gene signature predicted that 20 of 73 (27%) patients had mesenchymal tumors. Patients with mesenchymal subtype had diffuse GC, poorly-differentiated or signet ring cell carcinoma, and were microsatellite stable. The estimated hazard ratio for survival in patients with mesenchymal GC compared to those with non-mesenchymal tumors was 2.262 (95% confidence interval, 1.410 to 3.636; P=0.001). The survival difference remained significant when the subtypes were analyzed according to clinical prognostic parameters. This study suggested that the NanoString-based 71-gene signature for mesenchymal subtype is a strong predictor of the outcome in patients with GC.

  8. FEAT expression correlates with tumor size, PR status, HER2 expression, Ki67 index, and molecular subtype and predicts recurrence in breast cancer.

    Science.gov (United States)

    Wang, S M; Ye, M; Zhou, J; Ni, S M; Wei, Q C

    2017-01-01

    FEAT protein is uniformly overexpressed in a variety of human cancers but weakly expressed in normal tissue. FEAT has antiapoptotic activity and plays a role in carcinogenesis; however, the correlation between FEAT and clinicopathologic characteristics in cancer has not been reported. Our study explores the expression of FEAT protein and its clinicopathologic significance in breast cancer. We examined the expression of FEAT in tissues from 131 cases of breast cancer by immunohistochemistry and analyzed the correlation between FEAT expression and clinicopathologic parameters. The difference in FEAT expression between normal breast tissues and breast cancer tissues was also investigated. Finally, we analyzed the association between FEAT expression and disease-free survival or overall survival. Our data showed that FEAT was expressed in the cytoplasm. The expression of FEAT protein was significantly higher in breast cancer tissues than in normal breast tissues. Moreover, the expression of FEAT protein was higher in breast cancer with a larger tumor size (>2 cm), negative PR, positive HER2, or higher Ki67 index (≥14%) than in breast cancer with a smaller tumor size (≤2 cm), positive PR, negative HER2, or lower Ki67 index (Ki67 index, and molecular subtype. Survival analysis showed that disease-free survival and overall survival were significantly shorter in breast cancer patients with high FEAT expression than in those with low expression of FEAT (Pbreast cancer, but not for survival. In conclusion, FEAT may be a potential biomarker for recurrence of breast cancer.

  9. Liposomal Nanoparticles Carrying anti-IL6R Antibody to the Tumour Microenvironment Inhibit Metastasis in Two Molecular Subtypes of Breast Cancer Mouse Models.

    Science.gov (United States)

    Guo, Chunlei; Chen, Yanan; Gao, Wenjuan; Chang, Antao; Ye, Yujie; Shen, Wenzhi; Luo, Yunping; Yang, Shengyong; Sun, Peiqing; Xiang, Rong; Li, Na

    2017-01-01

    Tumour microenvironment (TME) contributes significantly towards potentiating the stemness and metastasis properties of cancer cells. IL6-Stat3 is one of the important cell signaling pathways in mediating the communication between tumour and immune cells. Here, we have systematically developed a novel anti-CD44 antibody-mediated liposomal nanoparticle delivery system loaded with anti-IL6R antibody, which could specifically target the TME of CD44 + breast cancer cells in different mouse models for triple negative and luminal breast cancer. This nanoparticle had an enhanced and specific tumour targeting efficacy with dramatic anti-tumour metastasis effects in syngeneic BALB/c mice bearing 4T1 cells as was in the syngeneic MMTV-PyMT mice. It inhibited IL6R-Stat3 signaling and moderated the TME, characterized by the reduced expression of genes encoding Stat3, Sox2, VEGFA, MMP-9 and CD206 in the breast tissues. Furthermore, this nanoparticle reduced the subgroups of Sox2 + and CD206 + cells in the lung metastatic foci, demonstrating its inhibitory effect on the lung metastatic niche for breast cancer stem cells. Taken together, the CD44 targeted liposomal nanoparticles encapsulating anti-IL6R antibody achieved a significant effect to inhibit the metastasis of breast cancer in different molecular subtypes of breast cancer mouse models. Our results shed light on the application of nanoparticle mediated cancer immune-therapy through targeting TME.

  10. Distinct physiological and molecular responses in Arabidopsis thaliana exposed to aluminum oxide nanoparticles and ionic aluminum.

    Science.gov (United States)

    Jin, Yujian; Fan, Xiaoji; Li, Xingxing; Zhang, Zhenyan; Sun, Liwei; Fu, Zhengwei; Lavoie, Michel; Pan, Xiangliang; Qian, Haifeng

    2017-09-01

    Nano-aluminium oxide (nAl 2 O 3 ) is one of the most widely used nanomaterials. However, nAl 2 O 3 toxicity mechanisms and potential beneficial effects on terrestrial plant physiology remain poorly understood. Such knowledge is essential for the development of robust nAl 2 O 3 risk assessment. In this study, we studied the influence of a 10-d exposure to a total selected concentration of 98 μM nAl 2 O 3 or to the equivalent molar concentration of ionic Al (AlCl 3 ) (196 μM) on the model plant Arabidopsis thaliana on the physiology (e.g., growth and photosynthesis, membrane damage) and the transcriptome using a high throughput state-of-the-art technology, RNA-seq. We found no evidence of nAl 2 O 3 toxicity on photosynthesis, growth and lipid peroxidation. Rather the nAl 2 O 3 treatment stimulated root weight and length by 48% and 39%, respectively as well as photosynthesis opening up the door to the use of nAl 2 O 3 in biotechnology and nano agriculture. Transcriptomic analyses indicate that the beneficial effect of nAl 2 O 3 was related to an increase in the transcription of several genes involved in root growth as well as in root nutrient uptake (e.g., up-regulation of the root hair-specific gene family and root development genes, POLARIS protein). By contrast, the ionic Al treatment decreased shoot and root weight of Arabidopsis thaliana by 57.01% and 45.15%, respectively. This toxic effect was coupled to a range of response at the gene transcription level including increase transcription of antioxidant-related genes and transcription of genes involved in plant defense response to pathogens. This work provides an integrated understanding at the molecular and physiological level of the effects of nAl 2 O 3 and ionic Al in Arabidopsis. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Muscarinic acetylcholine receptor subtypes: localization and structure/function

    DEFF Research Database (Denmark)

    Brann, M R; Ellis, J; Jørgensen, H

    1993-01-01

    Based on the sequence of the five cloned muscarinic receptor subtypes (m1-m5), subtype selective antibody and cDNA probes have been prepared. Use of these probes has demonstrated that each of the five subtypes has a markedly distinct distribution within the brain and among peripheral tissues. The...

  12. [Molecular subtyping of Vibrio cholerae isolates from outbreaks of cholera by pulsed-field gel electrophoresis in Hainan in 2008].

    Science.gov (United States)

    Wu, Jie; Diao, Bao-Wei; Zhou, Hai-Jian; Zhu, Jian-Hua; Wang, Duo-Chun; Pang, Bo; Wang, Rui-Bai; Kan, Biao; Wang, Shao-Ling; Su, Xin-Yuan; Ma, Yan

    2010-12-01

    To analyze the molecular characteristics and genetic correlations of Vibrio cholerae isolates in Hainan in 2008, so as to provide pathogenic proof to diagnose the plague. Seventy six cholera strains were isolated from this cholera epidemic.69 strains were obtained from patients, 7 were isolated from external environment, among which, one was from patient's toilet, one from water sample, three were isolated from fish pond near patient's home, one came from swab of the patient vomit on the ground of health center and one from swab of kitchen knife from Hainan University canteen respectively. With conventional aetiological methods, pulse-field gel electrophoresis was conducted and the patterns of the 76 isolates were analyzed. The PFGE image was analyzed using BioNumerics (Version4.0, Applied Maths BVBA, Belium). Image bands were identified and similarity coefficient was automatically generated. Seventy six strains were isolated from Vibrio cholerae outbreaks in Hainan in 2008.5 PFGE patterns of patient's isolates in June were the same, sharing a similarity coefficient of 100%. 70 PFGE patterns of patients and water in October and November were completely same, the similarity coefficient being 100%. But they were not same as that of June. 1 PFGE pattern of isolate from the sample in Hainan University was different, only sharing a similarity coefficient of 79.7%, which showed no correlation with the outbreak. Different outbreaks of Vibrio cholera occurred in Hainan in 2008. The epidemic in October and November at different counties was one outbreak. The pollution of water in environment was an important factor for outbreak.

  13. Alcoholic subtypes: are two sufficient?

    Science.gov (United States)

    Windle, Michael; Scheidt, Douglas M

    2004-12-01

    Guided by the literature on alcohol subtypes, cluster analytical solutions ranging from two to five were evaluated for a large (n = 802), ethnically diverse sample of alcoholic in-patients. Personal interview data were collected from in-patients regarding their substance abuse and psychiatric disorder status, risk factors for psychopathology and health outcomes. The data were collected at five alcohol in-patient treatment settings in New York; three settings were in New York City, one in Rochester and one in Buffalo. The sample included 802 participants (481 males and 321 females) with racial/ethnic group diversity (418 blacks, 180 whites, 187 Hispanics, 17 of other ethnic origin). Subjects were assessed with standardized measures of substance abuse and psychiatric disorders, family history of alcoholism, psychopathy, temperament, alcohol expectancies and clinical health variables. Based on internal and external criteria and compatibility with the existing literature, four subtypes were identified: mild course, polydrug, negative affect and chronic/antisocial. On external criteria, the polydrug subtype had the highest rate of family criminality, high-risk sexual behavior and intravenous drug use; the negative affect subtype had the highest rate of childhood sexual abuse, attempted suicide and childhood homelessness; the chronic/antisocial personality (ASP) subtype had the most severe pattern of drinking and antisocial behavior. Findings are discussed with regard to the etiological and clinical utility of the four-subtype formulation, and consistency with recent studies in molecular genetics and pharmacology.

  14. Subtypes of depression and their overlap in a naturalistic inpatient sample of major depressive disorder.

    Science.gov (United States)

    Musil, Richard; Seemüller, Florian; Meyer, Sebastian; Spellmann, Ilja; Adli, Mazda; Bauer, Michael; Kronmüller, Klaus-Thomas; Brieger, Peter; Laux, Gerd; Bender, Wolfram; Heuser, Isabella; Fisher, Robert; Gaebel, Wolfgang; Schennach, Rebecca; Möller, Hans-Jürgen; Riedel, Michael

    2018-03-01

    Subtyping depression is important in order to further delineate biological causes of depressive syndromes. The aim of this study was to evaluate clinical and outcome characteristics of distinct subtypes of depression and to assess proportion and features of patients fulfilling criteria for more than one subtype. Melancholic, atypical and anxious subtypes of depression were assessed in a naturalistic sample of 833 inpatients using DSM-IV specifiers based on operationalized criteria. Baseline characteristics and outcome criteria at discharge were compared between distinct subtypes and their overlap. A substantial proportion of patients (16%) were classified with more than one subtype of depression, 28% were of the distinct anxious, 7% of the distinct atypical and 5% of the distinct melancholic subtype. Distinct melancholic patients had shortest duration of episode, highest baseline depression severity, but were more often early improvers; distinct anxious patients had higher NEO-Five Factor Inventory (NEO-FFI) neuroticism scores compared with patients with unspecific subtype. Melancholic patients with overlap of anxious features had worse treatment outcome compared to distinct melancholic and distinct anxious subtype. Distinct subtypes differed in only few variables and patients with overlap of depression subtypes may have independent clinical and outcome characteristics. Studies investigating biological causes of subtypes of depression should take influence of features of other subtypes into account. Copyright © 2017 John Wiley & Sons, Ltd.

  15. Comprehensive immune transcriptomic analysis in bladder cancer reveals subtype specific immune gene expression patterns of prognostic relevance.

    Science.gov (United States)

    Ren, Runhan; Tyryshkin, Kathrin; Graham, Charles H; Koti, Madhuri; Siemens, D Robert

    2017-09-19

    Recent efforts on genome wide profiling of muscle invasive bladder cancer (MIBC) have led to its classification into distinct genomic and transcriptomic molecular subtypes that exhibit variability in prognosis. Evolving evidence from recent immunotherapy trials has demonstrated the significance of pre-existing tumour immune profiles that could guide treatment decisions. To identify immune gene expression patterns associated with the molecular subtypes, we performed a comprehensive in silico immune transcriptomic profiling, utilizing transcriptomic data from 347 MIBC cases from The Cancer Genome Atlas (TCGA). To investigate subtype-associated immune gene expression patterns, we assembled 924 immune response genes and specifically those involved in T-cell cytotoxicity and the Type I/II interferon pathways. A set of 157 ranked genes was able to distinguish the four subtypes in an unsupervised analysis in an original training cohort (n=122) and an expanded, validation cohort (n=225). The most common overrepresented pathways distinguishing the four molecular subtypes, included JAK/STAT signaling, Toll-like receptor signaling, interleukin signaling, and T-cell activation. Some of the most enriched biological processes were responses to IFN-γ, antigen processing and presentation, cytokine mediated signaling, hemopoeisis, cell proliferation and cellular defense response in the TCGA cluster IV. Our novel findings provide further insights into the association between genomic subtypes and immune activation in MIBC and may open novel opportunities for their exploitation towards precise treatment with immunotherapy.

  16. Integrated Multiple "-omics" Data Reveal Subtypes of Hepatocellular Carcinoma.

    Directory of Open Access Journals (Sweden)

    Gang Liu

    Full Text Available Hepatocellular carcinoma is one of the most heterogeneous cancers, as reflected by its multiple grades and difficulty to subtype. In this study, we integrated copy number variation, DNA methylation, mRNA, and miRNA data with the developed "cluster of cluster" method and classified 256 HCC samples from TCGA (The Cancer Genome Atlas into five major subgroups (S1-S5. We observed that this classification was associated with specific mutations and protein expression, and we detected that each subgroup had distinct molecular signatures. The subclasses were associated not only with survival but also with clinical observations. S1 was characterized by bulk amplification on 8q24, TP53 mutation, low lipid metabolism, highly expressed onco-proteins, attenuated tumor suppressor proteins and a worse survival rate. S2 and S3 were characterized by telomere hypomethylation and a low expression of TERT and DNMT1/3B. Compared to S2, S3 was associated with less copy number variation and some good prognosis biomarkers, including CRP and CYP2E1. In contrast, the mutation rate of CTNNB1 was higher in S3. S4 was associated with bulk amplification and various molecular characteristics at different biological levels. In summary, we classified the HCC samples into five subgroups using multiple "-omics" data. Each subgroup had a distinct survival rate and molecular signature, which may provide information about the pathogenesis of subtypes in HCC.

  17. Identification of distinct miRNA target regulation between breast cancer molecular subtypes using AGO2-PAR-CLIP and patient datasets

    NARCIS (Netherlands)

    Farazi, Thalia A.; ten Hoeve, Jelle J.; Brown, Miguel; Mihailovic, Aleksandra; Horlings, Hugo M.; van de Vijver, Marc J.; Tuschl, Thomas; Wessels, Lodewyk F. A.

    2014-01-01

    Various microRNAs (miRNAs) are up- or downregulated in tumors. However, the repression of cognate miRNA targets responsible for the phenotypic effects of this dysregulation in patients remains largely unexplored. To define miRNA targets and associated pathways, together with their relationship to

  18. Cardiac potassium channel subtypes

    DEFF Research Database (Denmark)

    Schmitt, Nicole; Grunnet, Morten; Olesen, Søren-Peter

    2014-01-01

    . The underlying posttranscriptional and posttranslational remodeling of the individual K(+) channels changes their activity and significance relative to each other, and they must be viewed together to understand their role in keeping a stable heart rhythm, also under menacing conditions like attacks of reentry......About 10 distinct potassium channels in the heart are involved in shaping the action potential. Some of the K(+) channels are primarily responsible for early repolarization, whereas others drive late repolarization and still others are open throughout the cardiac cycle. Three main K(+) channels...... that they could constitute targets for new pharmacological treatment of atrial fibrillation. The interplay between the different K(+) channel subtypes in both atria and ventricle is dynamic, and a significant up- and downregulation occurs in disease states such as atrial fibrillation or heart failure...

  19. Zucchini tigré mosaic virus is a distinct potyvirus in the papaya ringspot virus cluster: molecular and biological insights.

    Science.gov (United States)

    Romay, G; Lecoq, H; Desbiez, C

    2014-02-01

    In recent years, three new potyviruses have been described in the papaya ringspot virus (PRSV) cluster. In addition, two types of PRSV are recognized, type W, infecting cucurbit plants, and type P, infecting papaya and also cucurbits. A third type, PRSV-T, was also partially described in Guadeloupe. Complete genome sequencing of four PRSV-T isolates showed that this virus is a related virus that is distinct from PRSV, and the name zucchini tigré mosaic virus (ZTMV) is proposed, in reference to the typical symptoms observed in zucchini squash. Eleven other viral isolates from different geographic origins were confirmed as ZTMV isolates using the complete sequence of the cylindrical inclusion (CI) coding region, whereas pairwise sequence similarities in the coat protein (CP) coding region did not unambiguously distinguish ZTMV isolates from PRSV isolates. The use of the CI coding region for species demarcation appears more suitable than the CP coding region for closely related viruses. Principal coordinates analysis based on the biological behavior of the viral isolates studied clustered PRSV-P, PRSV-W and ZTMV isolates into three different groups. Therefore, ZTMV is different from PRSV in its molecular and biological properties.

  20. Two distinct states of the HAMP domain from sensory rhodopsin transducer observed in unbiased molecular dynamics simulations.

    Directory of Open Access Journals (Sweden)

    Ivan Gushchin

    Full Text Available HAMP domain is a ubiquitous module of bacterial and archaeal two-component signaling systems. Considerable progress has been made recently in studies of its structure and conformational changes. However, the mechanism of signal transduction through the HAMP domain is not clear. It remains a question whether all the HAMPs have the same mechanism of action and what are the differences between the domains from different protein families. Here, we present the results of unbiased molecular dynamics simulations of the HAMP domain from the archaeal phototaxis signal transducer NpHtrII. Two distinct conformational states of the HAMP domain are observed, that differ in relative position of the helices AS1 and AS2. The longitudinal shift is roughly equal to a half of an α-helix turn, although sometimes it reaches one full turn. The states are closely related to the position of bulky hydrophobic aminoacids at the HAMP domain core. The observed features are in good agreement with recent experimental results and allow us to propose that the states detected in the simulations are the resting state and the signaling state of the NpHtrII HAMP domain. To the best of our knowledge, this is the first observation of the same HAMP domain in different conformations. The simulations also underline the difference between AMBER ff99-SB-ILDN and CHARMM22-CMAP forcefields, as the former favors the resting state and the latter favors the signaling state.

  1. Tumor necrosis factor-α regulates distinct molecular pathways and gene networks in cultured skeletal muscle cells.

    Directory of Open Access Journals (Sweden)

    Shephali Bhatnagar

    2010-10-01

    Full Text Available Skeletal muscle wasting is a debilitating consequence of large number of disease states and conditions. Tumor necrosis factor-α (TNF-α is one of the most important muscle-wasting cytokine, elevated levels of which cause significant muscular abnormalities. However, the underpinning molecular mechanisms by which TNF-α causes skeletal muscle wasting are less well-understood.We have used microarray, quantitative real-time PCR (QRT-PCR, Western blot, and bioinformatics tools to study the effects of TNF-α on various molecular pathways and gene networks in C2C12 cells (a mouse myoblastic cell line. Microarray analyses of C2C12 myotubes treated with TNF-α (10 ng/ml for 18h showed differential expression of a number of genes involved in distinct molecular pathways. The genes involved in nuclear factor-kappa B (NF-kappaB signaling, 26s proteasome pathway, Notch1 signaling, and chemokine networks are the most important ones affected by TNF-α. The expression of some of the genes in microarray dataset showed good correlation in independent QRT-PCR and Western blot assays. Analysis of TNF-treated myotubes showed that TNF-α augments the activity of both canonical and alternative NF-κB signaling pathways in myotubes. Bioinformatics analyses of microarray dataset revealed that TNF-α affects the activity of several important pathways including those involved in oxidative stress, hepatic fibrosis, mitochondrial dysfunction, cholesterol biosynthesis, and TGF-β signaling. Furthermore, TNF-α was found to affect the gene networks related to drug metabolism, cell cycle, cancer, neurological disease, organismal injury, and abnormalities in myotubes.TNF-α regulates the expression of multiple genes involved in various toxic pathways which may be responsible for TNF-induced muscle loss in catabolic conditions. Our study suggests that TNF-α activates both canonical and alternative NF-κB signaling pathways in a time-dependent manner in skeletal muscle cells

  2. Multi-Scale Molecular Deconstruction of the Serotonin Neuron System.

    Science.gov (United States)

    Okaty, Benjamin W; Freret, Morgan E; Rood, Benjamin D; Brust, Rachael D; Hennessy, Morgan L; deBairos, Danielle; Kim, Jun Chul; Cook, Melloni N; Dymecki, Susan M

    2015-11-18

    Serotonergic (5HT) neurons modulate diverse behaviors and physiology and are implicated in distinct clinical disorders. Corresponding diversity in 5HT neuronal phenotypes is becoming apparent and is likely rooted in molecular differences, yet a comprehensive approach characterizing molecular variation across the 5HT system is lacking, as is concomitant linkage to cellular phenotypes. Here we combine intersectional fate mapping, neuron sorting, and genome-wide RNA-seq to deconstruct the mouse 5HT system at multiple levels of granularity-from anatomy, to genetic sublineages, to single neurons. Our unbiased analyses reveal principles underlying system organization, 5HT neuron subtypes, constellations of differentially expressed genes distinguishing subtypes, and predictions of subtype-specific functions. Using electrophysiology, subtype-specific neuron silencing, and conditional gene knockout, we show that these molecularly defined 5HT neuron subtypes are functionally distinct. Collectively, this resource classifies molecular diversity across the 5HT system and discovers sertonergic subtypes, markers, organizing principles, and subtype-specific functions with potential disease relevance. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Profile of the HIV Epidemic in Cape Verde: Molecular Epidemiology and Drug Resistance Mutations among HIV-1 and HIV-2 Infected Patients from Distinct Islands of the Archipelago

    Science.gov (United States)

    de Pina-Araujo, Isabel Inês M.; Guimarães, Monick L.; Bello, Gonzalo; Vicente, Ana Carolina P.; Morgado, Mariza G.

    2014-01-01

    HIV-1 and HIV-2 have been detected in Cape Verde since 1987, but little is known regarding the genetic diversity of these viruses in this archipelago, located near the West African coast. In this study, we characterized the molecular epidemiology of HIV-1 and HIV-2 and described the occurrence of drug resistance mutations (DRM) among antiretroviral therapy naïve (ARTn) patients and patients under treatment (ARTexp) from different Cape Verde islands. Blood samples, socio-demographic and clinical-laboratory data were obtained from 221 HIV-positive individuals during 2010–2011. Phylogenetic and bootscan analyses of the pol region (1300 bp) were performed for viral subtyping. HIV-1 and HIV-2 DRM were evaluated for ARTn and ARTexp patients using the Stanford HIV Database and HIV-GRADE e.V. Algorithm Homepage, respectively. Among the 221 patients (169 [76.5%] HIV-1, 43 [19.5%] HIV-2 and 9 [4.1%] HIV-1/HIV-2 co-infections), 67% were female. The median ages were 34 (IQR = 1–75) and 47 (IQR = 12–84) for HIV-1 and HIV-2, respectively. HIV-1 infections were due to subtypes G (36.6%), CRF02_AG (30.6%), F1 (9.7%), URFs (10.4%), B (5.2%), CRF05_DF (3.0%), C (2.2%), CRF06_cpx (0.7%), CRF25_cpx (0.7%) and CRF49_cpx (0.7%), whereas all HIV-2 infections belonged to group A. Transmitted DRM (TDRM) was observed in 3.4% (2/58) of ARTn HIV-1-infected patients (1.7% NRTI, 1.7% NNRTI), but not among those with HIV-2. Among ARTexp patients, DRM was observed in 47.8% (33/69) of HIV-1 (37.7% NRTI, 37.7% NNRTI, 7.4% PI, 33.3% for two classes) and 17.6% (3/17) of HIV-2-infections (17.6% NRTI, 11.8% PI, 11.8% both). This study indicates that Cape Verde has a complex and unique HIV-1 molecular epidemiological scenario dominated by HIV-1 subtypes G, CRF02_AG and F1 and HIV-2 subtype A. The occurrence of TDRM and the relatively high level of DRM among treated patients are of concern. Continuous monitoring of patients on ART, including genotyping, are public policies to be

  4. Profile of the HIV epidemic in Cape Verde: molecular epidemiology and drug resistance mutations among HIV-1 and HIV-2 infected patients from distinct islands of the archipelago.

    Directory of Open Access Journals (Sweden)

    Isabel Inês M de Pina-Araujo

    Full Text Available HIV-1 and HIV-2 have been detected in Cape Verde since 1987, but little is known regarding the genetic diversity of these viruses in this archipelago, located near the West African coast. In this study, we characterized the molecular epidemiology of HIV-1 and HIV-2 and described the occurrence of drug resistance mutations (DRM among antiretroviral therapy naïve (ARTn patients and patients under treatment (ARTexp from different Cape Verde islands. Blood samples, socio-demographic and clinical-laboratory data were obtained from 221 HIV-positive individuals during 2010-2011. Phylogenetic and bootscan analyses of the pol region (1300 bp were performed for viral subtyping. HIV-1 and HIV-2 DRM were evaluated for ARTn and ARTexp patients using the Stanford HIV Database and HIV-GRADE e.V. Algorithm Homepage, respectively. Among the 221 patients (169 [76.5%] HIV-1, 43 [19.5%] HIV-2 and 9 [4.1%] HIV-1/HIV-2 co-infections, 67% were female. The median ages were 34 (IQR = 1-75 and 47 (IQR = 12-84 for HIV-1 and HIV-2, respectively. HIV-1 infections were due to subtypes G (36.6%, CRF02_AG (30.6%, F1 (9.7%, URFs (10.4%, B (5.2%, CRF05_DF (3.0%, C (2.2%, CRF06_cpx (0.7%, CRF25_cpx (0.7% and CRF49_cpx (0.7%, whereas all HIV-2 infections belonged to group A. Transmitted DRM (TDRM was observed in 3.4% (2/58 of ARTn HIV-1-infected patients (1.7% NRTI, 1.7% NNRTI, but not among those with HIV-2. Among ARTexp patients, DRM was observed in 47.8% (33/69 of HIV-1 (37.7% NRTI, 37.7% NNRTI, 7.4% PI, 33.3% for two classes and 17.6% (3/17 of HIV-2-infections (17.6% NRTI, 11.8% PI, 11.8% both. This study indicates that Cape Verde has a complex and unique HIV-1 molecular epidemiological scenario dominated by HIV-1 subtypes G, CRF02_AG and F1 and HIV-2 subtype A. The occurrence of TDRM and the relatively high level of DRM among treated patients are of concern. Continuous monitoring of patients on ART, including genotyping, are public policies to be implemented.

  5. Molecular cloning and in vitro evaluation of an infectious simian-human immunodeficiency virus containing env of a primary Chinese HIV-1 subtype C isolate.

    Science.gov (United States)

    Wu, YingYun; Hong, KunXue; Chenine, Agnès-Laurence; Whitney, James B; Xu, Weidong; Chen, QiMin; Geng, YunQi; Ruprecht, Ruth M; Shao, Yiming

    2005-04-01

    Human immunodeficiency virus (HIV) clade C is the most prevalent subtype and accounts for approximately 50% of all HIV infections worldwide. In China, the prevalent HIV strains are B'/C subtypes, in which the envelope belongs to subtype C. To evaluate potential AIDS vaccines targeting Chinese viral strains in non-human primate models, we constructed an infectious simian-human immunodeficiency virus (SHIV) that expresses most of the envelope of a primary HIV strain, which was isolated from a HIV-positive intravenous drug user from XinJiang province in China. The resulting chimeric SHIV-XJ02170 was infectious in human, rhesus monkey and cynomolgus monkey peripheral blood mononuclear cells (PBMC) and used CCR5 exclusively as coreceptor.

  6. Reliability of Rapid Subtyping Tools Compared to That of Phylogenetic Analysis for Characterization of Human Immunodeficiency Virus Type 1 Non-B Subtypes and Recombinant Forms▿

    OpenAIRE

    Holguín, África; López, Marisa; Soriano, Vincent

    2008-01-01

    Human immunodeficiency virus type 1 (HIV-1) subtyping is often estimated on the basis of pol sequences by using online websites instead of phylogenetic analysis (phy). We evaluated the reliability of distinct rapid subtyping tools versus phy with a large panel of HIV-1 non-B subtypes and circulating recombinant forms (CRF). pol sequences (277 protease [PR] and 171 reverse transcriptase [RT] sequences) previously assigned by phy to eight distinct HIV-1 non-B subtypes were obtained from 277 HIV...

  7. Distinct Molecular Regulation of Glycogen Synthase Kinase-3α Isozyme Controlled by Its N-terminal Region

    Science.gov (United States)

    Azoulay-Alfaguter, Inbar; Yaffe, Yakey; Licht-Murava, Avital; Urbanska, Malgorzata; Jaworski, Jacek; Pietrokovski, Shmuel; Hirschberg, Koret; Eldar-Finkelman, Hagit

    2011-01-01

    Glycogen synthase kinase-3 (GSK-3) is expressed as two isozymes α and β. They share high similarity in their catalytic domains but differ in their N- and C-terminal regions, with GSK-3α having an extended glycine-rich N terminus. Here, we undertook live cell imaging combined with molecular and bioinformatic studies to understand the distinct functions of the GSK-3 isozymes focusing on GSK-3α N-terminal region. We found that unlike GSK-3β, which shuttles between the nucleus and cytoplasm, GSK-3α was excluded from the nucleus. Deletion of the N-terminal region of GSK-3α resulted in nuclear localization, and treatment with leptomycin B resulted in GSK-3α accumulation in the nucleus. GSK-3α rapidly accumulated in the nucleus in response to calcium or serum deprivation, and accumulation was strongly inhibited by the calpain inhibitor calpeptin. This nuclear accumulation was not mediated by cleavage of the N-terminal region or phosphorylation of GSK-3α. Rather, we show that calcium-induced GSK-3α nuclear accumulation was governed by GSK-3α binding with as yet unknown calpain-sensitive protein or proteins; this binding was mediated by the N-terminal region. Bioinformatic and experimental analyses indicated that nuclear exclusion of GSK-3α was likely an exclusive characteristic of mammalian GSK-3α. Finally, we show that nuclear localization of GSK-3α reduced the nuclear pool of β-catenin and its target cyclin D1. Taken together, these data suggest that the N-terminal region of GSK-3α is responsible for its nuclear exclusion and that binding with a calcium/calpain-sensitive product enables GSK-3α nuclear retention. We further uncovered a novel link between calcium and nuclear GSK-3α-mediated inhibition of the canonical Wnt/β-catenin pathway. PMID:21266584

  8. High nitrogen fertilization and stem leaning have overlapping effects on wood formation in poplar but invoke largely distinct molecular pathways.

    Science.gov (United States)

    Pitre, Frederic E; Lafarguette, Florian; Boyle, Brian; Pavy, Nathalie; Caron, Sébastien; Dallaire, Nancy; Poulin, Pier-Luc; Ouellet, Mario; Morency, Marie-Josée; Wiebe, Nicholas; Ly Lim, Emilia; Urbain, Aurélie; Mouille, Gregory; Cooke, Janice E K; Mackay, John J

    2010-10-01

    Previous studies indicated that high nitrogen fertilization may impact secondary xylem development and alter fibre anatomy and composition. The resulting wood shares some resemblance with tension wood, which has much thicker cell walls than normal wood due to the deposition of an additional layer known as the G-layer. This report compares the short-term effects of high nitrogen fertilization and tree leaning to induce tension wood, either alone or in combination, upon wood formation in young trees of Populus trichocarpa (Torr. & Gray) × P. deltoides Bartr. ex Marsh. Fibre anatomy, chemical composition and transcript profiles were examined in newly formed secondary xylem. Each of the treatments resulted in thicker cell walls relative to the controls. High nitrogen and tree leaning had overlapping effects on chemical composition based on Fourier transform infrared analysis, specifically indicating that secondary cell wall composition was shifted in favour of cellulose and hemicelluloses relative to lignin content. In contrast, the high-nitrogen trees had shorter fibres, whilst the leaning trees had longer fibres that the controls. Microarray transcript profiling carried out after 28 days of treatment identified 180 transcripts that accumulated differentially in one or more treatments. Only 10% of differentially expressed transcripts were affected in all treatments relative to the controls. Several of the affected transcripts were related to carbohydrate metabolism, secondary cell wall formation, nitrogen metabolism and osmotic stress. RT-qPCR analyses at 1, 7 and 28 days showed that several transcripts followed very different accumulation profiles in terms of rate and level of accumulation, depending on the treatment. Our findings suggest that high nitrogen fertilization and tension wood induction elicit largely distinct and molecular pathways with partial overlap. When combined, the two types of environmental cue yielded additive effects.

  9. Single-nucleotide polymorphism typing analysis for molecular subtyping ofSalmonellaTennessee isolates associated with the 2007 nationwide peanut butter outbreak in the United States.

    Science.gov (United States)

    Dong, Hee-Jin; Cho, Seongbeom; Boxrud, David; Rankin, Shelly; Downe, Francis; Lovchik, Judith; Gibson, Jim; Erdman, Matt; Saeed, A Mahdi

    2017-01-01

    In 2007, a nationwide Salmonella Tennessee outbreak occurred via contaminated peanut butter. Here, we developed a single-nucleotide polymorphism (SNP)-typing method for S . Tennessee to determine the clonal subtypes of S . Tennessee that were associated with the peanut butter outbreak. One seventy-six S . Tennessee isolates from various sources, including humans, animals, food, and the environment, were analyzed by using the SNP technique. Eighty-four representative SNP markers were selected by comparing the sequences of three representative S . Tennessee strains with different multi-locus sequence typing and variable number tandem repeats from our collection. The set of eighty-four SNP markers showed 100% typeability for the 176 strains, with the nucleotide diversity ranging from 0.011 to 0.107 (mean = 0.049 ± 0.018, median = 0.044) for each marker. Among the four clades and nine subtypes generated by the SNP typing, subtype 1, which comprised 142 S . Tennessee strains, was the most predominant. The dominance of single-strain clones in subtype 1 revealed that S . Tennessee is highly clonal regardless of outbreak-association, source, or period of isolation, suggesting the presence of an S . Tennessee strain prototype. Notably, a minimum 18 SNP set was able to determine clonal S . Tennessee strains with similar discrimination power, potentially allowing more rapid and economic strain genotyping for both outbreaks and sporadic cases. The SNP-typing method described here might aid the investigation of the epidemiology and microevolution of pathogenic bacteria by discriminating between outbreak-related and sporadic clinical cases. In addition, this approach enables us to understand the population structure of the bacterial subtypes involved in the outbreak.

  10. Molecular analysis of human T-cell lymphotropic virus type II from Wayuu Indians of Colombia demonstrates two subtypes of HTLV-IIb.

    Science.gov (United States)

    Switzer, W M; Owen, S M; Pieniazek, D A; Nerurkar, V R; Duenas-Barajas, E; Heneine, W; Lal, R B

    1995-01-01

    Studies of the genetic heterogeneity of human T-cell lymphotropic virus type II (HTLV-II) have revealed the presence of two genetic subtypes, termed HTLV-IIa and HTLV-IIb. The HTLV-IIb subtype encodes an immunodominant epitope present at the C-terminus of the extended Tax protein and, by using an LTR-based, restriction fragment-length polymorphism (RFLP) assay, can be further classified into IIb60-IIb5, with HTLV-IIb1 (Central Amerindian-like) and HTLV-IIb5 (North Amerindian-like) being characteristic subtypes for Native American Indians. To determine the antigenic and genetic heterogeneity among HTLV-II-infected South Amerindians, we used a Tax synthetic peptide immunoassay on serum, and RFLP and phylogenetic analysis on LTR sequences amplified from genomic DNA from four Wayuu Indians of Colombia. The Wayuu specimens displayed seroreactivity to the immunodominant epitope located in the extended Tax region, as predicted, and demonstrated genetic heterogeneity by the presence of both the IIB1 (Wyu1, Zuc31) and IIb5 (Wyu2, Zuc42) subtypes sequences within separate phylogroups represented by the Guaymi Indian (IIb1) and North Amerindian (IIb5) sequences, respectively. Sequence analysis showed that major LTR regulatory motifs and the cis-acting repressive elements in the LTR RNA secondary structure were relatively conserved in both Wayuu subtypes, but the predicted secondary structure of the rex response stem loop in the Wyu2 (IIb5) LTR sequence was 45 nucleotides (nt) and 95 nt longer than that observed in the Wyu1 (IIb1) and G12.1 (IIb1) LTR sequences, respectively. These results extend our knowledge of the genetic heterogeneity of HTLV-II in South Amerindians.

  11. The Striatal Balancing Act in Drug Addiction: Distinct Roles of Direct and Indirect Pathway Medium Spiny Neurons

    Directory of Open Access Journals (Sweden)

    Mary Kay eLobo

    2011-07-01

    Full Text Available The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum. Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum’s two major subtypes of medium spiny neuron (MSN in drug addiction remained elusive. Recent advances in cell-type specific technologies, including fluorescent reporter mice, transgenic or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction.

  12. Prevention of mother-to-child HIV-1 transmission in Burkina Faso: evaluation of vertical transmission by PCR, molecular characterization of subtypes and determination of antiretroviral drugs resistance.

    Science.gov (United States)

    Sagna, Tani; Bisseye, Cyrille; Compaore, Tegewende R; Kagone, Therese S; Djigma, Florencia W; Ouermi, Djeneba; Pirkle, Catherine M; Zeba, Moctar T A; Bazie, Valerie J T; Douamba, Zoenabo; Moret, Remy; Pietra, Virginio; Koama, Adjirita; Gnoula, Charlemagne; Sia, Joseph D; Nikiema, Jean-Baptiste; Simpore, Jacques

    2015-01-01

    Vertical human immunodeficiency virus (HIV) transmission is a public health problem in Burkina Faso. The main objective of this study on the prevention of mother-to-child HIV-1 transmission was to determine the residual risk of HIV transmission in infants born to mothers receiving highly active antiretroviral therapy (HAART). Moreover, we detect HIV antiretroviral (ARV) drug resistance among mother-infant pairs and identify subtypes and circulating recombinant forms (CRF) in Burkina Faso. In this study, 3,215 samples of pregnant women were analyzed for HIV using rapid tests. Vertical transmission was estimated by polymerase chain reaction in 6-month-old infants born to women who tested HIV positive. HIV-1 resistance to ARV, subtypes, and CRFs was determined through ViroSeq kit using the ABI PRISM 3,130 sequencer. In this study, 12.26% (394/3,215) of the pregnant women were diagnosed HIV positive. There was 0.52% (2/388) overall vertical transmission of HIV, with rates of 1.75% (2/114) among mothers under prophylaxis and 0.00% (0/274) for those under HAART. Genetic mutations were also isolated that induce resistance to ARV such as M184V, Y115F, K103N, Y181C, V179E, and G190A. There were subtypes and CRF of HIV-1 present, the most common being: CRF06_CPX (58.8%), CRF02_AG (35.3%), and subtype G (5.9%). ARV drugs reduce the residual rate of HIV vertical transmission. However, the virus has developed resistance to ARV, which could limit future therapeutic options when treatment is needed. Resistance to ARV therefore requires a permanent interaction between researchers, physicians, and pharmacists, to strengthen the network of monitoring and surveillance of drug resistance in Burkina Faso.

  13. Regulation of the O-glycan-type Sialyl-Lewis X (sLex) Bio-synthesis Pathway during Cell Transformation Programs: Epithelial-Mesenchymal Transition (EMT) and Molecular Subtypes in Breast Carcinoma and Human T Cell Activation

    KAUST Repository

    AbuElela, Ayman

    2017-12-01

    During tumor progression and development of distant metastases, a subset of cancer cells undergoes transformation programs, such as epithelial-mesenchymal transition (EMT), to acquire enhanced migratory attributes to commence the metastatic cascade with the intension of achieving an active cell adhesion molecule-mediated organ-specific homing. Similarly, naive T cells reform the assemblage of their surface adhesion molecules during differentiation to activated T cells in order to successfully home to sites of inflammation and other extra-lymphoid organs for surveillance purposes. Sialyl-Lewis X (sLex) is well-known for mediating the homing of epithelial circulating tumor cellss (CTCs) and activated T cells to target sites through the interaction with endothelial selectins. Since glycan structures are not directly encoded by the genome, their expression is dependent on the glycosyltransferase (GT) expression and activity. Yet, the modulation of GTs during breast cancer transformation and in different molecular subtypes is still unknown. In addition, although the regulation of GTs during T cell activation is well-understood, the regulation at the epigenetic level is lacking. O-glycan-type sLex expression and E-selectin binding under static and flow conditions varies among molecular subtypes of breast cancer and upon the induction of EMT which is linked to the expression patterns of GTs. GTs displayed a significant prognostic value of in the association with the patients\\' survival profiles and in the ability to predict the breast cancer molecular subtypes from the expression data of a random patient sample. Also, GTs were able to differentiate between tumor and their normal counterparts as well as cancer types and glioblastoma subtypes. On the other hand, we studied the regulation of GTs in human CD4+ memory T cells compared to the naive cells at the epigenetic level. Memory T cell subsets demonstrated differential chromatin accessibility and histone marks within

  14. Ameloblastoma Phenotypes Reflected in Distinct Transcriptome Profiles

    Science.gov (United States)

    Hu, Shijia; Parker, Joel; Divaris, Kimon; Padilla, Ricardo; Murrah, Valerie; Wright, John Timothy

    2016-01-01

    Ameloblastoma is a locally invasive benign neoplasm derived from odontogenic epithelium and presents with diverse phenotypes yet to be characterized molecularly. High recurrence rates of 50–80% with conservative treatment in some sub-types warrants radical surgical resections resulting in high morbidity. The objective of the study was to characterize the transcriptome of ameloblastoma and identify relevant genes and molecular pathways using normal odontogenic tissue (human “dentome”) for comparison. Laser capture microdissection was used to obtain neoplastic epithelial tissue from 17 tumors which were examined using the Agilent 44 k whole genome microarray. Ameloblastoma separated into 2 distinct molecular clusters that were associated with pre-secretory ameloblast and odontoblast. Within the pre-secretory cluster, 9/10 of samples were of the follicular type while 6/7 of the samples in the odontoblast cluster were of the plexiform type (p ameloblastoma sub-types and have implications for the use of tailored treatment. PMID:27491308

  15. Ultrahigh pyroelectric figures of merit associated with distinct bistable dielectric phase transition in a new molecular compound: di-n-butylaminium trifluoroacetate.

    Science.gov (United States)

    Sun, Zhihua; Tang, Yuanyuan; Zhang, Shuquan; Ji, Chengmin; Chen, Tianliang; Luo, Junhua

    2015-08-26

    Ultrahigh pyroelectric figures of merit are achieved in a new phase-transition material, di-n-butylaminium trifluoroacetate, of which the peak values are an order of magnitude larger than those of their inorganic counterparts. Such an attractive behavior of pyroelectric detectivity is strongly related to its distinct bistable dielectric behavior, which recalls excellent thermoelectric response in organic molecular phase-transition systems. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. A mathematical prediction model incorporating molecular subtype for risk of non-sentinel lymph node metastasis in sentinel lymph node-positive breast cancer patients: a retrospective analysis and nomogram development.

    Science.gov (United States)

    Wang, Na-Na; Yang, Zheng-Jun; Wang, Xue; Chen, Li-Xuan; Zhao, Hong-Meng; Cao, Wen-Feng; Zhang, Bin

    2018-04-25

    Molecular subtype of breast cancer is associated with sentinel lymph node status. We sought to establish a mathematical prediction model that included breast cancer molecular subtype for risk of positive non-sentinel lymph nodes in breast cancer patients with sentinel lymph node metastasis and further validate the model in a separate validation cohort. We reviewed the clinicopathologic data of breast cancer patients with sentinel lymph node metastasis who underwent axillary lymph node dissection between June 16, 2014 and November 16, 2017 at our hospital. Sentinel lymph node biopsy was performed and patients with pathologically proven sentinel lymph node metastasis underwent axillary lymph node dissection. Independent risks for non-sentinel lymph node metastasis were assessed in a training cohort by multivariate analysis and incorporated into a mathematical prediction model. The model was further validated in a separate validation cohort, and a nomogram was developed and evaluated for diagnostic performance in predicting the risk of non-sentinel lymph node metastasis. Moreover, we assessed the performance of five different models in predicting non-sentinel lymph node metastasis in training cohort. Totally, 495 cases were eligible for the study, including 291 patients in the training cohort and 204 in the validation cohort. Non-sentinel lymph node metastasis was observed in 33.3% (97/291) patients in the training cohort. The AUC of MSKCC, Tenon, MDA, Ljubljana, and Louisville models in training cohort were 0.7613, 0.7142, 0.7076, 0.7483, and 0.671, respectively. Multivariate regression analysis indicated that tumor size (OR = 1.439; 95% CI 1.025-2.021; P = 0.036), sentinel lymph node macro-metastasis versus micro-metastasis (OR = 5.063; 95% CI 1.111-23.074; P = 0.036), the number of positive sentinel lymph nodes (OR = 2.583, 95% CI 1.714-3.892; P model based on the results of multivariate analysis was established to predict the risk of non

  17. Identification of Personalized Chemoresistance Genes in Subtypes of Basal-Like Breast Cancer Based on Functional Differences Using Pathway Analysis.

    Directory of Open Access Journals (Sweden)

    Tong Wu

    Full Text Available Breast cancer is a highly heterogeneous disease that is clinically classified into several subtypes. Among these subtypes, basal-like breast cancer largely overlaps with triple-negative breast cancer (TNBC, and these two groups are generally studied together as a single entity. Differences in the molecular makeup of breast cancers can result in different treatment strategies and prognoses for patients with different breast cancer subtypes. Compared with other subtypes, basal-like and other ER+ breast cancer subtypes exhibit marked differences in etiologic factors, clinical characteristics and therapeutic potential. Anthracycline drugs are typically used as the first-line clinical treatment for basal-like breast cancer subtypes. However, certain patients develop drug resistance following chemotherapy, which can lead to disease relapse and death. Even among patients with basal-like breast cancer, there can be significant molecular differences, and it is difficult to identify specific drug resistance proteins in any given patient using conventional variance testing methods. Therefore, we designed a new method for identifying drug resistance genes. Subgroups, personalized biomarkers, and therapy targets were identified using cluster analysis of differentially expressed genes. We found that basal-like breast cancer could be further divided into at least four distinct subgroups, including two groups at risk for drug resistance and two groups characterized by sensitivity to pharmacotherapy. Based on functional differences among these subgroups, we identified nine biomarkers related to drug resistance: SYK, LCK, GAB2, PAWR, PPARG, MDFI, ZAP70, CIITA and ACTA1. Finally, based on the deviation scores of the examined pathways, 16 pathways were shown to exhibit varying degrees of abnormality in the various subgroups, indicating that patients with different subtypes of basal-like breast cancer can be characterized by differences in the functional status of

  18. A Novel and Lethal De Novo LQT-3 Mutation in a Newborn with Distinct Molecular Pharmacology and Therapeutic Response

    Science.gov (United States)

    Chung, Wendy; Spyres, Meghan; Pass, Robert H.; Silver, Eric; Sampson, Kevin J.; Kass, Robert S.

    2007-01-01

    Background SCN5A encodes the α-subunit (Nav1.5) of the principle Na+ channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS) variant 3 (LQT-3) in adults by disrupting inactivation of the Nav1.5 channel. Pharmacological targeting of mutation-altered Na+ channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS) and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults. Methods and Results Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C) discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na+ channel blockers flecainide and mexiletine. Our goal was to determine the Na+ channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na+ channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C) and a common variant in KCNH2 (K897T). Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na+ channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically. Significance The results of our study provide further evidence of the grave vulnerability of newborns to Na+ channel defects and suggest that both genetic background

  19. A novel and lethal de novo LQT-3 mutation in a newborn with distinct molecular pharmacology and therapeutic response.

    Directory of Open Access Journals (Sweden)

    John R Bankston

    2007-12-01

    Full Text Available SCN5A encodes the alpha-subunit (Na(v1.5 of the principle Na(+ channel in the human heart. Genetic lesions in SCN5A can cause congenital long QT syndrome (LQTS variant 3 (LQT-3 in adults by disrupting inactivation of the Na(v1.5 channel. Pharmacological targeting of mutation-altered Na(+ channels has proven promising in developing a gene-specific therapeutic strategy to manage specifically this LQTS variant. SCN5A mutations that cause similar channel dysfunction may also contribute to sudden infant death syndrome (SIDS and other arrhythmias in newborns, but the prevalence, impact, and therapeutic management of SCN5A mutations may be distinct in infants compared with adults.Here, in a multidisciplinary approach, we report a de novo SCN5A mutation (F1473C discovered in a newborn presenting with extreme QT prolongation and differential responses to the Na(+ channel blockers flecainide and mexiletine. Our goal was to determine the Na(+ channel phenotype caused by this severe mutation and to determine whether distinct effects of different Na(+ channel blockers on mutant channel activity provide a mechanistic understanding of the distinct therapeutic responsiveness of the mutation carrier. Sequence analysis of the proband revealed the novel missense SCN5A mutation (F1473C and a common variant in KCNH2 (K897T. Patch clamp analysis of HEK 293 cells transiently transfected with wild-type or mutant Na(+ channels revealed significant changes in channel biophysics, all contributing to the proband's phenotype as predicted by in silico modeling. Furthermore, subtle differences in drug action were detected in correcting mutant channel activity that, together with both the known genetic background and age of the patient, contribute to the distinct therapeutic responses observed clinically.The results of our study provide further evidence of the grave vulnerability of newborns to Na(+ channel defects and suggest that both genetic background and age are

  20. Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis.

    Science.gov (United States)

    Azzoni, Cinzia; Bottarelli, Lorena; Campanini, Nicoletta; Di Cola, Gabriella; Bader, Giovanni; Mazzeo, Antonio; Salvemini, Carlo; Morari, Silvia; Di Mauro, Davide; Donadei, Enrico; Roncoroni, Luigi; Bordi, Cesare; Sarli, Leopoldo

    2007-02-01

    Colorectal cancer (CRC) ranks as the fourth most frequently diagnosed cancer worldwide. CRCs that arise proximally or distally to the splenic flexure show differences in epidemiologic incidence, morphology, and molecular alterations, suggesting the existence of two categories of CRC based on the site of origin. The aim of the present work is to investigate the histological and molecular differences between CRCs located proximally and distally to the splenic flexure, and their potential involvement in tumor prognosis and therapeutic strategies. We evaluated 120 patients affected by sporadic CRC for clinicopathologic features, microsatellite instability (MSI), loss of heterozygosity (LOH) of chromosomes 18q, 8p, and 4p; they were also investigated for hMlh1, hMsh2, Fhit, p27, and Cox-2 immunostaining. The mucinous histotype was more frequent in the proximal than in the distal CRCs (pcancer development between the proximal and the distal colon, with potential implications in the therapeutic approach.

  1. Phenotypic and Molecular Evidence Suggest That Decrements in Morning and Evening Energy Are Distinct But Related Symptoms

    Science.gov (United States)

    Aouizerat, Bradley E.; Dhruva, Anand; Paul, Steven M.; Cooper, Bruce A.; Kober, Kord M.; Miaskowski, Christine

    2015-01-01

    Context Little is known about energy levels in oncology patients and their family caregivers (FCs). Objectives This study sought to identify latent classes of participants, based on self-reported energy levels and to evaluate for differences in phenotypic and genotypic characteristics between these classes. Methods Energy subscale scores from the Lee Fatigue Scale were used to determine latent class membership. Morning and evening energy scores were obtained just prior to, during, and for four months following the completion of radiation therapy. Genetic associations were evaluated for fifteen pro- and anti-inflammatory cytokine genes. Results Two latent classes with distinct morning energy trajectories were identified. Participants who were younger, female, not married/partnered, Black, and had more comorbidities, and a lower functional status were more likely to be in the Low Morning Energy class. Two polymorphisms (IL2 rs1479923, NFKB1 rs4648110) were associated with morning energy latent class membership. Two latent classes with distinct evening energy trajectories were identified. Participants who were younger and male and who had more comorbidities, decreased body weight, and a lower functional status were more likely to be in the Moderate Evening Energy class. Five different polymorphisms (IL1R2 rs4141134, IL6 rs4719714, IL17A rs8193036, NFKB2 rs1056890, TNFA rs1800683) were associated with evening energy latent class membership. Conclusion This study provides preliminary evidence that decrements in morning and evening energy are associated with different phenotypic risk factors as well as cytokine gene variations. PMID:26031709

  2. The Dual Edema-Preventing Molecular Mechanism of the Crataegus Extract WS 1442 Can Be Assigned to Distinct Phytochemical Fractions.

    Science.gov (United States)

    Fuchs, Simone; Bischoff, Iris; Willer, Elisabeth A; Bräutigam, Jacqueline; Bubik, Martin F; Erdelmeier, Clemens A J; Koch, Egon; Faleschini, Maria T; De Mieri, Maria; Bauhart, Milena; Zahler, Stefan; Hensel, Andreas; Hamburger, Matthias; Potterat, Olivier; Fürst, Robert

    2017-05-01

    The hawthorn ( Crataegus spp.) extract WS 1442 is used against mild forms of chronic heart failure. This disease is associated with endothelial barrier dysfunction and edema formation. We have recently shown that WS 1442 protects against this dysfunction by a dual mechanism: it both promotes endothelial barrier integrity by activation of a barrier-enhancing pathway (cortactin activation) and inhibits endothelial hyperpermeability by blocking a barrier disruptive pathway (calcium signaling). In this study, we aimed to identify the bioactive compounds responsible for these actions by using a bioactivity-guided fractionation approach. From the four fractions generated from WS 1442 by successive elution with water, 95 % ethanol, methanol, and 70 % acetone, only the water fraction was inactive, whereas the other three triggered a reduction of endothelial hyperpermeability. Analyses of intracellular calcium levels and cortactin phosphorylation were used as readouts to estimate the bioactivity of subfractions and isolated compounds. Interestingly, only the ethanolic fraction interfered with the calcium signaling, whereas only the methanolic fraction led to an activation of cortactin. Thus, the dual mode of action of WS 1442 could be clearly assigned to two distinct fractions. Although the identification of the calcium-active substance(s) was not successful, we could exclude an involvement of phenolic compounds. Cortactin activation, however, could be clearly attributed to oligomeric procyanidins with a distinct degree of polymerization. Taken together, our study provides the first approach to identify the active constituents of WS 1442 that address different cellular pathways leading to the inhibition of endothelial barrier dysfunction. Georg Thieme Verlag KG Stuttgart · New York.

  3. CAsubtype: An R Package to Identify Gene Sets Predictive of Cancer Subtypes and Clinical Outcomes.

    Science.gov (United States)

    Kong, Hualei; Tong, Pan; Zhao, Xiaodong; Sun, Jielin; Li, Hua

    2018-03-01

    In the past decade, molecular classification of cancer has gained high popularity owing to its high predictive power on clinical outcomes as compared with traditional methods commonly used in clinical practice. In particular, using gene expression profiles, recent studies have successfully identified a number of gene sets for the delineation of cancer subtypes that are associated with distinct prognosis. However, identification of such gene sets remains a laborious task due to the lack of tools with flexibility, integration and ease of use. To reduce the burden, we have developed an R package, CAsubtype, to efficiently identify gene sets predictive of cancer subtypes and clinical outcomes. By integrating more than 13,000 annotated gene sets, CAsubtype provides a comprehensive repertoire of candidates for new cancer subtype identification. For easy data access, CAsubtype further includes the gene expression and clinical data of more than 2000 cancer patients from TCGA. CAsubtype first employs principal component analysis to identify gene sets (from user-provided or package-integrated ones) with robust principal components representing significantly large variation between cancer samples. Based on these principal components, CAsubtype visualizes the sample distribution in low-dimensional space for better understanding of the distinction between samples and classifies samples into subgroups with prevalent clustering algorithms. Finally, CAsubtype performs survival analysis to compare the clinical outcomes between the identified subgroups, assessing their clinical value as potentially novel cancer subtypes. In conclusion, CAsubtype is a flexible and well-integrated tool in the R environment to identify gene sets for cancer subtype identification and clinical outcome prediction. Its simple R commands and comprehensive data sets enable efficient examination of the clinical value of any given gene set, thus facilitating hypothesis generating and testing in biological and

  4. MORPHOMETRIC SUBTYPING FOR A PANEL OF BREAST CANCER CELL LINES

    Energy Technology Data Exchange (ETDEWEB)

    Han, Ju; Chang, Hang; Fontenay, Gerald; Wang, Nicholas J.; Gray, Joe W.; Parvin, Bahram

    2009-05-08

    A panel of cell lines of diverse molecular background offers an improved model system for high-content screening, comparative analysis, and cell systems biology. A computational pipeline has been developed to collect images from cell-based assays, segment individual cells and colonies, represent segmented objects in a multidimensional space, and cluster them for identifying distinct subpopulations. While each segmentation strategy can vary for different imaging assays, representation and subpopulation analysis share a common thread. Application of this pipeline to a library of 41 breast cancer cell lines is demonstrated. These cell lines are grown in 2D and imaged through immunofluorescence microscopy. Subpopulations in this panel are identified and shown to correlate with previous subtyping literature that was derived from transcript data.

  5. Salmonella source attribution based on microbial subtyping

    DEFF Research Database (Denmark)

    Barco, Lisa; Barrucci, Federica; Olsen, John Elmerdahl

    2013-01-01

    Source attribution of cases of food-borne disease represents a valuable tool for identifying and prioritizing effective food-safety interventions. Microbial subtyping is one of the most common methods to infer potential sources of human food-borne infections. So far, Salmonella microbial subtyping...... source attribution through microbial subtyping approach. It summarizes the available microbial subtyping attribution models and discusses the use of conventional phenotypic typing methods, as well as of the most commonly applied molecular typing methods in the European Union (EU) laboratories...

  6. Hepatitis E virus subtype 3f strains isolated from Japanese hepatitis patients with no history of travel to endemic areas - The origin analyzed by molecular evolution.

    Science.gov (United States)

    Nakano, Tatsunori; Takahashi, Masaharu; Takahashi, Kazuaki; Nagashima, Shigeo; Suzuki, Yusuke; Nishigaki, Yoichi; Tomita, Eiichi; Okano, Hiroshi; Oya, Yumi; Shiraki, Katsuya; Takase, Kojiro; Sugimoto, Kazushi; Koyama, Junichi; Mizuo, Hitoshi; Ikezawa, Kazuto; Aikawa, Tatsuya; Arai, Masahiro; Okamoto, Hiroaki

    2018-01-01

    Hepatitis E virus subtype 3f (HEV-3f) strains are usually isolated in Europe and Thailand. Recently, HEV-3f strains were detected from six acute hepatitis E patients in Japan, none of whom had a history of travel to endemic areas. We inferred the origin and transmission route of the six HEV-3f strains. A time-scaled phylogenetic tree of the six strains with reference strains was constructed using a Bayesian statistical inference framework. The time-scaled tree indicated that the six strains independently derived from similar European strains between 2008 and 2014. The pattern suggested recent inflow of multiple HEV-3f strains from Europe to Japan. Japan imports a substantial amount of pork from European countries every year. The emergence of acute hepatitis cases caused by HEV-3f strains in Japan, in patients with no history of travel abroad, might be influenced by the increased opportunities to consume pork products imported from European countries. Copyright © 2017. Published by Elsevier Inc.

  7. Distinctive molecular and biochemical characteristics of a glycoside hydrolase family 20 β-N-acetylglucosaminidase and salt tolerance.

    Science.gov (United States)

    Zhou, Junpei; Song, Zhifeng; Zhang, Rui; Liu, Rui; Wu, Qian; Li, Junjun; Tang, Xianghua; Xu, Bo; Ding, Junmei; Han, Nanyu; Huang, Zunxi

    2017-04-11

    Enzymatic degradation of chitin has attracted substantial attention because chitin is an abundant renewable natural resource, second only to lignocellulose, and because of the promising applications of N-acetylglucosamine in the bioethanol, food and pharmaceutical industries. However, the low activity and poor tolerance to salts and N-acetylglucosamine of most reported β-N-acetylglucosaminidases limit their applications. Mining for novel enzymes from new microorganisms is one way to address this problem. A glycoside hydrolase family 20 (GH 20) β-N-acetylglucosaminidase (GlcNAcase) was identified from Microbacterium sp. HJ5 harboured in the saline soil of an abandoned salt mine and was expressed in Escherichia coli. The purified recombinant enzyme showed specific activities of 1773.1 ± 1.1 and 481.4 ± 2.3 μmol min -1 mg -1 towards p-nitrophenyl β-N-acetylglucosaminide and N,N'-diacetyl chitobiose, respectively, a V max of 3097 ± 124 μmol min -1 mg -1 towards p-nitrophenyl β-N-acetylglucosaminide and a K i of 14.59 mM for N-acetylglucosamine inhibition. Most metal ions and chemical reagents at final concentrations of 1.0 and 10.0 mM or 0.5 and 1.0% (v/v) had little or no effect (retaining 84.5 - 131.5% activity) on the enzyme activity. The enzyme can retain more than 53.6% activity and good stability in 3.0-20.0% (w/v) NaCl. Compared with most GlcNAcases, the activity of the enzyme is considerably higher and the tolerance to salts and N-acetylglucosamine is much better. Furthermore, the enzyme had higher proportions of aspartic acid, glutamic acid, alanine, glycine, random coils and negatively charged surfaces but lower proportions of cysteine, lysine, α-helices and positively charged surfaces than its homologs. These molecular characteristics were hypothesised as potential factors in the adaptation for salt tolerance and high activity of the GH 20 GlcNAcase. Biochemical characterization revealed that the GlcNAcase had novel salt

  8. Dissecting molecular events in thyroid neoplasia provides evidence for distinct evolution of follicular thyroid adenoma and carcinoma.

    Science.gov (United States)

    Krause, Kerstin; Prawitt, Susanne; Eszlinger, Markus; Ihling, Christian; Sinz, Andrea; Schierle, Katrin; Gimm, Oliver; Dralle, Henning; Steinert, Frank; Sheu, Sien-Yi; Schmid, Kurt W; Fuhrer, Dagmar

    2011-12-01

    Benign hypofunctional cold thyroid nodules (CTNs) are a frequent scintiscan finding and need to be distinguished from thyroid carcinomas. The origin of CTNs with follicular morphologic features is unresolved. The DNA damage response might act as a physiologic barrier, inhibiting the progression of preneoplastic lesions to neoplasia. We investigated the following in hypofunctional follicular adenoma (FA) and follicular thyroid cancer (FTC): i) the mutation rate of frequently activated oncogenes, ii) the activation of DNA damage response checkpoints, and iii) the differential proteomic pattern between FA and FTC. Both FTC and FA, which did not harbor RAS, phosphoinositide-3-kinase, or PAX/peroxisome proliferator activated receptor-γ mutations, express various proteins in common and others that are more distinctly expressed in FTC rather than in FA or normal thyroid tissue. This finding is in line with the finding of constitutive DNA damage checkpoint activation (p-Chk2, γ-H2AX) and evidence for replicative stress causing genomic instability (increased cyclin E, retinoblastoma, or E2F1 mRNA expression) in FTC but not FA. We discuss the findings of the increased expression of translationally controlled tumor protein, phosphatase 2A inhibitor, and DJ-1 in FTC compared with FA identified by proteomics and their potential implication in follicular thyroid carcinogenesis. Our present findings argue for the definition of FA as a truly benign entity and against progressive development of FA to FTC. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  9. Identification of neural transcription factors required for the differentiation of three neuronal subtypes in the sea urchin embryo.

    Science.gov (United States)

    Slota, Leslie A; McClay, David R

    2018-01-10

    Correct patterning of the nervous system is essential for an organism's survival and complex behavior. Embryologists have used the sea urchin as a model for decades, but our understanding of sea urchin nervous system patterning is incomplete. Previous histochemical studies identified multiple neurotransmitters in the pluteus larvae of several sea urchin species. However, little is known about how, where and when neural subtypes are differentially specified during development. Here, we examine the molecular mechanisms of neuronal subtype specification in 3 distinct neural subtypes in the Lytechinus variegatus larva. We show that these subtypes are specified through Delta/Notch signaling and identify a different transcription factor required for the development of each neural subtype. Our results show achaete-scute and neurogenin are proneural for the serotonergic neurons of the apical organ and cholinergic neurons of the ciliary band, respectively. We also show that orthopedia is not proneural but is necessary for the differentiation of the cholinergic/catecholaminergic postoral neurons. Interestingly, these transcription factors are used similarly during vertebrate neurogenesis. We believe this study is a starting point for building a neural gene regulatory network in the sea urchin and for finding conserved deuterostome neurogenic mechanisms. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Value of Breast Cancer Molecular Subtypes and Ki67 Expression for the Prediction of Efficacy and Prognosis of Neoadjuvant Chemotherapy in a Chinese Population.

    Science.gov (United States)

    Wang, Jiayu; Sang, Die; Xu, Binghe; Yuan, Peng; Ma, Fei; Luo, Yang; Li, Qing; Zhang, Pin; Cai, Ruigang; Fan, Ying; Chen, Shanshan; Li, Qiao

    2016-05-01

    The aim of the study was to determine the predictive role of breast cancer subtypes in the efficacy and prognosis of neoadjuvant chemotherapy (NCT) regimens combining taxanes and anthracyclines.Data from 240 patients with breast cancer who received surgery after 4 to 6 weeks of NCT were retrospectively analyzed. The patients were classified into luminal A, luminal B, HER2 overexpression, and triple negative breast cancer (TNBC) as well as low Ki67 (≤ 14%) and high Ki67 (> 14%) expression groups using immunohistochemistry. NCT outcome parameters were pathological complete response (pCR), clinical complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) 4 weeks after surgery. Long-term outcome parameters were disease-free survival (DFS) with a follow-up time of 3 to 56 months.pCR rates were 1.6%, 13.4%, 22.6%, and 23.8% in patients with luminal A, luminal B, HER2, and TNBC cancers, respectively. High pCR rates correlated with high Ki67 expression (> 40%) (P breast cancer was the highest compared to all other groups, but only significantly higher compared to luminal B (P = 0.035, HR = 1.480, 95% CI: 1.060-1.967) patients and correlated with Ki67 expression > 40% (P = 0.005).Luminal A type patients derived the least benefit from neoadjuvant chemotherapy but had better long-term prognoses. ER status and Ki67 expression served as efficacy predictors for NCT, whereas only Ki67 expression > 40% correlated with long-term treatment outcomes.

  11. Pan-cancer subtyping in a 2D-map shows substructures that are driven by specific combinations of molecular characteristics

    NARCIS (Netherlands)

    Taskesen, E.; Huisman, S.M.H.; Mahfouz, A.M.E.T.A.; Krijthe, J.H.; de Ridder, J.; van de Stolpe, A; van den Akker, E.B.; Verhaegh, Wim; Reinders, M.J.T.

    2016-01-01

    The use of genome-wide data in cancer research, for the identification of groups of patients with similar molecular characteristics, has become a standard approach for applications in therapy-response, prognosis-prediction, and drug-development. To progress in these applications, the trend is to

  12. Distinct high molecular weight organic compound (HMW-OC) types in aerosol particles collected at a coastal urban site

    Science.gov (United States)

    Dall'Osto, M.; Healy, R. M.; Wenger, J. C.; O'Dowd, C.; Ovadnevaite, J.; Ceburnis, D.; Harrison, Roy M.; Beddows, D. C. S.

    2017-12-01

    Organic oligomers were discovered in laboratory-generated atmospheric aerosol over a decade ago. However, evidence for the presence of oligomers in ambient aerosols is scarce and mechanisms for their formation have yet to be fully elucidated. In this work, three unique aerosol particle types internally mixed with High molecular weight organic compounds (HMW-OC) species - likely oligomers - were detected in ambient air using single particle Aerosol Time-Of-Flight Mass Spectrometry (ATOFMS) in Cork (Ireland) during winter 2009. These particle types can be described as follows: (1) HMW-OCs rich in organic nitrogen - possibly containing nitrocatechols and nitroguaiacols - originating from primary emissions of biomass burning particles during evening times; (2) HMW-OCs internally mixed with nitric acid, occurring in stagnant conditions during night time; and (3) HMW-OCs internally mixed with sea salt, likely formed via photochemical reactions during day time. The study exemplifies the power of methodologies capable of monitoring the simultaneous formation of organic and inorganic particle-phase reaction products. Primary emissions and atmospheric aging of different types of HMW-OC contributes to aerosol with a range of acidity, hygroscopic and optical properties, which can have different impacts on climate and health.

  13. Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Manesia, Javed K; Franch, Monica; Tabas-Madrid, Daniel; Nogales-Cadenas, Ruben; Vanwelden, Thomas; Van Den Bosch, Elisa; Xu, Zhuofei; Pascual-Montano, Alberto; Khurana, Satish; Verfaillie, Catherine M

    2017-04-15

    During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function.

  14. Histone modification profiling in breast cancer cell lines highlights commonalities and differences among subtypes.

    Science.gov (United States)

    Xi, Yuanxin; Shi, Jiejun; Li, Wenqian; Tanaka, Kaori; Allton, Kendra L; Richardson, Dana; Li, Jing; Franco, Hector L; Nagari, Anusha; Malladi, Venkat S; Coletta, Luis Della; Simper, Melissa S; Keyomarsi, Khandan; Shen, Jianjun; Bedford, Mark T; Shi, Xiaobing; Barton, Michelle C; Lee Kraus, W; Li, Wei; Dent, Sharon Y R

    2018-02-20

    Epigenetic regulators are frequently mutated or aberrantly expressed in a variety of cancers, leading to altered transcription states that result in changes in cell identity, behavior, and response to therapy. To define alterations in epigenetic landscapes in breast cancers, we profiled the distributions of 8 key histone modifications by ChIP-Seq, as well as primary (GRO-seq) and steady state (RNA-Seq) transcriptomes, across 13 distinct cell lines that represent 5 molecular subtypes of breast cancer and immortalized human mammary epithelial cells. Using combinatorial patterns of distinct histone modification signals, we defined subtype-specific chromatin signatures to nominate potential biomarkers. This approach identified AFAP1-AS1 as a triple negative breast cancer-specific gene associated with cell proliferation and epithelial-mesenchymal-transition. In addition, our chromatin mapping data in basal TNBC cell lines are consistent with gene expression patterns in TCGA that indicate decreased activity of the androgen receptor pathway but increased activity of the vitamin D biosynthesis pathway. Together, these datasets provide a comprehensive resource for histone modification profiles that define epigenetic landscapes and reveal key chromatin signatures in breast cancer cell line subtypes with potential to identify novel and actionable targets for treatment.

  15. Community structure analysis of transcriptional networks reveals distinct molecular pathways for early- and late-onset temporal lobe epilepsy with childhood febrile seizures.

    Directory of Open Access Journals (Sweden)

    Carlos Alberto Moreira-Filho

    Full Text Available Age at epilepsy onset has a broad impact on brain plasticity and epilepsy pathomechanisms. Prolonged febrile seizures in early childhood (FS constitute an initial precipitating insult (IPI commonly associated with mesial temporal lobe epilepsy (MTLE. FS-MTLE patients may have early disease onset, i.e. just after the IPI, in early childhood, or late-onset, ranging from mid-adolescence to early adult life. The mechanisms governing early (E or late (L disease onset are largely unknown. In order to unveil the molecular pathways underlying E and L subtypes of FS-MTLE we investigated global gene expression in hippocampal CA3 explants of FS-MTLE patients submitted to hippocampectomy. Gene coexpression networks (GCNs were obtained for the E and L patient groups. A network-based approach for GCN analysis was employed allowing: i the visualization and analysis of differentially expressed (DE and complete (CO - all valid GO annotated transcripts - GCNs for the E and L groups; ii the study of interactions between all the system's constituents based on community detection and coarse-grained community structure methods. We found that the E-DE communities with strongest connection weights harbor highly connected genes mainly related to neural excitability and febrile seizures, whereas in L-DE communities these genes are not only involved in network excitability but also playing roles in other epilepsy-related processes. Inversely, in E-CO the strongly connected communities are related to compensatory pathways (seizure inhibition, neuronal survival and responses to stress conditions while in L-CO these communities harbor several genes related to pro-epileptic effects, seizure-related mechanisms and vulnerability to epilepsy. These results fit the concept, based on fMRI and behavioral studies, that early onset epilepsies, although impacting more severely the hippocampus, are associated to compensatory mechanisms, while in late MTLE development the brain is less

  16. Relationship between Self-Typicality and the In-Group Subtypes Effect.

    Science.gov (United States)

    Wallace, David S.; And Others

    1995-01-01

    Examined whether group members differ in the number of in-group subtype distinctions that they draw. Drawing on results of two studies, found that members of groups whose primary function is intragroup interaction (fraternities, sororities, athletic teams) draw more subtype distinctions within their own group than within other groups. (RJM)

  17. Particle infectivity of HIV-1 full-length genome infectious molecular clones in a subtype C heterosexual transmission pair following high fidelity amplification and unbiased cloning

    OpenAIRE

    Deymier, Martin J.; Claiborne, Daniel T.; Ende, Zachary; Ratner, Hannah K.; Kilembe, William; Allen, Susan; Hunter, Eric

    2014-01-01

    The high genetic diversity of HIV-1 impedes high throughput, large-scale sequencing and full-length genome cloning by common restriction enzyme based methods. Applying novel methods that employ a high-fidelity polymerase for amplification and an unbiased fusion-based cloning strategy, we have generated several HIV-1 full-length genome infectious molecular clones from an epidemiologically linked transmission pair. These clones represent the transmitted/founder virus and phylogenetically divers...

  18. Morphological and Molecular Data Reveal Three Distinct Populations of Indian Wild Rice Oryza rufipogon Griff. Species Complex

    Science.gov (United States)

    Singh, Balwant; Singh, Nisha; Mishra, Shefali; Tripathi, Kabita; Singh, Bikram P.; Rai, Vandna; Singh, Ashok K.; Singh, Nagendra K.

    2018-01-01

    Wild relatives of crops possess adaptive mutations for agronomically important traits, which could play significant role in crop improvement for sustainable agriculture. However, global climate change and human activities pose serious threats to the natural habitats leading to erosion of genetic diversity of wild rice populations. The purpose of this study was to explore and characterize India’s huge untapped wild rice diversity in Oryza rufipogon Griff. species complex from a wide range of ecological niches. We made strategic expeditions around diversity hot spots in 64 districts of nine different agro-climatic zones of the country and collected 418 wild rice accessions. Significant variation was observed among the accessions for 46 morphological descriptors, allowing classification into O. nivara, O. rufipogon, and O. sativa f. spontanea morpho-taxonomic groups. Genome-specific pSINE1 markers confirmed all the accessions having AA genome, which were further classified using ecotype-specific pSINE1 markers into annual, perennial, intermediate, and an unknown type. Principal component analysis revealed continuous variation for the morphological traits in each ecotype group. Genetic diversity analysis based on multi-allelic SSR markers clustered these accessions into three major groups and analysis of molecular variance for nine agro-climatic zones showed that 68% of the genetic variation was inherent amongst individuals while only 11% of the variation separated the zones, though there was significant correlation between genetic and spatial distances of the accessions. Model based population structure analysis using genome wide bi-allelic SNP markers revealed three sub-populations designated ‘Pro-Indica,’ ‘Pro-Aus,’ and ‘Mid-Gangetic,’ which showed poor correspondence with the morpho-taxonomic classification or pSINE1 ecotypes. There was Pan-India distribution of the ‘Pro-Indica’ and ‘Pro-Aus’ sub-populations across agro-climatic zones

  19. Morphological and Molecular Data Reveal Three Distinct Populations of Indian Wild Rice Oryza rufipogon Griff. Species Complex

    Directory of Open Access Journals (Sweden)

    Balwant Singh

    2018-02-01

    Full Text Available Wild relatives of crops possess adaptive mutations for agronomically important traits, which could play significant role in crop improvement for sustainable agriculture. However, global climate change and human activities pose serious threats to the natural habitats leading to erosion of genetic diversity of wild rice populations. The purpose of this study was to explore and characterize India’s huge untapped wild rice diversity in Oryza rufipogon Griff. species complex from a wide range of ecological niches. We made strategic expeditions around diversity hot spots in 64 districts of nine different agro-climatic zones of the country and collected 418 wild rice accessions. Significant variation was observed among the accessions for 46 morphological descriptors, allowing classification into O. nivara, O. rufipogon, and O. sativa f. spontanea morpho-taxonomic groups. Genome-specific pSINE1 markers confirmed all the accessions having AA genome, which were further classified using ecotype-specific pSINE1 markers into annual, perennial, intermediate, and an unknown type. Principal component analysis revealed continuous variation for the morphological traits in each ecotype group. Genetic diversity analysis based on multi-allelic SSR markers clustered these accessions into three major groups and analysis of molecular variance for nine agro-climatic zones showed that 68% of the genetic variation was inherent amongst individuals while only 11% of the variation separated the zones, though there was significant correlation between genetic and spatial distances of the accessions. Model based population structure analysis using genome wide bi-allelic SNP markers revealed three sub-populations designated ‘Pro-Indica,’ ‘Pro-Aus,’ and ‘Mid-Gangetic,’ which showed poor correspondence with the morpho-taxonomic classification or pSINE1 ecotypes. There was Pan-India distribution of the ‘Pro-Indica’ and ‘Pro-Aus’ sub-populations across agro

  20. Molecular Surface of JZTX-V (β-Theraphotoxin-Cj2a Interacting with Voltage-Gated Sodium Channel Subtype NaV1.4

    Directory of Open Access Journals (Sweden)

    Ji Luo

    2014-07-01

    Full Text Available Voltage-gated sodium channels (VGSCs; NaV1.1–NaV1.9 have been proven to be critical in controlling the function of excitable cells, and human genetic evidence shows that aberrant function of these channels causes channelopathies, including epilepsy, arrhythmia, paralytic myotonia, and pain. The effects of peptide toxins, especially those isolated from spider venom, have shed light on the structure–function relationship of these channels. However, most of these toxins have not been analyzed in detail. In particular, the bioactive faces of these toxins have not been determined. Jingzhaotoxin (JZTX-V (also known as β-theraphotoxin-Cj2a is a 29-amino acid peptide toxin isolated from the venom of the spider Chilobrachys jingzhao. JZTX-V adopts an inhibitory cysteine knot (ICK motif and has an inhibitory effect on voltage-gated sodium and potassium channels. Previous experiments have shown that JZTX-V has an inhibitory effect on TTX-S and TTX-R sodium currents on rat DRG cells with IC50 values of 27.6 and 30.2 nM, respectively, and is able to shift the activation and inactivation curves to the depolarizing and the hyperpolarizing direction, respectively. Here, we show that JZTX-V has a much stronger inhibitory effect on NaV1.4, the isoform of voltage-gated sodium channels predominantly expressed in skeletal muscle cells, with an IC50 value of 5.12 nM, compared with IC50 values of 61.7–2700 nM for other heterologously expressed NaV1 subtypes. Furthermore, we investigated the bioactive surface of JZTX-V by alanine-scanning the effect of toxin on NaV1.4 and demonstrate that the bioactive face of JZTX-V is composed of three hydrophobic (W5, M6, and W7 and two cationic (R20 and K22 residues. Our results establish that, consistent with previous assumptions, JZTX-V is a Janus-faced toxin which may be a useful tool for the further investigation of the structure and function of sodium channels.

  1. Distinct gene expression profiles in ovarian cancer linked to Lynch syndrome

    DEFF Research Database (Denmark)

    Jönsson, Jenny-Maria; Bartuma, Katarina; Dominguez-Valentin, Mev

    2014-01-01

    Ovarian cancer linked to Lynch syndrome represents a rare subset that typically presents at young age as early-stage tumors with an overrepresentation of endometrioid and clear cell histologies. We investigated the molecular profiles of Lynch syndrome-associated and sporadic ovarian cancer...... with the aim to identify key discriminators and central tumorigenic mechanisms in hereditary ovarian cancer. Global gene expression profiling using whole-genome c-DNA-mediated Annealing, Selection, extension, and Ligation was applied to 48 histopathologically matched Lynch syndrome-associated and sporadic...... for histologic subtype, hierarchical clustering confirmed distinct differences related to heredity in the endometrioid and serous subtypes. Furthermore, separate clustering was achieved in an independent, publically available data set. The distinct genetic signatures in Lynch syndrome-associated and sporadic...

  2. Molecular Basis for the Recognition of Structurally Distinct Autoinducer Mimics by the Pseudomonas aeruginosa LasR Quorum-Sensing Signaling Receptor

    Energy Technology Data Exchange (ETDEWEB)

    Zou, Yaozhong; Nair, Satish K.; (UIUC)

    2010-01-12

    The human pathogen Pseudomonas aeruginosa coordinates the expression of virulence factors using quorum sensing, a signaling cascade triggered by the activation of signal receptors by small-molecule autoinducers. These homoserine lactone autoinducers stabilize their cognate receptors and activate their functions as transcription factors. Because quorum sensing regulates the progression of infection and host immune resistance, significant efforts have been devoted toward the identification of small molecules that disrupt this process. Screening efforts have identified a class of triphenyl compounds that are structurally distinct from the homoserine lactone autoinducer, yet interact specifically and potently with LasR receptor to modulate quorum sensing (Muh et al., 2006a). Here we present the high-resolution crystal structures of the ligand binding domain of LasR in complex with the autoinducer N-3-oxo-dodecanoyl homoserine lactone (1.4 {angstrom} resolution), and with the triphenyl mimics TP-1, TP-3, and TP-4 (to between 1.8 {angstrom} and 2.3 {angstrom} resolution). These crystal structures provide a molecular rationale for understanding how chemically distinct compounds can be accommodated by a highly selective receptor, and provide the framework for the development of novel quorum-sensing regulators, utilizing the triphenyl scaffold.

  3. Genetic and Epigenetic Tumor Suppressor Gene Silencing are Distinct Molecular Phenotypes Driven by Growth Promoting Mutations in Non small Cell Lung Cancer

    International Nuclear Information System (INIS)

    Marsit, C. J.; Kelsey, K. T.; Houseman, E. A.; Kelsey, K. T.; Houseman, E. A.; Nelson, H. H.

    2008-01-01

    Both genetic and epigenetic alterations characterize human non small cell lung cancer (NSCLC), but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hyper methylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hyper methylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hyper methylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hyper methylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.

  4. Stability and transitions of depressive subtypes over a 2-year follow-up.

    Science.gov (United States)

    Lamers, F; Rhebergen, D; Merikangas, K R; de Jonge, P; Beekman, A T F; Penninx, B W J H

    2012-10-01

    Identifying depressive subtypes is an important tool in reducing the heterogeneity of major depressive disorder. However, few studies have examined the stability of putative subtypes of depression over time. The sample included 488 persons from the Netherlands Study of Depression and Anxiety (NESDA) who had major depressive disorder at baseline and at the 2-year follow-up assessment. A latent transition analysis (LTA) was applied to examine the stability of depressive subtypes across time-points. Differences in demographic, clinical, psychosocial and health correlates between subtypes were evaluated in a subsample of persons with stable subtypes. Three subtypes were identified at each time-point: a moderate subtype (prevalence T0 39%, T1 42%), a severe typical subtype (T0 30%, T1 25%), and a severe atypical subtype (T0 31%, T1 34%). The LTA showed 76% stability across the 2-year follow-up, with the greatest stability in the severe atypical class (79%). Analyses of correlates in the stable subtypes showed a predominance of women and more overweight and obesity in the severe atypical subtype, and a greater number of negative life events and higher neuroticism and functioning scores in the severe typical subtype. Subtypes of major depressive disorder were found to be stable across a 2-year follow-up and to have distinct determinants, supporting the notion that the identified subtypes are clinically meaningful.

  5. Particle infectivity of HIV-1 full-length genome infectious molecular clones in a subtype C heterosexual transmission pair following high fidelity amplification and unbiased cloning

    Energy Technology Data Exchange (ETDEWEB)

    Deymier, Martin J., E-mail: mdeymie@emory.edu [Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329 (United States); Claiborne, Daniel T., E-mail: dclaibo@emory.edu [Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329 (United States); Ende, Zachary, E-mail: zende@emory.edu [Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329 (United States); Ratner, Hannah K., E-mail: hannah.ratner@emory.edu [Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329 (United States); Kilembe, William, E-mail: wkilembe@rzhrg-mail.org [Zambia-Emory HIV Research Project (ZEHRP), B22/737 Mwembelelo, Emmasdale Post Net 412, P/BagE891, Lusaka (Zambia); Allen, Susan, E-mail: sallen5@emory.edu [Zambia-Emory HIV Research Project (ZEHRP), B22/737 Mwembelelo, Emmasdale Post Net 412, P/BagE891, Lusaka (Zambia); Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA (United States); Hunter, Eric, E-mail: eric.hunter2@emory.edu [Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road NE, Atlanta, GA 30329 (United States); Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA (United States)

    2014-11-15

    The high genetic diversity of HIV-1 impedes high throughput, large-scale sequencing and full-length genome cloning by common restriction enzyme based methods. Applying novel methods that employ a high-fidelity polymerase for amplification and an unbiased fusion-based cloning strategy, we have generated several HIV-1 full-length genome infectious molecular clones from an epidemiologically linked transmission pair. These clones represent the transmitted/founder virus and phylogenetically diverse non-transmitted variants from the chronically infected individual's diverse quasispecies near the time of transmission. We demonstrate that, using this approach, PCR-induced mutations in full-length clones derived from their cognate single genome amplicons are rare. Furthermore, all eight non-transmitted genomes tested produced functional virus with a range of infectivities, belying the previous assumption that a majority of circulating viruses in chronic HIV-1 infection are defective. Thus, these methods provide important tools to update protocols in molecular biology that can be universally applied to the study of human viral pathogens. - Highlights: • Our novel methodology demonstrates accurate amplification and cloning of full-length HIV-1 genomes. • A majority of plasma derived HIV variants from a chronically infected individual are infectious. • The transmitted/founder was more infectious than the majority of the variants from the chronically infected donor.

  6. Particle infectivity of HIV-1 full-length genome infectious molecular clones in a subtype C heterosexual transmission pair following high fidelity amplification and unbiased cloning.

    Science.gov (United States)

    Deymier, Martin J; Claiborne, Daniel T; Ende, Zachary; Ratner, Hannah K; Kilembe, William; Allen, Susan; Hunter, Eric

    2014-11-01

    The high genetic diversity of HIV-1 impedes high throughput, large-scale sequencing and full-length genome cloning by common restriction enzyme based methods. Applying novel methods that employ a high-fidelity polymerase for amplification and an unbiased fusion-based cloning strategy, we have generated several HIV-1 full-length genome infectious molecular clones from an epidemiologically linked transmission pair. These clones represent the transmitted/founder virus and phylogenetically diverse non-transmitted variants from the chronically infected individual׳s diverse quasispecies near the time of transmission. We demonstrate that, using this approach, PCR-induced mutations in full-length clones derived from their cognate single genome amplicons are rare. Furthermore, all eight non-transmitted genomes tested produced functional virus with a range of infectivities, belying the previous assumption that a majority of circulating viruses in chronic HIV-1 infection are defective. Thus, these methods provide important tools to update protocols in molecular biology that can be universally applied to the study of human viral pathogens. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Particle infectivity of HIV-1 full-length genome infectious molecular clones in a subtype C heterosexual transmission pair following high fidelity amplification and unbiased cloning

    International Nuclear Information System (INIS)

    Deymier, Martin J.; Claiborne, Daniel T.; Ende, Zachary; Ratner, Hannah K.; Kilembe, William; Allen, Susan; Hunter, Eric

    2014-01-01

    The high genetic diversity of HIV-1 impedes high throughput, large-scale sequencing and full-length genome cloning by common restriction enzyme based methods. Applying novel methods that employ a high-fidelity polymerase for amplification and an unbiased fusion-based cloning strategy, we have generated several HIV-1 full-length genome infectious molecular clones from an epidemiologically linked transmission pair. These clones represent the transmitted/founder virus and phylogenetically diverse non-transmitted variants from the chronically infected individual's diverse quasispecies near the time of transmission. We demonstrate that, using this approach, PCR-induced mutations in full-length clones derived from their cognate single genome amplicons are rare. Furthermore, all eight non-transmitted genomes tested produced functional virus with a range of infectivities, belying the previous assumption that a majority of circulating viruses in chronic HIV-1 infection are defective. Thus, these methods provide important tools to update protocols in molecular biology that can be universally applied to the study of human viral pathogens. - Highlights: • Our novel methodology demonstrates accurate amplification and cloning of full-length HIV-1 genomes. • A majority of plasma derived HIV variants from a chronically infected individual are infectious. • The transmitted/founder was more infectious than the majority of the variants from the chronically infected donor

  8. Molecular characterization of antigen-peptide pulsed dendritic cells: immature dendritic cells develop a distinct molecular profile when pulsed with antigen peptide.

    Directory of Open Access Journals (Sweden)

    Amy X Yang

    Full Text Available As dendritic cells (DCs are the most potent professional antigen-presenting cells, they are being tested as cancer vaccines for immunotherapy of established cancers. Although numerous studies have characterized DCs by their phenotype and function, few have identified potential molecular markers of antigen presentation prior to vaccination of host. In this study we generated pre-immature DC (piDC, immature DC (iDC, and mature DC (mDC from human peripheral blood monocytes (PBMC obtained from HLA-A2 healthy donors, and pulsed them with human papillomavirus E7 peptide (p11-20, a class I HLA-A2 binding antigen. We then characterized DCs for cell surface phenotype and gene expression profile by microarray technology. We identified a set of 59 genes that distinguished three differentiation stages of DCs (piDC, iDC and mDC. When piDC, iDC and mDC were pulsed with E7 peptide for 2 hrs, the surface phenotype did not change, however, iDCs rather than mDCs showed transcriptional response by up-regulation of a set of genes. A total of 52 genes were modulated in iDC upon antigen pulsing. Elongation of pulse time for iDCs to 10 and 24 hrs did not significantly bring further changes in gene expression. The E7 peptide up-modulated immune response (KPNA7, IGSF6, NCR3, TREM2, TUBAL3, IL8, NFKBIA, pro-apoptosis (BTG1, SEMA6A, IGFBP3 and SRGN, anti-apoptosis (NFKBIA, DNA repair (MRPS11, RAD21, TXNRD1, and cell adhesion and cell migration genes (EPHA1, PGF, IL8 and CYR61 in iDCs. We confirmed our results by Q-PCR analysis. The E7 peptide but not control peptide (PADRE induced up-regulation of NFKB1A gene only in HLA-A2 positive iDCs and not in HLA-A2 negative iDCs. These results suggest that E7 up-regulation of genes is specific and HLA restricted and that these genes may represent markers of antigen presentation and help rapidly assess the quality of dendritic cells prior to administration to the host.

  9. Retinal Ganglion Cell Diversity and Subtype Specification from Human Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Kirstin B. Langer

    2018-04-01

    Full Text Available Summary: Retinal ganglion cells (RGCs are the projection neurons of the retina and transmit visual information to postsynaptic targets in the brain. While this function is shared among nearly all RGCs, this class of cell is remarkably diverse, comprised of multiple subtypes. Previous efforts have identified numerous RGC subtypes in animal models, but less attention has been paid to human RGCs. Thus, efforts of this study examined the diversity of RGCs differentiated from human pluripotent stem cells (hPSCs and characterized defined subtypes through the expression of subtype-specific markers. Further investigation of these subtypes was achieved using single-cell transcriptomics, confirming the combinatorial expression of molecular markers associated with these subtypes, and also provided insight into more subtype-specific markers. Thus, the results of this study describe the derivation of RGC subtypes from hPSCs and will support the future exploration of phenotypic and functional diversity within human RGCs. : In this article, Langer and colleagues present extensive characterization of RGC subtypes derived from human pluripotent stem cells, with multiple subtypes identified by subtype-specific molecular markers. Their results present a more detailed analysis of RGC diversity in human cells and yield the use of different markers to identify RGC subtypes. Keywords: iPSC, retina, retinal ganglion cell, RGC subtype, stem cell, ipRGC, alpha RGC, direction selective RGC, RNA-seq

  10. Identification of different subtypes of breast cancer using tissue microarray.

    Science.gov (United States)

    Munirah, M A; Siti-Aishah, M A; Reena, M Z; Sharifah, N A; Rohaizak, M; Norlia, A; Rafie, M K M; Asmiati, A; Hisham, A; Fuad, I; Shahrun, N S; Das, S

    2011-01-01

    Breast cancer may be classified into luminal A, luminal B, HER2+/ER-, basal-like and normal-like subtypes based on gene expression profiling or immunohistochemical (IHC) characteristics. The main aim of the present study was to classify breast cancer into molecular subtypes based on immunohistochemistry findings and correlate the subtypes with clinicopathological factors. Two hundred and seventeen primary breast carcinomas tumor tissues were immunostained for ER, PR, HER2, CK5/6, EGFR, CK8/18, p53 and Ki67 using tissue microarray technique. All subtypes were significantly associated with Malay ethnic background (p=0.035) compared to other racial origins. The most common subtypes of breast cancers were luminal A and was significantly associated with low histological grade (p<0.000) and p53 negativity (p=0.003) compared to HER2+/ER-, basal-like and normal-like subtypes with high histological grade (p<0.000) and p53 positivity (p=0.003). Luminal B subtype had the smallest mean tumor size (p=0.009) and also the highest mean number of lymph nodes positive (p=0.032) compared to other subtypes. All markers except EGFR and Ki67 were significantly associated with the subtypes. The most common histological type was infiltrating ductal carcinoma, NOS. Majority of basal-like subtype showed comedo-type necrosis (68.8%) and infiltrative margin (81.3%). Our studies suggest that IHC can be used to identify the different subtypes of breast cancer and all subtypes were significantly associated with race, mean tumor size, mean number of lymph node positive, histological grade and all immunohistochemical markers except EGFR and Ki67.

  11. The implications of breast cancer molecular phenotype for radiation oncology

    Directory of Open Access Journals (Sweden)

    Shirin eSioshansi

    2011-06-01

    Full Text Available The identification of distinct molecular subtypes of breast cancer has advanced the understanding and treatment of breast cancer by providing insight into prognosis, patterns of recurrence and effectiveness of therapy. The prognostic significance of molecular phenotype with regard to distant recurrences and overall survival are well established in the literature and has been readily incorporated into systemic therapy management decisions. However, despite the accumulating data suggesting similar prognostic significance for locoregional recurrence, integration of molecular phenotype into local management decision making has lagged. Although there are some conflicting reports, collectively the literature supports a low risk of local recurrence in the hormone receptor positive luminal subtypes compared to hormone receptor negative subtypes (triple negative and HER2-enriched. The development of targeted therapies, such as trastuzumab for the treatment of HER2-enriched subtype, has been shown to mitigate the increased risk of local recurrence. Unfortunately, no such remedy exists to address the increased risk of local recurrence for patients with triple negative tumors, making it a clinical challenge for radiation oncologists. In this review we discuss the correlation between molecular subtype and local recurrence following either breast conservation therapy or mastectomy. We also explore the possible mechanisms for increased local recurrence in triple negative breast cancer and radiotherapeutic implications for this population, such as the safety of breast conservation, consideration of dose escalation and the appropriateness of accelerated partial breast irradiation.

  12. Associations of two-pore domain potassium channels and triple negative breast cancer subtype in The Cancer Genome Atlas: systematic evaluation of gene expression and methylation.

    Science.gov (United States)

    Dookeran, Keith A; Zhang, Wei; Stayner, Leslie; Argos, Maria

    2017-09-12

    It is unclear whether 2-pore domain potassium channels are novel molecular markers with differential expression related to biologically aggressive triple-negative type breast tumors. Our objective was to systematically evaluate associations of 2-pore domain potassium channel gene expression and DNA methylation with triple-negative subtype in The Cancer Genome Atlas invasive breast cancer dataset. Methylation and expression data for all fifteen 2-pore domain potassium family genes were examined for 1040 women, and associations with triple-negative subtype (vs. luminal A) were evaluated using age/race adjusted generalized-linear models, with Bonferroni-corrected significance thresholds. Subtype associated CpG loci were evaluated for functionality related to expression using Spearman's correlation. Overexpression of KCNK5, KCNK9 and KCNK12, and underexpression of KCNK6 and KCNK15, were significantly associated with triple-negative subtype (Bonferroni-corrected p < 0.0033). A total of 195 (114 hypomethylated and 81 hypermethylated) CpG loci were found to be significantly associated with triple-negative subtype (Bonferroni-corrected p < 8.22 × 10 -8 ). Significantly negatively correlated expression patterns that were differentially observed in triple-negative vs. luminal A subtype were demonstrated for: KCNK2 (gene body: cg04923840, cg13916421), KCNK5 (gene body: cg05255811, cg18705155, cg09130674, cg21388745, cg00859574) and KCNK9 (TSS1500: cg21415530, cg12175729; KCNK9/TRAPPC9 intergenic region: cg17336929, cg25900813, cg03919980). CpG loci listed for KCNK5 and KCNK9 all showed relative hypomethylation for probability of triple-negative vs. luminal A subtype. Triple-negative subtype was associated with distinct 2-pore domain potassium channel expression patterns. Both KCNK5 and KCNK9 overexpression appeared to be functionally related to CpG loci hypomethylation.

  13. Integrative Analysis of Prognosis Data on Multiple Cancer Subtypes

    Science.gov (United States)

    Liu, Jin; Huang, Jian; Zhang, Yawei; Lan, Qing; Rothman, Nathaniel; Zheng, Tongzhang; Ma, Shuangge

    2014-01-01

    Summary In cancer research, profiling studies have been extensively conducted, searching for genes/SNPs associated with prognosis. Cancer is diverse. Examining the similarity and difference in the genetic basis of multiple subtypes of the same cancer can lead to a better understanding of their connections and distinctions. Classic meta-analysis methods analyze each subtype separately and then compare analysis results across subtypes. Integrative analysis methods, in contrast, analyze the raw data on multiple subtypes simultaneously and can outperform meta-analysis methods. In this study, prognosis data on multiple subtypes of the same cancer are analyzed. An AFT (accelerated failure time) model is adopted to describe survival. The genetic basis of multiple subtypes is described using the heterogeneity model, which allows a gene/SNP to be associated with prognosis of some subtypes but not others. A compound penalization method is developed to identify genes that contain important SNPs associated with prognosis. The proposed method has an intuitive formulation and is realized using an iterative algorithm. Asymptotic properties are rigorously established. Simulation shows that the proposed method has satisfactory performance and outperforms a penalization-based meta-analysis method and a regularized thresholding method. An NHL (non-Hodgkin lymphoma) prognosis study with SNP measurements is analyzed. Genes associated with the three major subtypes, namely DLBCL, FL, and CLL/SLL, are identified. The proposed method identifies genes that are different from alternatives and have important implications and satisfactory prediction performance. PMID:24766212

  14. Experimentally-derived fibroblast gene signatures identify molecular pathways associated with distinct subsets of systemic sclerosis patients in three independent cohorts.

    Directory of Open Access Journals (Sweden)

    Michael E Johnson

    Full Text Available Genome-wide expression profiling in systemic sclerosis (SSc has identified four 'intrinsic' subsets of disease (fibroproliferative, inflammatory, limited, and normal-like, each of which shows deregulation of distinct signaling pathways; however, the full set of pathways contributing to this differential gene expression has not been fully elucidated. Here we examine experimentally derived gene expression signatures in dermal fibroblasts for thirteen different signaling pathways implicated in SSc pathogenesis. These data show distinct and overlapping sets of genes induced by each pathway, allowing for a better understanding of the molecular relationship between profibrotic and immune signaling networks. Pathway-specific gene signatures were analyzed across a compendium of microarray datasets consisting of skin biopsies from three independent cohorts representing 80 SSc patients, 4 morphea, and 26 controls. IFNα signaling showed a strong association with early disease, while TGFβ signaling spanned the fibroproliferative and inflammatory subsets, was associated with worse MRSS, and was higher in lesional than non-lesional skin. The fibroproliferative subset was most strongly associated with PDGF signaling, while the inflammatory subset demonstrated strong activation of innate immune pathways including TLR signaling upstream of NF-κB. The limited and normal-like subsets did not show associations with fibrotic and inflammatory mediators such as TGFβ and TNFα. The normal-like subset showed high expression of genes associated with lipid signaling, which was absent in the inflammatory and limited subsets. Together, these data suggest a model by which IFNα is involved in early disease pathology, and disease severity is associated with active TGFβ signaling.

  15. Distinct Subtypes of Apathy Revealed by the Apathy Motivation Index

    OpenAIRE

    Ang, Yuen-Siang; Lockwood, Patricia; Apps, Matthew A. J.; Muhammed, Kinan; Husain, Masud

    2017-01-01

    Apathy is a debilitating but poorly understood disorder characterized by a reduction in motivation. As well as being associated with several brain disorders, apathy is also prevalent in varying degrees in healthy people. Whilst many tools have been developed to assess levels of apathy in clinical disorders, surprisingly there are no measures of apathy suitable for healthy people. Moreover, although apathy is commonly comorbid with symptoms of depression, anhedonia and fatigue, how and why the...

  16. Targeting N-glycan cryptic sugar moieties for broad-spectrum virus neutralization: progress in identifying conserved molecular targets in viruses of distinct phylogenetic origins.

    Science.gov (United States)

    Wang, Denong; Tang, Jin; Tang, Jiulai; Wang, Lai-Xi

    2015-03-12

    Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA), for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV), and human cytomegalovirus (HCMV). In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9)-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn). These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  17. Targeting N-Glycan Cryptic Sugar Moieties for Broad-Spectrum Virus Neutralization: Progress in Identifying Conserved Molecular Targets in Viruses of Distinct Phylogenetic Origins

    Directory of Open Access Journals (Sweden)

    Denong Wang

    2015-03-01

    Full Text Available Identifying molecular targets for eliciting broadly virus-neutralizing antibodies is one of the key steps toward development of vaccines against emerging viral pathogens. Owing to genomic and somatic diversities among viral species, identifying protein targets for broad-spectrum virus neutralization is highly challenging even for the same virus, such as HIV-1. However, viruses rely on host glycosylation machineries to synthesize and express glycans and, thereby, may display common carbohydrate moieties. Thus, exploring glycan-binding profiles of broad-spectrum virus-neutralizing agents may provide key information to uncover the carbohydrate-based virus-neutralizing epitopes. In this study, we characterized two broadly HIV-neutralizing agents, human monoclonal antibody 2G12 and Galanthus nivalis lectin (GNA, for their viral targeting activities. Although these agents were known to be specific for oligomannosyl antigens, they differ strikingly in virus-binding activities. The former is HIV-1 specific; the latter is broadly reactive and is able to neutralize viruses of distinct phylogenetic origins, such as HIV-1, severe acute respiratory syndrome coronavirus (SARS-CoV, and human cytomegalovirus (HCMV. In carbohydrate microarray analyses, we explored the molecular basis underlying the striking differences in the spectrum of anti-virus activities of the two probes. Unlike 2G12, which is strictly specific for the high-density Man9GlcNAc2Asn (Man9-clusters, GNA recognizes a number of N-glycan cryptic sugar moieties. These include not only the known oligomannosyl antigens but also previously unrecognized tri-antennary or multi-valent GlcNAc-terminating N-glycan epitopes (Tri/m-Gn. These findings highlight the potential of N-glycan cryptic sugar moieties as conserved targets for broad-spectrum virus neutralization and suggest the GNA-model of glycan-binding warrants focused investigation.

  18. Machine learning integration of rheumatoid arthritis synovial histology and RNAseq data identifies three disease subtypes.

    Science.gov (United States)

    Orange, Dana E; Agius, Phaedra; DiCarlo, Edward F; Robine, Nicolas; Geiger, Heather; Szymonifka, Jackie; McNamara, Michael; Cummings, Ryan; Andersen, Kathleen M; Mirza, Serene; Figgie, Mark; Ivashkiv, Lionel; Pernis, Alessandra B; Jiang, Caroline; Frank, Mayu; Darnell, Robert; Lingampali, Nithya; William, Robinson; Gravallese, Ellen; Bykerk, Vivian P; Goodman, Susan M; Donlin, Laura T

    2018-02-22

    We sought to refine histologic scoring of rheumatoid arthritis synovial tissue by training with gene expression data and machine learning. Twenty histologic features were assessed on 129 synovial tissue samples. Consensus clustering was performed on gene expression data from a subset of 45 synovial samples. Support vector machine learning was used to predict gene expression subtypes using histology data as input. Corresponding clinical data were compared across subtypes. Consensus clustering of gene expression data revealed three distinct synovial subtypes, including a highly inflammatory subtype characterized by extensive infiltration of leukocytes, a low inflammatory subtype characterized by enrichment in pathways including TGF-β, glycoproteins and neuronal genes, and a mixed subtype. Machine learning applied to histology features using gene expression subtypes as labels generated an algorithm for scoring histology features. Patients with highly inflammatory synovial subtypes exhibited higher levels of markers of systemic inflammation and autoantibodies. CRP was significantly correlated with pain in the high inflammatory group but not the others. Gene expression analysis of synovial tissue revealed three distinct synovial subtypes. We used these labels to generate a histology scoring algorithm that associates with levels of ESR, CRP and autoantibodies. Comparison of gene expression patterns to clinical features revealed a potentially clinically important distinction: mechanisms of pain may differ in patients with different synovial subtypes. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. Leukocyte Telomere Length and Serum Levels of High-Molecular-Weight Adiponectin and Dehydroepiandrosterone-Sulfate Could Reflect Distinct Aspects of Longevity in Japanese Centenarians

    Directory of Open Access Journals (Sweden)

    Yuji Aoki MD, PhD

    2017-03-01

    Full Text Available Leukocyte telomere length and serum levels of high-molecular-weight adiponectin and dehydroepiandrosterone-sulfate (DHEA-S were assessed in association with nutrition and performance status (PS in Japanese centenarians. Twenty-three centenarians (five men, 18 women were classified according to their PS 1 (nearly fully ambulatory, n = 2, 2 (in bed less than 50% of daytime, n = 10, 3 (in bed greater than 50%, n = 6, and 4 (completely bedridden, n = 5. Leukocyte telomere length was determined by the hybridization protection assay, and the adiponectin and DHEA-S levels were measured by chemiluminescent enzyme immunoassay. Among variables of PS, body mass index (BMI, albumin, adiponectin, DHEA-S, and telomere length, there were significant correlations between PS and albumin ( r = −.694, p < .01, between telomere length and BMI ( r = .522, p < .05, between adiponectin and BMI ( r = −.574, p < .01, and between DHEA-S and albumin ( r = .530, p < .01. When excluding two cancer-bearing centenarians with short telomere, telomere length significantly correlated with PS ( r = −.632, p < .01. It was indicated that the short leukocyte telomere was associated with poor PS and cancer development and that the adiponectin or DHEA-S was associated with adiposity or nutritional status. Despite a small number of subjects, these biomarkers seemed to reflect distinct aspects of longevity in Japanese centenarians.

  20. IDH2 Mutations Define a Unique Subtype of Breast Cancer with Altered Nuclear Polarity

    Science.gov (United States)

    Chiang, Sarah; Weigelt, Britta; Wen, Huei-Chi; Pareja, Fresia; Raghavendra, Ashwini; Martelotto, Luciano G.; Burke, Kathleen A.; Basili, Thais; Li, Anqi; Geyer, Felipe C.; Piscuoglio, Salvatore; Ng, Charlotte K.Y.; Jungbluth, Achim A.; Balss, Jörg; Pusch, Stefan; Baker, Gabrielle M.; Cole, Kimberly S.; von Deimling, Andreas; Batten, Julie M.; Marotti, Jonathan D.; Soh, Hwei-Choo; McCalip, Benjamin L.; Serrano, Jonathan; Lim, Raymond S.; Siziopikou, Kalliopi P.; Lu, Song; Liu, Xiaolong; Hammour, Tarek; Brogi, Edi; Snuderl, Matija; Iafrate, A. John; Reis-Filho, Jorge S.; Schnitt, Stuart J.

    2017-01-01

    Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1. One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. PMID:27913435

  1. Appreciating HIV-1 diversity: subtypic differences in ENV

    Energy Technology Data Exchange (ETDEWEB)

    Gnanakaran, S [Los Alamos National Laboratory; Shen, Tongye [Los Alamos National Laboratory; Lynch, Rebecca M [NON LANL; Derdeyn, Cynthia A [NON LANL

    2008-01-01

    Human immunodeficiency virus type 1 (HIV-1) group M is responsible for the current AIDS pandemic and exhibits exceedingly high levels of viral genetic diversity around the world, necessitating categorization of viruses into distinct lineages, or subtypes. These subtypes can differ by around 35% in the envelope (Env) glycoproteins of the virus, which are displayed on the surface of the virion and are targets for both neutralizing antibody and cell-mediated immune responses. This diversity reflects the remarkable ability of the virus to adapt to selective pressures, the bulk of which is applied by the host immune response, and represents a serious obstacle for developing an effective vaccine with broad coverage. Thus, it is important to understand the underlying biological consequences of inter-subtype diversity. Recent studies have revealed that the HIV-1 subtypes exhibit phenotypic differences that result from subtle differences in Env structure, particularly within the highly immunogenic V3 domain, which participates directly in viral entry. This review will therefore explore current research that describes subtypic differences in Env at the genetic and phenotypic level, focusing in particular on V3, and highlighting recent discoveries about the unique features of subtype C Env, which is the most prevalent subtype globally.

  2. Molecular Classification of Gastric Cancer: A new paradigm

    Science.gov (United States)

    Shah, Manish A.; Khanin, Raya; Tang, Laura; Janjigian, Yelena Y.; Klimstra, David S.; Gerdes, Hans; Kelsen, David P.

    2011-01-01

    Purpose Gastric cancer may be subdivided into three distinct subtypes –proximal, diffuse, and distal gastric cancer– based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology. Our aim is to test the hypothesis that these distinct gastric cancer subtypes may also be distinguished by gene expression analysis. Experimental Design Patients with localized gastric adenocarcinoma being screened for a phase II preoperative clinical trial (NCI 5917) underwent endoscopic biopsy for fresh tumor procurement. 4–6 targeted biopsies of the primary tumor were obtained. Macrodissection was performed to ensure >80% carcinoma in the sample. HG-U133A GeneChip (Affymetrix) was used for cDNA expression analysis, and all arrays were processed and analyzed using the Bioconductor R-package. Results Between November 2003 and January 2006, 57 patients were screened to identify 36 patients with localized gastric cancer who had adequate RNA for expression analysis. Using supervised analysis, we built a classifier to distinguish the three gastric cancer subtypes, successfully classifying each into tightly grouped clusters. Leave-one-out cross validation error was 0.14, suggesting that >85% of samples were classified correctly. Gene set analysis with the False Discovery Rate set at 0.25 identified several pathways that were differentially regulated when comparing each gastric cancer subtype to adjacent normal stomach. Conclusions Subtypes of gastric cancer that have epidemiologic and histologic distinction are also distinguished by gene expression data. These preliminary data suggest a new classification of gastric cancer with implications for improving our understanding of disease biology and identification of unique molecular drivers for each gastric cancer subtype. PMID:21430069

  3. Molecular classification of gastric cancer: a new paradigm.

    Science.gov (United States)

    Shah, Manish A; Khanin, Raya; Tang, Laura; Janjigian, Yelena Y; Klimstra, David S; Gerdes, Hans; Kelsen, David P

    2011-05-01

    Gastric cancer may be subdivided into 3 distinct subtypes--proximal, diffuse, and distal gastric cancer--based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology. Our aim is to test the hypothesis that these distinct gastric cancer subtypes may also be distinguished by gene expression analysis. Patients with localized gastric adenocarcinoma being screened for a phase II preoperative clinical trial (National Cancer Institute, NCI #5917) underwent endoscopic biopsy for fresh tumor procurement. Four to 6 targeted biopsies of the primary tumor were obtained. Macrodissection was carried out to ensure more than 80% carcinoma in the sample. HG-U133A GeneChip (Affymetrix) was used for cDNA expression analysis, and all arrays were processed and analyzed using the Bioconductor R-package. Between November 2003 and January 2006, 57 patients were screened to identify 36 patients with localized gastric cancer who had adequate RNA for expression analysis. Using supervised analysis, we built a classifier to distinguish the 3 gastric cancer subtypes, successfully classifying each into tightly grouped clusters. Leave-one-out cross-validation error was 0.14, suggesting that more than 85% of samples were classified correctly. Gene set analysis with the false discovery rate set at 0.25 identified several pathways that were differentially regulated when comparing each gastric cancer subtype to adjacent normal stomach. Subtypes of gastric cancer that have epidemiologic and histologic distinctions are also distinguished by gene expression data. These preliminary data suggest a new classification of gastric cancer with implications for improving our understanding of disease biology and identification of unique molecular drivers for each gastric cancer subtype. ©2011 AACR.

  4. Brief report: Further evidence of sensory subtypes in autism.

    Science.gov (United States)

    Lane, Alison E; Dennis, Simon J; Geraghty, Maureen E

    2011-06-01

    Distinct sensory processing (SP) subtypes in autism have been reported previously. This study sought to replicate the previous findings in an independent sample of thirty children diagnosed with an Autism Spectrum Disorder. Model-based cluster analysis of parent-reported sensory functioning (measured using the Short Sensory Profile) confirmed the triad of sensory subtypes reported earlier. Subtypes were differentiated from each other based on degree of SP dysfunction, taste/smell sensitivity and vestibular/proprioceptive processing. Further elucidation of two of the subtypes was also achieved in this study. Children with a primary pattern of sensory-based inattention could be further described as sensory seekers or non-seekers. Children with a primary pattern of vestibular/proprioceptive dysfunction were also differentiated on movement and tactile sensitivity.

  5. Distinct molecular regulation of glycogen synthase kinase-3alpha isozyme controlled by its N-terminal region: functional role in calcium/calpain signaling.

    Science.gov (United States)

    Azoulay-Alfaguter, Inbar; Yaffe, Yakey; Licht-Murava, Avital; Urbanska, Malgorzata; Jaworski, Jacek; Pietrokovski, Shmuel; Hirschberg, Koret; Eldar-Finkelman, Hagit

    2011-04-15

    Glycogen synthase kinase-3 (GSK-3) is expressed as two isozymes α and β. They share high similarity in their catalytic domains but differ in their N- and C-terminal regions, with GSK-3α having an extended glycine-rich N terminus. Here, we undertook live cell imaging combined with molecular and bioinformatic studies to understand the distinct functions of the GSK-3 isozymes focusing on GSK-3α N-terminal region. We found that unlike GSK-3β, which shuttles between the nucleus and cytoplasm, GSK-3α was excluded from the nucleus. Deletion of the N-terminal region of GSK-3α resulted in nuclear localization, and treatment with leptomycin B resulted in GSK-3α accumulation in the nucleus. GSK-3α rapidly accumulated in the nucleus in response to calcium or serum deprivation, and accumulation was strongly inhibited by the calpain inhibitor calpeptin. This nuclear accumulation was not mediated by cleavage of the N-terminal region or phosphorylation of GSK-3α. Rather, we show that calcium-induced GSK-3α nuclear accumulation was governed by GSK-3α binding with as yet unknown calpain-sensitive protein or proteins; this binding was mediated by the N-terminal region. Bioinformatic and experimental analyses indicated that nuclear exclusion of GSK-3α was likely an exclusive characteristic of mammalian GSK-3α. Finally, we show that nuclear localization of GSK-3α reduced the nuclear pool of β-catenin and its target cyclin D1. Taken together, these data suggest that the N-terminal region of GSK-3α is responsible for its nuclear exclusion and that binding with a calcium/calpain-sensitive product enables GSK-3α nuclear retention. We further uncovered a novel link between calcium and nuclear GSK-3α-mediated inhibition of the canonical Wnt/β-catenin pathway.

  6. Molecular Signatures of Chronic Pain Subtypes

    Science.gov (United States)

    2015-03-01

    Mauro K. Cognitive and cardiovascular benefits of docosahexaenoic acid in aging and cognitive decline. Curr Alzheimer Res 2010; 7(3):190–6. 13...glucose-induced proinflammatory cytokine pro- duction in monocytes by curcumin . J Nutr Biochem 2011;22(5):450–8. 115 Ke J, Long X, Liu Y, et al. Role of NF

  7. Molecular Signatures of Chronic Pain Subtypes

    Science.gov (United States)

    2013-01-01

    How many hours since last meal ? __________________________________ Collected whole blood in one EDTA tube? No Yes Collected whole blood...analysis in human gastric cancer cell line treated with trichostatin A and S-adenosyl-L-homocysteine using cDNA microarray. Biol Pharm Bull 2004;27(10...McCaffrey AP, Meuse L, Pham TT, et al. RNA inter- ference in adult mice. Nature 2002;418(6893):38–9. 180 Tan PH , Yang LC, Shih HC, Lan KC, Cheng JT. Gene

  8. Breast cancer Molecular subtypes and their clinicopathological ...

    African Journals Online (AJOL)

    2010-01-20

    Jan 20, 2010 ... Bloom and Richardson classification. Immunohistochemical techniques. Immunohistochemical staining was done manually us- ing estrogen receptor (Er) (clone 1D5 Dako), proges- terone receptor (Pr) (clone PgR636 Dako), epidermal growth factor receptor 1 (HER1) (Mouse Anti-Her-1. Dako), epidermal ...

  9. Age-Specific Vascular Risk Factor Profiles According to Stroke Subtype

    NARCIS (Netherlands)

    Hauer, Allard J.; Ruigrok, Ynte M.; Algra, Ale; van Dijk, Ewoud J.; Koudstaal, Peter J.; Luijckx, Gert-Jan; Nederkoorn, Paul J.; van Oostenbrugge, Robert J.; Visser, Marieke C.; Wermer, Marieke J.; Kappelle, L. Jaap; Klijn, Catharina J. M.

    2017-01-01

    Background--Ischemic and hemorrhagic stroke are increasingly recognized as heterogeneous diseases with distinct subtypes and etiologies. Information on variation in distribution of vascular risk factors according to age in stroke subtypes is limited. We investigated the prevalence of vascular risk

  10. Identification of nine novel loci associated with white blood cell subtypes in a Japanese population

    NARCIS (Netherlands)

    Y. Okada (Yukinori); T. Hirota (Tomomitsu); Y. Kamatani (Yoichiro); A. Takahashi (Atsushi); H. Ohmiya (Hiroko); N. Kumasaka (Natsuhiko); K. Higasa (Koichiro); Y. Yamaguchi-Kabata (Yumi); N. Hosono (Naoya); M.A. Nalls (Michael); M-H. Chen (Ming-Huei); F.J.A. van Rooij (Frank); A.V. Smith (Albert Vernon); T. Tanaka (Toshiko); D. Couper (David); N.A. Zakai (Neil); L. Ferrucci (Luigi); D.L. Longo (Dan); D.G. Hernandez (Dena); J.C.M. Witteman (Jacqueline); T.B. Harris (Tamara); C.J. O'Donnell (Christopher); S.K. Ganesh (Santhi); K. Matsuda (Koichi); T. Tsunoda (Tatsuhiko); M. Kubo (Michiaki); Y. Nakamura (Yusuke); M. Tamari (Mayumi); K. Yamamoto (Kazuhiko)

    2011-01-01

    textabstractWhite blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this

  11. Epidemic dynamics of two coexisting hepatitis C virus subtypes.

    Science.gov (United States)

    Jiménez-Hernández, Nuria; Torres-Puente, Manuela; Bracho, Maria Alma; García-Robles, Inmaculada; Ortega, Enrique; del Olmo, Juan; Carnicer, Fernando; González-Candelas, Fernando; Moya, Andrés

    2007-01-01

    Hepatitis C virus (HCV) infection affects about 3% of the human population. Phylogenetic analyses have grouped its variants into six major genotypes, which have a star-like distribution and several minor subtypes. The most abundant genotype in Europe is the so-called genotype 1, with two prevalent subtypes, 1a and 1b. In order to explain the higher prevalence of subtype 1b over 1a, a large-scale sequence analysis (100 virus clones) has been carried out over 25 patients of both subtypes in two regions of the HCV genome: one comprising hypervariable region 1 and another including the interferon sensitivity-determining region. Neither polymorphism analysis nor molecular variance analysis (attending to intra- and intersubtype differences, age, sex and previous history of antiviral treatment) was able to show any particular difference between subtypes that might account for their different prevalence. Only the demographic history of the populations carrying both subtypes and analysis of molecular variance (AMOVA) for risk practice suggested that the route of transmission may be the most important factor to explain the observed difference.

  12. Sensory Processing Subtypes in Autism: Association with Adaptive Behavior

    Science.gov (United States)

    Lane, Alison E.; Young, Robyn L.; Baker, Amy E. Z.; Angley, Manya T.

    2010-01-01

    Children with autism are frequently observed to experience difficulties in sensory processing. This study examined specific patterns of sensory processing in 54 children with autistic disorder and their association with adaptive behavior. Model-based cluster analysis revealed three distinct sensory processing subtypes in autism. These subtypes…

  13. Longitudinal Stability of Phonological and Surface Subtypes of Developmental Dyslexia

    Science.gov (United States)

    Peterson, Robin L.; Pennington, Bruce F.; Olson, Richard K.; Wadsworth, Sally J.

    2014-01-01

    Limited evidence supports the external validity of the distinction between developmental phonological and surface dyslexia. We previously identified children ages 8 to 13 meeting criteria for these subtypes (Peterson, Pennington, & Olson, 2013) and now report on their reading and related skills approximately 5 years later. Longitudinal…

  14. Brief Report: Further Evidence of Sensory Subtypes in Autism

    Science.gov (United States)

    Lane, Alison E.; Dennis, Simon J.; Geraghty, Maureen E.

    2011-01-01

    Distinct sensory processing (SP) subtypes in autism have been reported previously. This study sought to replicate the previous findings in an independent sample of thirty children diagnosed with an Autism Spectrum Disorder. Model-based cluster analysis of parent-reported sensory functioning (measured using the Short Sensory Profile) confirmed the…

  15. The HIV-1 epidemic in Bolivia is dominated by subtype B and CRF12_BF "family" strains

    Directory of Open Access Journals (Sweden)

    Guimarães Monick L

    2012-01-01

    Full Text Available Abstract Background Molecular epidemiological studies of HIV-1 in South America have revealed the occurrence of subtypes B, F1 and BF1 recombinants. Even so, little information concerning the HIV-1 molecular epidemiology in Bolivia is available. In this study we performed phylogenetic analyses from samples collected in Bolivia at two different points in time over a 10 year span. We analyzed these samples to estimate the trends in the HIV subtype and recombinant forms over time. Materials and methods Fifty one HIV-1 positive samples were collected in Bolivia over two distinct periods (1996 and 2005. These samples were genetically characterized based on partial pol protease/reverse transcriptase (pr/rt and env regions. Alignment and neighbor-joining (NJ phylogenetic analyses were established from partial env (n = 37 and all pol sequences using Mega 4. The remaining 14 env sequences from 1996 were previously characterized based on HMA-env (Heteroduplex mobility assay. The Simplot v.3.5.1 program was used to verify intragenic recombination, and SplitsTree 4.0 was employed to confirm the phylogenetic relationship of the BF1 recombinant samples. Results Phylogenetic analysis of both env and pol regions confirmed the predominance of "pure" subtype B (72.5% samples circulating in Bolivia and revealed a high prevalence of BF1 genotypes (27.5%. Eleven out of 14 BF1 recombinants displayed a mosaic structure identical or similar to that described for the CRF12_BF variant, one sample was classified as CRF17_BF, and two others were F1pol/Benv. No "pure" HIV-1 subtype F1 or B" variant of subtype B was detected in the present study. Of note, samples characterized as CRF12_BF-related were depicted only in 2005. Conclusion HIV-1 genetic diversity in Bolivia is mostly driven by subtype B followed by BF1 recombinant strains from the CRF12_BF "family". No significant temporal changes were detected between the mid-1990s and the mid-2000s for subtype B (76.2% vs 70

  16. The HIV-1 epidemic in Bolivia is dominated by subtype B and CRF12_BF "family" strains.

    Science.gov (United States)

    Guimarães, Monick L; Velarde-Dunois, Ketty G; Segurondo, David; Morgado, Mariza G

    2012-01-16

    Molecular epidemiological studies of HIV-1 in South America have revealed the occurrence of subtypes B, F1 and BF1 recombinants. Even so, little information concerning the HIV-1 molecular epidemiology in Bolivia is available. In this study we performed phylogenetic analyses from samples collected in Bolivia at two different points in time over a 10 year span. We analyzed these samples to estimate the trends in the HIV subtype and recombinant forms over time. Fifty one HIV-1 positive samples were collected in Bolivia over two distinct periods (1996 and 2005). These samples were genetically characterized based on partial pol protease/reverse transcriptase (pr/rt) and env regions. Alignment and neighbor-joining (NJ) phylogenetic analyses were established from partial env (n = 37) and all pol sequences using Mega 4. The remaining 14 env sequences from 1996 were previously characterized based on HMA-env (Heteroduplex mobility assay). The Simplot v.3.5.1 program was used to verify intragenic recombination, and SplitsTree 4.0 was employed to confirm the phylogenetic relationship of the BF1 recombinant samples. Phylogenetic analysis of both env and pol regions confirmed the predominance of "pure" subtype B (72.5%) samples circulating in Bolivia and revealed a high prevalence of BF1 genotypes (27.5%). Eleven out of 14 BF1 recombinants displayed a mosaic structure identical or similar to that described for the CRF12_BF variant, one sample was classified as CRF17_BF, and two others were F1pol/Benv. No "pure" HIV-1 subtype F1 or B" variant of subtype B was detected in the present study. Of note, samples characterized as CRF12_BF-related were depicted only in 2005. HIV-1 genetic diversity in Bolivia is mostly driven by subtype B followed by BF1 recombinant strains from the CRF12_BF "family". No significant temporal changes were detected between the mid-1990s and the mid-2000s for subtype B (76.2% vs 70.0%) or BF1 recombinant (23.8% vs 30.0%) samples from Bolivia.

  17. Molecular subtyping of Campylobacter jejuni subsp. jejuni strains isolated from different animal species in the state of São Paulo, Brazil Subtipagem molecular de estirpes de Campylobacter jejuni subsp. jejuni isoladas de diferentes espécies animais do Estado de São Paulo, Brasil

    Directory of Open Access Journals (Sweden)

    Eliana Scarcelli

    2005-12-01

    Full Text Available The objective of the present trial was to characterize genetically strains of Campylobacter jejuni subsp. jejuni isolated from humans and several animal sources (bovines, swine, dogs, primates, wild boars and poultry. A total of 828 different animal samples (feces, carcass, aborted fetus and hysterectomized uterus were analysed by means of routine bacteriological methods, and 36 C. jejuni strains were isolated. Thirty strains of human fecal origin were obtained in clinical analysis laboratories in the city of São Paulo. The 66 C. jejuni strains isolated were submitted to genetic characterization. Primers based on fla A gene were used in a polymerase chain reaction (PCR and amplified a fragment of the 702 bp. PCR products were evaluated by means of sequencing and genealogic analysis. Genetic variability analysis of 66 strains showed 44 different subtypes of C. jejuni. One subtype was identical to a C. jejuni strain of human origin with the sequence in the GenBank (GENBANK accession number AF050186. Subtyping analysis of C. jejuni strains based on sequencing of the fla A gene variable region and analysis of sequence alignment by the Maximum Parsimony method showed to be highly discriminatory, providing the best conditions to differentiate strains involved in outbreaks from those sporadically isolated. This is the first study of molecular subtyping analysis of human and animal C. jejuni strains using sequencing technique and genealogic analysis in the state of São Paulo, Brazil.O objetivo do presente trabalho foi caracterizar geneticamente estirpes de Campylobacter jejuni subsp. jejuni isoladas de humanos e de diferentes origens animais (bovinas, suínas, cães, primatas, javalis, suínos e aves de corte. Um total de 828 amostras (fezes, carcaças, fetos abortados e útero histerectomizado foram analisadas por métodos de rotina bacteriológica e 36 estirpes de C. jejuni foram isoladas. Trinta estirpes de origem fecal humana foram obtidas de

  18. Comparison by restriction fragment pattern analyses and molecular characterization of some European isolates of Suid herpesvirus 1: A contribution to strain differentiation of European isolates

    DEFF Research Database (Denmark)

    Christensen, Laurids Siig

    1988-01-01

    Eleven European isolates of Suid herpesvirus type 1 (SHV-1) were compared by restriction fragment pattern analyses and Southern blot hybridization using different genomic probes. The presence of strain discriminative 4 major genome types and several subtypes as well as the molecular distinctions...

  19. Psychopathy subtypes and psychopathic violence

    OpenAIRE

    Koshkina Ekaterina Nikolaevna

    2015-01-01

    This article analyses two main subtypes of psychopathy and its characteristic traits that allow to differ them from each other. Following that, the existence of more specific subtypes of psychopathy and sociopathy is argued on the basis of the recent researches. Also, the inclination of psychopaths and sociopaths to various kinds of violence is examined.

  20. Subtyping aggression and predicting cognitive behavioral treatment response in adolescents. What works for whom?

    NARCIS (Netherlands)

    Smeets, K.C.

    2017-01-01

    This dissertation describes the clinical relevance of the distinction between proactive and reactive aggression in adolescents with aggression problems. These subtypes of aggression can be clinical distinguished on the level of severity rather than typology; proactive aggression is always

  1. Molecular characterization and epidemiological investigation of Cryptosporidium hominis IkA18G1 and C. hominis monkey genotype IiA17, two unusual subtypes diagnosed in Swedish patients.

    Science.gov (United States)

    Lebbad, Marianne; Winiecka-Krusnell, Jadwiga; Insulander, Mona; Beser, Jessica

    2018-03-06

    Cryptosporidium hominis is considered a strictly human-adapted species, and it is only occasionally diagnosed in animals. However, two variants, C. hominis monkey genotype and C. hominis Ik, were originally described in non-human hosts, monkeys and horses, respectively. During a Swedish national Cryptosporidium study, where all samples were analyzed at the small subunit rRNA and the 60 kDa (gp60) glycoprotein loci, we identified two patients infected with C. hominis monkey genotype (subtype IiA17) and two infected with C. hominis subtype IkA18G1. The isolates were further analyzed at the actin and the 70 kDa heat shock protein loci, and these analyses showed that these two subtype families are closely related to each other and to human-adapted C. hominis as well as to Cryptosporidium cuniculus. The two patients with C. hominis monkey genotype infection (a father and son) had visited a monkey farm in Thailand prior to infection, while the two cases with C. hominis Ik were unrelated, both probably infected in Sweden. This is the first time that a monkey genotype infection in humans has been related to contact with monkeys and where the gp60 subtype was identified. It is also the first time that human infection caused by C. hominis subtype Ik is described. Even though we were not able to detect any parasites in the animal samples, zoonotic transmission cannot be ruled out in any of these cases because both subtype families are regarded as animal adapted. Copyright © 2018 Elsevier Inc. All rights reserved.

  2. Molecular profiling of intrahepatic cholangiocarcinoma

    DEFF Research Database (Denmark)

    Oliveira, Douglas V N P; Zhang, Shanshan; Chen, Xin

    2017-01-01

    . Areas covered: The present review article outlines the main studies and resulting discoveries on the molecular profiling of iCCA, with a special emphasis on the different techniques used for this purpose, the diagnostic and prognostic markers identified, as well as the genes and pathways that could......INTRODUCTION: Intrahepatic cholangiocarcinoma (iCCA) is the second most frequent primary tumor of the liver and a highly lethal disease. Therapeutic options for advanced iCCA are limited and ineffective due to the largely incomplete understanding of the molecular pathogenesis of this deadly tumor...... be potentially targeted with innovative therapies. Expert commentary: Molecular profiling has led to the identification of distinct iCCA subtypes, characterized by peculiar genetic alterations and transcriptomic features. Targeted therapies against some of the identified genes are ongoing and hold great promise...

  3. Subclass mapping: identifying common subtypes in independent disease data sets.

    Directory of Open Access Journals (Sweden)

    Yujin Hoshida

    Full Text Available Whole genome expression profiles are widely used to discover molecular subtypes of diseases. A remaining challenge is to identify the correspondence or commonality of subtypes found in multiple, independent data sets generated on various platforms. While model-based supervised learning is often used to make these connections, the models can be biased to the training data set and thus miss inherent, relevant substructure in the test data. Here we describe an unsupervised subclass mapping method (SubMap, which reveals common subtypes between independent data sets. The subtypes within a data set can be determined by unsupervised clustering or given by predetermined phenotypes before applying SubMap. We define a measure of correspondence for subtypes and evaluate its significance building on our previous work on gene set enrichment analysis. The strength of the SubMap method is that it does not impose the structure of one data set upon another, but rather uses a bi-directional approach to highlight the common substructures in both. We show how this method can reveal the correspondence between several cancer-related data sets. Notably, it identifies common subtypes of breast cancer associated with estrogen receptor status, and a subgroup of lymphoma patients who share similar survival patterns, thus improving the accuracy of a clinical outcome predictor.

  4. Diagnosis Molekuler Virus Flu Burung-A Subtipe H5 Berdasarkan Amplifikasi Gen M dan H5 dengan Metode Onestep Simplex RT-PCR (MOLECULAR DIAGNOSIS OF AVIAN INFLUENZA VIRUS TYPE A AND SUBTYPE H5 BY AMPLIFICATION OF ITS M AND H5 GENES USING ONE STEP SIMPLEX R

    Directory of Open Access Journals (Sweden)

    Aris Haryanto

    2014-08-01

    Full Text Available Influenza A viruses which belong to the Family of Orthomyxoviridae are a group of viruses withsegmented ssRNA genome. The viruses can be subgroupped into many subtypes on the basis of theirsurface glycoproteins, hemagglutinin (HA and neuraminidase (NA proteins. Among the HA subtypes, H5and H7 have been found to be the most pathogenic. Conventional diagnosis of the viruses is usuallyperformed by isolation of the viruses in embryonated eggs, and hemagglutination (HA and hemagglutinationinhibition test. Although those methods are sensitive and accurate, they are time consuming and requirelaboratory facilities with high biosafety level. Commercial methods such as emzyme-linked immonosorbentassay (ELISA and immunoflurescense assay also provide a rapid result but less sensitive and specificthan conventional methods. Molecular diagnosis by amplification of M and H5 genes using one strepsimplex reverse transcriptase-polymerase chain eraction (RT-PCR provices a rapid and accurate diagnosisfor the viruses. A study was therefore conducted to evaluate the accurate and rapidity of such the moleculartests for diagnosis of avian influenza A virus, subtype H5. As many as 10 sample of the virus isolateswhich were available at the Animal Desease investigation Center in Wates, Yogyakarta, were uses in thisstudy. The virus isolates were firstly propagated in specific antigen negative (SAN chicken embryos andtested by HA/HI test. The viruses were then subjected for the RT-PCR test with varying annealingtemperatures of 500C and 520C. The result showed that all 10 isolates were type A influenza virus and 8out of 10 were influenza A subtype H5 influenza virus. RT-PCR used in this study appears to be moresensitive, rapid and accurate as compared to those by serological and isolation of the virus in embryonatedeggs.

  5. Targeted Inactivation of Bax Reveals a Subtype-Specific Mechanism of Cajal-Retzius Neuron Death in the Postnatal Cerebral Cortex

    Directory of Open Access Journals (Sweden)

    Fanny Ledonne

    2016-12-01

    Full Text Available Cajal-Retzius cells (CRs, the first-born neurons in the developing cerebral cortex, coordinate crucial steps in the construction of functional circuits. CRs are thought to be transient, as they disappear during early postnatal life in both mice and humans, where their abnormal persistence is associated with pathological conditions. Embryonic CRs comprise at least three molecularly and functionally distinct subtypes: septum, ventral pallium/pallial-subpallial boundary (PSB, and hem. However, whether subtype-specific features exist postnatally and through which mechanisms they disappear remain unknown. We report that CR subtypes display unique distributions and dynamics of death in the postnatal mouse cortex. Surprisingly, although all CR subtypes undergo cell death, septum, but not hem, CRs die in a Bax-dependent manner. Bax-inactivated rescued septum-CRs maintain immature electrophysiological properties. These results underlie the existence of an exquisitely refined control of developmental cell death and provide a model to test the effect of maintaining immature circuits in the adult neocortex.

  6. The molecular dimension of microbial species: 1. Ecological distinctions among, and homogeneity within, putative ecotypes of Synechococcus inhabiting the cyanobacterial mat of Mushroom Spring, Yellowstone National Park

    DEFF Research Database (Denmark)

    Becraft, Eric D.; Wood, Jason M.; Rusch, Douglas B.

    2015-01-01

    and transcripts over a large number of habitat types in the Mushroom Spring microbial mat. Putative ecological species [putative ecotypes (PEs)], which were predicted by an evolutionary simulation based on the Stable Ecotype Model (Ecotype Simulation), exhibited distinct distributions relative to temperature...

  7. Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder

    NARCIS (Netherlands)

    Stewart, Douglas R.; Brems, Hilde; Gomes, Alicia G.; Ruppert, Sarah L.; Callens, Tom; Williams, Jennifer; Claes, Kathleen; Bober, Michael B.; Hachen, Rachel; Kaban, Leonard B.; Li, Hua; Lin, Angela; McDonald, Marie; Melancon, Serge; Ortenberg, June; Radtke, Heather B.; Samson, Ignace; Saul, Robert A.; Shen, Joseph; Siqveland, Elizabeth; Toler, Tomi L.; van Maarle, Merel; Wallace, Margaret; Williams, Misti; Legius, Eric; Messiaen, Ludwine

    2014-01-01

    "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of

  8. Sensory processing subtypes in autism: association with adaptive behavior.

    Science.gov (United States)

    Lane, Alison E; Young, Robyn L; Baker, Amy E Z; Angley, Manya T

    2010-01-01

    Children with autism are frequently observed to experience difficulties in sensory processing. This study examined specific patterns of sensory processing in 54 children with autistic disorder and their association with adaptive behavior. Model-based cluster analysis revealed three distinct sensory processing subtypes in autism. These subtypes were differentiated by taste and smell sensitivity and movement-related sensory behavior. Further, sensory processing subtypes predicted communication competence and maladaptive behavior. The findings of this study lay the foundation for the generation of more specific hypotheses regarding the mechanisms of sensory processing dysfunction in autism, and support the continued use of sensory-based interventions in the remediation of communication and behavioral difficulties in autism.

  9. Breast cancer lung metastasis: molecular biology and therapeutic implications.

    Science.gov (United States)

    Jin, Liting; Han, Bingchen; Siegel, Emily; Cui, Yukun; Giuliano, Armando; Cui, Xiaojiang

    2018-03-26

    Distant metastasis accounts for the vast majority of deaths in patients with cancer. Breast cancer exhibits a distinct metastatic pattern commonly involving bone, liver, lung, and brain. Breast cancer can be divided into different subtypes based on gene expression profiles, and different breast cancer subtypes show preference to distinct organ sites of metastasis. Luminal breast tumors tend to metastasize to bone while basal-like breast cancer (BLBC) displays a lung tropism of metastasis. However, the mechanisms underlying this organ-specific pattern of metastasis still remain to be elucidated. In this review, we will summarize the recent advances regarding the molecular signaling pathways as well as the therapeutic strategies for treating breast cancer lung metastasis.

  10. Diagnosis and subtypes of adolescent antisocial personality disorder.

    Science.gov (United States)

    Jones, Meredith; Westen, Drew

    2010-04-01

    The present study examined the application of the Antisocial Personality Disorder (APD) diagnosis to adolescents and investigated the possibility of subtypes of APD adolescents. As part of a broader study of adolescent personality in clinically-referred patients, experienced clinicians provided personality data on a randomly selected patient in their care using the SWAP-II-A personality pathology instrument. Three hundred thirteen adolescents met adult DSM-IV diagnostic criteria for APD. To characterize adolescents with the disorder, we aggregated the data to identify the items most descriptive and distinctive of APD adolescents relative to other teenagers in the sample (N = 950). Q-factor analysis identified five personality subtypes: psychopathic-like, socially withdrawn, impulsive-histrionic, emotionally dysregulated, and attentionally dysregulated. The five subtypes differed in predictable ways on a set of external criteria related to global adaptive functioning, childhood family environment, and family history of psychiatric illness. Both the APD diagnosis and the empirically derived APD subtypes provided incremental validity over and above the DSM-IV disruptive behavior disorders in predicting global adaptive functioning, number of arrests, early-onset severe externalizing pathology, and quality of peer relationships. Although preliminary, these results provide support for the use of both APD and personality-based subtyping systems in adolescents.

  11. Clinically-inspired automatic classification of ovarian carcinoma subtypes

    Directory of Open Access Journals (Sweden)

    Aicha BenTaieb

    2016-01-01

    Full Text Available Context: It has been shown that ovarian carcinoma subtypes are distinct pathologic entities with differing prognostic and therapeutic implications. Histotyping by pathologists has good reproducibility, but occasional cases are challenging and require immunohistochemistry and subspecialty consultation. Motivated by the need for more accurate and reproducible diagnoses and to facilitate pathologists′ workflow, we propose an automatic framework for ovarian carcinoma classification. Materials and Methods: Our method is inspired by pathologists′ workflow. We analyse imaged tissues at two magnification levels and extract clinically-inspired color, texture, and segmentation-based shape descriptors using image-processing methods. We propose a carefully designed machine learning technique composed of four modules: A dissimilarity matrix, dimensionality reduction, feature selection and a support vector machine classifier to separate the five ovarian carcinoma subtypes using the extracted features. Results: This paper presents the details of our implementation and its validation on a clinically derived dataset of eighty high-resolution histopathology images. The proposed system achieved a multiclass classification accuracy of 95.0% when classifying unseen tissues. Assessment of the classifier′s confusion (confusion matrix between the five different ovarian carcinoma subtypes agrees with clinician′s confusion and reflects the difficulty in diagnosing endometrioid and serous carcinomas. Conclusions: Our results from this first study highlight the difficulty of ovarian carcinoma diagnosis which originate from the intrinsic class-imbalance observed among subtypes and suggest that the automatic analysis of ovarian carcinoma subtypes could be valuable to clinician′s diagnostic procedure by providing a second opinion.

  12. Temporal trends and molecular epidemiology of HIV type 1 infection in Rio de Janeiro, Brazil.

    Science.gov (United States)

    Pimentel, Victor F; Morgado, Mariza G; Bello, Gonzalo; Guimarães, Mark D C; Castilho, Euclides A; Veloso, Valdilea G; Guimarães, Monick L

    2013-12-01

    HIV-1 molecular epidemiology studies carried out in Rio de Janeiro, Brazil have identified the prevalence of subtypes B, F1 and BF1 recombinants. A high percentage of HIV-1 subtype B isolates in Rio de Janeiro harbor the GWG motif at the V3 tip (B'' variant) instead of the canonical GPG motif (B variant). To trace the dynamics of the HIV-1 variants over time in different exposure categories in Rio de Janeiro, the HIV-1 proviral DNA from heterosexual men (HET) and men who have sex with men (MSM) from two distinct time periods (1990-1992 and 2008-2010) were extracted, and the env-gp120 region was amplified. Neighbor-joining phylogenetic analysis was performed to determine the viral subtype, and Bayesian analysis was used to trace the HIV-1 transmission networks. A predominance of subtype B was observed in both study periods, independent of the exposure risk category. An increase of non-B subtypes was observed in the HET group, but these subtypes were maintained among the MSM group. The distribution of HIV-1 subtype B signatures in the first and second periods studied were, respectively, HET (GPG) [44.8-51.5%], (GWG) [13.8-33.3%], and (GXG) [41.4-15.2%] and MSM (GPG) [34-50%], (GWG) [55.3-30.6%], and (GXG) [10.7-19.4%]. In the first period, an association between GWG and MSM was verified while a significant reduction of this association was observed during the second period. The phylogenetic tree and the BaTS program detected the clustering of isolates only according to the B signatures but not by exposure risk category. Our findings indicate a stable prevalence of HIV-1 subtypes B and F over time in Rio de Janeiro and further suggest that the B'' subclade of subtype B was possibly introduced into the MSM group in this area of Brazil.

  13. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability.

    Science.gov (United States)

    Frielink, N; Schuengel, C; Embregts, P

    2017-07-01

    According to self-determination theory, motivation is ordered in types, including amotivation, extrinsic motivation and intrinsic motivation. Self-determination theory defines four subtypes of extrinsic motivation: external motivation, introjected motivation, identified motivation and integrated motivation. Although it has been argued theoretically that the different types of motivation are universally applicable, Reid et al. () proposed a dichotomy of broad subtypes of extrinsic motivation for people with intellectual disability (ID) due to their cognitive limitations. The current study challenges this proposal by testing whether the four subtypes of extrinsic motivation can be differentiated among people with ID as well. The subtypes of extrinsic motivation were measured using two adapted versions of the Self-Regulation Questionnaire, one regarding exercise and one regarding support. In total, 186 adults with mild to borderline ID participated in the study. Results supported the distinction between the four subtypes of extrinsic motivation regarding both exercise and support. In addition, the correlation coefficients supported a quasi-simplex pattern of correlations among the subtypes, indicating that adjacent subtypes were more closely related than non-adjacent subtypes. Moreover, the study showed sufficient Cronbach's alphas and test-retest reliabilities for early stage research. Overall, the results of the current study provide initial evidence for the universality of the four subtypes of extrinsic motivation across populations with and without ID. © 2017 The Authors. Journal of Intellectual Disability Research published by MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disibilities and John Wiley & Sons Ltd.

  14. A molecular census of arcuate hypothalamus and median eminence cell types

    DEFF Research Database (Denmark)

    Campbell, John N; Macosko, Evan Z; Fenselau, Henning

    2017-01-01

    The hypothalamic arcuate-median eminence complex (Arc-ME) controls energy balance, fertility and growth through molecularly distinct cell types, many of which remain unknown. To catalog cell types in an unbiased way, we profiled gene expression in 20,921 individual cells in and around the adult...... mouse Arc-ME using Drop-seq. We identify 50 transcriptionally distinct Arc-ME cell populations, including a rare tanycyte population at the Arc-ME diffusion barrier, a new leptin-sensing neuron population, multiple agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) subtypes, and an orexigenic...... somatostatin neuron population. We extended Drop-seq to detect dynamic expression changes across relevant physiological perturbations, revealing cell type-specific responses to energy status, including distinct responses in AgRP and POMC neuron subtypes. Finally, integrating our data with human genome...

  15. CCR 20th Anniversary Commentary: Divide and Conquer-Breast Cancer Subtypes and Response to Therapy.

    Science.gov (United States)

    Pusztai, Lajos; Rouzier, Roman; Symmans, W Fraser

    2015-08-15

    The article by Rouzier and colleagues, published in the August 15, 2005, issue of Clinical Cancer Research, demonstrated that different molecular subtypes of breast cancer have different degrees of sensitivity to chemotherapy, but the extent of response to neoadjuvant therapy has a different meaning by subtype. Several molecular subtype-specific clinical trials are under way to maximize pathologic complete response rates in triple-negative breast cancer and HER2-positive cancers, and to provide adjuvant treatment options for patients with residual invasive disease. See related article by Rouzier et al., Clin Cancer Res 2005;11(16) Aug 15, 2005;5678-85. ©2015 American Association for Cancer Research.

  16. The molecular dimension of microbial species: 1. Ecological distinctions among, and homogeneity within, putative ecotypes of Synechococcus inhabiting the cyanobacterial mat of Mushroom Spring, Yellowstone National Park

    Directory of Open Access Journals (Sweden)

    Eric Daniel Becraft

    2015-06-01

    Full Text Available Based on the Stable Ecotype Model, evolution leads to the divergence of ecologically distinct populations (e.g., with different niches and/or behaviors of ecologically interchangeable membership. In this study, pyrosequencing was used to provide deep sequence coverage of Synechococcus psaA genes and transcripts over a large number of habitat types in the Mushroom Spring microbial mat. Putative ecological species (putative ecotypes, which were predicted by an evolutionary simulation based on the Stable Ecotype Model (Ecotype Simulation, exhibited distinct distributions relative to temperature-defined positions in the effluent channel and vertical position in the upper 1 mm-thick mat layer. Importantly, in most cases variants predicted to belong to the same putative ecotype formed unique clusters relative to temperature and depth in the mat in canonical correspondence analysis, supporting the hypothesis that while the putative ecotypes are ecologically distinct, the members of each ecotype are ecologically homogeneous. Putative ecotypes responded differently to experimental perturbations of temperature and light, but the genetic variation within each putative ecotype was maintained as the relative abundances of putative ecotypes changed, further indicating that each population responded as a set of ecologically interchangeable individuals. Compared to putative ecotypes that predominate deeper within the mat photic zone, the timing of transcript abundances for selected genes differed for putative ecotypes that predominate in microenvironments closer to upper surface of the mat with spatiotemporal differences in light and O2 concentration. All of these findings are consistent with the hypotheses that Synechococcus species in hot spring mats are sets of ecologically interchangeable individuals that are differently adapted, that these adaptations control their distributions, and that the resulting distributions constrain the activities of the species

  17. PO and ID BCG vaccination in humans induce distinct mucosal and systemic immune responses and CD4+T cell transcriptomal molecular signatures.

    Science.gov (United States)

    Hoft, D F; Xia, M; Zhang, G L; Blazevic, A; Tennant, J; Kaplan, C; Matuschak, G; Dube, T J; Hill, H; Schlesinger, L S; Andersen, P L; Brusic, V

    2017-08-30

    Protective efficacy of Bacillus Calmette-Guérin (BCG) may be affected by the methods and routes of vaccine administration. We have studied the safety and immunogenicity of oral (PO) and/or intradermal (ID) administration of BCG in healthy human subjects. No major safety concerns were detected in the 68 healthy adults vaccinated with PO and/or ID BCG. Although both PO and ID BCG could induce systemic Th1 responses capable of IFN-γ production, ID BCG more strongly induced systemic Th1 responses. In contrast, stronger mucosal responses (TB-specific secretory IgA and bronchoalveolar lavage T cells) were induced by PO BCG vaccination. To generate preliminary data comparing the early gene signatures induced by mucosal and systemic BCG vaccination, CD4 + memory T cells were isolated from subsets of BCG vaccinated subjects pre- (Day 0) and post-vaccination (Days 7 and 56), rested or stimulated with BCG infected dendritic cells, and then studied by Illumina BeadArray transcriptomal analysis. Notably, distinct gene expression profiles were identified both on Day 7 and Day 56 comparing the PO and ID BCG vaccinated groups by GSEA analysis. Future correlation analyses between specific gene expression patterns and distinct mucosal and systemic immune responses induced will be highly informative for TB vaccine development.Mucosal Immunology advance online publication 30 August 2017; doi:10.1038/mi.2017.67.

  18. Explosive HIV-1 subtype B' epidemics in Asia driven by geographic and risk group founder events.

    Science.gov (United States)

    Li, Yue; Uenishi, Rie; Hase, Saiki; Liao, Huanan; Li, Xiao-Jie; Tsuchiura, Takayo; Tee, Kok Keng; Pybus, Oliver G; Takebe, Yutaka

    2010-07-05

    We explored the timescale, spatial spread, and risk group population structure of HIV-1 subtype B', the cause of explosive blood-borne HIV-1 epidemics among injecting drug users (IDUs) and former plasma donors (FPDs) in Asia. Sequences from FPDs in China formed a distinct monophyletic cluster within subtype B'. Further analysis revealed that subtype B' was founded by a single lineage of pandemic subtype B around 1985. Subsequently, the FPD cluster appears to have derived from a single subtype B' lineage around 1991, corroborating the hypothesis that FPD outbreaks stemmed from the preceding epidemic among IDUs in Southeast Asia, most likely from the Golden-Triangle region. Copyright 2010 Elsevier Inc. All rights reserved.

  19. The Region of Difference Four is a Robust Genetic Marker for Subtyping Mycobacterium caprae Isolates and is Linked to Spatial Distribution of Three Subtypes.

    Science.gov (United States)

    Rettinger, A; Broeckl, S; Fink, M; Prodinger, W M; Blum, H; Krebs, S; Domogalla, J; Just, F; Gellert, S; Straubinger, R K; Büttner, M

    2017-06-01

    Alpine Mycobacterium caprae isolates found in cattle and red deer display at least three genetic variations in the region of difference four (RD4) that can be used for further differentiation of the isolates into the subtypes 'Allgäu', 'Karwendel' and 'Lechtal'. Each genomic subtype is thereby characterized by a specific nucleotide deletion pattern in the 12.7-kb RD4 region. Even though M. caprae infections are frequently documented in cattle and red deer, little is known about the transmission routes. Hence, robust markers for M. caprae subtyping are needed to gain insight into the molecular epidemiology. For this reason, a rapid and robust multiplex PCR was developed for the simultaneous detection of three M. caprae RD4 subtypes and was used to subtype a total number of 241 M. caprae isolates from animals (145 cattle, 95 red deer and one fox) from Bavaria and Austria. All three subtypes occur spatially distributed and are found in cattle and in red deer suggesting transmission between the two species. As subtypes are genetically stable in both species it is hypothesized that the described genetic variations developed within the host due to 'within-host replication'. The results of this study recommend the genomic RD4 region as a reliable diagnostic marker for M. caprae subtype differentiation. © 2015 Blackwell Verlag GmbH.

  20. Exposure of honey bees (Apis mellifera) to different classes of insecticides exhibit distinct molecular effect patterns at concentrations that mimic environmental contamination.

    Science.gov (United States)

    Christen, Verena; Fent, Karl

    2017-07-01

    Pesticides are implicated in the decline of honey bee populations. Many insecticides are neurotoxic and act by different modes of actions. Although a link between insecticide exposure and changed behaviour has been made, molecular effects underlying these effects are poorly understood. Here we elucidated molecular effects at environmental realistic concentrations of two organophosphates, chlorpyrifos and malathion, the pyrethroid cypermethrin, and the ryanodine receptor activator, chlorantraniliprole. We assessed transcriptional alterations of selected genes at three exposure times (24 h, 48 h, 72 h) in caged honey bees exposed to different concentrations of these compounds. Our targeted gene expression concept focused on several transcripts, including nicotinic acetylcholine receptor α 1 and α 2 (nAChRα1, nAChRα2) subunits, the multifunctional gene vitellogenin, immune system related genes of three immune system pathways, genes belonging to the detoxification system and ER stress genes. Our data indicate a dynamic pattern of expressional changes at different exposure times. All four insecticides induced strong alterations in the expression of immune system related genes suggesting negative implications for honey bee health, as well as cytochrome P450 enzyme transcripts suggesting an interference with metabolism. Exposure to neurotoxic chlorpyrifos, malathion and cypermethrin resulted in up-regulation of nAChRα1 and nAChRα2. Moreover, alterations in the expression of vitellogenin occurred, which suggests implications on foraging activity. Chlorantraniliprole induced ER stress which may be related to toxicity. The comparison of all transcriptional changes indicated that the expression pattern is rather compound-specific and related to its mode of action, but clusters of common transcriptional changes between different compounds occurred. As transcriptional alterations occurred at environmental concentrations our data provide a molecular basis for observed

  1. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

    Energy Technology Data Exchange (ETDEWEB)

    Verhaak, Roel GW; Hoadley, Katherine A; Purdom, Elizabeth; Wang, Victoria; Qi, Yuan; Wilkerson, Matthew D; Miller, C Ryan; Ding, Li; Golub, Todd; Mesirov, Jill P; Alexe, Gabriele; Lawrence, Michael; O' Kelly, Michael; Tamayo, Pablo; Weir, Barbara A; Gabriel, Stacey; Winckler, Wendy; Gupta, Supriya; Jakkula, Lakshmi; Feiler, Heidi S; Hodgson, J Graeme; James, C David; Sarkaria, Jann N; Brennan, Cameron; Kahn, Ari; Spellman, Paul T; Wilson, Richard K; Speed, Terence P; Gray, Joe W; Meyerson, Matthew; Getz, Gad; Perou, Charles M; Hayes, D Neil; Network, The Cancer Genome Atlas Research

    2009-09-03

    The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.

  2. Molecular mechanisms of protein-cholesterol interactions in plasma membranes: Functional distinction between topological (tilted) and consensus (CARC/CRAC) domains.

    Science.gov (United States)

    Fantini, Jacques; Di Scala, Coralie; Baier, Carlos J; Barrantes, Francisco J

    2016-09-01

    The molecular mechanisms that control the multiple possible modes of protein association with membrane cholesterol are remarkably convergent. These mechanisms, which include hydrogen bonding, CH-π stacking and dispersion forces, are used by a wide variety of extracellular proteins (e.g. microbial or amyloid) and membrane receptors. Virus fusion peptides penetrate the membrane of host cells with a tilted orientation that is compatible with a transient interaction with cholesterol; this tilted orientation is also characteristic of the process of insertion of amyloid proteins that subsequently form oligomeric pores in the plasma membrane of brain cells. Membrane receptors that are associated with cholesterol generally display linear consensus binding motifs (CARC and CRAC) characterized by a triad of basic (Lys/Arg), aromatic (Tyr/phe) and aliphatic (Leu/Val) amino acid residues. In some cases, the presence of both CARC and CRAC within the same membrane-spanning domain allows the simultaneous binding of two cholesterol molecules, one in each membrane leaflet. In this review the molecular basis and the functional significance of the different modes of protein-cholesterol interactions in plasma membranes are discussed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  3. Regional brain network organization distinguishes the combined and inattentive subtypes of Attention Deficit Hyperactivity Disorder

    OpenAIRE

    Jacqueline F. Saad; Kristi R. Griffiths; Michael R. Kohn; Simon Clarke; Leanne M. Williams; Mayuresh S. Korgaonkar

    2017-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is characterized clinically by hyperactive/impulsive and/or inattentive symptoms which determine diagnostic subtypes as Predominantly Hyperactive-Impulsive (ADHD-HI), Predominantly Inattentive (ADHD-I), and Combined (ADHD-C). Neuroanatomically though we do not yet know if these clinical subtypes reflect distinct aberrations in underlying brain organization. We imaged 34 ADHD participants defined using DSM-IV criteria as ADHD-I (n?=?16) or as ADH...

  4. Subtype-specific reduction of olfactory bulb interneurons in Pax6 heterozygous mutant mice.

    Science.gov (United States)

    Haba, Hasumi; Nomura, Tadashi; Suto, Fumikazu; Osumi, Noriko

    2009-09-01

    Interneurons in the olfactory bulb (OB) play essential roles in the processing of olfactory information. They are classified into several subpopulations by the expression of different neurochemical markers. Here we focused on a transcription factor Pax6, and examined its expression and function in distinct subtypes of OB interneurons. We identified Pax6 expression in specific subtypes of interneurons in the external plexiform layer (EPL). The number of these interneuron subtypes was dramatically decreased in Pax6 heterozygous mutant mice. These results indicate that Pax6 is required for differentiation and/or maintenance of EPL interneurons in the adult mouse OB.

  5. Selective labeling and localization of the M4 (m4) muscarinic receptor subtype.

    Science.gov (United States)

    Ferrari-Dileo, G; Waelbroeck, M; Mash, D C; Flynn, D D

    1994-12-01

    We report here a novel strategy for the selective labeling and localization of the M4 (m4) muscarinic receptor subtype, based on the distinct kinetics of the muscarinic antagonists dexetimide and N-methylscopolamine (NMS) and on the selectivity profile of guanylpirenzepine and AF-DX 116 for the m1-m5 muscarinic receptor subtypes expressed in CHO-K1 cells. Incubation with 10 nM dexetimide, a nonselective antagonist, resulted in > 90% occupancy of each of the m1-m5 receptor subtypes. The relatively rapid rates of dexetimide dissociation from the m1, m2, and m4 receptor subtypes (t1/2 values of m4 receptor subtypes with short incubations with [3H]NMS. Inclusion of 200 nM guanylpirenzepine and 250 nM AF-DX 116 prevented the binding of [3H]NMS to the majority of the m1 and m2 receptor subtypes, respectively, resulting in primary labeling of the m4 receptor subtype. Brief dissociation of the radioligand in the presence of 1 microM atropine improved the ratio of m4 to m2 labeling by selectively removing [3H]NMS from the m2 subtype. Under these conditions, the ratio of [3H]NMS binding to the m4 versus m1, m2, m3, and m5 receptor subtypes was 4:1. In vitro autoradiography combined with these m4-selective labeling conditions demonstrated that the M4 (m4) receptor subtype was localized to the primary visual area (V1, area 17, occipital cortex) and the basal ganglia, a distribution distinct from that demonstrated for the M1 (m1), M2 (m2), and M3 (m3) receptor subtypes. These results demonstrate that a combination of the distinct kinetics of dexetimide and NMS and the receptor subtype selectivity of guanylpirenzepine and AF-DX 116 provides a valuable labeling strategy to examine the distribution and localization of the M4 (m4) muscarinic receptor subtype in brain, peripheral tissues, and cell lines.

  6. Molecular and Biological Characterization of Distinct Strains of Jatropha mosaic virus from the Dominican Republic Reveal a Potential to Infect Crop Plants.

    Science.gov (United States)

    Melgarejo, Tomas A; Kon, Tatsuya; Gilbertson, Robert L

    2015-01-01

    In the Dominican Republic (DO), jatropha plants with yellow mosaic symptoms are commonly observed in and around fields of various crop plants. Complete nucleotide sequences of DNA-A and DNA-B components of four bipartite begomovirus isolates associated with symptomatic jatropha plants collected from three geographical locations in the DO were determined. Sequence comparisons revealed highest identities (91 to 92%) with the DNA-A component of an isolate of Jatropha mosaic virus (JMV) from Jamaica, indicating that the bipartite begomovirus isolates from the DO are strains of JMV. When introduced into jatropha seedlings by particle bombardment, the cloned components of the JMV strains from the DO induced stunting and yellow mosaic, indistinguishable from symptoms observed in the field, thereby fulfilling Koch's postulates for the disease. The JMV strains also induced disease symptoms in Nicotiana benthamiana, tobacco, and several cultivars of common bean from the Andean gene pool, including one locally grown in the DO. Asymmetry in the infectivity and symptomatology of pseudorecombinants provided further support for the strain designation of the JMV isolates from the DO. Thus, JMV in the DO is a complex of genetically distinct strains that have undergone local evolution and have the potential to cause disease in crop plants.

  7. The Complex Subtype-Dependent Role of Connexin 43 (GJA1) in Breast Cancer

    Science.gov (United States)

    Busby, Mélanie; Hallett, Michael T.; Plante, Isabelle

    2018-01-01

    Gap junction transmembrane channels allow the transfer of small molecules between the cytoplasm of adjacent cells. They are formed by proteins named connexins (Cxs) that have long been considered as a tumor suppressor. This widespread view has been challenged by recent studies suggesting that the role of Connexin 43 (Cx43) in cancer is tissue- and stage-specific and can even promote tumor progression. High throughput profiling of invasive breast cancer has allowed for the construction of subtyping schemes that partition patients into at least four distinct intrinsic subtypes. This study characterizes Cx43 expression during cancer progression with each of the tumor subtypes using a compendium of publicly available gene expression data. In particular, we show that Cx43 expression depends greatly on intrinsic subtype. Tumor grade also co-varies with patient subtype, resulting in Cx43 co-expression with grade in a subtype-dependent manner. Better survival was associated with a high expression of Cx43 in unstratified and luminal tumors but with a low expression in Her2e subtype. A better understanding of Cx43 regulation in a subtype-dependent manner is needed to clarify the context in which Cx43 is associated with tumor suppression or cancer progression. PMID:29495625

  8. Clinical criteria for subtyping Parkinson's disease: biomarkers and longitudinal progression.

    Science.gov (United States)

    Fereshtehnejad, Seyed-Mohammad; Zeighami, Yashar; Dagher, Alain; Postuma, Ronald B

    2017-07-01

    Parkinson's disease varies widely in clinical manifestations, course of progression and biomarker profiles from person to person. Identification of distinct Parkinson's disease subtypes is of great priority to illuminate underlying pathophysiology, predict progression and develop more efficient personalized care approaches. There is currently no clear way to define and divide subtypes in Parkinson's disease. Using data from the Parkinson's Progression Markers Initiative, we aimed to identify distinct subgroups via cluster analysis of a comprehensive dataset at baseline (i.e. cross-sectionally) consisting of clinical characteristics, neuroimaging, biospecimen and genetic information, then to develop criteria to assign patients to a Parkinson's disease subtype. Four hundred and twenty-one individuals with de novo early Parkinson's disease were included from this prospective longitudinal multicentre cohort. Hierarchical cluster analysis was performed using data on demographic and genetic information, motor symptoms and signs, neuropsychological testing and other non-motor manifestations. The key classifiers in cluster analysis were a motor summary score and three non-motor features (cognitive impairment, rapid eye movement sleep behaviour disorder and dysautonomia). We then defined three distinct subtypes of Parkinson's disease patients: 223 patients were classified as 'mild motor-predominant' (defined as composite motor and all three non-motor scores below the 75th percentile), 52 as 'diffuse malignant' (composite motor score plus either ≥1/3 non-motor score >75th percentile, or all three non-motor scores >75th percentile) and 146 as 'intermediate'. On biomarkers, people with diffuse malignant Parkinson's disease had the lowest level of cerebrospinal fluid amyloid-β (329.0 ± 96.7 pg/ml, P = 0.006) and amyloid-β/total-tau ratio (8.2 ± 3.0, P = 0.032). Data from deformation-based magnetic resonance imaging morphometry demonstrated a Parkinson's disease

  9. Impact of age, intrinsic subtype and local treatment on long-term local-regional recurrence and breast cancer mortality among low-risk breast cancer patients

    DEFF Research Database (Denmark)

    Laurberg, Tinne; Alsner, Jan; Tramm, Trine

    2017-01-01

    -, HER2 receptor and Ki67.RESULTS: The majority of the tumors had a luminal subtype: 70% Luminal-A (LumA), 16% Luminal-B (LumB), and 10% Luminal-HER2 + (Lum-HER2+). The distribution of intrinsic subtypes between younger (≤45 years) and older (>45 years) patients was similar. Intrinsic subtypes had......, no distinct mortality pattern was observed, and the 20-year breast cancer mortality was not associated with intrinsic subtypes.CONCLUSION: Among low-risk patients, 96% of the tumors were Luminal and the distribution of intrinsic subtypes between younger (≤45 years) and older (>45 years) patients was similar...

  10. Subtypes of nonmedical prescription drug misuse

    Science.gov (United States)

    McCabe, Sean Esteban; Boyd, Carol J.; Teter, Christian J.

    2010-01-01

    This study used three characteristics (i.e., motive, route of administration, and co-ingestion with alcohol) of nonmedical prescription drug misuse across four separate classes (i.e., pain, sedative/anxiety, sleeping and stimulant medications) to examine subtypes and drug related problems. A Web survey was self-administered by a randomly selected sample of 3,639 undergraduate students attending a large Midwestern 4-year U.S. university. Self-treatment subtypes were characterized by motives consistent with the prescription drug's pharmaceutical main indication, oral only routes of administration, and no co-ingestion with alcohol. Recreational subtypes were characterized by recreational motives, oral or non-oral routes, and co-ingestion. Mixed subtypes consisted of other combinations of motives, routes, and co-ingestion. Among those who reported nonmedical prescription drug misuse, approximately 13% were classified into the recreational subtype, while 39% were in the self-treatment subtype, and 48% were in the mixed subtype. There were significant differences in the subtypes in terms of gender, race and prescription drug class. Approximately 50% of those in subtypes other than self-treatment screened positive for drug abuse. The odds of substance use and abuse were generally lower among self-treatment subtypes than other subtypes. The findings indicate subtypes should be considered when examining nonmedical prescription drug misuse, especially for pain medication. PMID:19278795

  11. Cognitive subtypes of mathematics learning difficulties in primary education.

    Science.gov (United States)

    Bartelet, Dimona; Ansari, Daniel; Vaessen, Anniek; Blomert, Leo

    2014-03-01

    It has been asserted that children with mathematics learning difficulties (MLD) constitute a heterogeneous group. To date, most researchers have investigated differences between predefined MLD subtypes. Specifically MLD children are frequently categorized a priori into groups based on the presence or absence of an additional disorder, such as a reading disorder, to examine cognitive differences between MLD subtypes. In the current study 226 third to six grade children (M age=131 months) with MLD completed a selection of number specific and general cognitive measures. The data driven approach was used to identify the extent to which performance of the MLD children on these measures could be clustered into distinct groups. In particular, after conducting a factor analysis, a 200 times repeated K-means clustering approach was used to classify the children's performance. Results revealed six distinguishable clusters of MLD children, specifically (a) a weak mental number line group, (b) weak ANS group, (c) spatial difficulties group, (d) access deficit group, (e) no numerical cognitive deficit group and (f) a garden-variety group. These findings imply that different cognitive subtypes of MLD exist and that these can be derived from data-driven approaches to classification. These findings strengthen the notion that MLD is a heterogeneous disorder, which has implications for the way in which intervention may be tailored for individuals within the different subtypes. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. The Correlation Between Candida Colonization of Distinct Body Sites and Invasive Candidiasis in Emergency Intensive Care Units: Statistical and Molecular Biological Analysis.

    Science.gov (United States)

    Li, Zhen; Jiang, Cen; Dong, Danfeng; Zhang, Lihua; Tian, Yuan; Ni, Qi; Mao, Enqiang; Peng, Yibing

    2016-08-01

    Both statistical and molecular biological methods were used to evaluate the association between Candida colonization of different body sites and invasive candidiasis (IC) and analyse the potential infection sources of IC. Candida surveillance cultures from the urine, sputum, rectum and skin were performed on patients admitted to an emergency intensive care units (EICU) of a tertiary care hospital in Shanghai, China, from February 2014 to January 2015. Specimens were collected once a week at admission and thereafter. The patients' clinical data were collected, and Candida isolates were genotyped using polymorphic microsatellite markers. A total of 111 patients were enrolled. Patients with positive urine (23.3 vs. 2.5 %, p = 0.001) and rectal swab (13.6 vs. 0 %, p = 0.010) cultures were more likely to develop IC. However, the risk for IC was not significantly different among patients with and without respiratory (10.0 vs. 5.8 %, p = 0.503) and skin (33.3 vs. 6.5 %, p = 0.056) colonization. Gene microevolution frequently occurred at rectal swab and urine sites, and IC with possible source of infection was caused by rectal isolates (2/7), urine isolates (4/7) and sputum isolate (1/7).The colonization of gut and urinary tract maybe more relevant indicators of IC, which should be taken into consideration when selecting practical body sites for Candida surveillance cultures.

  13. A Molecular Antenna Coordination Polymer from Cadmium(II and 4,4’-Bipyridine Featuring Three Distinct Polymer Strands in the Crystal

    Directory of Open Access Journals (Sweden)

    Iris M. Oppel

    2011-09-01

    Full Text Available Reaction of cadmium perchlorate and the prototypical linear bridging ligand 4,4’-bipyridine (4,4’-bipy in an ethanol/water mixture affords the one-dimensional coordination polymer, [{Cd(m-4,4’-bipy(4,4’-bipy2(H2O2}(ClO42 × 2 4,4’-bipy × 4.5 H2O]n (1. The Cd2+ ions adopt an octahedral coordination sphere and are joined into linear chains by 4,4’-bipy via two trans coordination sites. The remaining two trans sites in the equatorial plane carry terminally monodentate-bound 4,4’-bipy ligands, resulting in a molecular antenna arrangement. The two axial sites of each Cd2+ ion are occupied by aqua ligands. Compound 1 crystallizes in the non-centrosymmetric, monoclinic space group C2 with three similar, crystallographically independent, cationic coordination polymer strands in the unit cell, which essentially differ only in the conformations of the 4,4’-bipyridyl ligands. Consistent with the similarity of the local coordination environments of the three independent Cd atoms in the structure, 113Cd MAS NMR spectroscopy reveals a single resonance line at 89 ppm.

  14. Molecular characterization of coat protein gene of Garlic common latent virus isolates from India: an evidence for distinct phylogeny and recombination.

    Science.gov (United States)

    Pramesh, D; Baranwal, Virendra K

    2013-08-01

    The coat protein (CP) gene of five Indian Garlic common latent virus (GarCLV) isolates was sequenced and it was 960 bp long in all the five isolates, encoding a protein of 319 amino acids. Comparative nucleotide sequence analysis revealed diversity of 4.3% among the Indian isolates and of 11.9% among all isolates worldwide. Amino acid sequence comparison showed a significant variability in the N-terminal of CP of GarCLV. Various protein analysis tools identified thirteen conserved domains and motifs including Carlavirus and Potexvirus-specific Flexi CP and Flexi N CP. Phylogenetic analysis clustered GarCLV isolates in the subgroup II with isolates from Australia, Brazil, Japan, and South Korea. Intraspecies recombination study revealed that only one of the Indian isolates was a recombinant. Interspecies recombination study suggested the absence of genetic exchange from Carlavirus species to GarCLV; conversely, GarCLV was identified as a putative donor for at least two other Carlavirus species. This is the first report of molecular variability and recombination in GarCLV isolates.

  15. CRISPR-cas subtype I-Fb in Acinetobacter baumannii: evolution and utilization for strain subtyping.

    Science.gov (United States)

    Karah, Nabil; Samuelsen, Ørjan; Zarrilli, Raffaele; Sahl, Jason W; Wai, Sun Nyunt; Uhlin, Bernt Eric

    2015-01-01

    Clustered regularly interspaced short palindromic repeats (CRISPR) are polymorphic elements found in the genome of some or all strains of particular bacterial species, providing them with a system of acquired immunity against invading bacteriophages and plasmids. Two CRISPR-Cas systems have been identified in Acinetobacter baumannii, an opportunistic pathogen with a remarkable capacity for clonal dissemination. In this study, we investigated the mode of evolution and diversity of spacers of the CRISPR-cas subtype I-Fb locus in a global collection of 76 isolates of A. baumannii obtained from 14 countries and 4 continents. The locus has basically evolved from a common ancestor following two main lineages and several pathways of vertical descent. However, this vertical passage has been interrupted by occasional events of horizontal transfer of the whole locus between distinct isolates. The isolates were assigned into 40 CRISPR-based sequence types (CST). CST1 and CST23-24 comprised 18 and 9 isolates, representing two main sub-clones of international clones CC1 and CC25, respectively. Epidemiological data showed that some of the CST1 isolates were acquired or imported from Iraq, where it has probably been endemic for more than one decade and occasionally been able to spread to USA, Canada, and Europe. CST23-24 has shown a remarkable ability to cause national outbreaks of infections in Sweden, Argentina, UAE, and USA. The three isolates of CST19 were independently imported from Thailand to Sweden and Norway, raising a concern about the prevalence of CST19 in Thailand. Our study highlights the dynamic nature of the CRISPR-cas subtype I-Fb locus in A. baumannii, and demonstrates the possibility of using a CRISPR-based approach for subtyping a significant part of the global population of A. baumannii.

  16. Distinctly Different Glass Transition Behaviors of Trehalose Mixed with Na2HPO 4 or NaH 2PO 4: Evidence for its Molecular Origin.

    Science.gov (United States)

    Weng, Lindong; Elliott, Gloria D

    2015-07-01

    The present study is aimed at understanding how the interactions between sugar molecules and phosphate ions affect the glass transition temperature of their mixtures, and the implications for pharmaceutical formulations. The glass transition temperature (Tg) and the α-relaxation temperature (Tα) of dehydrated trehalose/sodium phosphate mixtures (monobasic or dibasic) were determined by differential scanning calorimetry and dynamic mechanical analysis, respectively. Molecular dynamics simulations were also conducted to investigate the microscopic interactions between sugar molecules and phosphate ions. The hydrogen-bonding characteristics and the self-aggregation features of these mixtures were quantified and compared. Thermal analysis measurements demonstrated that the addition of NaH2PO4 decreased both the glass transition temperature and the α-relaxation temperature of the dehydrated trehalose/NaH2PO4 mixture compared to trehalose alone while both Tg and Tα were increased by adding Na2HPO4 to pure trehalose. The hydrogen-bonding interactions between trehalose and HPO4(2-) were found to be stronger than both the trehalose-trehalose hydrogen bonds and those formed between trehalose and H2PO4(-). The HPO4(2-) ions also aggregated into smaller clusters than H2PO4(-) ions. The trehalose/Na2HPO4 mixture yielded a higher T g than pure trehalose because marginally self-aggregated HPO4(2-) ions established a strengthened hydrogen-bonding network with trehalose molecules. In contrast H2PO4(-) ions served only as plasticizers, resulting in a lower Tg of the mixtures than trehalose alone, creating large-sized ionic pockets, weakening interactions, and disrupting the original hydrogen-bonding network amongst trehalose molecules.

  17. Comparative volumetric analysis of the extent of resection of molecularly and histologically distinct low grade gliomas and its role on survival.

    Science.gov (United States)

    Eseonu, Chikezie I; Eguia, Francisco; ReFaey, Karim; Garcia, Oscar; Rodriguez, Fausto J; Chaichana, Kaisorn; Quinones-Hinojosa, Alfredo

    2017-08-01

    The authors investigate the role of extent of resection (EOR) and genetic markers on patient outcome and survival for LGGs. We conducted a retrospective cohort between 2005 and 2015, of 109 adult patients who underwent surgery for a LGG by a single surgeon. Volumetric computations of MRI studies were conducted to evaluate the EOR, and genetic markers (IDH1, 1p/19q co-deletion, and p53) were assessed and their effects on survival and neurological outcome were evaluated. The median EOR was 88.1%. Permanent postoperative neurological deficits were seen in 4.6% of patients. EOR was a significant predictor for both overall survival (OS) (hazard ratio [HR] = 0.979, 95% CI 0.961-0.980, p = 0.029) and progression free survival (PFS) (HR = 0.982, 95% CI 0.968-0.997, p = 0.018). Malignant progression free survival (MPFS) was predicted by the 1p/19q co-deletion (HR = 0.148, 95% CI 0.019-1.148, p = 0.048). Patients with EOR of 100% had a significantly better OS than EOR less than 90% (p = 0.038). Patients with an EOR of at least 76% had a better OS than EOR less than 76% (p = 0.025). Patients with an EOR of at least 71% had a better PFS than EOR less than 71% (p = 0.030). Preoperative tumor volume was found to have significant association with EOR (R 2  = 0.049, p = 0.031). Increased EOR is associated with improved OS and PFS survival outcomes, while 1p/19q co-deletion provides improved MPFS. Understanding both surgical resections and molecular markers of the tumor are important for effective management of LGG patients.

  18. The rise of a novel classification system for endometrial carcinoma; integration of molecular subclasses.

    Science.gov (United States)

    McAlpine, Jessica; Leon-Castillo, Alicia; Bosse, Tjalling

    2018-04-01

    Endometrial cancer is a clinically heterogeneous disease and it is becoming increasingly clear that this heterogeneity may be a function of the diversity of the underlying molecular alterations. Recent large-scale genomic studies have revealed that endometrial cancer can be divided into at least four distinct molecular subtypes, with well-described underlying genomic aberrations. These subtypes can be reliably delineated and carry significant prognostic as well as predictive information; embracing and incorporating them into clinical practice is thus attractive. The road towards the integration of molecular features into current classification systems is not without obstacles. Collaborative studies engaging research teams from across the world are working to define pragmatic assays, improve risk stratification systems by combining molecular features and traditional clinicopathological parameters, and determine how molecular classification can be optimally utilized to direct patient care. Pathologists and clinicians caring for women with endometrial cancer need to engage with and understand the possibilities and limitations of this new approach, because integration of molecular classification of endometrial cancers is anticipated to become an essential part of gynaecological pathology practice. This review will describe the challenges in current systems of endometrial carcinoma classification, the evolution of new molecular technologies that define prognostically distinct molecular subtypes, and potential applications of molecular classification as a step towards precision medicine and refining care for individuals with the most common gynaecological cancer in the developed world. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  19. A Novel Diagnostic Tool for Selecting Patients With Mesenchymal-Type Colon Cancer Reveals Intratumor Subtype Heterogeneity

    NARCIS (Netherlands)

    Ubink, Inge; Elias, Sjoerd G; Moelans, CB; Laclé, Miangela M; van Grevenstein, Wilhelmina M U; van Diest, Paul J; Borel Rinkes, Inne H M; Kranenburg, OW

    2017-01-01

    Background: Consensus molecular subtype 4 (CMS4) is a recently identified aggressive colon cancer subtype for which platelet-derived growth factor receptors (PDGFRs) and KIT are potential therapeutic targets. We aimed to develop a clinically applicable CMS4 reverse transcription polymerase chain

  20. - and Cross-Polarization 13C NMR Evidence of Alterations in Molecular Composition of Humic Substances Following Afforestation with Eucalypt in Distinct Brazilian Biomes

    Science.gov (United States)

    Silva, I. R.; Soares, E. M.; Schmidt-Rohr, K.; Novais, R.; Barros, N.; Fernandes, S.

    2010-12-01

    The effect of planting fast growing tree species on SOM quality in tropical regions has been overlooked. In the present study 13C-NMR approaches were used to evaluate the impact of eucalypt cultivation on humic and fulvic acids molecular composition. The results indicate that the replacement of native vegetation by eucalypt plantations increased the relative contribution of aliphatic groups in HA from soils previously under Atlantic Forest, Grassland, and the Cerrado (Curvelo site only). The same trend was observed for FA, except in the Curvelo site. A trend for degradation and smaller contribution of O-alkyl C (carbohydrates) in HA was observed in soils under eucalyptus in Atlantic Forest and Cerrado. For FA such decreases were seen in Cerrado and Grassland biomes after eucalypt planting. In the area cultivated with pasture in the Atlantic Forest biome and in the Grassland soil, the largest contributions of lignin-derived compounds were detected in HA. The HA from the Cerrado at the Curvelo site, where the woody vegetation is virtually devoid of grassy species, showed the lowest intensity of lignin signal then those from the Cerrado sensu stricto in Itacambira, where grass species are more abundant. At our study sites, charred material are most likely derived from burning of the native vegetation, as naturally occurs in the Cerrado region, or anthropogenic fires in the Grassland biome. Burning of harvest residues in eucalypt fields was also a common practice in the early rotations. The replacement of native vegetation by eucalypt plantations increases the relative contribution of nonpolar alkyl groups in HA from soils previously under Atlantic Forest, Grassland, and the Cerrado (Curvelo site only) biomes. There is evidence of substantial contribution of lignin-derived C to HA and FA, especially in sites planted with Brachiaria sp pastures. Eucalypt introduction decreases the relative contribution of carbohydrates in HA and FA. 13C DP/MAS NMR functional groups in

  1. Analysis of HIV subtypes and the phylogenetic tree in HIV-positive samples from Saudi Arabia

    International Nuclear Information System (INIS)

    Al-Zahrani, Alhusain J.

    2008-01-01

    Objective was to assess the prevalence of HIV-1 genetic subtypes in Saudi Arabia in samples that are serologically positive for HIV-1 and compare the HIV-1 genetic subtypes prevalent in Saudi Arabia with the subtypes prevalent in other countries. Thirty-nine HIV-1 positive samples were analyzed for HIV-1 subtypes using molecular techniques. The study is retrospective study that was conducted in Dammam, Kingdom of Saudi Arabia and in Abbott laboratories (United States of America) from2004 to 2007. All samples were seropositive for HIV-1 group M. Of the 39 seropositive samples, only 12 were polymerase chain reaction positive. Subtype C is the most common virus strain as it occurred in 58% of these samples; subtype B occurred in 17%; subtypes A, D and G were found in 8% each. The phylogenetic tree was also identified for the isolates. Detection of HIV subtypes is important for epidemiological purposes and may help in tracing the source of HIV infections in the Kingdom of Saudi Arabia. (author)

  2. Distribution And Clinicopathological Features Of Breast Cancer Histological Subtypes In Latvia

    Directory of Open Access Journals (Sweden)

    Srebnijs Andrejs

    2015-04-01

    Full Text Available Breast cancer is a heterogenous disease. It consists of several histological subtypes that can be separated by morphology and immunohistochemistry. The aim of our study was to determine the distribution of breast cancer histological and molecular subtypes, and their relationship with clinical and pathological characteristics. A total of 561 patients who underwent breast carcinoma surgical treatment from January 2003 till December 2012 were enrolled in the study. In total, invasive ductal carcinomas not otherwise specified (IDC-NOS plus invasive ductal carcinomas no special type (IDC-NST were observed in 430 patients (76.65% of cases, medullar carcinoma in 14 patients (2.45%, other rare ductal carcinoma subtypes in 13 patients (2.31%, lobular carcinoma in 81 patients (14.4% and tubulolobular carcinoma in 23 patients (4.19%. Ductal carcinoma, lobular and tubulolobular carcinoma had predominantly luminal A and B subtype, whereas medullar carcinoma had HER2-positive and triple-negative (TN subtype. Tubular, cribriform, mucinous, papillary, and apocrine carcinomas had predominantly luminal A subtype. Significant differences between breast cancer histological subtypes and clinicopathological characteristics were observed. Our study for the first time reported the distribution and characteristics of breast cancer histological subtypes in Latvian women and relationship to clinical and tumour histopathological characteristics.

  3. Avian metapneumovirus subtypes circulating in Brazilian vaccinated and nonvaccinated chicken and turkey farms.

    Science.gov (United States)

    Chacón, Jorge Luis; Mizuma, Matheus; Vejarano, Maria P; Toquín, Didier; Eterradossi, Nicolas; Patnayak, Devi P; Goyal, Sagar M; Ferreira, Antonio J Piantino

    2011-03-01

    Avian metapneumovirus (AMPV) causes turkey rhinotracheitis and is associated with swollen head syndrome in chickens, which is usually accompanied by secondary infections that increase mortality. AMPVs circulating in Brazilian vaccinated and nonvaccinated commercial chicken and turkey farms were detected using a universal reverse transcriptase (RT)-PCR assay that can detect the four recognized subtypes of AMPV. The AMPV status of 228 farms with respiratory and reproductive disturbances was investigated. AMPV was detected in broiler, hen, breeder, and turkey farms from six different geographic regions of Brazil. The detected viruses were subtyped using a nested RT-PCR assay and sequence analysis of the G gene. Only subtypes A and B were detected in both vaccinated and nonvaccinated farms. AMPV-A and AMPV-B were detected in 15 and 23 farms, respectively, while both subtypes were simultaneously found in one hen farm. Both vaccine and field viruses were detected in nonvaccinated farms. In five cases, the detected subtype was different than the vaccine subtype. Field subtype B virus was detected mainly during the final years of the survey period. These viruses showed high molecular similarity (more than 96% nucleotide similarity) among themselves and formed a unique phylogenetic group, suggesting that they may have originated from a common strain. These results demonstrate the cocirculation of subtypes A and B in Brazilian commercial farms.

  4. Diabetes and Breast Cancer Subtypes.

    Directory of Open Access Journals (Sweden)

    Heleen K Bronsveld

    Full Text Available Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes.This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (≤50 and >50 years, women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR, HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211 and women without diabetes (n = 101, irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%CI:1.07-5.55, HER2-negative (OR = 2.84(95%CI:1.11-7.22, and basal-like (OR = 3.14(95%CI:1.03-9.60 tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95-6.45 and triple negative (OR = 2.60(95%CI:0.88-7.67 tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general.We found no compelling evidence that women with diabetes

  5. Diabetes and Breast Cancer Subtypes.

    Science.gov (United States)

    Bronsveld, Heleen K; Jensen, Vibeke; Vahl, Pernille; De Bruin, Marie L; Cornelissen, Sten; Sanders, Joyce; Auvinen, Anssi; Haukka, Jari; Andersen, Morten; Vestergaard, Peter; Schmidt, Marjanka K

    2017-01-01

    Women with diabetes have a worse survival after breast cancer diagnosis compared to women without diabetes. This may be due to a different etiological profile, leading to the development of more aggressive breast cancer subtypes. Our aim was to investigate whether insulin and non-insulin treated women with diabetes develop specific clinicopathological breast cancer subtypes compared to women without diabetes. This cross-sectional study included randomly selected patients with invasive breast cancer diagnosed in 2000-2010. Stratified by age at breast cancer diagnosis (≤50 and >50 years), women with diabetes were 2:1 frequency-matched on year of birth and age at breast cancer diagnosis (both in 10-year categories) to women without diabetes, to select ~300 patients with tumor tissue available. Tumor MicroArrays were stained by immunohistochemistry for estrogen and progesterone receptor (ER, PR), HER2, Ki67, CK5/6, CK14, and p63. A pathologist scored all stains and revised morphology and grade. Associations between diabetes/insulin treatment and clinicopathological subtypes were analyzed using multivariable logistic regression. Morphology and grade were not significantly different between women with diabetes (n = 211) and women without diabetes (n = 101), irrespective of menopausal status. Premenopausal women with diabetes tended to have more often PR-negative (OR = 2.44(95%CI:1.07-5.55)), HER2-negative (OR = 2.84(95%CI:1.11-7.22)), and basal-like (OR = 3.14(95%CI:1.03-9.60) tumors than the women without diabetes, with non-significantly increased frequencies of ER-negative (OR = 2.48(95%CI:0.95-6.45)) and triple negative (OR = 2.60(95%CI:0.88-7.67) tumors. After adjustment for age and BMI, the associations remained similar in size but less significant. We observed no evidence for associations of clinicopathological subtypes with diabetes in postmenopausal women, or with insulin treatment in general. We found no compelling evidence that women with diabetes, treated

  6. Chronic peroxisome proliferator-activated receptor gamma (PPARgamma) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes

    DEFF Research Database (Denmark)

    Petrovic, Natasa; Walden, Tomas B; Shabalina, Irina G

    2009-01-01

    The recent insight that brown adipocytes and muscle cells share a common origin and in this respect are distinct from white adipocytes has spurred questions concerning the origin and molecular characteristics of the UCP1-expressing cells observed in classic white adipose tissue depots under certain...... physiological or pharmacological conditions. Examining precursors from the purest white adipose tissue depot (epididymal), we report here that chronic treatment with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone promotes not only the expression of PGC-1alpha and mitochondriogenesis...... associated with classic brown adipocytes (Zic1, Lhx8, Meox2, and characteristically PRDM16) or for myocyte-associated genes (myogenin and myomirs (muscle-specific microRNAs)) and retain white fat characteristics such as Hoxc9 expression. Co-culture experiments verify that the UCP1-expressing cells...

  7. Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

    Science.gov (United States)

    Tsuji, Motonori; Shudo, Koichi; Kagechika, Hiroyuki

    2017-03-01

    Understanding and identifying the receptor subtype selectivity of a ligand is an important issue in the field of drug discovery. Using a combination of classical molecular mechanics and quantum mechanical calculations, this report assesses the receptor subtype selectivity for the human retinoid X receptor (hRXR) and retinoic acid receptor (hRAR) ligand-binding domains (LBDs) complexed with retinoid ligands. The calculated energies show good correlation with the experimentally reported binding affinities. The technique proposed here is a promising method as it reveals the origin of the receptor subtype selectivity of selective ligands.

  8. Detection and subtyping avian metapneumovirus from turkeys in Iran.

    Science.gov (United States)

    Mayahi, Mansour; Momtaz, Hassan; Jafari, Ramezan Ali; Zamani, Pejman

    2017-01-01

    Avian metapneumovirus (aMPV) causes diseases like rhinotracheitis in turkeys, swollen head syndrome in chickens and avian rhinotracheitis in other birds. Causing respiratory problems, aMPV adversely affects production and inflicts immense economic losses and mortalities, especially in turkey flocks. In recent years, several serological and molecular studies have been conducted on this virus, especially in poultry in Asia and Iran. The purpose of the present study was detecting and subtyping aMPV by reverse transcriptase polymerase chain reaction (RT-PCR) from non-vaccinated, commercial turkey flocks in Iran for the first time. Sixty three meat-type unvaccinated turkey flocks from several provinces of Iran were sampled in major turkey abattoirs. Samples were tested by RT-PCR for detecting and subtyping aMPV. The results showed that 26 samples from three flocks (4.10%) were positive for viral RNA and all of the viruses were found to be subtype B of aMPV. As a result, vaccination especially against subtype B of aMPV should be considered in turkey flocks in Iran to control aMPV infections.

  9. Markers of subtypes in inflammatory breast cancer studied by immunohistochemistry: Prominent expression of P-cadherin

    International Nuclear Information System (INIS)

    Ben Hamida, Azza; Birnbaum, Daniel; Jacquemier, Jocelyne; Labidi, Intidhar S; Mrad, Karima; Charafe-Jauffret, Emmanuelle; Ben Arab, Saïda; Esterni, Benjamin; Xerri, Luc; Viens, Patrice; Bertucci, François

    2008-01-01

    Inflammatory breast cancer (IBC) is a distinct and aggressive form of locally-advanced breast cancer with high metastatic potential. In Tunisia, IBC is associated with a high death rate. Among the major molecular subtypes, basal breast carcinomas are poorly differentiated, have metastatic potential and poor prognosis, but respond relatively well to chemotherapy. The aim of this study was to determine the distribution of molecular subtypes in IBC and identify factors that may explain the poor prognosis of IBC. To determine breast cancer subtypes we studied by immunohistochemistry the expression of 12 proteins in a series of 91 Tunisian IBC and 541 non-IBC deposited in tissue microarrays. We considered infiltrating ductal cases only. We found 33.8% of basal cases in IBC vs 15.9% in non-IBC (p < 0.001), 33.3% of ERBB2-overexpressing cases in IBC vs 14.5% in non-IBC (p < 0.001), and 29.3% of luminal cases in IBC vs 59.9% in non-IBC (p < 0.001). The most differentially-expressed protein between IBCs and non-IBCs was P-cadherin. P-cadherin expression was found in 75.9% of all IBC vs 48.2% of all non-IBC (p < 0.001), 95% of IBC vs 69% of non-IBC (p = 0.02) in basal cases, and 82% of IBC vs 43% of non-IBC (p < 0.001) in luminal cases. Logistic regression determined that the most discriminating markers between IBCs and non-IBCs were P-cadherin (OR = 4.9, p = 0.0019) MIB1 (OR = 3.6, p = 0.001), CK14 (OR = 2.7, p = 0.02), and ERBB2 (OR = 2.3, p = 0.06). Tunisian IBCs are characterized by frequent basal and ERBB2 phenotypes. Surprisingly, luminal IBC also express the basal marker P-cadherin. This profile suggests a specificity that needs further investigation

  10. Gene specific actions of thyroid hormone receptor subtypes.

    Directory of Open Access Journals (Sweden)

    Jean Z Lin

    Full Text Available There are two homologous thyroid hormone (TH receptors (TRs α and β, which are members of the nuclear hormone receptor (NR family. While TRs regulate different processes in vivo and other highly related NRs regulate distinct gene sets, initial studies of TR action revealed near complete overlaps in their actions at the level of individual genes. Here, we assessed the extent that TRα and TRβ differ in target gene regulation by comparing effects of equal levels of stably expressed exogenous TRs +/- T(3 in two cell backgrounds (HepG2 and HeLa. We find that hundreds of genes respond to T(3 or to unliganded TRs in both cell types, but were not able to detect verifiable examples of completely TR subtype-specific gene regulation. TR actions are, however, far from identical and we detect TR subtype-specific effects on global T(3 response kinetics in HepG2 cells and many examples of TR subtype specificity at the level of individual genes, including effects on magnitude of response to TR +/- T(3, TR regulation patterns and T(3 dose response. Cycloheximide (CHX treatment confirms that at least some differential effects involve verifiable direct TR target genes. TR subtype/gene-specific effects emerge in the context of widespread variation in target gene response and we suggest that gene-selective effects on mechanism of TR action highlight differences in TR subtype function that emerge in the environment of specific genes. We propose that differential TR actions could influence physiologic and pharmacologic responses to THs and selective TR modulators (STRMs.

  11. IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma.

    Science.gov (United States)

    Gorovets, Daniel; Kannan, Kasthuri; Shen, Ronglai; Kastenhuber, Edward R; Islamdoust, Nasrin; Campos, Carl; Pentsova, Elena; Heguy, Adriana; Jhanwar, Suresh C; Mellinghoff, Ingo K; Chan, Timothy A; Huse, Jason T

    2012-05-01

    Diffuse gliomas represent the most prevalent class of primary brain tumor. Despite significant recent advances in the understanding of glioblastoma [World Health Organization (WHO) IV], its most malignant subtype, lower grade (WHO II and III) glioma variants remain comparatively understudied, especially in light of their notable clinical heterogeneity. Accordingly, we sought to identify and characterize clinically relevant molecular subclasses of lower grade diffuse astrocytic gliomas. We conducted multidimensional molecular profiling, including global transcriptional analysis, on 101 lower grade diffuse astrocytic gliomas collected at our own institution and validated our findings using publically available gene expression and copy number data from large independent patient cohorts. We found that IDH mutational status delineated molecularly and clinically distinct glioma subsets, with IDH mutant (IDH mt) tumors exhibiting TP53 mutations, platelet-derived growth factor receptor (PDGFR)A overexpression, and prolonged survival, and IDH wild-type (IDH wt) tumors exhibiting EGFR amplification, PTEN loss, and unfavorable disease outcome. Furthermore, global expression profiling revealed three robust molecular subclasses within lower grade diffuse astrocytic gliomas, two of which were predominantly IDH mt and one almost entirely IDH wt. IDH mt subclasses were distinguished from each other on the basis of TP53 mutations, DNA copy number abnormalities, and links to distinct stages of neurogenesis in the subventricular zone. This latter finding implicates discrete pools of neuroglial progenitors as cells of origin for the different subclasses of IDH mt tumors. We have elucidated molecularly distinct subclasses of lower grade diffuse astrocytic glioma that dictate clinical behavior and show fundamental associations with both IDH mutational status and neuroglial developmental stage. ©2012 AACR.

  12. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features.

    Science.gov (United States)

    Stewart, W F; Liberman, J N; Sandler, R S; Woods, M S; Stemhagen, A; Chee, E; Lipton, R B; Farup, C E

    1999-12-01

    . Outlet type was more common in nonwhites compared to whites. Finally, 45% of individuals with constipation reported having the condition for 5 yr or more. Constipation is a heterogeneous condition. Differences in epidemiological profile by age, sex ratio, and relation to other sociodemographical factors support the distinction of two and possibly more symptom-based subtypes.

  13. Technical validation of an RT-qPCR in vitro diagnostic test system for the determination of breast cancer molecular subtypes by quantification of ERBB2, ESR1, PGR and MKI67 mRNA levels from formalin-fixed paraffin-embedded breast tumor specimens.

    Science.gov (United States)

    Laible, Mark; Schlombs, Kornelia; Kaiser, Katharina; Veltrup, Elke; Herlein, Stefanie; Lakis, Sotiris; Stöhr, Robert; Eidt, Sebastian; Hartmann, Arndt; Wirtz, Ralph M; Sahin, Ugur

    2016-07-07

    MammaTyper is a novel CE-marked in vitro diagnostic RT-qPCR assay which assigns routinely processed breast cancer specimens into the molecular subtypes Luminal A-like, Luminal B-like (HER2 positive or negative), HER2 positive (non-luminal) and Triple negative (ductal) according to the mRNA expression of ERBB2, ESR1, PGR and MKI67 and the St Gallen consensus surrogate clinical definition. Until now and regarding formalin-fixed, paraffin-embedded material (FFPE), this has been a task mostly accomplished by immunohistochemistry (IHC). However the discrepancy rates of IHC for the four breast cancer biomarkers are frequently under debate, especially for Ki-67 which carries the highest degree of inter- and even intra-observer variability. Herein we describe a series of studies in FFPE specimens which aim to fully validate the analytical performance of the MammaTyper assay, including the site to site reproducibility of the individual marker measurements. Tumor RNA was extracted with the novel RNXtract RNA extraction kit. Synthetic RNA was used to assess the sensitivity of the RNXtract kit. DNA and RNA specific qPCR assays were used so as to determine analyte specificity of RNXtract. For the assessment of limit of blank, limit of detection, analytical measurement range and PCR efficiency of the MammaTyper kit serial dilutions of samples were used. Analytical precision studies of MammaTyper were built around two different real time PCR platforms and involved breast tumor samples belonging to different subtypes analyzed across multiple sites and under various stipulated conditions. The MammaTyper assay robustness was tested against RNA input variations, alternative extraction methods and tumor cell content. Individual assays were linear up to at least 32.33 and 33.56 Cqs (quantification cycles) for the two qPCR platforms tested. PCR efficiency ranged from 99 to 109 %. In qPCR platform 1, estimates for assay specific inter-site standard deviations (SD) were between 0.14 and

  14. Technical validation of an RT-qPCR in vitro diagnostic test system for the determination of breast cancer molecular subtypes by quantification of ERBB2, ESR1, PGR and MKI67 mRNA levels from formalin-fixed paraffin-embedded breast tumor specimens

    International Nuclear Information System (INIS)

    Laible, Mark; Schlombs, Kornelia; Kaiser, Katharina; Veltrup, Elke; Herlein, Stefanie; Lakis, Sotiris; Stöhr, Robert; Eidt, Sebastian; Hartmann, Arndt; Wirtz, Ralph M.; Sahin, Ugur

    2016-01-01

    MammaTyper is a novel CE-marked in vitro diagnostic RT-qPCR assay which assigns routinely processed breast cancer specimens into the molecular subtypes Luminal A-like, Luminal B-like (HER2 positive or negative), HER2 positive (non-luminal) and Triple negative (ductal) according to the mRNA expression of ERBB2, ESR1, PGR and MKI67 and the St Gallen consensus surrogate clinical definition. Until now and regarding formalin-fixed, paraffin-embedded material (FFPE), this has been a task mostly accomplished by immunohistochemistry (IHC). However the discrepancy rates of IHC for the four breast cancer biomarkers are frequently under debate, especially for Ki-67 which carries the highest degree of inter- and even intra-observer variability. Herein we describe a series of studies in FFPE specimens which aim to fully validate the analytical performance of the MammaTyper assay, including the site to site reproducibility of the individual marker measurements. Tumor RNA was extracted with the novel RNXtract RNA extraction kit. Synthetic RNA was used to assess the sensitivity of the RNXtract kit. DNA and RNA specific qPCR assays were used so as to determine analyte specificity of RNXtract. For the assessment of limit of blank, limit of detection, analytical measurement range and PCR efficiency of the MammaTyper kit serial dilutions of samples were used. Analytical precision studies of MammaTyper were built around two different real time PCR platforms and involved breast tumor samples belonging to different subtypes analyzed across multiple sites and under various stipulated conditions. The MammaTyper assay robustness was tested against RNA input variations, alternative extraction methods and tumor cell content. Individual assays were linear up to at least 32.33 and 33.56 Cqs (quantification cycles) for the two qPCR platforms tested. PCR efficiency ranged from 99 to 109 %. In qPCR platform 1, estimates for assay specific inter-site standard deviations (SD) were between 0.14 and 0

  15. Motoric subtypes of delirium in geriatric patients

    Directory of Open Access Journals (Sweden)

    Sandeep Grover

    2014-01-01

    Results: On amended DMSS, hyperactive subtype (N = 45; 45.9% was the most common motoric subtype of delirium, followed by hypoactive subtype (N = 23; 23.5%, and mixed subtype (N = 21; 21.4%. On DRS-R-98, all patients fulfilled the criteria of ′acute (temporal onset of symptoms′, ′presence of an underlying physical disorder′ and ′difficulty in attention′. In the total sample, >90% of the patients had disturbances in sleep-wake cycle, orientation and fluctuation of symptoms. The least common symptoms were delusions, visuospatial disturbances and motor retardation. When compared to hypoactive group, significantly higher proportion of patients with hyperactive subtype had delusions, perceptual disturbances, and motor agitation. Whereas, compared to hyperactive subtype, significantly higher proportion of patients with hypoactive subtype had thought process abnormality and motor retardation. When the hyperactive and mixed motoric subtype groups were compared, patients with mixed subtype group had significantly higher prevalence of thought process abnormality and motor retardation. Comparison of hypoactive and mixed subtype revealed significant differences in the frequency of perceptual disturbances, delusions and motor agitation and all these symptoms being found more commonly in patients with the mixed subtype. Severity of symptoms were found to be significantly different across the various motoric subtypes for some of the non-cognitive symptoms, but significant differences were not seen for the cognitive symptoms as assessed on DRS-R-98. Conclusion: In elderly patients, motor subtypes of delirium differ from each other on non-cognitive symptom profile in terms of frequency and severity.

  16. Social phobia subtypes in the general population revealed by cluster analysis.

    Science.gov (United States)

    Furmark, T; Tillfors, M; Stattin, H; Ekselius, L; Fredrikson, M

    2000-11-01

    Epidemiological data on subtypes of social phobia are scarce and their defining features are debated. Hence, the present study explored the prevalence and descriptive characteristics of empirically derived social phobia subgroups in the general population. To reveal subtypes, data on social distress, functional impairment, number of social fears and criteria fulfilled for avoidant personality disorder were extracted from a previously published epidemiological study of 188 social phobics and entered into an hierarchical cluster analysis. Criterion validity was evaluated by comparing clusters on the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS). Finally, profile analyses were performed in which clusters were compared on a set of sociodemographic and descriptive characteristics. Three clusters emerged, consisting of phobics scoring either high (generalized subtype), intermediate (non-generalized subtype) or low (discrete subtype) on all variables. Point prevalence rates were 2.0%, 5.9% and 7.7% respectively. All subtypes were distinguished on both SPS and SIAS. Generalized or severe social phobia tended to be over-represented among individuals with low levels of educational attainment and social support. Overall, public-speaking was the most common fear. Although categorical distinctions may be used, the present data suggest that social phobia subtypes in the general population mainly differ dimensionally along a mild moderate-severe continuum, and that the number of cases declines with increasing severity.

  17. Distribution of human immunodeficiency virus type 1 subtypes in the State of Amazonas, Brazil, and subtype C identification

    International Nuclear Information System (INIS)

    Cunha, L.K.H.; Kashima, S.; Amarante, M.F.C.; Haddad, R.; Rodrigues, E.S.; Silva, K.L.T.; Lima, T.A.; Castro, D.B.; Brito, F.C.; Almeida, E.G.; Covas, D.T.; Malheiro, A.

    2012-01-01

    Few studies have reported the molecular epidemiological characterization of HIV-1 in the Northern region of Brazil. The present study reports the molecular and epidemiological characterization of 31 HIV-1 isolates from blood donors from the State of Amazonas who donated blood between April 2006 and March 2007. Serum/plasma samples from all donors were screened for HIV antibodies by ELISA and the results confirmed by Western blot analysis. Genomic DNA was extracted from the buffy coat using the Super Quik-Gene-DNA Isolation kit. Nested PCR was performed on the env, gag, and pol regions of HIV-1 using the Gene Amp PCR System 9700. Sequencing reactions were performed using the inner PCR primers and the DYEnamic™ ET Dye Terminator Kit, and phylogenetic analysis was performed using the gag, pol, and env gene sequences. We collected samples from 31 blood donors who tested positive for HIV-1 in confirmatory experiments. The male:female ratio of blood donors was 3.4:1, and the mean age was 32.4 years (range: 19 to 61 years). Phylogenetic analysis showed that subtype B is the most prevalent among Northern Brazilian HIV-1-seropositive blood donors. One HIV-1 subtype C and one circulating recombinant form (CRF-BF) of HIV-1 were identified in the State of Amazonas. This is the first study showing the occurrence of a possible “homogenous” subtype C in this region of Brazil. This finding could contribute to a better characterization of the HIV-1 strains that circulate in the country. Key words: HIV-1; Subtypes; Phylogenetic analysis; Blood donors; Molecular and epidemiological characterization

  18. Distribution of human immunodeficiency virus type 1 subtypes in the State of Amazonas, Brazil, and subtype C identification

    Energy Technology Data Exchange (ETDEWEB)

    Cunha, L.K.H. [Departamento de Parasitologia, Universidade Federal do Amazonas, Manaus, AM (Brazil); Kashima, S.; Amarante, M.F.C.; Haddad, R.; Rodrigues, E.S. [Laboratório de Biologia Molecular, Hemocentro de Ribeirão Preto, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Silva, K.L.T.; Lima, T.A.; Castro, D.B.; Brito, F.C.; Almeida, E.G. [Diretoria de Ensino e Pesquisa,Fundação de Hematologia e Hemoterapia do Amazonas, Manaus, AM (Brazil); Covas, D.T. [Laboratório de Biologia Molecular, Hemocentro de Ribeirão Preto, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Malheiro, A. [Departamento de Parasitologia, Universidade Federal do Amazonas, Manaus, AM (Brazil); Diretoria de Ensino e Pesquisa,Fundação de Hematologia e Hemoterapia do Amazonas, Manaus, AM (Brazil)

    2012-01-20

    Few studies have reported the molecular epidemiological characterization of HIV-1 in the Northern region of Brazil. The present study reports the molecular and epidemiological characterization of 31 HIV-1 isolates from blood donors from the State of Amazonas who donated blood between April 2006 and March 2007. Serum/plasma samples from all donors were screened for HIV antibodies by ELISA and the results confirmed by Western blot analysis. Genomic DNA was extracted from the buffy coat using the Super Quik-Gene-DNA Isolation kit. Nested PCR was performed on the env, gag, and pol regions of HIV-1 using the Gene Amp PCR System 9700. Sequencing reactions were performed using the inner PCR primers and the DYEnamic™ ET Dye Terminator Kit, and phylogenetic analysis was performed using the gag, pol, and env gene sequences. We collected samples from 31 blood donors who tested positive for HIV-1 in confirmatory experiments. The male:female ratio of blood donors was 3.4:1, and the mean age was 32.4 years (range: 19 to 61 years). Phylogenetic analysis showed that subtype B is the most prevalent among Northern Brazilian HIV-1-seropositive blood donors. One HIV-1 subtype C and one circulating recombinant form (CRF-BF) of HIV-1 were identified in the State of Amazonas. This is the first study showing the occurrence of a possible “homogenous” subtype C in this region of Brazil. This finding could contribute to a better characterization of the HIV-1 strains that circulate in the country. Key words: HIV-1; Subtypes; Phylogenetic analysis; Blood donors; Molecular and epidemiological characterization.

  19. Rhinitis Subtypes, Endotypes, and Definitions.

    Science.gov (United States)

    Papadopoulos, Nikolaos G; Guibas, George V

    2016-05-01

    Rhinitis is often seen as posing a small burden. However, rhinitis is a complex disease that is underpinned by a plethora of different mechanisms and causes. Rhinitis is frequently associated with other comorbid conditions but, by itself, is a source of considerable morbidity for patients and creates a significant financial burden on health systems worldwide. This article approaches this condition from both a phenotypic and mechanistic standpoint, focusing on the complexity of characterizing these subtypes. Developing a clearer demarcation of the currently obscure rhinitis phenotypes and endotypes will substantially improve their future prevention and treatment. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. GDE2 regulates subtype-specific motor neuron generation through inhibition of Notch signaling.

    Science.gov (United States)

    Sabharwal, Priyanka; Lee, Changhee; Park, Sungjin; Rao, Meenakshi; Sockanathan, Shanthini

    2011-09-22

    The specification of spinal interneuron and motor neuron identities initiates within progenitor cells, while motor neuron subtype diversification is regulated by hierarchical transcriptional programs implemented postmitotically. Here we find that mice lacking GDE2, a six-transmembrane protein that triggers motor neuron generation, exhibit selective losses of distinct motor neuron subtypes, specifically in defined subsets of limb-innervating motor pools that correlate with the loss of force-generating alpha motor neurons. Mechanistically, GDE2 is expressed by postmitotic motor neurons but utilizes extracellular glycerophosphodiester phosphodiesterase activity to induce motor neuron generation by inhibiting Notch signaling in neighboring motor neuron progenitors. Thus, neuronal GDE2 controls motor neuron subtype diversity through a non-cell-autonomous feedback mechanism that directly regulates progenitor cell differentiation, implying that subtype specification initiates within motor neuron progenitor populations prior to their differentiation into postmitotic motor neurons. Copyright © 2011 Elsevier Inc. All rights reserved.

  1. Origin and dynamics of HIV-1 subtype C infection in India.

    Directory of Open Access Journals (Sweden)

    Chengli Shen

    Full Text Available To investigate the geographical origin and evolution dynamics of HIV-1 subtype C infection in India.Ninety HIV-1 subtype C env gp120 subtype C sequences from India were compared with 312 env gp120 reference subtype C sequences from 27 different countries obtained from Los Alamos HIV database. All the HIV-1 subtype C env gp120 sequences from India were used for the geographical origin analysis and 61 subtype C env gp120 sequences with known sampling year (from 1991 to 2008 were employed to determine the origin of HIV infection in India.Phylogenetic analysis of HIV-1 env sequences was used to investigate the geographical origin and tMRCA of Indian HIV-1 subtype C. Evolutionary parameters including origin date and demographic growth patterns of Indian subtype C were estimated using a Bayesian coalescent-based approach under relaxed molecular clock models.The majority of the analyzed Indian and South African HIV-1 subtype C sequences formed a single monophyletic cluster. The most recent common ancestor date was calculated to be 1975.56 (95% HPD, 1968.78-1981.52. Reconstruction of the effective population size revealed three phases of epidemic growth: an initial slow growth, followed by exponential growth, and then a plateau phase approaching present time. Stabilization of the epidemic growth phase correlated with the foundation of National AIDS Control Organization in India.Indian subtype C originated from a single South African lineage in the middle of 1970s. The current study emphasizes not only the utility of HIV-1 sequence data for epidemiological studies but more notably highlights the effectiveness of community or government intervention strategies in controlling the trend of the epidemic.

  2. Molecular Pathology of Human Prion Diseases

    Directory of Open Access Journals (Sweden)

    2009-03-01

    Full Text Available Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis.

  3. Hypertension Subtypes among Hypertensive Patients in Ibadan

    OpenAIRE

    Abiodun M. Adeoye; Adewole Adebiyi; Bamidele O. Tayo; Babatunde L. Salako; Adesola Ogunniyi; Richard S. Cooper

    2014-01-01

    Background. Certain hypertension subtypes have been shown to increase the risk for cardiovascular morbidity and mortality and may be related to specific underlying genetic determinants. Inappropriate characterization of subtypes of hypertension makes efforts at elucidating the genetic contributions to the etiology of hypertension largely vapid. We report the hypertension subtypes among patients with hypertension from South-Western Nigeria. Methods. A total of 1858 subjects comprising 76% fema...

  4. ADHD-hyperactive/impulsive subtype in adults

    OpenAIRE

    Gibbins, Christopher; Weiss, Margaret D.; Goodman, David W.; Hodgkins, Paul S.; Landgraf, Jeanne M.; Faraone, Stephen V.

    2010-01-01

    This is the first study to evaluate ADHD-hyperactive/impulsive subtype in a large clinical sample of adults with ADHD. The Quality of Life, Effectiveness, Safety and Tolerability (QuEST) study included 725 adults who received clinician diagnoses of any ADHD subtype. Cross-sectional baseline data from 691 patients diagnosed with the hyperactive/impulsive (HI), inattentive (IA) and combined subtypes were used to compare the groups on the clinician administered ADHD-RS, clinical features and hea...

  5. Two UV-Sensitive Photoreceptor Proteins, Opn5m and Opn5m2 in Ray-Finned Fish with Distinct Molecular Properties and Broad Distribution in the Retina and Brain.

    Science.gov (United States)

    Sato, Keita; Yamashita, Takahiro; Haruki, Yoshihiro; Ohuchi, Hideyo; Kinoshita, Masato; Shichida, Yoshinori

    2016-01-01

    Opn5 is a group within the opsin family of proteins that is responsible for visual and non-visual photoreception in animals. It consists of several subgroups, including Opn5m, the only subgroup containing members found in most vertebrates, including mammals. In addition, recent genomic information has revealed that some ray-finned fishes carry paralogous genes of Opn5m while other fishes have no such genes. Here, we report the molecular properties of the opsin now called Opn5m2 and its distributions in both the retina and brain. Like Opn5m, Opn5m2 exhibits UV light-sensitivity when binding to 11-cis-retinal and forms a stable active state that couples with Gi subtype of G protein. However, Opn5m2 does not bind all-trans-retinal and exhibits exclusive binding to 11-cis-retinal, whereas many bistable opsins, including fish Opn5m, can bind directly to all-trans-retinal as well as 11-cis-retinal. Because medaka fish has lost the Opn5m2 gene from its genome, we compared the tissue distribution patterns of Opn5m in medaka fish, zebrafish, and spotted gar, in addition to the distribution patterns of Opn5m2 in zebrafish and spotted gar. Opn5m expression levels showed a gradient along the dorsal-ventral axis of the retina, and preferential expression was observed in the ventral retina in the three fishes. The levels of Opn5m2 showed a similar gradient with preferential expression observed in the dorsal retina. Opn5m expression was relatively abundant in the inner region of the inner nuclear layer, while Opn5m2 was expressed in the outer edge of the inner nuclear layer. Additionally, we could detect Opn5m expression in several brain regions, including the hypothalamus, of these fish species. Opn5m2 expression could not be detected in zebrafish brain, but was clearly observed in limited brain regions of spotted gar. These results suggest that ray-finned fishes can generally utilize UV light information for non-image-forming photoreception in a wide range of cells in the

  6. Validity of DSM-IV attention–deficit/hyperactivity disorder symptom dimensions and subtypes

    Science.gov (United States)

    Willcutt, Erik G.; Nigg, Joel T.; Pennington, Bruce F.; Solanto, Mary V.; Rohde, Luis A.; Tannock, Rosemary; Loo, Sandra K.; Carlson, Caryn L.; McBurnett, Keith; Lahey, Benjamin B.

    2013-01-01

    DSM-IV criteria for ADHD specify two dimensions of inattention and hyperactivity-impulsivity symptoms that are used to define three nominal subtypes: predominantly hyperactive-impulsive type (ADHD-H), predominantly inattentive type (ADHD-I), and combined type (ADHD-C). To aid decision-making for DSM-5 and other future diagnostic systems, a comprehensive literature review and meta-analysis of 546 studies was completed to evaluate the validity of the DSM-IV model of ADHD. Results indicated that DSM-IV criteria identify individuals with significant and persistent impairment in social, academic, occupational, and adaptive functioning when intelligence, demographic factors, and concurrent psychopathology are controlled. Available data overwhelmingly support the concurrent, predictive, and discriminant validity of the distinction between inattention and hyperactivity-impulsivity symptoms, and indicate that nearly all differences among the nominal subtypes are consistent with the relative levels of inattention and hyperactivity-impulsivity symptoms that define the subtypes. In contrast, the validity of the DSM-IV subtype model is compromised by weak evidence for the validity of ADHD-H after first grade, minimal support for the distinction between ADHD-I and ADHD-C in studies of etiological influences, academic and cognitive functioning, and treatment response, and the marked longitudinal instability of all three subtypes. Overall, it is concluded that the DSM-IV ADHD subtypes provide a convenient clinical shorthand to describe the functional and behavioral correlates of current levels of inattention and hyperactivity-impulsivity symptoms, but do not identify discrete subgroups with sufficient long-term stability to justify the classification of distinct forms of the disorder. Empirical support is stronger for an alternative model that would replace the subtypes with dimensional modifiers that reflect the number of inattention and hyperactivity-impulsivity symptoms at the

  7. RESEARCH ARTICLE Distinct classical and molecular cytogenetics ...

    Indian Academy of Sciences (India)

    Navya

    2017-01-27

    Jan 27, 2017 ... Mogi-Guaçu river (Ouro Fino, Minas Gerais State – MG; Cachoeira de Emas, Pirassununga,. São Paulo State – SP; Barrinha – SP, Brazil) and observed a similar pattern of constitutive heterochromatin organization on the forms with 2n = 46 and 2n = 48 chromosomes (in the telomeric region on long arms of ...

  8. RESEARCH ARTICLE Distinct classical and molecular cytogenetics ...

    Indian Academy of Sciences (India)

    Navya

    2017-01-27

    ,. Universidade Estadual Paulista “Júlio de Mesquita Filho” (UNESP), Av. 24A, 1515, ZIP: 13506-900, Rio Claro, SP, Brazil. 2Instituto de Biociências, Laboratório de Citogenética e Genética Animal, Universidade. Federal de ...

  9. Oppositional defiant disorder dimensions and subtypes among detained male adolescent offenders.

    Science.gov (United States)

    Aebi, Marcel; Barra, Steffen; Bessler, Cornelia; Steinhausen, Hans-Christoph; Walitza, Susanne; Plattner, Belinda

    2016-06-01

    In adolescent offenders, oppositional defiant disorder (ODD) and its dimensions/subtypes have been frequently ignored due to the stronger focus on criminal behaviours. The revised criteria of the DSM-5 now allow diagnosing ODD in older youths independent of conduct disorder (CD). This study aimed at analysing ODD dimensions/subtypes and their relation to suicidality, comorbid psychiatric disorders, and criminal behaviours after release from detention in a sample of detained male adolescents. Suicidality and psychiatric disorders (including ODD symptoms) were assessed in a consecutive sample of 158 male adolescents (Mage  = 16.89 years) from the Zurich Juvenile Detention Centre. Based on previous research findings, an irritable ODD dimension and a defiant/vindictive ODD dimension based on ODD symptoms were defined. Latent Class Analysis (LCA) was used to identify distinct subtypes of adolescent offenders according to their ODD symptom profiles. Logistic regression and Cox regression were used to analyse the relations of ODD dimensions/ODD subtypes to comorbid psychopathology and criminal reoffenses from official data. The ODD-irritable dimension, but not the ODD defiant/vindictive dimension predicted comorbid anxiety, suicidality and violent reoffending. LCA identified four subtypes, namely, a no-ODD subtype, a severe ODD subtype and two moderate ODD subtypes with either defiant or irritable symptoms. The irritable ODD subtype and the severe ODD subtype were related to suicidality and comorbid affective/anxiety disorders. The irritable ODD subtype was the strongest predictor of criminal (violent) reoffending even when controlling for CD. The present findings confirm the presence of ODD dimensions/subtypes in a highly disturbed adolescent offender sample. Irritable youths were at risk of suicide and persistent criminal behaviours. Due to the severe consequences of irritability, a standardized assessment approach and a specific treatment is needed in prison to

  10. Multilocus sequence typing of an emerging Cryptosporidium hominis subtype in the United States.

    Science.gov (United States)

    Feng, Yaoyu; Tiao, Narry; Li, Na; Hlavsa, Michele; Xiao, Lihua

    2014-02-01

    The United States has experienced a substantial increase in the reported incidence of cryptosporidiosis since 2005. Accompanying this is the emergence of a new subtype of Cryptosporidium hominis based on variation at the 60-kDa glycoprotein (gp60) locus, IaA28R4, which has become a frequently identified subtype in both sporadic and outbreak-related cases. In this study, using multilocus sequence typing (MLST) at eight genetic loci, we characterized 62 specimens of IaA28R4 and 33 specimens of three other gp60 subtypes of C. hominis from four U.S. states with increased cryptosporidiosis incidences during the summer of 2008. Extensive genetic heterogeneity was seen within the gp60 subtype IaA28R4, but specimens from Ohio and southwestern states formed two distinct subpopulations, suggesting that there were at least two origins of IaA28R4 within the United States. Discordance in typing results was observed between gp60 and other genetic markers, especially DZ-HRGP, and this discordance was largely the result of genetic recombination within the gp60 subtype IaA28R4. The results of population genetic analyses supported the presence of two subpopulations of IaA28R4 and the occurrence of genetic recombination within this gp60 subtype. Thus, the IaA28R4 subtype at gp60 is likely a fitness marker for C. hominis, and genetic recombination is potentially a driving force in the emergence of the virulent IaA28R4 subtype in the United States. A rapid evolution of IaA28R4 was indicated by the observation of multiple MLST subtypes of IaA28R4 within two large outbreaks that lasted for extended periods and involved multiple swimming pools.

  11. Peculiarities of diagnostics and clinical course of different immunohistochemical subtypes of breast cancer

    Directory of Open Access Journals (Sweden)

    El Khazhzh M.Kh.

    2014-09-01

    Full Text Available Modern global guidelines in oncology consider treatment of various forms of breast cancer according to molecular tumor subtype. Steroid receptors, epidermal growth factor receptors, p53, Ki67 proliferative activity index and others are the key indicators of aggressiveness of malignant breast tumors. The material for this study was the retrospective study of the standard set of breast cancer immuno¬histochemical markers (estrogen receptors, progesterone, epidermal growth factor type 2 in 8171 patients. 4 groups of patients - luminal A, luminal B, triple negative and HER2-neu positive subtypes of tumors were identified according to immunohistochemical status. We analyzed overall survival without relapse in 491 patients with breast cancer, clinical data and data of immunohistochemical studies were matched. Based on the investigation it was determined that in the early stages of the disease (1-2 luminal A subtype of cancer is often diagnosed. In the late stages the most common subtype is HER2-neu positive breast cancer. Herewith, patients with luminal A subtype of cancer have the best performance of the overall survival (OS (32,91±2,33 months, and the worst results were found in patients with HER2 - neu positive breast cancer (22,58±1,28 months. The data obtained determine HER2 - neu positive subtype as the most aggressive type of breast cancer, and the luminal A subtype – as the least aggressive one.

  12. HIV-1 epidemiology and circulating subtypes in the countryside of South Brazil

    Directory of Open Access Journals (Sweden)

    Carina Sperotto Librelotto

    2015-06-01

    Full Text Available INTRODUCTION: Human immunodeficiency virus type 1 (HIV-1 has spread worldwide, with several subtypes and circulating recombinant forms. Brazil has an incidence of 20.5 HIV-1/acquired immunodeficiency syndrome (AIDS patients per 100,000 inhabitants; however, the Southernmost State of Rio Grande do Sul (RS has more than twice the number of HIV-1-infected people (41.3/100,000 inhabitants and a different pattern of subtype frequencies, as previously reported in studies conducted in the capital (Porto Alegre and its metropolitan region. This study examined HIV-1/AIDS epidemiological and molecular aspects in the countryside of Rio Grande do Sul. METHODS: Socio-demographic, clinical and risk behavioral characteristics were obtained from HIV-1-positive adult patients using a structured questionnaire. HIV-1 subtypes were determined by nested-polymerase chain reaction (PCR and sequencing of the pol and env genes. RESULTS: The study sample included 149 (55% women patients with a mean age of 41.8 ± 11.9 years. Most (73.8% patients had a low education level and reported heterosexual practices as the most (91.9% probable transmission route. HIV-1 subtypes were detected in 26 patients: 18 (69.2% infected with subtype C, six (23.1% infected with subtype B and two (7.7% infected with BC recombinant forms. CONCLUSIONS: These data highlight the increasing number of HIV-1 subtype C infections in the countryside of South Brazil.

  13. Diagnostic Features and Subtyping of Thymoma Lymph Node Metastases

    Science.gov (United States)

    Sioletic, Stefano; Lauriola, Libero; Martucci, Robert; Evoli, Amelia; Palmieri, Giovannella; Melis, Enrico; Rinaldi, Massimo; Lalle, Maurizio; Pescarmona, Edoardo; Granone, Pierluigi; Facciolo, Francesco

    2014-01-01

    Aim. The purpose of the present study was to characterize the morphological features of thymoma metastases in lymph nodes and to evaluate the possibility of their subtyping according to the 2004 WHO classification of thymus tumors. Materials and Methods. We reviewed 210 thymoma cases in our series of thymic epithelial tumors (TET), including their recurrences and lymphogenous metastases. Three cases of lymph node metastases, one case occurring synchronously with the primary tumor and one synchronously with the first relapse (both in intrathoracic location) and one case of metastasis observed in a laterocervical lymph node subsequently to two thymoma relapses were found. Results. The metastatic nodes were variably but extensively involved in all cases. The histological features were similar in both primary tumors and metastases. Thymoma metastases were subtyped according to the WHO classification as B3 (one case) and B2 (two cases), and distinctive features in comparison to metastatic epithelial neoplasias from other sites were observed. Conclusion. Thymoma lymph node metastases, although rare, can be subtyped according to the WHO classification on the basis of their morphological and immunohistochemical features. Clinically, the presence of nodal metastases may herald subsequent relapses and further metastases even in extrathoracic sites. PMID:25105128

  14. Subtypes versus Severity Differences in Attention-Deficit/Hyperactivity Disorder in the Northern Finnish Birth Cohort

    Science.gov (United States)

    Lubke, Gitta H.; Muthen, Bengt; Moilanen, Irma K.; McGough, James J.; Loo, Sandra K.; Swanson, James M.; Yang, May H.; Taanila, Anja; Hurtig, Tuula; Jarvelin, Marjo-Riitta; Smalley, Susan L.

    2007-01-01

    A study aims to analyze whether behaviors of attention-deficit, hyperactivity among adolescents in Northern Finland reflect distinct subtypes of attention deficit hyperactivity disorder (ADHD). The results conclude that the majority of the Cohort falls into low-scoring groups of unaffecteds while a high-scoring minority group reflects an ADHD…

  15. The distinctive nature of adenocarcinoma of the lung

    Directory of Open Access Journals (Sweden)

    Roviello G

    2015-09-01

    Full Text Available Giandomenico RovielloDepartment of Molecular and Translational Medicine, University of Brescia, Brescia, ItalyAbstract: In recent years, many personalized treatments have been developed for NSCLC (non-small-cell lung cancer patients. Among these, gefitinib, erlotinib, and afatinib are selective epidermal growth factor receptor (EGFR tyrosine kinase inhibitors for patients with EGFR gene mutations, while crizotinib and ceritinib are two new tyrosine kinase inhibitors directed against the echinoderm microtubule-like protein 4-anaplastic lymphoma kinase translocation. The possibility of these new molecules being used to treat patients without adenocarcinoma histology is notably small. For example, EGFR mutations and anaplastic lymphoma kinase fusion gene rearrangement are rare in patients with squamous cell carcinoma (generally <1%. Additionally, the benefit of targeted treatment approaches in patients with small-cell lung cancer histology is limited. All of these findings highlight the distinctive nature of adenocarcinoma of the lung among all lung cancer subtypes. Unfortunately, to date, less than 15% of patients with adenocarcinoma of the lung are ideal candidates for these targeted therapies.Keywords: lung cancer, adenocarcinoma, EGFR, ALK

  16. Molecular classification of basal cell carcinoma of skin by gene expression profiling.

    Science.gov (United States)

    Jee, Byul A; Lim, Hyoseob; Kwon, So Mee; Jo, Yuna; Park, Myong Chul; Lee, Il Jae; Woo, Hyun Goo

    2015-12-01

    Non-melanoma skin cancers (NMSC) including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are more common kinds of skin cancer. Although these tumors share common pathological and clinical features, their similarity and heterogeneity at molecular levels are not fully elaborated yet. Here, by performing comparative analysis of gene expression profiling of BCC, SCC, and normal skin tissues, we could classify the BCC into three subtypes of classical, SCC-like, and normal-like BCCs. Functional enrichment and pathway analyses revealed the molecular characteristics of each subtype. The classical BCC showed the enriched expression and transcription signature with the activation of Wnt and Hedgehog signaling pathways, which were well known key features of BCC. By contrast, the SCC-like BCC was enriched with immune-response genes and oxidative stress-related genes. Network analysis revealed the PLAU/PLAUR as a key regulator of SCC-like BCC. The normal-like BCC showed prominent activation of metabolic processes particularly the fatty acid metabolism. The existence of these molecular subtypes could be validated in an independent dataset, which demonstrated the three subgroups of BCC with distinct functional enrichment. In conclusion, we suggest a novel molecular classification of BCC providing insights on the heterogeneous progression of BCC. © 2014 Wiley Periodicals, Inc.

  17. Transsexual subtypes : Clinical and theoretical significance

    NARCIS (Netherlands)

    Smith, YLS; van Goozen, SHM; Kuiper, AJ; Cohen-Kettenis, PT

    2005-01-01

    The present study was designed to investigate whether transsexuals can be validly subdivided into subtypes on the basis of sexual orientation, and whether differences between subtypes of transsexuals are similar for male-to-female (ME) and female-to-male transsexuals (FMs). Within a large

  18. Somatostatin receptor subtype expression in human thyroid tumours.

    Science.gov (United States)

    Klagge, A; Krause, K; Schierle, K; Steinert, F; Dralle, H; Fuhrer, D

    2010-04-01

    Somatostatin receptors (SSTR) are expressed in various endocrine tumours. The expression of SSTR at the tumour cell surface confers the possibility for diagnostic imaging and therapy of tumours using radiolabeled somatostatin analogues. The majority of currently available somatostatin analogues show a higher binding affinity for the SSTR2 subtype. To date, the precise expression pattern of the SSTR subtypes 1-5 in thyroid epithelial tumours remains to be determined. We investigated the mRNA expression of SSTR1-5 in benign and malignant epithelial thyroid tumours [20 cold thyroid nodules (CTNs), 20 toxic thyroid nodules (TTNs), 20 papillary, 20 follicular, and 5 anaplastic carcinomas (PTCs, FTCs, ATCs, respectively)] and compared them to normal surrounding thyroid tissues. Four out of five SSTR subtypes were detected in malignant thyroid tumours, benign neoplasia, and normal surrounding tissue with a predominant expression of SSTR2 and SSTR5, and a weak expression of SSTR1 and SSTR3. Weak SSTR4 mRNA expression was detected in some PTCs. Compared to normal thyroid tissue, SSTR2 was significantly upregulated in PTC and ATC. In addition significant upregulation of SSTR3 was found in PTC. SSTR5 mRNA expression was increased in PTC and FTC and significantly decreased in CTN and TTN compared to normal thyroid tissue. SSTR2 is the predominant subtype in thyroid epithelial tumours with a high expression pattern, in particular, in PTC . Perspectively, the expression of distinct SSTR in thyroid epithelial tumours might represent a promising avenue for diagnostics and therapy of advanced thyroid cancer with somatostatin analogues. Georg Thieme Verlag KG Stuttgart New York.

  19. Reliability of Rapid Subtyping Tools Compared to That of Phylogenetic Analysis for Characterization of Human Immunodeficiency Virus Type 1 Non-B Subtypes and Recombinant Forms▿

    Science.gov (United States)

    Holguín, África; López, Marisa; Soriano, Vincent

    2008-01-01

    Human immunodeficiency virus type 1 (HIV-1) subtyping is often estimated on the basis of pol sequences by using online websites instead of phylogenetic analysis (phy). We evaluated the reliability of distinct rapid subtyping tools versus phy with a large panel of HIV-1 non-B subtypes and circulating recombinant forms (CRF). pol sequences (277 protease [PR] and 171 reverse transcriptase [RT] sequences) previously assigned by phy to eight distinct HIV-1 non-B subtypes were obtained from 277 HIV-infected patients. Phy was run again to identify CRF. Subtyping was then performed using three rapid tools (the Stanford, NCBI, and REGA online tools). Thirty-three additional clade B sequences were tested as controls. New phylogenetic analyses reclassified two-thirds of pol sequences previously assigned to HIV-1 non-B clades as CRF. CRF02_AG variants were correctly assigned by the Stanford and NCBI tools for 92 to 97% and 96 to 99% of PR-RT sequences, respectively, while they were correctly assigned by the REGA tool for only 18 to 32% of PR-RT sequences. The Stanford, NCBI, and REGA tools failed to assign pure non-B clades correctly for 24 to 33%, 35%, and 57 to 64% of PR-RT sequences, respectively. For PR-RT sequences from CRF other than CRF02_AG, discrepancies occurred in 98 to 100%, 18 to 43%, and 80 to 87% of sequences, respectively. The concordance between those tools and phy was almost complete for subtype B assignment. Rapid subtyping tools show relatively low agreement with phy in identifying HIV-1 non-B clades and CRF other than CRF02_AG. The Stanford tool shows the best concordance with phy for the assignment of pure non-B clades, while the NCBI tool performs better at identifying CRF. Before entering routine clinical use, rapid subtyping tools should be optimized and updated periodically. Larger numbers of different non-B subtypes and CRF sequences should be included. PMID:18842935

  20. Reliability of rapid subtyping tools compared to that of phylogenetic analysis for characterization of human immunodeficiency virus type 1 non-B subtypes and recombinant forms.

    Science.gov (United States)

    Holguín, Africa; López, Marisa; Soriano, Vincent

    2008-12-01

    Human immunodeficiency virus type 1 (HIV-1) subtyping is often estimated on the basis of pol sequences by using online websites instead of phylogenetic analysis (phy). We evaluated the reliability of distinct rapid subtyping tools versus phy with a large panel of HIV-1 non-B subtypes and circulating recombinant forms (CRF). pol sequences (277 protease [PR] and 171 reverse transcriptase [RT] sequences) previously assigned by phy to eight distinct HIV-1 non-B subtypes were obtained from 277 HIV-infected patients. Phy was run again to identify CRF. Subtyping was then performed using three rapid tools (the Stanford, NCBI, and REGA online tools). Thirty-three additional clade B sequences were tested as controls. New phylogenetic analyses reclassified two-thirds of pol sequences previously assigned to HIV-1 non-B clades as CRF. CRF02_AG variants were correctly assigned by the Stanford and NCBI tools for 92 to 97% and 96 to 99% of PR-RT sequences, respectively, while they were correctly assigned by the REGA tool for only 18 to 32% of PR-RT sequences. The Stanford, NCBI, and REGA tools failed to assign pure non-B clades correctly for 24 to 33%, 35%, and 57 to 64% of PR-RT sequences, respectively. For PR-RT sequences from CRF other than CRF02_AG, discrepancies occurred in 98 to 100%, 18 to 43%, and 80 to 87% of sequences, respectively. The concordance between those tools and phy was almost complete for subtype B assignment. Rapid subtyping tools show relatively low agreement with phy in identifying HIV-1 non-B clades and CRF other than CRF02_AG. The Stanford tool shows the best concordance with phy for the assignment of pure non-B clades, while the NCBI tool performs better at identifying CRF. Before entering routine clinical use, rapid subtyping tools should be optimized and updated periodically. Larger numbers of different non-B subtypes and CRF sequences should be included.

  1. Multivariate neuroanatomical classification of cognitive subtypes in schizophrenia: A support vector machine learning approach

    Directory of Open Access Journals (Sweden)

    Ian C. Gould

    2014-01-01

    Full Text Available Heterogeneity in the structural brain abnormalities associated with schizophrenia has made identification of reliable neuroanatomical markers of the disease difficult. The use of more homogenous clinical phenotypes may improve the accuracy of predicting psychotic disorder/s on the basis of observable brain disturbances. Here we investigate the utility of cognitive subtypes of schizophrenia – ‘cognitive deficit’ and ‘cognitively spared’ – in determining whether multivariate patterns of volumetric brain differences can accurately discriminate these clinical subtypes from healthy controls, and from each other. We applied support vector machine classification to grey- and white-matter volume data from 126 schizophrenia patients previously allocated to the cognitive spared subtype, 74 cognitive deficit schizophrenia patients, and 134 healthy controls. Using this method, cognitive subtypes were distinguished from healthy controls with up to 72% accuracy. Cross-validation analyses between subtypes achieved an accuracy of 71%, suggesting that some common neuroanatomical patterns distinguish both subtypes from healthy controls. Notably, cognitive subtypes were best distinguished from one another when the sample was stratified by sex prior to classification analysis: cognitive subtype classification accuracy was relatively low (<60% without stratification, and increased to 83% for females with sex stratification. Distinct neuroanatomical patterns predicted cognitive subtype status in each sex: sex-specific multivariate patterns did not predict cognitive subtype status in the other sex above chance, and weight map analyses demonstrated negative correlations between the spatial patterns of weights underlying classification for each sex. These results suggest that in typical mixed-sex samples of schizophrenia patients, the volumetric brain differences between cognitive subtypes are relatively minor in contrast to the large common disease

  2. ADHD-hyperactive/impulsive subtype in adults

    Directory of Open Access Journals (Sweden)

    Stephen V. Faraone

    2010-01-01

    Full Text Available This is the first study to evaluate ADHD-hyperactive/impulsive subtype in a large clinical sample of adults with ADHD. The Quality of Life, Effectiveness, Safety and Tolerability (QuEST study included 725 adults who received clinician diagnoses of any ADHD subtype. Cross-sectional baseline data from 691 patients diagnosed with the hyperactive/impulsive (HI, inattentive (IA and combined subtypes were used to compare the groups on the clinician administered ADHD-RS, clinical features and health-related quality of life. A consistent pattern of differences was found between the ADHD-I and combined subtypes, with the combined subtype being more likely to be diagnosed in childhood, more severe symptom severity and lower HRQL. Twenty-three patients out of the total sample of 691 patients (3% received a clinician diagnosis of ADHD - hyperactive/impulsive subtype. Review of the ratings on the ADHD-RS-IV demonstrated, however, that this group had ratings of inattention comparable to the inattentive group. There were no significant differences found between the ADHD-HI and the other subtypes in symptom severity, functioning or quality of life. The hyperactive/impulsive subtype group identified by clinicians in this study was not significantly different from the rest of the sample. By contrast, significant differences were found between the inattentive and combined types. This suggests that in adults, hyperactivity declines and inattention remains significant, making the hyperactive/impulsive subtype as defined by childhood criteria a very rare condition and raising questions as to the validity of the HI subtype in adults.

  3. Role of HIV Subtype Diversity in the Development of Resistance to Antiviral Drugs

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    Bluma G. Brenner

    2010-11-01

    Full Text Available Despite the fact that over 90% of HIV-1 infected people worldwide harbor non‑subtype B variants of HIV-1, knowledge of resistance mutations in non-B HIV-1 and their clinical relevance is limited. Due to historical delays in access to antiretroviral therapy (ART on a worldwide basis, the vast majority of reports on drug resistance deal with subtype B infections in developed countries. However, both enzymatic and virological data support the concept that naturally occurring polymorphisms among different nonB subtypes can affect HIV-1 susceptibility to antiretroviral drugs (ARVs, the magnitude of resistance conferred by major mutations, and the propensity to acquire some resistance mutations. Tools need to be optimized to assure accurate measurements of drug susceptibility of non-B subtypes. Furthermore, there is a need to recognize that each subtype may have a distinct resistance profile and that differences in resistance pathways may also impact on cross-resistance and the selection of second-line regimens. It will be essential to pay attention to newer drug combinations in well designed long-term longitudinal studies involving patients infected by viruses of different subtypes.

  4. Hepatitis C virus sequences from different patients confirm the existence and transmissibility of subtype 2q, a rare subtype circulating in the metropolitan area of Barcelona, Spain.

    Science.gov (United States)

    Martró, Elisa; Valero, Ana; Jordana-Lluch, Elena; Saludes, Verónica; Planas, Ramón; González-Candelas, Fernando; Ausina, Vicente; Bracho, Maria Alma

    2011-05-01

    The hepatitis C virus (HCV) has been classified into six genotypes and more than 70 subtypes with distinct geographical and epidemiological distributions. While 18 genotype 2 subtypes have been proposed, only 5 have had their complete sequence determined. The aim of this study was to characterize HCV isolates from three patients from the Barcelona metropolitan area of Spain for whom commercial genotyping methods provided discordant results. Full-length genome sequencing was carried out for 2 of the 3 patients; for the third patient only partial NS5B sequences could be obtained. The generated sequences were subjected to phylogenetic, recombination, and identity analyses. Sequences covering most of the HCV genome (9398 and 9566  nt in length) were obtained and showed a 90.3% identity to each other at the nucleotide level, while both sequences differed by 17.5-22.6% from the other fully sequenced genotype 2 subtypes. No evidence of recombination was found. The NS5B phylogenetic tree showed that sequences from the three patients cluster together with the only representative sequence of the provisionally designed 2q subtype, which also corresponds to a patient from Barcelona. Phylogenetic analysis of the full coding sequence showed that subtype 2q was more closely related to subtype 2k. The results obtained in this study suggest that subtype 2q now meets the requirements for confirmed designation status according to consensus criteria for HCV classification and nomenclature, and its epidemiological value is ensured as it has spread among several patients in the Barcelona metropolitan area. Copyright © 2011 Wiley-Liss, Inc.

  5. Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome.

    Science.gov (United States)

    Holsen, L M; Zarcone, J R; Chambers, R; Butler, M G; Bittel, D C; Brooks, W M; Thompson, T I; Savage, C R

    2009-02-01

    Differences in behavioral phenotypes between the two most common subtypes of Prader-Willi syndrome (PWS) (chromosome 15q deletions and maternal uniparental disomy 15 (UPD) indicate that distinct neural networks may be affected. Though both subtypes display hyperphagia, the deletion subgroup shows reduced behavioral inhibition around food, whereas those with UPD are generally more able to maintain cognitive control over food intake impulses. To examine the neural basis of phenotypic differences to better understand relationships between genetic subtypes and behavioral outcomes. We predicted greater food motivation circuitry activity in the deletion subtype and greater activity in higher order cognitive regions in the UPD group, especially after eating. Nine individuals with PWS due to UPD and nine individuals with PWS due to (type 2) deletion, matched for age, gender and body mass index, underwent functional magnetic resonance imaging (fMRI) while viewing food images during two food motivation states: one before (pre-meal) and one after (post-meal) eating a standardized 500 kcal meal. Both PWS subgroups showed greater activity in response to food pre- and post-meal compared with the healthy-weight group. Compared with UPD, the deletion subtype showed increased food motivation network activation both pre- and post-meal, especially in the medial prefrontal cortex (mPFC) and amygdala. In contrast, the UPD group showed greater activation than the deletion subtype post-meal in the dorsolateral prefrontal cortex (DLPFC) and parahippocampal gyrus (PHG). These preliminary findings are the first functional neuroimaging findings to support divergent neural mechanisms associated with behavioral phenotypes in genetic subtypes of PWS. Results are discussed within the framework of genetic mechanisms such as haploinsufficiency and gene dosage effects and their differential influence on deletion and UPD subtypes, respectively.

  6. Phylogenetics of HIV-1 subtype G env: Greater complexity and older origins than previously reported.

    Science.gov (United States)

    Tongo, Marcel; Essomba, René G; Nindo, Frederick; Abrahams, Fatima; Nanfack, Aubin Joseph; Fokam, Joseph; Takou, Desire; Torimiro, Judith N; Mpoudi-Ngole, Eitel; Burgers, Wendy A; Martin, Darren P; Dorfman, Jeffrey R

    2015-10-01

    HIV-1 subtype G has played an early and central role in the emergent complexity of the HIV-1 group M (HIV-1M) epidemic in central/west Africa. Here, we analysed new subtype G env sequences sampled from 8 individuals in Yaoundé, Cameroon during 2007-2010, together with all publically available subtype G-attributed full-length env sequences with known sampling dates and locations. We inferred that the most recent common ancestor (MRCA) of the analysed subtype G env sequences most likely occurred in ∼1953 (95% Highest Posterior Density interval [HPD] 1939-1963): about 15 years earlier than previous estimates. We found that the subtype G env phylogeny has a complex structure including seven distinct lineages, each likely dating back to the late 1960s or early 1970s. Sequences from Angola, Gabon and the Democratic Republic of Congo failed to group consistently in these lineages, possibly because they are related to more ancient sequences that are poorly sampled. The circulating recombinant form (CRF), CRF06_cpx env sequences but not CRF25_cpx env sequences are phylogenetically nested within the subtype G clade. This confirms that the CRF06_cpx env plausibly was derived through recombination from a subtype G parent, and suggests that the CRF25_cpx env was likely derived from an HIV-1M lineage related to the MRCA of subtype G that has remained undiscovered and may be extinct. Overall, this fills important gaps in our knowledge of the early events in the spread of HIV-1M. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Genetic background may contribute to PAM50 gene expression breast cancer subtype assignments.

    Directory of Open Access Journals (Sweden)

    Ying Hu

    Full Text Available Recent advances in genome wide transcriptional analysis have provided greater insights into the etiology and heterogeneity of breast cancer. Molecular signatures have been developed that stratify the conventional estrogen receptor positive or negative categories into subtypes that are associated with differing clinical outcomes. It is thought that the expression patterns of the molecular subtypes primarily reflect cell-of-origin or tumor driver mutations. In this study however, using a genetically engineered mouse mammary tumor model we demonstrate that the PAM50 subtype signature of tumors driven by a common oncogenic event can be significantly influenced by the genetic background on which the tumor arises. These results have important implications for interpretation of "snapshot" expression profiles, as well as suggesting that incorporation of genetic background effects may allow investigation into phenotypes not initially anticipated in individual mouse models of cancer.

  8. Verified Subtyping with Traits and Mixins

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    Asankhaya Sharma

    2014-07-01

    Full Text Available Traits allow decomposing programs into smaller parts and mixins are a form of composition that resemble multiple inheritance. Unfortunately, in the presence of traits, programming languages like Scala give up on subtyping relation between objects. In this paper, we present a method to check subtyping between objects based on entailment in separation logic. We implement our method as a domain specific language in Scala and apply it on the Scala standard library. We have verified that 67% of mixins used in the Scala standard library do indeed conform to subtyping between the traits that are used to build them.

  9. Hepatitis C virus (HCV genotype 1 subtype identification in new HCV drug development and future clinical practice.

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    Stéphane Chevaliez

    Full Text Available BACKGROUND: With the development of new specific inhibitors of hepatitis C virus (HCV enzymes and functions that may yield different antiviral responses and resistance profiles according to the HCV subtype, correct HCV genotype 1 subtype identification is mandatory in clinical trials for stratification and interpretation purposes and will likely become necessary in future clinical practice. The goal of this study was to identify the appropriate molecular tool(s for accurate HCV genotype 1 subtype determination. METHODOLOGY/PRINCIPAL FINDINGS: A large cohort of 500 treatment-naïve patients eligible for HCV drug trials and infected with either subtype 1a or 1b was studied. Methods based on the sole analysis of the 5' non-coding region (5'NCR by sequence analysis or reverse hybridization failed to correctly identify HCV subtype 1a in 22.8%-29.5% of cases, and HCV subtype 1b in 9.5%-8.7% of cases. Natural polymorphisms at positions 107, 204 and/or 243 were responsible for mis-subtyping with these methods. A real-time PCR method using genotype- and subtype-specific primers and probes located in both the 5'NCR and the NS5B-coding region failed to correctly identify HCV genotype 1 subtype in approximately 10% of cases. The second-generation line probe assay, a reverse hybridization assay that uses probes targeting both the 5'NCR and core-coding region, correctly identified HCV subtypes 1a and 1b in more than 99% of cases. CONCLUSIONS/SIGNIFICANCE: In the context of new HCV drug development, HCV genotyping methods based on the exclusive analysis of the 5'NCR should be avoided. The second-generation line probe assay is currently the best commercial assay for determination of HCV genotype 1 subtypes 1a and 1b in clinical trials and practice.

  10. Computational visual distinctness metric

    NARCIS (Netherlands)

    Martínez-Baena, J.; Toet, A.; Fdez-Vidal, X.R.; Garrido, A.; Rodríguez-Sánchez, R.

    1998-01-01

    A new computational visual distinctness metric based on principles of the early human visual system is presented. The metric is applied to quantify (1) the visual distinctness of targets in complex natural scenes and (2) the perceptual differences between compressed and uncompressed images. The new

  11. Beyond Neuronal Activity Markers: Select Immediate Early Genes in Striatal Neuron Subtypes Functionally Mediate Psychostimulant Addiction

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    Ramesh Chandra

    2017-06-01

    Full Text Available Immediate early genes (IEGs were traditionally used as markers of neuronal activity in striatum in response to stimuli including drugs of abuse such as psychostimulants. Early studies using these neuronal activity markers led to important insights in striatal neuron subtype responsiveness to psychostimulants. Such studies have helped identify striatum as a critical brain center for motivational, reinforcement and habitual behaviors in psychostimulant addiction. While the use of IEGs as neuronal activity markers in response to psychostimulants and other stimuli persists today, the functional role and implications of these IEGs has often been neglected. Nonetheless, there is a subset of research that investigates the functional role of IEGs in molecular, cellular and behavioral alterations by psychostimulants through striatal medium spiny neuron (MSN subtypes, the two projection neuron subtypes in striatum. This review article will address and highlight the studies that provide a functional mechanism by which IEGs mediate psychostimulant molecular, cellular and behavioral plasticity through MSN subtypes. Insight into the functional role of IEGs in striatal MSN subtypes could provide improved understanding into addiction and neuropsychiatric diseases affecting striatum, such as affective disorders and compulsive disorders characterized by dysfunctional motivation and habitual behavior.

  12. Detection of avian metapneumovirus subtypes in turkeys using RT-PCR.

    Science.gov (United States)

    Ongor, H; Karahan, M; Kalin, R; Bulut, H; Cetinkaya, B

    2010-03-20

    This study investigated the prevalence of avian metapneumovirus (aMPV) and the detection of molecular subtypes of field strains of the virus using RT-PCR in clinically healthy turkeys and those showing signs of respiratory disease. In the RT-PCR examination of 624 tracheal tissue samples collected from a local turkey abattoir, 2.9 per cent (18/624) of samples tested positive. In the examination of tracheal swab samples collected from flocks with respiratory problems, 18 of 20 samples tested positive. When the results were assessed at flock level, aMPV infection was detected in only one of the 23 clinically healthy turkey flocks, whereas all four flocks with respiratory problems were infected. Molecular typing using primers specific to the attachment glycoprotein (G) gene showed that all 36 positive samples belonged to subtype B. Partial sequence analysis of DNA samples showed 95 per cent homology between the field types and the reference strain aMPV subtype B. Whereas clinically healthy turkeys had been vaccinated with a subtype A virus vaccine, the flocks with respiratory problems had been vaccinated with a subtype B virus vaccine. Despite four blind passages of RT-PCR-positive samples on Vero and chicken embryo fibroblast cells, no cytopathic effect was detected by microscopic examination.

  13. Hypertension Subtypes among Hypertensive Patients in Ibadan

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    Abiodun M. Adeoye

    2014-01-01

    Full Text Available Background. Certain hypertension subtypes have been shown to increase the risk for cardiovascular morbidity and mortality and may be related to specific underlying genetic determinants. Inappropriate characterization of subtypes of hypertension makes efforts at elucidating the genetic contributions to the etiology of hypertension largely vapid. We report the hypertension subtypes among patients with hypertension from South-Western Nigeria. Methods. A total of 1858 subjects comprising 76% female, hypertensive, aged 18 and above were recruited into the study from two centers in Ibadan, Nigeria. Hypertension was identified using JNCVII definition and was further grouped into four subtypes: controlled hypertension (CH, isolated systolic hypertension (ISH, isolated diastolic hypertension (IDH, and systolic-diastolic hypertension (SDH. Results. Systolic-diastolic hypertension was the most prevalent. Whereas SDH (77.6% versus 73.5% and IDH (4.9% versus 4.7% were more prevalent among females, ISH (10.1% versus 6.2% was higher among males (P=0.048. Female subjects were more obese (P<0.0001 and SDH was prevalent among the obese group. Conclusion. Gender and obesity significantly influenced the distribution of the hypertension subtypes. Characterization of hypertension by subtypes in genetic association studies could lead to identification of previously unknown genetic variants involved in the etiology of hypertension. Large-scale studies among various ethnic groups may be needed to confirm these observations.

  14. Interferon α subtypes in HIV infection.

    Science.gov (United States)

    Sutter, Kathrin; Dickow, Julia; Dittmer, Ulf

    2018-02-13

    Type I interferons (IFN), which are immediately induced after most virus infections, are central for direct antiviral immunity and link innate and adaptive immune responses. However, several viruses have evolved strategies to evade the IFN response by preventing IFN induction or blocking IFN signaling pathways. Thus, therapeutic application of exogenous type I IFN or agonists inducing type I IFN responses are a considerable option for future immunotherapies against chronic viral infections. An important part of the type I IFN family are 12 IFNα subtypes, which all bind the same receptor, but significantly differ in their biological activities. Up to date only one IFNα subtype (IFNα2) is being used in clinical treatment against chronic virus infections, however its therapeutic success rate is rather limited, especially during Human Immunodeficiency Virus (HIV) infection. Recent studies addressed the important question if other IFNα subtypes would be more potent against retroviral infections in in vitro and in vivo experiments. Indeed, very potent IFNα subtypes were defined and their antiviral and immunomodulatory properties were characterized. In this review we summarize the recent findings on the role of individual IFNα subtypes during HIV and Simian Immunodeficiency Virus infection. This includes their induction during HIV/SIV infection, their antiretroviral activity and the regulation of immune response against HIV by different IFNα subtypes. The findings might facilitate novel strategies for HIV cure or functional cure studies. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Visual Neurons in the Superior Colliculus Innervated by Islet2+ or Islet2− Retinal Ganglion Cells Display Distinct Tuning Properties

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    Rachel B. Kay

    2017-10-01

    Full Text Available Throughout the visual system, different subtypes of neurons are tuned to distinct aspects of the visual scene, establishing parallel circuits. Defining the mechanisms by which such tuning arises has been a long-standing challenge for neuroscience. To investigate this, we have focused on the retina’s projection to the superior colliculus (SC, where multiple visual neuron subtypes have been described. The SC receives inputs from a variety of retinal ganglion cell (RGC subtypes; however, which RGCs drive the tuning of different SC neurons remains unclear. Here, we pursued a genetic approach that allowed us to determine the tuning properties of neurons innervated by molecularly defined subpopulations of RGCs. In homozygous Islet2-EphA3 knock-in (Isl2EA3/EA3 mice, Isl2+ and Isl2− RGCs project to non-overlapping sub-regions of the SC. Based on molecular and anatomic data, we show that significantly more Isl2− RGCs are direction-selective (DS in comparison with Isl2+ RGCs. Targeted recordings of visual responses from each SC sub-region in Isl2EA3/EA3 mice revealed that Isl2− RGC-innervated neurons were significantly more DS than those innervated by Isl2+ RGCs. Axis-selective (AS neurons were found in both sub-regions, though AS neurons innervated by Isl2+ RGCs were more tightly tuned. Despite this segregation, DS and AS neurons innervated by Isl2+ or Isl2− RGCs did not differ in their spatial summation or spatial frequency (SF tuning. Further, we did not observe alterations in receptive field (RF size or structure of SC neurons innervated by Isl2+ or Isl2− RGCs. Together, these data show that innervation by Isl2+ and Isl2− RGCs results in distinct tuning in the SC and set the stage for future studies investigating the mechanisms by which these circuits are built.

  16. Subtype differentiation of patients with borderline personality disorder using a circumplex model of interpersonal behavior.

    Science.gov (United States)

    Leihener, Florian; Wagner, Amy; Haaf, Brigitte; Schmidt, Carola; Lieb, Klaus; Stieglitz, Rolf; Bohus, Martin

    2003-04-01

    The considerable heterogeneity of symptomatology in persons with borderline personality disorder (BPD) has led some to suggest the existence of subtypes within this diagnosis. However, no study to date has examined subtypes according to differences in interpersonal functioning, despite the central role of interpersonal problems in the BPD diagnosis. The interpersonal problems of 95 patients with BPD were investigated using the German version of the Inventory of Interpersonal Problems, a self-report measure based on a circumplex model of interpersonal functioning. Data were analyzed by means of cluster analysis. The results supported the existence of two distinct subtypes of persons with BPD, labeled "autonomous" and "dependent." Four-month longitudinal assessment indicated that these types were stable over time, suggesting the categorization reflected trait, as opposed to state, patterns of interpersonal behavior. Implications of these findings for future research and management of BPD are discussed.

  17. Integrative clustering reveals a novel split in the luminal A subtype of breast cancer with impact on outcome

    DEFF Research Database (Denmark)

    Aure, Miriam Ragle; Vitelli, Valeria; Jernström, Sandra

    2017-01-01

    BACKGROUND: Breast cancer is a heterogeneous disease at the clinical and molecular level. In this study we integrate classifications extracted from five different molecular levels in order to identify integrated subtypes. METHODS: Tumor tissue from 425 patients with primary breast cancer from the...

  18. Distribution of human immunodeficiency virus type 1 subtypes in the State of Amazonas, Brazil, and subtype C identification.

    Science.gov (United States)

    Cunha, L K H; Kashima, S; Amarante, M F C; Haddad, R; Rodrigues, E S; Silva, K L T; Lima, T A; Castro, D B; Brito, F C; Almeida, E G; Covas, D T; Malheiro, A

    2012-02-01

    Few studies have reported the molecular epidemiological characterization of HIV-1 in the Northern region of Brazil. The present study reports the molecular and epidemiological characterization of 31 HIV-1 isolates from blood donors from the State of Amazonas who donated blood between April 2006 and March 2007. Serum/plasma samples from all donors were screened for HIV antibodies by ELISA and the results confirmed by Western blot analysis. Genomic DNA was extracted from the buffy coat using the Super Quik-Gene-DNA Isolation kit. Nested PCR was performed on the env, gag, and pol regions of HIV-1 using the Gene Amp PCR System 9700. Sequencing reactions were performed using the inner PCR primers and the DYEnamic™ ET Dye Terminator Kit, and phylogenetic analysis was performed using the gag, pol, and env gene sequences. We collected samples from 31 blood donors who tested positive for HIV-1 in confirmatory experiments. The male:female ratio of blood donors was 3.4:1, and the mean age was 32.4 years (range: 19 to 61 years). Phylogenetic analysis showed that subtype B is the most prevalent among Northern Brazilian HIV-1-seropositive blood donors. One HIV-1 subtype C and one circulating recombinant form (CRF_BF) of HIV-1 were identified in the State of Amazonas. This is the first study showing the occurrence of a possible "homogenous" subtype C in this region of Brazil. This finding could contribute to a better characterization of the HIV-1 strains that circulate in the country.

  19. Influence of Biologic Subtype of Inflammatory Breast Cancer on Response to Neoadjuvant Therapy and Cancer Outcomes.

    Science.gov (United States)

    Hieken, Tina J; Murphy, Brittany L; Boughey, Judy C; Degnim, Amy C; Glazebrook, Katrina N; Hoskin, Tanya L

    2017-10-07

    Few data exist on the influence of tumor biologic subtype on treatment response and outcomes for inflammatory breast cancer (IBC). We examined a contemporary cohort of IBC patients treated with current targeted systemic therapies, selected on the basis of tumor biologic subtype, to evaluate pathologic treatment response and cancer outcomes across biologic subtypes. We studied 57 clinical stage T4dM0 IBC patients operated on at our institution from October 2008 to July 2015. Comparisons across biologic subtypes were performed by Wilcoxon rank-sum or chi-square tests; Kaplan-Meier and log-rank tests were used to analyze survival outcomes. All patients received neoadjuvant systemic therapy; 54 (95%) completed postmastectomy radiation. Ninety-one percent (52/57) had clinically node-positive disease at presentation. Pathologic complete response (pCR) rates in the breast and axilla differed significantly by approximated biologic subtype, defined as estrogen receptor (ER) positive/human epidermal growth factor receptor 2 (HER-2) negative; and HER-2 positive and ER negative/HER-2 negative (all P biologic subtype. Five-year DFS was 46% for patients with ER-positive/HER-2-negative tumors, 82% for HER-2-positive tumors, and 33% for ER-negative/HER-2-negative tumors (P biologic subtypes. Multimodal treatment and modern systemic therapies have markedly improved DFS and BCSS. These data provide further evidence to suggest that IBC is not a distinct biologic entity transcending standard breast tumor marker subclassification. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Mild cognitive impairment (MCI) in long-term care patients: subtype classification and occurrence.

    Science.gov (United States)

    Mansbach, William E; Mace, Ryan A; Clark, Kristen M

    2016-01-01

    This study examines mild cognitive impairment (MCI) in long-term care settings by identifying and quantifying MCI subtypes in a combined sample of nursing home and assisted-living patients. We compared impairment thresholds of 1-SD and 1.5-SD to determine if different cut-offs differentially affect occurrence rates. One hundred and eight participants who met general criteria for MCI were included for the purposes of this study. The general diagnosis of MCI was based on criteria. Participants were further grouped into MCI subtypes. Based on previously established norms, Brief Cognitive Assessment Tool (BCAT) factor scores were used to assess whether MCI participants met either the 1-SD and 1.5-SD impairment thresholds for memory, executive functions, and attentional capacity. Using both 1-SD and 1.5-SD impairment thresholds, three clear MCI subtypes were identified: amnestic, single-domain; non-amnestic, single-domain (executive); and amnestic, multi-domain (memory and executive). A fourth category (undifferentiated) was identified in patients who did not meet criteria for a distinct MCI subtype, but still had cognitive impairments. The stricter impairment threshold of 1.5-SD resulted in fewer patients classified as having any of the three domain-specific subtypes. Based on a sample of nursing home and assisted-living patients, we identified three MCI subtypes, and a fourth category consisting of participants with general MCI, but without clear evidence of domain-specific cognitive impairment. When selecting impairment thresholds, one should consider the impact on the identification of MCI subtypes and the probability of misdiagnoses.

  1. The identification of family subtype based on the assessment of subclinical levels of psychosis in relatives

    Directory of Open Access Journals (Sweden)

    Derks Eske M

    2012-07-01

    Full Text Available Abstract Background Schizophrenia is a complex psychiatric disorder characterized by high phenotypic heterogeneity. Previous studies have distinguished between familial and sporadic forms of schizophrenia and have suggested clinical differentiation between patients and relatives from sporadic and multiplex families. We will introduce a more refined method to distinguish between family subtypes based on psychosis dimension profiles in the relatives of schizophrenia patients. Methods Positive, negative, disorganization, mania, and depression scores were assessed in 1,392 relatives. Mixed Model Latent Class Analysis was used to identify family subtypes. A family subtype is a relatively homogeneous group of families with similar symptom profiles in the relatives in these families. Next, we investigated in 616 schizophrenia patients whether family subtype was associated with symptom profiles, IQ, cannabis dependence/abuse, or age of onset of psychosis. Results Based on the data of relatives, we identified two different family types: “healthy” and “at risk for psychiatric disorder”. Patients from at risk families obtained higher positive scores compared to patients from healthy families (Wald(1 = 6.6293, p = 0.010. No significant differences were found in any of the remaining variables. Conclusions Our findings confirm the existence of high-risk families and although we did not establish an etiological basis for the distinction between family types, genetic studies might reveal whether family subtype is associated with genetic heterogeneity.

  2. A new HCV genotype 6 subtype designated 6v was confirmed with three complete genome sequences.

    Science.gov (United States)

    Wang, Yizhong; Xia, Xueshan; Li, Chunhua; Maneekarn, Niwat; Xia, Wenjie; Zhao, Wenhua; Feng, Yue; Kung, Hsiang Fu; Fu, Yongshui; Lu, Ling

    2009-03-01

    Although hepatitis C virus (HCV) genotype 6 is classified into 21 subtypes, 6a-6u, new variants continue to be identified. To characterize the full-length genomes of three novel HCV genotype 6 variants: KMN02, KM046 and KM181. From sera of patients with HCV infection, the entire HCV genome was amplified by RT-PCR followed by direct DNA sequencing and phylogenetic analysis. The sera contained HCV genomes of 9461, 9429, and 9461nt in length, and each harboured a single ORF of 9051nt. The genomes showed 95.3-98.1% nucleotide similarity to each other and 72.2-75.4% similarity to 23 genotype 6 reference sequences, which represent subtypes 6a-6u and unassigned variants km41 and gz52557. Phylogenetic analyses demonstrated that they were genotype 6, but were subtypically distinct. Based on the current criteria of HCV classification, they were designed to represent a new subtype, 6v. Analysis of E1 and NS5B region partial sequences revealed two additional related variants, CMBD-14 and CMBD-86 that had been previously reported in northern Thailand and sequences dropped into Genbank. Three novel HCV genotype 6 variants were entirely sequenced and designated subtype 6v.

  3. Social skills and social phobia: an investigation of DSM-IV subtypes.

    Science.gov (United States)

    Beidel, Deborah C; Rao, Patricia A; Scharfstein, Lindsay; Wong, Nina; Alfano, Candice A

    2010-10-01

    Social phobia is characterized as pervasive social timidity in social settings. Although much is known about this disorder, aspects of its clinical presentation remain unexplored, in particular characteristics that distinguish the generalized and non-generalized subtypes. For example, it remains unclear whether patients with the non-generalized subtype display social skills deficits in social interactions, and if so, are these deficits clinically, as well as statistically, significant? In this study, adults with either the non-generalized (NGSP; n=60) or generalized (GSP; n=119) subtype of social phobia and adults with no psychological disorder (n=200) completed an extensive behavioral assessment of social skill and social anxiety. As expected, adults with NGSP and GSP reported equal distress and displayed similar rates of avoidance during an Impromptu Speech Task when compared to adults with no disorder. In contrast, the three groups were distinctly different when interacting with another person in various social situations. Adults with NGSP displayed social skill deficits when compared to individuals with no disorder, but they had fewer deficits than the GSP subtype. However, the identified skill deficits were clinically as well as statistically significant only for the GSP subtype. The results are discussed in terms of the contribution of skill deficits to the conceptualization and treatment of social phobia. Copyright 2010 Elsevier Ltd. All rights reserved.

  4. Molecular Subtypes and Clinical Outcomes of Breast Cancer

    African Journals Online (AJOL)

    2010-01-04

    Jan 4, 2010 ... Breast cancer is a significant cause of worldwide morbid- ity and mortality in females (1). A major challenge in the diagnosis and treatment of breast cancer is its hetero- geneity, because individual breast tumours can exhibit tremendous variations in clinical presentation, disease aggressiveness and ...

  5. Molecular subtyping and erythromycin resistance of Campylobacter in China.

    Science.gov (United States)

    Zhang, A; Song, L; Liang, H; Gu, Y; Zhang, C; Liu, X; Zhang, J; Zhang, M

    2016-07-01

    To investigate the erythromycin resistance patterns and mechanism for Campylobacter isolates in China. The minimum inhibitory concentrations of erythromycin on 858 Chinese Campylobacter isolates were analysed. PCR and DNA sequencing were used to identify mutations in the 23S rRNA and the presence of the ermB gene in the 158 erythromycin resistance isolates (18·4%). About 83% (131/158) had A2075G mutation in their 23S rRNA; no A2074C/G mutants were found. The ermB gene was identified in 30 Campylobacter coli isolates (19%). Four types of multidrug-resistant gene islands (MDRGIs) were found. Fifty-three types were identified by multilocus sequence typing among the resistant isolates. All isolates of STs 6322 and 1145 had the ermB gene. The erythromycin resistance rate of Camp. coli (58·56%) was much higher than Campylobacter jejuni (0·67%). The insertion sites between cadF and CCO1582 and between nfsB and cinA on the chromosome might b