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Sample records for identifies distinct subtypes

  1. DNA methylation signatures identify biologically distinct thyroid cancer subtypes.

    PubMed

    Rodríguez-Rodero, Sandra; Fernández, Agustín F; Fernández-Morera, Juan Luís; Castro-Santos, Patricia; Bayon, Gustavo F; Ferrero, Cecilia; Urdinguio, Rocio G; Gonzalez-Marquez, Rocío; Suarez, Carlos; Fernández-Vega, Iván; Fresno Forcelledo, Manuel Florentino; Martínez-Camblor, Pablo; Mancikova, Veronika; Castelblanco, Esmeralda; Perez, Marco; Marrón, Pablo Isidro; Mendiola, Marta; Hardisson, David; Santisteban, Pilar; Riesco-Eizaguirre, Garcilaso; Matías-Guiu, Xavier; Carnero, Amancio; Robledo, Mercedes; Delgado-Álvarez, Elías; Menéndez-Torre, Edelmiro; Fraga, Mario F

    2013-07-01

    The purpose of this study was to determine the global patterns of aberrant DNA methylation in thyroid cancer. We have used DNA methylation arrays to determine, for the first time, the genome-wide promoter methylation status of papillary, follicular, medullary, and anaplastic thyroid tumors. We identified 262 and 352 hypermethylated and 13 and 21 hypomethylated genes in differentiated papillary and follicular tumors, respectively. Interestingly, the other tumor types analyzed displayed more hypomethylated genes (280 in anaplastic and 393 in medullary tumors) than aberrantly hypermethylated genes (86 in anaplastic and 131 in medullary tumors). Among the genes indentified, we show that 4 potential tumor suppressor genes (ADAMTS8, HOXB4, ZIC1, and KISS1R) and 4 potential oncogenes (INSL4, DPPA2, TCL1B, and NOTCH4) are frequently regulated by aberrant methylation in primary thyroid tumors. In addition, we show that aberrant promoter hypomethylation-associated overexpression of MAP17 might promote tumor growth in thyroid cancer. Thyroid cancer subtypes present differential promoter methylation signatures, and nondifferentiated subtypes are characterized by aberrant promoter hypomethylation rather than hypermethylation. Additional studies are needed to determine the potential clinical interest of the tumor subtype-specific DNA methylation signatures described herein and the role of aberrant promoter hypomethylation in nondifferentiated thyroid tumors.

  2. Identifying Etiologically Distinct Sub-Types of Cancer: A Demonstration Project Involving Breast Cancer

    PubMed Central

    Begg, Colin B; Orlow, Irene; Zabor, Emily C; Arora, Arshi; Sharma, Ajay; Seshan, Venkatraman E; Bernstein, Jonine L

    2015-01-01

    With the advent of increasingly detailed molecular portraits of tumor specimens, much attention has been directed toward identifying clinically distinct subtypes of cancer. Subtyping of tumors can also be accomplished with the goal of identifying distinct etiologies. We demonstrate the use of new methodologies to identify genes that distinguish etiologically heterogeneous subtypes of breast cancer using data from the case–control Cancer and Steroid Hormone Study. Tumor specimens were evaluated using a breast cancer expression panel of 196 genes. Using a statistical measure that distinguishes the degree of etiologic heterogeneity in tumor subtypes, each gene is ranked on the basis of its ability to distinguish etiologically distinct subtypes. This is accomplished independently using case–control comparisons and by examining the concordance odds ratios in double primaries. The estrogen receptor gene, and others in this pathway with expression levels that correlated strongly with estrogen receptor levels, demonstrate high degrees of etiologic heterogeneity in both methods. Our results are consistent with a growing literature that confirms the distinct etiologies of breast cancers classified on the basis of estrogen receptor expression levels. This proof-of-principle project demonstrates the viability of new strategies to identify genomic features that distinguish subtypes of cancer from an etiologic perspective. PMID:25974664

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

    PubMed

    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.

  4. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.

    PubMed

    Cristescu, Razvan; Lee, Jeeyun; Nebozhyn, Michael; Kim, Kyoung-Mee; Ting, Jason C; Wong, Swee Seong; Liu, Jiangang; Yue, Yong Gang; Wang, Jian; Yu, Kun; Ye, Xiang S; Do, In-Gu; Liu, Shawn; Gong, Lara; Fu, Jake; Jin, Jason Gang; Choi, Min Gew; Sohn, Tae Sung; Lee, Joon Ho; Bae, Jae Moon; Kim, Seung Tae; Park, Se Hoon; Sohn, Insuk; Jung, Sin-Ho; Tan, Patrick; Chen, Ronghua; Hardwick, James; Kang, Won Ki; Ayers, Mark; Hongyue, Dai; Reinhard, Christoph; Loboda, Andrey; Kim, Sung; Aggarwal, Amit

    2015-05-01

    Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.

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

    PubMed Central

    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

    2015-01-01

    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 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 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 analysis of TCGA tumor copy number and gene expression data with the PARADIGM algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by 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. PMID:26333934

  6. Integrated Genomics Identifies Five Medulloblastoma Subtypes with Distinct Genetic Profiles, Pathway Signatures and Clinicopathological Features

    PubMed Central

    Kool, Marcel; Koster, Jan; Bunt, Jens; Hasselt, Nancy E.; Lakeman, Arjan; van Sluis, Peter; Troost, Dirk; Meeteren, Netteke Schouten-van; Caron, Huib N.; Cloos, Jacqueline; Mršić, Alan; Ylstra, Bauke; Grajkowska, Wieslawa; Hartmann, Wolfgang; Pietsch, Torsten; Ellison, David; Clifford, Steven C.; Versteeg, Rogier

    2008-01-01

    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 β-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. Patients below 3 yrs of

  7. Functional genomics identifies five distinct molecular subtypes with clinical relevance and pathways for growth control in epithelial ovarian cancer

    PubMed Central

    Tan, Tuan Zea; Miow, Qing Hao; Huang, Ruby Yun-Ju; Wong, Meng Kang; Ye, Jieru; Lau, Jieying Amelia; Wu, Meng Chu; Bin Abdul Hadi, Luqman Hakim; Soong, Richie; Choolani, Mahesh; Davidson, Ben; Nesland, Jahn M; Wang, Ling-Zhi; Matsumura, Noriomi; Mandai, Masaki; Konishi, Ikuo; Goh, Boon-Cher; Chang, Jeffrey T; Thiery, Jean Paul; Mori, Seiichi

    2013-01-01

    Epithelial ovarian cancer (EOC) is hallmarked by a high degree of heterogeneity. To address this heterogeneity, a classification scheme was developed based on gene expression patterns of 1538 tumours. Five, biologically distinct subgroups — Epi-A, Epi-B, Mes, Stem-A and Stem-B — exhibited significantly distinct clinicopathological characteristics, deregulated pathways and patient prognoses, and were validated using independent datasets. To identify subtype-specific molecular targets, ovarian cancer cell lines representing these molecular subtypes were screened against a genome-wide shRNA library. Focusing on the poor-prognosis Stem-A subtype, we found that two genes involved in tubulin processing, TUBGCP4 and NAT10, were essential for cell growth, an observation supported by a pathway analysis that also predicted involvement of microtubule-related processes. Furthermore, we observed that Stem-A cell lines were indeed more sensitive to inhibitors of tubulin polymerization, vincristine and vinorelbine, than the other subtypes. This subtyping offers new insights into the development of novel diagnostic and personalized treatment for EOC patients. PMID:23666744

  8. Multiple Distinct Subtypes of GABAergic Neurons in Mouse Visual Cortex Identified by Triple Immunostaining

    PubMed Central

    Gonchar, Yuri; Wang, Quanxin; Burkhalter, Andreas

    2007-01-01

    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 identified 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 first 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. PMID:18958197

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

    PubMed Central

    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

    2016-01-01

    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. PMID:26729235

  10. Cluster Analysis in the COPDGene Study Identifies Subtypes of Smokers with Distinct Patterns of Airway Disease and Emphysema

    PubMed Central

    Castaldi, Peter J; Dy, Jennifer; Ross, James; Chang, Yale; Washko, George R; Curran-Everett, Douglas; Williams, Andre; Lynch, David A; Make, Barry J; Crapo, James D; Bowler, Russ P; Regan, Elizabeth A; Hokanson, John E; Kinney, Greg L; Han, Meilan K; Soler, Xavier; Ramsdell, Joseph W; Barr, R Graham; Foreman, Marilyn; van Beek, Edwin; Casaburi, Richard; Criner, Gerald J; Lutz, Sharon M; Rennard, Steven I; Santorico, Stephanie; Sciurba, Frank C; DeMeo, Dawn L; Hersh, Craig P; Silverman, Edwin K; Cho, Michael H

    2014-01-01

    Background There is notable heterogeneity in the clinical presentation of patients with COPD. To characterize this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene Study. Methods We applied a clustering method, k-means, to data from 10,192 smokers in the COPDGene Study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. Findings We identified four clusters that can be characterized as 1) relatively resistant smokers (i.e. no/mild obstruction and minimal emphysema despite heavy smoking), 2) mild upper zone emphysema predominant, 3) airway disease predominant, and 4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). Interpretation Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants. PMID:24563194

  11. Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema.

    PubMed

    Castaldi, Peter J; Dy, Jennifer; Ross, James; Chang, Yale; Washko, George R; Curran-Everett, Douglas; Williams, Andre; Lynch, David A; Make, Barry J; Crapo, James D; Bowler, Russ P; Regan, Elizabeth A; Hokanson, John E; Kinney, Greg L; Han, Meilan K; Soler, Xavier; Ramsdell, Joseph W; Barr, R Graham; Foreman, Marilyn; van Beek, Edwin; Casaburi, Richard; Criner, Gerald J; Lutz, Sharon M; Rennard, Steven I; Santorico, Stephanie; Sciurba, Frank C; DeMeo, Dawn L; Hersh, Craig P; Silverman, Edwin K; Cho, Michael H

    2014-05-01

    There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations). Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.

  12. Catatonia in autism: a distinct subtype?

    PubMed

    Ghaziuddin, M; Quinlan, P; Ghaziuddin, N

    2005-01-01

    Catatonia is a life-threatening disorder characterized by motor abnormalities, mutism, and disturbances of behaviour, which is increasingly being diagnosed in persons with autism. In this report, we describe the presentation and course of catatonia in an adolescent with autism who responded to electroconvulsive therapy (ECT). The illness started with depressive symptoms, but the predominant feature was one of extreme obsessive slowing and immobility. We propose that catatonia should be ruled out as a cause of regression sometimes seen in adolescents with autism, and that catatonia of autism may index a distinct subtype with a particularly poor outcome.

  13. Distinct DNA methylation profiles in subtypes of orofacial cleft.

    PubMed

    Sharp, Gemma C; Ho, Karen; Davies, Amy; Stergiakouli, Evie; Humphries, Kerry; McArdle, Wendy; Sandy, Jonathan; Davey Smith, George; Lewis, Sarah J; Relton, Caroline L

    2017-01-01

    Epigenetic data could help identify risk factors for orofacial clefts, either by revealing a causal role for epigenetic mechanisms in causing clefts or by capturing information about causal genetic or environmental factors. Given the evidence that different subtypes of orofacial cleft have distinct aetiologies, we explored whether children with different cleft subtypes showed distinct epigenetic profiles. In whole-blood samples from 150 children from the Cleft Collective cohort study, we measured DNA methylation at over 450,000 sites on the genome. We then carried out epigenome-wide association studies (EWAS) to test the association between methylation at each site and cleft subtype (cleft lip only (CLO) n = 50; cleft palate only (CPO) n = 50; cleft lip and palate (CLP) n = 50). We also compared methylation in the blood to methylation in the lip or palate tissue using genome-wide data from the same 150 children and conducted an EWAS of CLO compared to CLP in lip tissue. We found four genomic regions in blood differentially methylated in CLO compared to CLP, 17 in CPO compared to CLP and 294 in CPO compared to CLO. Several regions mapped to genes that have previously been implicated in the development of orofacial clefts (for example, TBX1, COL11A2, HOXA2, PDGFRA), and over 250 associations were novel. Methylation in blood correlated with that in lip/palate at some regions. There were 14 regions differentially methylated in the lip tissue from children with CLO and CLP, with one region (near KIAA0415) showing up in both the blood and lip EWAS. Our finding of distinct methylation profiles in different orofacial cleft (OFC) subtypes represents a promising first step in exploring the potential role of epigenetic modifications in the aetiology of OFCs and/or as clinically useful biomarkers of OFC subtypes.

  14. Do Distinct Functional Dyspepsia Subtypes Exist in Children?

    PubMed

    Turco, Rossella; Russo, Marina; Martinelli, Massimo; Castiello, Rosa; Coppola, Vincenzo; Miele, Erasmo; Staiano, Annamaria

    2016-03-01

    Two different subtypes of functional dyspepsia (FD) are recognized in adults: epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS). The aim of the study was to assess the presence of FD subtypes in childhood at diagnosis and to observe changes at follow-up. A total of 100 patients with a diagnosis of FD based on pediatric Rome III criteria were consecutively enrolled. FD subtypes were successively classified through adult Rome III classification. Children were revaluated after 6 months of follow-up (T1). At T0, 17 (17%) of 100 patients were classified as EPS, whereas 47 (47%) of 100 patients fulfilled criteria for PDS. In 36 (36%) of 100 children an overlap between the 2 subtypes was identified. Nausea was significantly higher in PDS and overlap groups when compared with EPS (χ = 21.7, P = 0.0001; χ = 20.7, P = 0.0001). Headache was significantly increased in PDS and overlap groups compared with patients with EPS (χ = 9.8, P = 0.001; χ = 13.1, P = 0.0001, respectively). At T1 among children belonging to PDS group at enrolment, 9 of 47 (19.1%) changed to EPS group, and 9 of 47 (19.1%) changed to the overlap group. Five (29.4%) of 17 patients and 2 (11.8%) of 17 children diagnosed as having EPS at T0 switched to PDS and overlap group, respectively. Of the 36 patients with overlap at enrollment, 11 (30.6%) satisfied criteria for PDS, and 7 (19.4%) switched to EPS group. Two distinct FD subtypes are identifiable in pediatric population. A high percentage of overlap and a variation of subtype over time were found, suggesting a common pathophysiologic mechanism.

  15. Distinct methylation profiles of glioma subtypes.

    PubMed

    Uhlmann, Karen; Rohde, Klaus; Zeller, Constanze; Szymas, Janusz; Vogel, Siegfried; Marczinek, Karola; Thiel, Gundula; Nürnberg, Peter; Laird, Peter W

    2003-08-10

    Gliomas are tumors of the central nervous system with a wide spectrum of different tumor types. They range from pilocytic astrocytoma, with a generally good prognosis, to the extremely aggressive malignant glioblastoma. In addition to these 2 types of contrasting neoplasms, several other subtypes can be distinguished, each characterized by specific phenotypic, as well as genotypic features. Recently, the epigenotype, as evident from differentially methylated DNA loci, has been proposed to be useful as a further criterion to distinguish between tumor types. In our study, we screened 139 tissue samples, including 33 pilocytic astrocytomas, 46 astrocytomas of different grades, 7 oligoastrocytomas, 10 oligodendrogliomas, 10 glioblastoma multiforme samples and 33 control tissues, for methylation at CpG islands of 15 different gene loci. We used the semiquantitative high throughput method MethyLight to analyze a gene panel comprising ARF, CDKN2B, RB1, APC, CDH1, ESR1, GSTP1, TGFBR2, THBS1, TIMP3, PTGS2, CTNNB1, CALCA, MYOD1 and HIC1. Seven of these loci showed tumor specific methylation changes. We found tissue as well as grade specific methylation profiles. Interestingly, pilocytic astrocytomas showed no evidence of CpG island hypermethylation, but were significantly hypomethylated, relative to control tissues, at MYOD1. Our results show that glioma subtypes have characteristic methylation profiles and, with the exception of pilocytic astrocytomas, show both locus specific hyper- as well as hypomethylation. Copyright 2003 Wiley-Liss, Inc.

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

    PubMed Central

    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 results suggest that a finite number of HIV subtypes exist and that the combined use of selected HIV isolates representing several subtypes may be necessary for the development of an effective vaccine. Images PMID:3357892

  17. Identifying subtypes of criminal psychopaths: A replication and extension

    PubMed Central

    Swogger, Marc T.; Kosson, David S.

    2009-01-01

    Psychopathy is an important construct in offender classification. Although several studies have suggested that there are two distinct subtypes of psychopaths, these studies have considerable limitations, including reliance on self-report measures, a failure to adequately address heterogeneity within the construct of psychopathy, and predictor-criterion contamination. A recent taxonomic study identified four subgroups of offenders, including primary and secondary psychopaths. We used cluster analysis to replicate and extend those findings to: 1) an independent sample; and 2) a PCL-R factor model that reduces predictor-criterion contamination. Additionally, we validated initial results using a novel clustering method. Results show that psychopathy subtypes are replicable across methods. Moreover, comparisons on other variables provide external validation of the subtypes consistent with prior theoretical conceptualizations. PMID:19458783

  18. Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

    PubMed Central

    Daemen, Anneleen; Peterson, David; Sahu, Nisebita; McCord, Ron; Du, Xiangnan; Liu, Bonnie; Kowanetz, Katarzyna; Hong, Rebecca; Moffat, John; Gao, Min; Boudreau, Aaron; Mroue, Rana; Corson, Laura; O’Brien, Thomas; Qing, Jing; Sampath, Deepak; Merchant, Mark; Yauch, Robert; Manning, Gerard; Settleman, Jeffrey; Hatzivassiliou, Georgia; Evangelista, Marie

    2015-01-01

    Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors. PMID:26216984

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

    PubMed

    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.

  20. Identifying molecular subtypes related to clinicopathologic factors in pancreatic cancer

    PubMed Central

    2014-01-01

    Background Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumors and usually presented with locally advanced and distant metastasis disease, which prevent curative resection or treatments. In this regard, we considered identifying molecular subtypes associated with clinicopathological factor as prognosis factors to stratify PDAC for appropriate treatment of patients. Results In this study, we identified three molecular subtypes which were significant on survival time and metastasis. We also identified significant genes and enriched pathways represented for each molecular subtype. Considering R0 resection patients included in each subtype, metastasis and survival times are significantly associated with subtype 1 and subtype 2. Conclusions We observed three PDAC molecular subtypes and demonstrated that those subtypes were significantly related with metastasis and survival time. The study may have utility in stratifying patients for cancer treatment. PMID:25560450

  1. IDENTIFYING PANIC DISORDER SUBTYPES USING FACTOR MIXTURE MODELING.

    PubMed

    Pattyn, Thomas; Van Den Eede, Filip; Lamers, Femke; Veltman, Dick; Sabbe, Bernard G; Penninx, Brenda W

    2015-07-01

    The clinical presentation of panic disorder (PD) is known to be highly heterogeneous, complicating research on its etiology, neurobiological pathways, and treatment. None of the attempts to identify PD subtypes have been independently reproduced, rendering the current literature inconclusive. Using a data-driven, case-centered approach (factor mixture modeling) on a broad range of anxiety symptoms assessed with the Beck anxiety inventory, the present study identifies PD disorder subtypes in a large (n = 658), well-documented mixed-population sample from the Netherlands Study of Depression and Anxiety (NESDA), with subtypes being validated and detailed using a variety of clinical characteristics. A three-class, one-factor model proved superior to all other possible models (Bayesian information criterion = 13,200; Lo-Mendel-Rubin = 0.0295; bootstrapped likelihood ratio test ≤ 0.0001), with the first class, a cognitive-autonomic subtype, accounting for 29.8%, the second class, the autonomic subtype, for 29.9%, and a third class, the aspecific subtype, for 40.3% of the population. The cognitive-autonomic and autonomic subtypes showed significant differences compared to the aspecific subtype (e.g., comorbidity and suicide attempts) but on severity differed between themselves only. Three qualitatively different PD subtypes were identified: a severe cognitive-autonomic subtype, a moderate autonomic subtype, and a mild aspecific subtype. Qualitative and quantitative differences were related to severity and clinical properties such as comorbidity, suicide attempts, sleep, and sense of mastery. © 2015 Wiley Periodicals, Inc.

  2. TCGA researchers identify 4 subtypes of stomach cancer

    Cancer.gov

    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

  3. Interpersonal Subtypes Within Social Anxiety: The Identification of Distinct Social Features.

    PubMed

    Cooper, Danielle; Anderson, Timothy

    2017-10-05

    Although social anxiety disorder is defined by anxiety-related symptoms, little research has focused on the interpersonal features of social anxiety. Prior studies (Cain, Pincus, & Grosse Holtforth, 2010; Kachin, Newman, & Pincus, 2001) identified distinct subgroups of socially anxious individuals' interpersonal circumplex problems that were blends of agency and communion, and yet inconsistencies remain. We predicted 2 distinct interpersonal subtypes would exist for individuals with high social anxiety, and that these social anxiety subtypes would differ on empathetic concern, paranoia, received peer victimization, perspective taking, and emotional suppression. From a sample of 175 undergraduate participants, 51 participants with high social anxiety were selected as above a clinical cutoff on the social phobia scale. Cluster analyses identified 2 interpersonal subtypes of socially anxious individuals: low hostility-high submissiveness (Cluster 1) and high hostility-high submissiveness (Cluster 2). Cluster 1 reported higher levels of empathetic concern, lower paranoia, less peer victimization, and lower emotional suppression compared to Cluster 2. There were no differences between subtypes on perspective taking or cognitive reappraisal. Findings are consistent with an interpersonal conceptualization of social anxiety, and provide evidence of distinct social features between these subtypes. Findings have implications for the etiology, classification, and treatment of social anxiety.

  4. Distinct neural signatures of cognitive subtypes of dyslexia with and without phonological deficits☆

    PubMed Central

    van Ermingen-Marbach, Muna; Grande, Marion; Pape-Neumann, Julia; Sass, Katharina; Heim, Stefan

    2013-01-01

    Developmental dyslexia can be distinguished as different cognitive subtypes with and without phonological deficits. However, despite some general agreement on the neurobiological basis of dyslexia, the neurofunctional mechanisms underlying these cognitive subtypes remain to be identified. The present BOLD fMRI study thus aimed at investigating by which distinct and/or shared neural activation patterns dyslexia subtypes are characterized. German dyslexic fourth graders with and without deficits in phonological awareness and age-matched normal readers performed a phonological decision task: does the auditory word contain the phoneme/a/? Both dyslexic subtypes showed increased activation in the right cerebellum (Lobule IV) compared to controls. Subtype-specific increased activation was systematically found for the phonological dyslexics as compared to those without this deficit and controls in the left inferior frontal gyrus (area 44: phonological segmentation), the left SMA (area 6), the left precentral gyrus (area 6) and the right insula. Non-phonological dyslexics revealed subtype-specific increased activation in the left supramarginal gyrus (area PFcm; phonological storage) and angular gyrus (area PGp). The study thus provides the first direct evidence for the neurobiological grounding of dyslexia subtypes. Moreover, the data contribute to a better understanding of the frequently encountered heterogeneous neuroimaging results in the field of dyslexia. PMID:24936406

  5. Distinct neural signatures of cognitive subtypes of dyslexia with and without phonological deficits.

    PubMed

    van Ermingen-Marbach, Muna; Grande, Marion; Pape-Neumann, Julia; Sass, Katharina; Heim, Stefan

    2013-01-01

    Developmental dyslexia can be distinguished as different cognitive subtypes with and without phonological deficits. However, despite some general agreement on the neurobiological basis of dyslexia, the neurofunctional mechanisms underlying these cognitive subtypes remain to be identified. The present BOLD fMRI study thus aimed at investigating by which distinct and/or shared neural activation patterns dyslexia subtypes are characterized. German dyslexic fourth graders with and without deficits in phonological awareness and age-matched normal readers performed a phonological decision task: does the auditory word contain the phoneme/a/? Both dyslexic subtypes showed increased activation in the right cerebellum (Lobule IV) compared to controls. Subtype-specific increased activation was systematically found for the phonological dyslexics as compared to those without this deficit and controls in the left inferior frontal gyrus (area 44: phonological segmentation), the left SMA (area 6), the left precentral gyrus (area 6) and the right insula. Non-phonological dyslexics revealed subtype-specific increased activation in the left supramarginal gyrus (area PFcm; phonological storage) and angular gyrus (area PGp). The study thus provides the first direct evidence for the neurobiological grounding of dyslexia subtypes. Moreover, the data contribute to a better understanding of the frequently encountered heterogeneous neuroimaging results in the field of dyslexia.

  6. Unique Transcriptional Programs Identify Subtypes of AKI.

    PubMed

    Xu, Katherine; Rosenstiel, Paul; Paragas, Neal; Hinze, Christian; Gao, Xiaobo; Huai Shen, Tian; Werth, Max; Forster, Catherine; Deng, Rong; Bruck, Efrat; Boles, Roger W; Tornato, Alexandra; Gopal, Tejashree; Jones, Madison; Konig, Justin; Stauber, Jacob; D'Agati, Vivette; Erdjument-Bromage, Hediye; Saggi, Subodh; Wagener, Gebhard; Schmidt-Ott, Kai M; Tatonetti, Nicholas; Tempst, Paul; Oliver, Juan A; Guarnieri, Paolo; Barasch, Jonathan

    2017-06-01

    Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function. Copyright © 2017 by the American Society of Nephrology.

  7. Molecular interrogation of hypothalamic organization reveals distinct dopamine neuronal subtypes.

    PubMed

    Romanov, Roman A; Zeisel, Amit; Bakker, Joanne; Girach, Fatima; Hellysaz, Arash; Tomer, Raju; Alpár, Alán; Mulder, Jan; Clotman, Frédéric; Keimpema, Erik; Hsueh, Brian; Crow, Ailey K; Martens, Henrik; Schwindling, Christian; Calvigioni, Daniela; Bains, Jaideep S; Máté, Zoltán; Szabó, Gábor; Yanagawa, Yuchio; Zhang, Ming-Dong; Rendeiro, Andre; Farlik, Matthias; Uhlén, Mathias; Wulff, Peer; Bock, Christoph; Broberger, Christian; Deisseroth, Karl; Hökfelt, Tomas; Linnarsson, Sten; Horvath, Tamas L; Harkany, Tibor

    2017-02-01

    The hypothalamus contains the highest diversity of neurons in the brain. Many of these neurons can co-release neurotransmitters and neuropeptides in a use-dependent manner. Investigators have hitherto relied on candidate protein-based tools to correlate behavioral, endocrine and gender traits with hypothalamic neuron identity. Here we map neuronal identities in the hypothalamus by single-cell RNA sequencing. We distinguished 62 neuronal subtypes producing glutamatergic, dopaminergic or GABAergic markers for synaptic neurotransmission and harboring the ability to engage in task-dependent neurotransmitter switching. We identified dopamine neurons that uniquely coexpress the Onecut3 and Nmur2 genes, and placed these in the periventricular nucleus with many synaptic afferents arising from neuromedin S(+) neurons of the suprachiasmatic nucleus. These neuroendocrine dopamine cells may contribute to the dopaminergic inhibition of prolactin secretion diurnally, as their neuromedin S(+) inputs originate from neurons expressing Per2 and Per3 and their tyrosine hydroxylase phosphorylation is regulated in a circadian fashion. Overall, our catalog of neuronal subclasses provides new understanding of hypothalamic organization and function.

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

    PubMed Central

    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. PMID:28076387

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

    PubMed

    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.

  10. Finding subtypes of transcription factor motif pairs with distinct regulatory roles

    PubMed Central

    Bais, Abha Singh; Kaminski, Naftali; Benos, Panayiotis V.

    2011-01-01

    DNA sequences bound by a transcription factor (TF) are presumed to contain sequence elements that reflect its DNA binding preferences and its downstream-regulatory effects. Experimentally identified TF binding sites (TFBSs) are usually similar enough to be summarized by a ‘consensus’ motif, representative of the TF DNA binding specificity. Studies have shown that groups of nucleotide TFBS variants (subtypes) can contribute to distinct modes of downstream regulation by the TF via differential recruitment of cofactors. A TFA may bind to TFBS subtypes a1 or a2 depending on whether it associates with cofactors TFB or TFC, respectively. While some approaches can discover motif pairs (dyads), none address the problem of identifying ‘variants’ of dyads. TFs are key components of multiple regulatory pathways targeting different sets of genes perhaps with different binding preferences. Identifying the discriminating TF–DNA associations that lead to the differential downstream regulation is thus essential. We present DiSCo (Discovery of Subtypes and Cofactors), a novel approach for identifying variants of dyad motifs (and their respective target sequence sets) that are instrumental for differential downstream regulation. Using both simulated and experimental datasets, we demonstrate how current motif discovery can be successfully leveraged to address this question. PMID:21486752

  11. Identifying Psychopathy Subtypes on the Basis of Personality Structure

    ERIC Educational Resources Information Center

    Hicks, Brian M.; Markon, Kristian E.; Patrick, Christopher J.; Krueger, Robert F.; Newman, Joseph P.

    2004-01-01

    The authors used model-based cluster analysis to identify subtypes of criminal psychopaths on the basis of differences in personality structure. Participants included 96 male prisoners diagnosed as psychopathic, using the Psychopathy Checklist Revised (PCL-R; R. D. Hare, 1991). Personality was assessed using the brief form of the Multidimensional…

  12. Identifying Psychopathy Subtypes on the Basis of Personality Structure

    ERIC Educational Resources Information Center

    Hicks, Brian M.; Markon, Kristian E.; Patrick, Christopher J.; Krueger, Robert F.; Newman, Joseph P.

    2004-01-01

    The authors used model-based cluster analysis to identify subtypes of criminal psychopaths on the basis of differences in personality structure. Participants included 96 male prisoners diagnosed as psychopathic, using the Psychopathy Checklist Revised (PCL-R; R. D. Hare, 1991). Personality was assessed using the brief form of the Multidimensional…

  13. Three differentiation states risk-stratify bladder cancer into distinct subtypes.

    PubMed

    Volkmer, Jens-Peter; Sahoo, Debashis; Chin, Robert K; Ho, Philip Levy; Tang, Chad; Kurtova, Antonina V; Willingham, Stephen B; Pazhanisamy, Senthil K; Contreras-Trujillo, Humberto; Storm, Theresa A; Lotan, Yair; Beck, Andrew H; Chung, Benjamin I; Alizadeh, Ash A; Godoy, Guilherme; Lerner, Seth P; van de Rijn, Matt; Shortliffe, Linda D; Weissman, Irving L; Chan, Keith S

    2012-02-07

    Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.

  14. Three differentiation states risk-stratify bladder cancer into distinct subtypes

    PubMed Central

    Volkmer, Jens-Peter; Sahoo, Debashis; Chin, Robert K.; Ho, Philip Levy; Tang, Chad; Kurtova, Antonina V.; Willingham, Stephen B.; Pazhanisamy, Senthil K.; Contreras-Trujillo, Humberto; Storm, Theresa A.; Lotan, Yair; Beck, Andrew H.; Chung, Benjamin I.; Alizadeh, Ash A.; Godoy, Guilherme; Lerner, Seth P.; van de Rijn, Matt; Shortliffe, Linda D.; Weissman, Irving L.; Chan, Keith S.

    2012-01-01

    Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population. PMID:22308455

  15. Distinct Response Time Distributions in Attention Deficit Hyperactivity Disorder Subtypes

    ERIC Educational Resources Information Center

    Querne, Laurent; Berquin, Patrick

    2009-01-01

    Objective: To address the issue of response time (RT) profiles in hyperactive-impulsive (ADHD-HI), inattentive (ADHD-IA), and combined (ADHD-C) subtypes of ADHD. We hypothesized that children with ADHD-HI should respond more rapidly than children without ADHD and children with ADHD-IA and ADHD-C should respond more slowly than children without…

  16. Distinct Response Time Distributions in Attention Deficit Hyperactivity Disorder Subtypes

    ERIC Educational Resources Information Center

    Querne, Laurent; Berquin, Patrick

    2009-01-01

    Objective: To address the issue of response time (RT) profiles in hyperactive-impulsive (ADHD-HI), inattentive (ADHD-IA), and combined (ADHD-C) subtypes of ADHD. We hypothesized that children with ADHD-HI should respond more rapidly than children without ADHD and children with ADHD-IA and ADHD-C should respond more slowly than children without…

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

    PubMed

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

    2017-01-21

    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

  18. Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes.

    PubMed

    Su, Dan; Wang, Xuting; Campbell, Michelle R; Porter, Devin K; Pittman, Gary S; Bennett, Brian D; Wan, Ma; Englert, Neal A; Crowl, Christopher L; Gimple, Ryan N; Adamski, Kelly N; Huang, Zhiqing; Murphy, Susan K; Bell, Douglas A

    2016-01-01

    Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell

  19. Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes

    PubMed Central

    Porter, Devin K.; Pittman, Gary S.; Bennett, Brian D.; Wan, Ma; Crowl, Christopher L.; Adamski, Kelly N.; Huang, Zhiqing; Murphy, Susan K.; Bell, Douglas A.

    2016-01-01

    Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking–associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6

  20. Genomic analyses identify molecular subtypes of pancreatic cancer.

    PubMed

    Bailey, Peter; Chang, David K; Nones, Katia; Johns, Amber L; Patch, Ann-Marie; Gingras, Marie-Claude; Miller, David K; Christ, Angelika N; Bruxner, Tim J C; Quinn, Michael C; Nourse, Craig; Murtaugh, L Charles; Harliwong, Ivon; Idrisoglu, Senel; Manning, Suzanne; Nourbakhsh, Ehsan; Wani, Shivangi; Fink, Lynn; Holmes, Oliver; Chin, Venessa; Anderson, Matthew J; Kazakoff, Stephen; Leonard, Conrad; Newell, Felicity; Waddell, Nick; Wood, Scott; Xu, Qinying; Wilson, Peter J; Cloonan, Nicole; Kassahn, Karin S; Taylor, Darrin; Quek, Kelly; Robertson, Alan; Pantano, Lorena; Mincarelli, Laura; Sanchez, Luis N; Evers, Lisa; Wu, Jianmin; Pinese, Mark; Cowley, Mark J; Jones, Marc D; Colvin, Emily K; Nagrial, Adnan M; Humphrey, Emily S; Chantrill, Lorraine A; Mawson, Amanda; Humphris, Jeremy; Chou, Angela; Pajic, Marina; Scarlett, Christopher J; Pinho, Andreia V; Giry-Laterriere, Marc; Rooman, Ilse; Samra, Jaswinder S; Kench, James G; Lovell, Jessica A; Merrett, Neil D; Toon, Christopher W; Epari, Krishna; Nguyen, Nam Q; Barbour, Andrew; Zeps, Nikolajs; Moran-Jones, Kim; Jamieson, Nigel B; Graham, Janet S; Duthie, Fraser; Oien, Karin; Hair, Jane; Grützmann, Robert; Maitra, Anirban; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Morgan, Richard A; Lawlor, Rita T; Corbo, Vincenzo; Bassi, Claudio; Rusev, Borislav; Capelli, Paola; Salvia, Roberto; Tortora, Giampaolo; Mukhopadhyay, Debabrata; Petersen, Gloria M; Munzy, Donna M; Fisher, William E; Karim, Saadia A; Eshleman, James R; Hruban, Ralph H; Pilarsky, Christian; Morton, Jennifer P; Sansom, Owen J; Scarpa, Aldo; Musgrove, Elizabeth A; Bailey, Ulla-Maja Hagbo; Hofmann, Oliver; Sutherland, Robert L; Wheeler, David A; Gill, Anthony J; Gibbs, Richard A; Pearson, John V; Waddell, Nicola; Biankin, Andrew V; Grimmond, Sean M

    2016-03-03

    Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

  1. Identifying distinct thermal components of a creek

    NASA Astrophysics Data System (ADS)

    Boughton, David A.; Hatch, Christine; Mora, Ethan

    2012-09-01

    Statistical and heat budget methods for analyzing temperature dynamics of creeks are limited by the ability to resolve thermal processes and fine-grained thermal structures, respectively. Here we describe a hybrid method that identifies distinct thermal components in a stream's heat budget using only temperature data and an algorithm that employs mutual information to "unmix" signals in the temperature data. Spatial resolution is limited only by the number of temperature-logging sensors, which can be quite high for distributed-temperature sensors. Process resolution is at the level of thermal components, defined as distinct collections of heat flux elements sharing coordinated (nonindependent) dynamics. Inference can be used to relate thermal components to meteorological forcing and structural heterogeneity in the fluvial system and to suggest novel hypotheses for further testing with targeted heat budget studies. Applying the method to a small, arid-land creek produced two novel hypotheses: (1) lateral conduction of heat from adjacent dry land (bed, terraces) appeared to cause a substantial heating of the stream, augmented by off-channel flow paths, and (2) riparian vegetation was associated with a subtraction of heat from the stream at a rate proportionate to solar insolation, exceeding the maximum decoupling effect of shade by at least 2°C at midday, and suggesting upwelling heat flux from water to tree canopy proportional to sunlight. The method appears useful for generating new hypotheses, for selecting informative sites for detailed heat budgets, for determining the dimensionality of heat budgets in natural streams, and more broadly for associating thermal components to fluvial structure and processes.

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

    PubMed Central

    2012-01-01

    Background 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. Methods 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. Results 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

  3. A novel functionally distinct subtype of striatal neuropeptide Y interneuron.

    PubMed

    Ibáñez-Sandoval, Osvaldo; Tecuapetla, Fatuel; Unal, Bengi; Shah, Fulva; Koós, Tibor; Tepper, James M

    2011-11-16

    We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic GFP (green fluorescent protein)-NPY reporter mice. In vitro whole-cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical, and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spike (NPY-PLTS) interneurons. The novel NPY interneuron type (NPY-neurogliaform) differed from previously described NPY-PLTS interneurons by exhibiting a significantly lower input resistance and hyperpolarized membrane potential, regular, nonaccommodating spiking in response to depolarizing current injections, and an absence of plateau depolarizations or low-threshold spikes. NPY-neurogliaform interneurons were also easily distinguished morphologically by their dense, compact, and highly branched dendritic and local axonal arborizations that contrasted sharply with the sparse and extended axonal and dendritic arborizations of NPY-PLTS interneurons. Furthermore, NPY-neurogliaform interneurons did not express immunofluorescence for somatostatin or nitric oxide synthase that was ubiquitous in NPY-PLTS interneurons. IPSP/Cs could only rarely be elicited in spiny projection neurons (SPNs) in paired recordings with NPY-PLTS interneurons. In contrast, the probability of SPN innervation by NPY-neurogliaform interneurons was extremely high, the synapse very reliable (no failures were observed), and the resulting postsynaptic response was a slow, GABA(A) receptor-mediated IPSC that has not been previously described in striatum but that has been elicited from NPY-GABAergic neurogliaform interneurons in cortex and hippocampus. These properties suggest unique and distinctive roles for NPY-PLTS and NPY-neurogliaform interneurons in the integrative properties of the neostriatum.

  4. A NOVEL FUNCTIONALLY DISTINCT SUBTYPE OF STRIATAL NPY INTERNEURON

    PubMed Central

    Ibáñez-Sandoval, Osvaldo; Tecuapetla, Fatuel; Unal, Bengi; Shah, Fulva; Koós, Tibor; Tepper, James M.

    2011-01-01

    We investigated the properties of neostriatal neuropeptide Y (NPY)-expressing interneurons in transgenic green fluorescent protein (GFP)-NPY reporter mice. In vitro whole cell recordings and biocytin staining demonstrated the existence of a novel class of neostriatal NPY-expressing GABAergic interneurons that exhibit electrophysiological, neurochemical and morphological properties strikingly different from those of previously described NPY-containing, plateau-depolarization low-threshold spike (NPY-PLTS) interneurons. The novel NPY interneuron type (NPY-neurogliaform) differed from previously described NPY-PLTS interneurons by exhibiting a significantly lower input resistance and hyperpolarized membrane potential, regular, non-accommodating spiking in response to depolarizing current injections and an absence of plateau depolarizations or low threshold spikes. NPY-neurogliaform interneurons were also easily distinguished morphologically by their dense compact and highly branched dendritic and local axonal arborizations that contrasted sharply with the sparse and extended axonal and dendritic arborizations of NPY-PLTS interneurons. Further, NPY-neurogliaform interneurons did not express immunofluorescence for somatostatin or nitric oxide synthase that was ubiquitous in NPY-PLTS interneurons. IPSP/Cs could only rarely be elicited in spiny projection neurons (SPN) in paired recordings with NPY-PLTS interneurons. In contrast, the probability of SPN innervation by NPY-neurogliaform interneurons was extremely high, the synapse very reliable (no failures were observed), and the resulting postsynaptic response was a slow, GABAA receptor-mediated inhibitory postsynaptic current (IPSC) that has not been previously described in striatum, but that has been elicited from NPY-GABAergic neurogliaform interneurons in cortex and hippocampus. These properties suggest unique and distinctive roles for NPY-PLTS and NPY-neurogliaform interneurons in the integrative properties of the

  5. Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes.

    PubMed

    Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Šćepanović, Petar; Miretti, Silvia; Morotti, Alessandro; Shern, Jack F; Khan, Javed; Ala, Ugo; Provero, Paolo; Sala, Valentina; Crepaldi, Tiziana; Gasparini, Patrizia; Casanova, Michela; Ferrari, Andrea; Sozzi, Gabriella; Chiarle, Roberto; Ponzetto, Carola; Taulli, Riccardo

    2016-03-17

    Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity.

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

    PubMed

    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.

  7. Distinct subtypes of behavioral-variant frontotemporal dementia based on patterns of network degeneration

    PubMed Central

    Ranasinghe, Kamalini G; Rankin, Katherine P; Pressman, Peter S; Perry, David C; Lobach, Iryna V; Seeley, William W; Coppola, Giovanni; Karydas, Anna M; Grinberg, Lea T; Shany-Ur, Tal; Lee, Suzee E; Rabinovici, Gil D; Rosen, Howard J; Gorno-Tempini, Maria Luisa; Boxer, Adam L; Miller, Zachary A; Chiong, Winston; DeMay, Mary; Kramer, Joel H; Possin, Katherine L; Sturm, Virginia E; Bettcher, Brianne M; Neylan, Michael; Zackey, Diana D; Nguyen, Lauren A; Ketelle, Robin; Block, Nikolas; Wu, Teresa Q; Dallich, Alison; Russek, Natanya; Caplan, Alyssa; Geschwind, Daniel H; Vossel, Keith A; Miller, Bruce L

    2016-01-01

    Importance Clearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms, and will improve clinicians’ ability to predict disease course and design targeted management strategies. Objective To identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD, using statistical classification approaches. Design, Setting and Participants In this retrospective observational study, 104 patients meeting the Frontotemporal Dementia Consortium consensus criteria for bvFTD were evaluated at the Memory and Aging Center of Department of Neurology at University of California, San Francisco. Patients underwent a multidisciplinary clinical evaluation, including clinical demographics, genetic testing, symptom evaluation, neurological exam, neuropsychological bedside testing, and socioemotional assessments. Ninety patients underwent structural Magnetic Resonance Imaging at their earliest evaluation at the memory clinic. From each patients’ structural imaging, the mean volumes of 18 regions of interest (ROI) comprising the functional networks specifically vulnerable in bvFTD, including the ‘salience network’ (SN), with key nodes in the frontoinsula and pregenual anterior cingulate, and the ‘semantic appraisal network’ (SAN) anchored in the anterior temporal lobe and subgenual cingulate, were estimated. Principal component and cluster analyses of ROI volumes were used to identify patient clusters with anatomically distinct atrophy patterns. Main Outcome Measures We evaluated brain morphology and other clinical features including presenting symptoms, neurologic exam signs, neuropsychological performance, rate of dementia progression, and socioemotional function in each patient cluster. Results We identified four subgroups of bvFTD patients with distinct anatomic patterns of

  8. Gingival Tissue Transcriptomes Identify Distinct Periodontitis Phenotypes

    PubMed Central

    Kebschull, M.; Demmer, R.T.; Grün, B.; Guarnieri, P.; Pavlidis, P.; Papapanou, P.N.

    2014-01-01

    The currently recognized principal forms of periodontitis—chronic and aggressive—lack an unequivocal, pathobiology-based foundation. We explored whether gingival tissue transcriptomes can serve as the basis for an alternative classification of periodontitis. We used cross-sectional whole-genome gene expression data from 241 gingival tissue biopsies obtained from sites with periodontal pathology in 120 systemically healthy nonsmokers with periodontitis, with available data on clinical periodontal status, subgingival microbial profiles, and serum IgG antibodies to periodontal microbiota. Adjusted model-based clustering of transcriptomic data using finite mixtures generated two distinct clusters of patients that did not align with the current classification of chronic and aggressive periodontitis. Differential expression profiles primarily related to cell proliferation in cluster 1 and to lymphocyte activation and unfolded protein responses in cluster 2. Patients in the two clusters did not differ with respect to age but presented with distinct phenotypes (statistically significantly different whole-mouth clinical measures of extent/severity, subgingival microbial burden by several species, and selected serum antibody responses). Patients in cluster 2 showed more extensive/severe disease and were more often male. The findings suggest that distinct gene expression signatures in pathologic gingival tissues translate into phenotypic differences and can provide a basis for a novel classification. PMID:24646639

  9. Gene Signature in Sessile Serrated Polyps Identifies Colon Cancer Subtype

    PubMed Central

    Kanth, Priyanka; Bronner, Mary P.; Boucher, Kenneth M.; Burt, Randall W.; Neklason, Deborah W.; Hagedorn, Curt H.; Delker, Don A.

    2016-01-01

    Sessile serrated colon adenoma/polyps (SSA/Ps) are found during routine screening colonoscopy and may account for 20–30% of colon cancers. However, differentiating SSA/Ps from hyperplastic polyps (HP) with little risk of cancer is challenging and complementary molecular markers are needed. Additionally, the molecular mechanisms of colon cancer development from SSA/Ps are poorly understood. RNA sequencing was performed on 21 SSA/Ps, 10 HPs, 10 adenomas, 21 uninvolved colon and 20 control colon specimens. Differential expression and leave-one-out cross validation methods were used to define a unique gene signature of SSA/Ps. Our SSA/P gene signature was evaluated in colon cancer RNA-Seq data from The Cancer Genome Atlas (TCGA) to identify a subtype of colon cancers that may develop from SSA/Ps. A total of 1422 differentially expressed genes were found in SSA/Ps relative to controls. Serrated polyposis syndrome (n=12) and sporadic SSA/Ps (n=9) exhibited almost complete (96%) gene overlap. A 51-gene panel in SSA/P showed similar expression in a subset of TCGA colon cancers with high microsatellite instability (MSI-H). A smaller seven-gene panel showed high sensitivity and specificity in identifying BRAF mutant, CpG island methylator phenotype high (CIMP-H) and MLH1 silenced colon cancers. We describe a unique gene signature in SSA/Ps that identifies a subset of colon cancers likely to develop through the serrated pathway. These gene panels may be utilized for improved differentiation of SSA/Ps from HPs and provide insights into novel molecular pathways altered in colon cancer arising from the serrated pathway. PMID:27026680

  10. (Non-V600) BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer.

    PubMed

    Jones, Jeremy C; Renfro, Lindsay A; Al-Shamsi, Humaid O; Schrock, Alexa B; Rankin, Andrew; Zhang, Ben Y; Kasi, Pashtoon M; Voss, Jesse S; Leal, Alexis D; Sun, James; Ross, Jeffrey; Ali, Siraj M; Hubbard, Joleen M; Kipp, Benjamin R; McWilliams, Robert R; Kopetz, Scott; Wolff, Robert A; Grothey, Axel

    2017-08-10

    Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 ((non-V600) BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of (non-V600) BRAF mutations in metastatic CRC. We pooled patients in whom (non-V600) BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with (non-V600) BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with (non-V600) BRAF mutations, compared with cancers with V600E BRAF ((V600E) BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with (non-V600) BRAF-mutant metastatic CRC compared with those with both (V600E) BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, (non-V600) BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion (Non-V600) BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.

  11. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways

    PubMed Central

    Lenz, Georg; Wright, George W.; Emre, N. C. Tolga; Kohlhammer, Holger; Dave, Sandeep S.; Davis, R. Eric; Carty, Shannon; Lam, Lloyd T.; Shaffer, A. L.; Xiao, Wenming; Powell, John; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D.; Connors, Joseph M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Rimsza, Lisa M.; Fisher, Richard I.; Weisenburger, Dennis D.; Chan, Wing C.; Staudt, Louis M.

    2008-01-01

    Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17–92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways. PMID:18765795

  12. Precision Subtypes of T Cell-Mediated Rejection Identified by Molecular Profiles

    PubMed Central

    Kadota, Paul Ostrom; Hajjiri, Zahraa; Finn, Patricia W.; Perkins, David L.

    2015-01-01

    Among kidney transplant recipients, the treatment of choice for acute T cell-mediated rejection (TCMR) with pulse steroids or antibody protocols has variable outcomes. Some rejection episodes are resistant to an initial steroid pulse, but respond to subsequent antibody protocols. The biological mechanisms causing the different therapeutic responses are not currently understood. Histological examination of the renal allograft is considered the gold standard in the diagnosis of acute rejection. The Banff Classification System was established to standardize the histopathological diagnosis and to direct therapy. Although widely used, it shows variability among pathologists and lacks criteria to guide precision individualized therapy. The analysis of the transcriptome in allograft biopsies, which we analyzed in this study, provides a strategy to develop molecular diagnoses that would have increased diagnostic precision and assist the development of individualized treatment. Our hypothesis is that the histological classification of TCMR contains multiple subtypes of rejection. Using R language algorithms to determine statistical significance, multidimensional scaling, and hierarchical, we analyzed differential gene expression based on microarray data from biopsies classified as TCMR. Next, we identified KEGG functions, protein–protein interaction networks, gene regulatory networks, and predicted therapeutic targets using the integrated database ConsesnsusPathDB (CPDB). Based on our analysis, two distinct clusters of biopsies termed TCMR01 and TCMR02 were identified. Despite having the same Banff classification, we identified 1933 differentially expressed genes between the two clusters. These genes were further divided into three major groups: a core group contained within both the TCMR01 and TCMR02 subtypes, as well as genes unique to TCMR01 or TCMR02. The subtypes of TCMR utilized different biological pathways, different regulatory networks and were predicted to

  13. Three distinct biochemical subtypes of C4 photosynthesis? A modelling analysis.

    PubMed

    Wang, Yu; Bräutigam, Andrea; Weber, Andreas P M; Zhu, Xin-Guang

    2014-07-01

    C4 photosynthesis has higher light-use, nitrogen-use, and water-use efficiencies than C3 photosynthesis. Historically, most of C4 plants were classified into three subtypes (NADP-malic enzyme (ME), NAD-ME, or phosphoenolpyruvate carboxykinase (PEPCK) subtypes) according to their major decarboxylation enzyme. However, a wealth of historic and recent data indicates that flexibility exists between different decarboxylation pathways in many C4 species, and this flexibility might be controlled by developmental and environmental cues. This work used systems modelling to theoretically explore the significance of flexibility in decarboxylation mechanisms and transfer acids utilization. The results indicate that employing mixed C4 pathways, either the NADP-ME type with the PEPCK type or the NAD-ME type with the PEPCK type, effectively decreases the need to maintain high concentrations and concentration gradients of transport metabolites. Further, maintaining a mixture of C4 pathways robustly affords high photosynthetic efficiency under a broad range of light regimes. A pure PEPCK-type C4 photosynthesis is not beneficial because the energy requirements in bundle sheath cells cannot be fulfilled due to them being shaded by mesophyll cells. Therefore, only two C4 subtypes should be considered as distinct subtypes, the NADP-ME type and NAD-ME types, which both inherently involve a supplementary PEPCK cycle.

  14. A diverse virome in kidney transplant patients contains multiple viral subtypes with distinct polymorphisms

    PubMed Central

    Rani, Asha; Ranjan, Ravi; McGee, Halvor S.; Metwally, Ahmed; Hajjiri, Zahraa; Brennan, Daniel C.; Finn, Patricia W.; Perkins, David L.

    2016-01-01

    Recent studies have established that the human urine contains a complex microbiome, including a virome about which little is known. Following immunosuppression in kidney transplant patients, BK polyomavirus (BKV) has been shown to induce nephropathy (BKVN), decreasing graft survival. In this study we investigated the urine virome profile of BKV+ and BKV− kidney transplant recipients. Virus-like particles were stained to confirm the presence of VLP in the urine samples. Metagenomic DNA was purified, and the virome profile was analyzed using metagenomic shotgun sequencing. While the BK virus was predominant in the BKV+ group, it was also found in the BKV− group patients. Additional viruses were also detected in all patients, notably including JC virus (JCV) and Torque teno virus (TTV) and interestingly, we detected multiple subtypes of the BKV, JCV and TTV. Analysis of the BKV subtypes showed that nucleotide polymorphisms were detected in the VP1, VP2 and Large T Antigen proteins, suggesting potential functional effects for enhanced pathogenicity. Our results demonstrate a complex urinary virome in kidney transplant patients with multiple viruses with several distinct subtypes warranting further analysis of virus subtypes in immunosuppressed hosts. PMID:27633952

  15. Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGFβ1

    PubMed Central

    Challen, Grant A.; Boles, Nathan C.; Chambers, Stuart M.; Goodell, Margaret A.

    2010-01-01

    Summary The traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers. These phenotypes are stable under natural (aging) or artificial (serial transplantation) stress and are exacerbated in the presence of competing HSCs. My- and Ly-HSCs respond differently to TGFβ1, presenting a possible mechanism for differential regulation of HSC subtype activation. This study demonstrates definitive isolation of lineage-biased HSC subtypes and contributes to the fundamental change in view that the hematopoietic system is maintained by a continuum of HSC subtypes, rather than a functionally uniform pool. PMID:20207229

  16. Three distinct biochemical subtypes of C4 photosynthesis? A modelling analysis

    PubMed Central

    Wang, Yu; Bräutigam, Andrea; Weber, Andreas P. M.; Zhu, Xin-Guang

    2014-01-01

    C4 photosynthesis has higher light-use, nitrogen-use, and water-use efficiencies than C3 photosynthesis. Historically, most of C4 plants were classified into three subtypes (NADP-malic enzyme (ME), NAD-ME, or phosphoenolpyruvate carboxykinase (PEPCK) subtypes) according to their major decarboxylation enzyme. However, a wealth of historic and recent data indicates that flexibility exists between different decarboxylation pathways in many C4 species, and this flexibility might be controlled by developmental and environmental cues. This work used systems modelling to theoretically explore the significance of flexibility in decarboxylation mechanisms and transfer acids utilization. The results indicate that employing mixed C4 pathways, either the NADP-ME type with the PEPCK type or the NAD-ME type with the PEPCK type, effectively decreases the need to maintain high concentrations and concentration gradients of transport metabolites. Further, maintaining a mixture of C4 pathways robustly affords high photosynthetic efficiency under a broad range of light regimes. A pure PEPCK-type C4 photosynthesis is not beneficial because the energy requirements in bundle sheath cells cannot be fulfilled due to them being shaded by mesophyll cells. Therefore, only two C4 subtypes should be considered as distinct subtypes, the NADP-ME type and NAD-ME types, which both inherently involve a supplementary PEPCK cycle. PMID:24609651

  17. Significant contribution of subtype G to HIV-1 genetic complexity in Nigeria identified by a newly developed subtyping assay specific for subtype G and CRF02_AG

    PubMed Central

    Heipertz, Richard A.; Ayemoba, Ojor; Sanders-Buell, Eric; Poltavee, Kultida; Pham, Phuc; Kijak, Gustavo H.; Lei, Esther; Bose, Meera; Howell, Shana; O'Sullivan, Anne Marie; Bates, Adam; Cervenka, Taylor; Kuroiwa, Janelle; Akintunde, Akindiran; Ibezim, Onyekachukwu; Alabi, Abraham; Okoye, Obumneke; Manak, Mark; Malia, Jennifer; Peel, Sheila; Maisaka, Mohammed; Singer, Darrell; O’Connell, Robert J.; Robb, Merlin L.; Kim, Jerome H.; Michael, Nelson L.; Njoku, Ogbonnaya; Tovanabutra, Sodsai

    2016-01-01

    Abstract While abundant sequence information is available from human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C and CRF01_AE for HIV-1 vaccine design, sequences from West Africa are less represented. We sought to augment our understanding of HIV-1 variants circulating in 6 Nigerian cities as a step to subsequent HIV-1 vaccine development. The G/CRF02_AG multi-region hybridization assay (MHA) was developed to differentiate subtype G, CRF02_AG and their recombinants from other subtypes based on 7 HIV-1 segments. Plasma from 224 HIV-1 infected volunteers enrolled in a cohort examining HIV-1 prevalence, risk factor, and subtype from Makurdi (30), Abuja (18), Enugu (11), Kaduna (12), Tafa (95), and Ojo/Lagos (58) was analyzed using MHA. HIV-1 genomes from 42 samples were sequenced to validate the MHA and fully explore the recombinant structure of G and CRF02_AG variants. The sensitivity and specificity of MHA varied between 73–100% and 90–100%, respectively. The subtype distribution as identified by MHA among 224 samples revealed 38% CRF02_AG, 28% G, and 26% G/CRF02_AG recombinants while 8% remained nontypeable strains. In envelope (env) gp120, 38.84% of the samples reacted to a G probe while 31.25% reacted to a CRF02 (subtype A) probe. Full genome characterization of 42 sequences revealed the complexity of Nigerian HIV-1 variants. CRF02_AG, subtype G, and their recombinants were the major circulating HIV-1 variants in 6 Nigerian cities. High proportions of samples reacted to a G probe in env gp120 confirms that subtype G infections are abundant and should be considered in strategies for global HIV-1 vaccine development. PMID:27512845

  18. Hepatocyte Growth Factor-mediated satellite cells niche perturbation promotes development of distinct sarcoma subtypes

    PubMed Central

    Morena, Deborah; Maestro, Nicola; Bersani, Francesca; Forni, Paolo Emanuele; Lingua, Marcello Francesco; Foglizzo, Valentina; Šćepanović, Petar; Miretti, Silvia; Morotti, Alessandro; Shern, Jack F; Khan, Javed; Ala, Ugo; Provero, Paolo; Sala, Valentina; Crepaldi, Tiziana; Gasparini, Patrizia; Casanova, Michela; Ferrari, Andrea; Sozzi, Gabriella; Chiarle, Roberto; Ponzetto, Carola; Taulli, Riccardo

    2016-01-01

    Embryonal Rhabdomyosarcoma (ERMS) and Undifferentiated Pleomorphic Sarcoma (UPS) are distinct sarcoma subtypes. Here we investigate the relevance of the satellite cell (SC) niche in sarcoma development by using Hepatocyte Growth Factor (HGF) to perturb the niche microenvironment. In a Pax7 wild type background, HGF stimulation mainly causes ERMS that originate from satellite cells following a process of multistep progression. Conversely, in a Pax7 null genotype ERMS incidence drops, while UPS becomes the most frequent subtype. Murine EfRMS display genetic heterogeneity similar to their human counterpart. Altogether, our data demonstrate that selective perturbation of the SC niche results in distinct sarcoma subtypes in a Pax7 lineage-dependent manner, and define a critical role for the Met axis in sarcoma initiation. Finally, our results provide a rationale for the use of combination therapy, tailored on specific amplifications and activated signaling pathways, to minimize resistance emerging from sarcomas heterogeneity. DOI: http://dx.doi.org/10.7554/eLife.12116.001 PMID:26987019

  19. Distinctive patterns on CT angiography characterize acute internal carotid artery occlusion subtypes

    PubMed Central

    Hong, Ji Man; Lee, Sung Eun; Lee, Seong-Joon; Lee, Jin Soo; Demchuk, Andrew M.

    2017-01-01

    Abstract Noninvasive computed tomography angiography (CTA) is widely used in acute ischemic stroke, even for diagnosing various internal carotid artery (ICA) occlusion sites, which often need cerebral digital subtraction angiography (DSA) confirmation. We evaluated whether clinical outcomes vary depending on the DSA-based occlusion sites and explored correlating features on baseline CTA that predict DSA-based occlusion site. We analyzed consecutive patients with acute ICA occlusion who underwent DSA and CTA. Occlusion site was classified into cervical, cavernous, petrous, and carotid terminus segments by DSA confirmation. Clinical and radiological features associated with poor outcome at 3 months (3–6 of modified Rankin scale) were analyzed. Baseline CTA findings were categorized according to carotid occlusive shape (stump, spearhead, and streak), presence of cervical calcification, Willisian occlusive patterns (T-type, L-type, and I-type), and status of leptomeningeal collaterals (LMC). We identified 49 patients with occlusions in the cervical (n = 17), cavernous (n = 22), and carotid terminus (n = 10) portions: initial NIH Stroke Scale (11.4 ± 4.2 vs 16.1 ± 3.7 vs 18.2 ± 5.1; P < 0.001), stroke volume (27.9 ± 29.6 vs 127.4 ± 112.6 vs 260.3 ± 151.8 mL; P < 0.001), and poor outcome (23.5 vs 77.3 vs 90.0%; P < 0.001). Cervical portion occlusion was characterized as rounded stump (82.4%) with calcification (52.9%) and fair LMC (94.1%); cavernous as spearhead occlusion (68.2%) with fair LMC (86.3%) and no calcification (95.5%); and terminus as streak-like occlusive pattern (60.0%) with poor LMC (60.0%), and no calcification (100%) on CTA. Our study indicates that acute ICA occlusion can be subtyped into cervical, cavernous, and terminus. Distinctive findings on initial CTA can help differentiate ICA-occlusion subtypes with specific characteristics. PMID:28151850

  20. BIOCHEMICAL CHARACTERIZATION OF MEMBRANE FRACTIONS IN MURINE SPERM: IDENTIFICATION OF THREE DISTINCT SUB-TYPES OF MEMBRANE RAFTS

    PubMed Central

    Asano, Atsushi; Selvaraj, Vimal; Buttke, Danielle E.; Nelson, Jacquelyn L.; Green, Karin M.; Evans, James E.; Travis, Alexander J.

    2009-01-01

    Despite enormous interest in membrane raft microdomains, no studies in any cell type have defined the relative compositions of the raft fractions on the basis of their major components—sterols, phospholipids, and proteins—or additional raft-associating lipids such as the ganglioside, GM1. Our previous localization data in live sperm showed that the plasma membrane overlying the acrosome represents a stabilized platform enriched in GM1 and sterols. These findings, along with the physiological requirement for sterol efflux for sperm to function, prompted us to characterize sperm membrane fractions biochemically. After confirming limitations of commonly-used detergent-based approaches, we utilized a non-detergent-based method, separating membrane fractions that were reproducibly distinct based on sterol, GM1, phospholipid and protein compositions (both mass amounts and molar ratios). Based on fraction buoyancy and biochemical composition, we identified at least three highly reproducible subtypes of membrane raft. Electron microscopy revealed that raft fractions were free of visible contaminants and were separated by buoyancy rather than morphology. Quantitative proteomic comparisons and fluorescence localization of lipids suggested that different organelles contributed differentially to individual raft sub-types, but that multiple membrane microdomain sub-types could exist within individual domains. This has important implications for scaffolding functions broadly associated with rafts. Most importantly, we show that the common practice of characterizing membrane domains as either “raft” or “non-raft” oversimplifies the actual biochemical complexity of cellular membranes. PMID:19006178

  1. A Cross-Species Analysis in Pancreatic Neuroendocrine Tumors Reveals Molecular Subtypes with Distinctive Clinical, Metastatic, Developmental, and Metabolic Characteristics

    PubMed Central

    Sadanandam, Anguraj; Wullschleger, Stephan; Lyssiotis, Costas A.; Grötzinger, Carsten; Barbi, Stefano; Bersani, Samantha; Körner, Jan; Wafy, Ismael; Mafficini, Andrea; Lawlor, Rita T.; Simbolo, Michele; Asara, John M.; Bläker, Hendrik; Cantley, Lewis C.; Wiedenmann, Bertram; Scarpa, Aldo; Hanahan, Douglas

    2016-01-01

    Seeking to assess the representative and instructive value of an engineered mouse model of pancreatic neuroendocrine tumors (PanNET) for its cognate human cancer, we profiled and compared mRNA and miRNA transcriptomes of tumors from both. Mouse PanNET tumors could be classified into two distinctive subtypes, well-differentiated islet/insulinoma tumors (IT) and poorly differentiated tumors associated with liver metastases, dubbed metastasis-like primary (MLP). Human PanNETs were independently classified into these same two subtypes, along with a third, specific gene mutation–enriched subtype. The MLP subtypes in human and mouse were similar to liver metastases in terms of miRNA and mRNA transcriptome profiles and signature genes. The human/mouse MLP subtypes also similarly expressed genes known to regulate early pancreas development, whereas the IT subtypes expressed genes characteristic of mature islet cells, suggesting different tumorigenesis pathways. In addition, these subtypes exhibit distinct metabolic profiles marked by differential pyruvate metabolism, substantiating the significance of their separate identities. SIGNIFICANCE This study involves a comprehensive cross-species integrated analysis of multi-omics profiles and histology to stratify PanNETs into subtypes with distinctive characteristics. We provide support for the RIP1-TAG2 mouse model as representative of its cognate human cancer with prospects to better understand PanNET heterogeneity and consider future applications of personalized cancer therapy. PMID:26446169

  2. Understanding patient outcomes after acute respiratory distress syndrome: identifying subtypes of physical, cognitive and mental health outcomes.

    PubMed

    Brown, Samuel M; Wilson, Emily L; Presson, Angela P; Dinglas, Victor D; Greene, Tom; Hopkins, Ramona O; Needham, Dale M

    2017-08-04

    With improving short-term mortality in acute respiratory distress syndrome (ARDS), understanding survivors' posthospitalisation outcomes is increasingly important. However, little is known regarding associations among physical, cognitive and mental health outcomes. Identification of outcome subtypes may advance understanding of post-ARDS morbidities. We analysed baseline variables and 6-month health status for participants in the ARDS Network Long-Term Outcomes Study. After division into derivation and validation datasets, we used weighted network analysis to identify subtypes from predictors and outcomes in the derivation dataset. We then used recursive partitioning to develop a subtype classification rule and assessed adequacy of the classification rule using a kappa statistic with the validation dataset. Among 645 ARDS survivors, 430 were in the derivation and 215 in the validation datasets. Physical and mental health status, but not cognitive status, were closely associated. Four distinct subtypes were apparent (percentages in the derivation cohort): (1) mildly impaired physical and mental health (22% of patients), (2) moderately impaired physical and mental health (39%), (3) severely impaired physical health with moderately impaired mental health (15%) and (4) severely impaired physical and mental health (24%). The classification rule had high agreement (kappa=0.89 in validation dataset). Female Latino smokers had the poorest status, while male, non-Latino non-smokers had the best status. We identified four post-ARDS outcome subtypes that were predicted by sex, ethnicity, pre-ARDS smoking status and other baseline factors. These subtypes may help develop tailored rehabilitation strategies, including investigation of combined physical and mental health interventions, and distinct interventions to improve cognitive outcomes. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use

  3. Total Survivin and acetylated Survivin correlate with distinct molecular subtypes of breast cancer.

    PubMed

    Yakirevich, Evgeny; Samkari, Ayman; Holloway, Michael P; Lu, Shaolei; Singh, Kamaljeet; Yu, Jovian; Fenton, Mary Anne; Altura, Rachel A

    2012-06-01

    Global gene expression profiling studies led to the recent classification of breast cancer into 4 distinct molecular subtypes including luminal, human epidermal growth factor receptor 2 enriched, basal like, and unclassified. Here, we used immunohistochemistry to evaluate expression of the antiapoptotic protein Survivin and its recently described acetylated form, Survivin acetyl129, in normal breast tissue and in 226 primary breast tumors of different molecular subtypes. Correlation of Survivin expression with molecular markers and its impact on patient outcomes were analyzed. Eighty-four percent of basal-like tumors expressed high levels of total Survivin, whereas 52% of luminal tumors expressed high levels of acetylated Survivin (P < .001). Overall survival (91%) for tumors expressing low levels of total Survivin was better than that for tumors expressing high levels of total Survivin (72%, P = .02), whereas the reverse was true for tumors expressing acetylated Survivin. In hierarchical cluster analysis, total Survivin clustered with basal marker expression, whereas acetylated Survivin clustered with luminal marker expression. In multivariate analysis, high total Survivin expression was an independent predictor of worse overall survival in patients with breast cancer (relative risk, 11; P < .01). These data indicate that high levels of total Survivin predict poor outcome in patients with grade 3 invasive ductal carcinoma and correlate directly with a basal-like phenotype. In contrast, high expression of the acetylated form of the protein associates with a favorable outcome and preferentially correlates with luminal-type tumors. Survivin likely has different functions in distinct breast cancer subtypes, and diagnostic strategies that incorporate immunohistochemical markers that detect both Survivin forms may help better strategize patient risk and direct therapy.

  4. Response to clozapine in a clinically identifiable subtype of schizophrenia

    PubMed Central

    Butcher, Nancy J.; Fung, Wai Lun Alan; Fitzpatrick, Laura; Guna, Alina; Andrade, Danielle M.; Lang, Anthony E.; Chow, Eva W. C.; Bassett, Anne S.

    2015-01-01

    Background Genetic testing in psychiatry promises to improve patient care through advances in personalised medicine. However, there are few clinically relevant examples. Aims To determine whether patients with a well-established genetic subtype of schizophrenia show a different response profile to the antipsychotic clozapine than those with idiopathic schizophrenia. Method We retrospectively studied the long-term safety and efficacy of clozapine in 40 adults with schizophrenia, half with a 22q11.2 deletion (22q11.2DS group) and half matched for age and clinical severity but molecularly confirmed to have no pathogenic copy number variant (idiopathic group). Results Both groups showed similar clinical improvement and significant reductions in hospitalisations, achieved at a lower median dose for those in the 22q11.2DS group. Most common side-effects were similarly prevalent between the two groups, however, half of the 22q11.2DS group experienced at least one rare serious adverse event compared with none of the idiopathic group. Many were successfully retried on clozapine. Conclusions Individuals with 22q11.2DS-schizophrenia respond as well to clozapine treatment as those with other forms of schizophrenia, but may represent a disproportionate number of those with serious adverse events, primarily seizures. Lower doses and prophylactic (for example anticonvulsant) management strategies can help ameliorate side-effect risks. This first systematic evaluation of antipsychotic response in a genetic subtype of schizophrenia provides a proof-of-principle for personalised medicine and supports the utility of clinical genetic testing in schizophrenia. PMID:25745132

  5. Distinct patterns of DNA copy number alteration are associated with different clinicopathological features and gene-expression subtypes of breast cancer.

    PubMed

    Bergamaschi, Anna; Kim, Young H; Wang, Pei; Sørlie, Therese; Hernandez-Boussard, Tina; Lonning, Per E; Tibshirani, Robert; Børresen-Dale, Anne-Lise; Pollack, Jonathan R

    2006-11-01

    Breast cancer is a leading cause of cancer-death among women, where the clinicopathological features of tumors are used to prognosticate and guide therapy. DNA copy number alterations (CNAs), which occur frequently in breast cancer and define key pathogenetic events, are also potentially useful prognostic or predictive factors. Here, we report a genome-wide array-based comparative genomic hybridization (array CGH) survey of CNAs in 89 breast tumors from a patient cohort with locally advanced disease. Statistical analysis links distinct cytoband loci harboring CNAs to specific clinicopathological parameters, including tumor grade, estrogen receptor status, presence of TP53 mutation, and overall survival. Notably, distinct spectra of CNAs also underlie the different subtypes of breast cancer recently defined by expression-profiling, implying these subtypes develop along distinct genetic pathways. In addition, higher numbers of gains/losses are associated with the "basal-like" tumor subtype, while high-level DNA amplification is more frequent in "luminal-B" subtype tumors, suggesting also that distinct mechanisms of genomic instability might underlie their pathogenesis. The identified CNAs may provide a basis for improved patient prognostication, as well as a starting point to define important genes to further our understanding of the pathobiology of breast cancer. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat

  6. Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes.

    PubMed

    Teicher, Martin H; Samson, Jacqueline A

    2013-10-01

    Childhood maltreatment increases risk for psychopathology. For some highly prevalent disorders (major depression, substance abuse, anxiety disorders, and posttraumatic stress disorder) a substantial subset of individuals have a history of maltreatment and a substantial subset do not. The authors examined the evidence to assess whether those with a history of maltreatment represent a clinically and biologically distinct subtype. The authors reviewed the literature on maltreatment as a risk factor for these disorders and on the clinical differences between individuals with and without a history of maltreatment who share the same diagnoses. Neurobiological findings in maltreated individuals were reviewed and compared with findings reported for these disorders. Maltreated individuals with depressive, anxiety, and substance use disorders have an earlier age at onset, greater symptom severity, more comorbidity, a greater risk for suicide, and poorer treatment response than nonmaltreated individuals with the same diagnoses. Imaging findings associated with these disorders, such as reduced hippocampal volume and amygdala hyperreactivity, are more consistently observed in maltreated individuals and may represent a maltreatment-related risk factor. Maltreated individuals also differ from others as a result of epigenetic modifications and genetic polymorphisms that interact with experience to increase risk for psychopathology. Phenotypic expression of psychopathology may be strongly influenced by exposure to maltreatment, leading to a constellation of ecophenotypes. While these ecophenotypes fit within conventional diagnostic boundaries, they likely represent distinct subtypes. Recognition of this distinction may be essential in determining the biological bases of these disorders. Treatment guidelines and algorithms may be enhanced if maltreated and nonmaltreated individuals with the same diagnostic labels are differentiated.

  7. Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes

    PubMed Central

    Teicher, Martin H.; Samson, Jacqueline A.

    2014-01-01

    Objective Childhood maltreatment increases risk for psychopathology. For some highly prevalent disorders (i.e., major depression, substance abuse, anxiety disorders and posttraumatic stress disorder) there is a substantial subset of individuals with maltreatment histories and a substantial subset without. Do those with maltreatment histories represent a clinically and biologically distinct subtype? Method The authors review literature on maltreatment as a risk factor for these disorders and on the clinical differences between individuals with and without maltreatment who share the same diagnoses. Neurobiological findings in maltreated individuals are reviewed and compared to findings reported for these disorders. Results Maltreated individuals with depressive, anxiety and substance use disorders show an earlier age of onset, greater symptom severity, more comorbidity, increased risk for suicide and poorer treatment response than non-maltreated individuals with the same diagnoses. Imaging findings associated with these disorders, such as reduced hippocampal volume and amygdala hyperreactivity are more consistently observed in maltreated individuals and may represent a maltreatment-related risk factor. Maltreated individuals also differ from others due to epigenetic modifications and genetic polymorphisms that interact with experience to increase risk for psychopathology. Conclusions Phenotypic expression of psychopathology may be strongly influenced by exposure to maltreatment leading to a constellation of ecophenotypes. While these ecophenotypes fit within conventional diagnostic boundaries, they likely represent distinct subtypes. Recognition of this distinction may be essential in determining the biological bases of these disorders. Further, treatment guidelines and algorithms may be enhanced if maltreated and non-maltreated individuals with the same diagnostic labels are differentiated. PMID:23982148

  8. Using Polymorphisms in FKBP5 to Define Biologically Distinct Subtypes of Posttraumatic Stress Disorder

    PubMed Central

    Mehta, Divya; Gonik, Mariya; Klengel, Torsten; Rex-Haffner, Monika; Menke, Andreas; Rubel, Jennifer; Mercer, Kristina B.; Pütz, Benno; Bradley, Bekh; Holsboer, Florian; Ressler, Kerry J.; Müller-Myhsok, Bertram; Binder, Elisabeth B.

    2013-01-01

    that the inheritance of GR sensitivity–moderating FKBP5 polymorphisms can determine specific types of hypothalamic-pituitary-adrenal axis dysfunction within PTSD, which are also reflected in gene-expression changes of a subset of GR-responsive genes. Thus, these findings indicate that functional variants in FKBP5 are associated with biologically distinct subtypes of PTSD. PMID:21536970

  9. Characterization of molecular subtypes of Korean breast cancer: An ethnically and clinically distinct population

    PubMed Central

    HAN, WONSHIK; NICOLAU, MONICA; NOH, DONG-YOUNG; JEFFREY, STEFANIE S.

    2015-01-01

    We aimed to investigate the molecular characteristics of Korean breast cancer. A cDNA microarray study (>42k clones) was performed on 69 breast cancers and three normal breast tissues. The subjects had a high percentage of HER-2 expression, hormone receptor negativity, and young onset. Molecular subtypes according to gene expression profiles were determined and their correlations to the clinicopathologic characteristics and patients outcome were analyzed. The tumors were subdivided into luminal-, normal breast-like, ERBB2+, and basal-like subtypes according to the correlations to the previously described intrinsic genes and five centroids. Only a few tumors were highly correlated to the luminal B and normal-like centroids. The high grade tumors with high p53 and Ki-67 were found more commonly in non-luminal tumors. Distant recurrence-free survival was worse in ERBB2+ and basal-like subgroups than luminal tumors. In an unsupervised clustering with 864 genes, many interesting gene clusters were observed, some of which had not been previously described. Although the Korean breast cancers showed generally similar molecular phenotypes as Western studies, some distinct gene expression patterns and their association to clinical outcomes were observed. PMID:20514396

  10. Characterization of molecular subtypes of Korean breast cancer: an ethnically and clinically distinct population.

    PubMed

    Han, Wonshik; Nicolau, Monica; Noh, Dong-Young; Jeffrey, Stefanie S

    2010-07-01

    We aimed to investigate the molecular characteristics of Korean breast cancer. A cDNA microarray study (>42k clones) was performed on 69 breast cancers and three normal breast tissues. The subjects had a high percentage of HER-2 expression, hormone receptor negativity, and young onset. Molecular subtypes according to gene expression profiles were determined and their correlations to the clinicopathologic characteristics and patients outcome were analyzed. The tumors were subdivided into luminal-, normal breast-like, ERBB2+, and basal-like subtypes according to the correlations to the previously described intrinsic genes and five centroids. Only a few tumors were highly correlated to the luminal B and normal-like centroids. The high grade tumors with high p53 and Ki-67 were found more commonly in non-luminal tumors. Distant recurrence-free survival was worse in ERBB2+ and basal-like subgroups than luminal tumors. In an unsupervised clustering with 864 genes, many interesting gene clusters were observed, some of which had not been previously described. Although the Korean breast cancers showed generally similar molecular phenotypes as Western studies, some distinct gene expression patterns and their association to clinical outcomes were observed.

  11. Biologically distinct subtypes of Mycobacterium avium differ in possession of insertion sequence IS901.

    PubMed

    Kunze, Z M; Portaels, F; McFadden, J J

    1992-09-01

    Mycobacterium avium causes disease, principally tuberculosis in immunocompromised individuals. It is the most frequent cause of disseminated infections in AIDS patients in the West. The pathogen is also associated with disease in animals, chiefly birds and livestock, and may be isolated from environmental samples such as soil and water. Analysis of strains of M. avium isolated from clinical, veterinary, and environmental sources for the presence of the mycobacterial insertion sequences IS900 and IS901 demonstrates the specific association of IS901 to animal pathogenic M. avium strains. In contrast, most clinical M. avium strains and all AIDS-derived strains examined so far lacked IS901. Significant differences in the plasmid contents and serotypes of strains with and without IS901 were also found. We therefore suggest that the presence of IS901 divides M. avium into two clearly distinct subtypes with differing host range, virulence, plasmid possession, and serotyping antigens. By using DNA sequence data from IS901 and M. avium DNA, a set of polymerase chain reactions were developed for the specific detection and differentiation of these subtypes.

  12. Identifying ultrasound and clinical features of breast cancer molecular subtypes by ensemble decision

    PubMed Central

    Zhang, Lei; Li, Jing; Xiao, Yun; Cui, Hao; Du, Guoqing; Wang, Ying; Li, Ziyao; Wu, Tong; Li, Xia; Tian, Jiawei

    2015-01-01

    Breast cancer is molecularly heterogeneous and categorized into four molecular subtypes: Luminal-A, Luminal-B, HER2-amplified and Triple-negative. In this study, we aimed to apply an ensemble decision approach to identify the ultrasound and clinical features related to the molecular subtypes. We collected ultrasound and clinical features from 1,000 breast cancer patients and performed immunohistochemistry on these samples. We used the ensemble decision approach to select unique features and to construct decision models. The decision model for Luminal-A subtype was constructed based on the presence of an echogenic halo and post-acoustic shadowing or indifference. The decision model for Luminal-B subtype was constructed based on the absence of an echogenic halo and vascularity. The decision model for HER2-amplified subtype was constructed based on the presence of post-acoustic enhancement, calcification, vascularity and advanced age. The model for Triple-negative subtype followed two rules. One was based on irregular shape, lobulate margin contour, the absence of calcification and hypovascularity, whereas the other was based on oval shape, hypovascularity and micro-lobulate margin contour. The accuracies of the models were 83.8%, 77.4%, 87.9% and 92.7%, respectively. We identified specific features of each molecular subtype and expanded the scope of ultrasound for making diagnoses using these decision models. PMID:26046791

  13. Identifying the receptor subtype selectivity of retinoid X and retinoic acid receptors via quantum mechanics.

    PubMed

    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.

  14. Both overlapping and distinct signaling pathways for somatostatin receptor subtypes SSTR1 and SSTR2 in pituitary cells.

    PubMed

    Chen, L; Fitzpatrick, V D; Vandlen, R L; Tashjian, A H

    1997-07-25

    To elucidate the signaling events mediated by specific somatostatin receptor (SSTR) subtypes, we expressed SSTR1 and SSTR2 individually in rat pituitary GH12C1 and F4C1 cells, which lack endogenous somatostatin receptors. In transfected GH12C1 cells, both SSTR1 and SSTR2 coupled to inhibition of Ca2+ influx and hyperpolarization of membrane potential via a pertussis toxin (PTx)-sensitive mechanism. These effects reflected modulation of ion channel activities which are important for regulation of hormone secretion. Somatostatin analogs MK678 and CH275 acted as subtype selective agonists as expected. In transfected F4C1 cells, both SSTR1 and SSTR2 mediated somatostatin-induced inhibition of adenylyl cyclase via a PTx-sensitive pathway. In addition, activation of SSTR2 in F4C1 cells, but not SSTR1, stimulated phospholipase C (PLC) activity and an increase in [Ca2+]i due to release of Ca2+ from intracellular stores. Unlike adenylyl cyclase inhibition, the PLC-mediated response was only partially sensitive to PTx. To determine the structural determinants in SSTR2 necessary for activation of PLC, we constructed chimeric receptors in which domains of SSTR2 were introduced into SSTR1. Chimeric receptors containing only the third intracellular loop, or all three intracellular loops from SSTR2, mediated inhibition of adenylyl cyclase, but failed to stimulate PLC activity as did wild-type SSTR2. Furthermore, the C-terminal tail of SSTR2 was not required for coupling to PLC. Thus, by expressing individual somatostatin receptor subtypes in pituitary cells, we have identified both overlapping and distinct signaling pathways for SSTR1 and SSTR2, and have shown that sequences other than simply the intracellular domains are required for SSTR2 to couple to the PLC signaling pathway.

  15. Distinct neural signatures detected for ADHD subtypes after controlling for micro-movements in resting state functional connectivity MRI data

    PubMed Central

    Fair, Damien A.; Nigg, Joel T.; Iyer, Swathi; Bathula, Deepti; Mills, Kathryn L.; Dosenbach, Nico U. F.; Schlaggar, Bradley L.; Mennes, Maarten; Gutman, David; Bangaru, Saroja; Buitelaar, Jan K.; Dickstein, Daniel P.; Di Martino, Adriana; Kennedy, David N.; Kelly, Clare; Luna, Beatriz; Schweitzer, Julie B.; Velanova, Katerina; Wang, Yu-Feng; Mostofsky, Stewart; Castellanos, F. Xavier; Milham, Michael P.

    2012-01-01

    be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical heterogeneity of ADHD. PMID:23382713

  16. Clueless or Powerful? Identifying Subtypes of Bullies in Adolescence

    ERIC Educational Resources Information Center

    Peeters, Margot; Cillessen, Antonius H. N.; Scholte, Ron H. J.

    2010-01-01

    This study examined the heterogeneity of bullying among adolescents. It was hypothesized that bullying behavior serves different social functions and, depending on these functions, bullies will differ in their skills, status and social behavior. In a total sample of 806 8th graders, 120 adolescents (52 boys, 68 girls) were identified as bullies…

  17. Clueless or Powerful? Identifying Subtypes of Bullies in Adolescence

    ERIC Educational Resources Information Center

    Peeters, Margot; Cillessen, Antonius H. N.; Scholte, Ron H. J.

    2010-01-01

    This study examined the heterogeneity of bullying among adolescents. It was hypothesized that bullying behavior serves different social functions and, depending on these functions, bullies will differ in their skills, status and social behavior. In a total sample of 806 8th graders, 120 adolescents (52 boys, 68 girls) were identified as bullies…

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

    PubMed

    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.

  19. Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma

    DOE PAGES

    Jusakul, Apinya; Cutcutache, Ioana; Yong, Chern Han; ...

    2017-06-30

    Cholangiocarcinoma (CCA) is a hepatobiliary malignancy exhibiting high incidence in countries with endemic liver-fluke infection. We analysed 489 CCAs from 10 countries, combining whole-genome (71 cases), targeted/exome, copy-number, gene expression, and DNA methylation information. Integrative clustering defined four CCA clusters - Fluke- Positive CCAs (Clusters 1/2) are enriched in ERBB2 amplifications and TP53 mutations, conversely Fluke-Negative CCAs (Clusters 3/4) exhibit high copy-number alterations and PD-1/PD-L2 expression, or epigenetic mutations (IDH1/2, BAP1) and FGFR/PRKA-related gene rearrangements. Whole-genome analysis highlighted FGFR2 3’UTR deletion as a mechanism of FGFR2 upregulation. Integration of non-coding promoter mutations with protein-DNA binding profiles demonstrates pervasive modulation ofmore » H3K27me3-associated sites in CCA. Clusters 1 and 4 exhibit distinct DNA hypermethylation patterns targeting either CpG islands or shores - mutation signature and subclonality analysis suggests that these reflect different mutational pathways. Lastly, our results exemplify how genetics, epigenetics and environmental carcinogens can interplay across different geographies to generate distinct molecular subtypes of cancer.« less

  20. Global changes in processing of mRNA 3' untranslated regions characterize clinically distinct cancer subtypes.

    PubMed

    Singh, Priyam; Alley, Travis L; Wright, Sarah M; Kamdar, Sonya; Schott, William; Wilpan, Robert Y; Mills, Kevin D; Graber, Joel H

    2009-12-15

    Molecular cancer diagnostics are an important clinical advance in cancer management, but new methods are still needed. In this context, gene expression signatures obtained by microarray represent a useful molecular diagnostic. Here, we describe novel probe-level microarray analyses that reveal connections between mRNA processing and neoplasia in multiple tumor types, with diagnostic potential. We now show that characteristic differences in mRNA processing, primarily in the 3'-untranslated region, define molecular signatures that can distinguish similar tumor subtypes with different survival characteristics, with at least 74% accuracy. Using a mouse model of B-cell leukemia/lymphoma, we find that differences in transcript isoform abundance are likely due to both alternative polyadenylation (APA) and differential degradation. While truncation of the 3'-UTR is the most common observed pattern, genes with elongated transcripts were also observed, and distinct groups of affected genes are found in related but distinct tumor types. Genes with elongated transcripts are overrepresented in ontology categories related to cell-cell adhesion and morphology. Analysis of microarray data from human primary tumor samples revealed similar phenomena. Western blot analysis of selected proteins confirms that changes in the 3'-UTR can correlate with changes in protein expression. Our work suggests that alternative mRNA processing, particularly APA, can be a powerful molecular biomarker with prognostic potential. Finally, these findings provide insights into the molecular mechanisms of gene deregulation in tumorigenesis.

  1. Bioinformatic analyses reveal a distinct Notch activation induced by STAT3 phosphorylation in the mesenchymal subtype of glioblastoma.

    PubMed

    Cheng, Wen; Zhang, Chuanbao; Ren, Xiufang; Jiang, Yang; Han, Sheng; Liu, Yang; Cai, Jinquan; Li, Mingyang; Wang, Kuanyu; Liu, Yanwei; Hu, Huimin; Li, Qingbin; Yang, Pei; Bao, Zhaoshi; Wu, Anhua

    2017-01-01

    OBJECTIVE Glioblastoma (GBM) is the most common and lethal type of malignant glioma. The Cancer Genome Atlas divides the gene expression-based classification of GBM into classical, mesenchymal, neural, and proneural subtypes, which is important for understanding GBM etiology and for designing effective personalized therapy. Signal transducer and activator of transcription 3 (STAT3), a critical transcriptional activator in tumorigenesis, is persistently phosphorylated and associated with an unfavorable prognosis in GBM. Although a set of specific targets has been identified, there have been no systematic analyses of STAT3 signaling based on GBM subtype. METHODS This study compared STAT3-associated messenger RNA, protein, and microRNA expression profiles across different subtypes of GBM. RESULTS The analyses revealed a prominent role for STAT3 in the mesenchymal but not in other GBM subtypes, which can be reliably used to classify patients with mesenchymal GBM into 2 groups according to phosphorylated STAT3 expression level. Differentially expressed genes suggest an association between Notch and STAT3 signaling in the mesenchymal subtype. Their association was validated in the U87 cell, a malignant glioma cell line annotated as mesenchymal subtype. Specific associated proteins and microRNAs further profile the STAT3 signaling among GBM subtypes. CONCLUSIONS These findings suggest a prominent role for STAT3 signaling in mesenchymal GBM and highlight the importance of identifying signaling pathways that contribute to specific cancer subtypes.

  2. Segregation of non-p.R132H mutations in IDH1 in distinct molecular subtypes of glioma.

    PubMed

    Gravendeel, Lonneke A M; Kloosterhof, Nanne K; Bralten, Linda B C; van Marion, Ronald; Dubbink, Hendrikus Jan; Dinjens, Winand; Bleeker, Fonnet E; Hoogenraad, Casper C; Michiels, Erna; Kros, Johan M; van den Bent, Martin; Smitt, Peter A E Sillevis; French, Pim J

    2010-03-01

    Mutations in the gene encoding the isocitrate dehydrogenase 1 gene (IDH1) occur at a high frequency (up to 80%) in many different subtypes of glioma. In this study, we have screened for IDH1 mutations in a cohort of 496 gliomas. IDH1 mutations were most frequently observed in low grade gliomas with c.395G>A (p.R132H) representing >90% of all IDH1 mutations. Interestingly, non-p.R132H mutations segregate in distinct histological and molecular subtypes of glioma. Histologically, they occur sporadically in classic oligodendrogliomas and at significantly higher frequency in other grade II and III gliomas. Genetically, non-p.R132H mutations occur in tumors with TP53 mutation, are virtually absent in tumors with loss of heterozygosity on 1p and 19q and accumulate in distinct (gene-expression profiling based) intrinsic molecular subtypes. The IDH1 mutation type does not affect patient survival. Our results were validated on an independent sample cohort, indicating that the IDH1 mutation spectrum may aid glioma subtype classification. Functional differences between p.R132H and non-p.R132H mutated IDH1 may explain the segregation in distinct glioma subtypes.

  3. Dkk4 and Eda Regulate Distinctive Developmental Mechanisms for Subtypes of Mouse Hair

    PubMed Central

    Cui, Chang-Yi; Kunisada, Makoto; Piao, Yulan; Childress, Victoria; Ko, Minoru S. H.; Schlessinger, David

    2010-01-01

    The mouse hair coat comprises protective “primary” and thermo-regulatory “secondary” hairs. Primary hair formation is ectodysplasin (Eda) dependent, but it has been puzzling that Tabby (Eda-/y) mice still make secondary hair. We report that Dickkopf 4 (Dkk4), a Wnt antagonist, affects an auxiliary pathway for Eda-independent development of secondary hair. A Dkk4 transgene in wild-type mice had no effect on primary hair, but secondary hairs were severely malformed. Dkk4 action on secondary hair was further demonstrated when the transgene was introduced into Tabby mice: the usual secondary follicle induction was completely blocked. The Dkk4-regulated secondary hair pathway, like the Eda-dependent primary hair pathway, is further mediated by selective activation of Shh. The results thus reveal two complex molecular pathways that distinctly regulate subtype-based morphogenesis of hair follicles, and provide a resolution for the longstanding puzzle of hair formation in Tabby mice lacking Eda. PMID:20386733

  4. Diversity of Group I and II Clostridium botulinum Strains from France Including Recently Identified Subtypes

    PubMed Central

    Mazuet, Christelle; Legeay, Christine; Sautereau, Jean; Ma, Laurence; Bouchier, Christiane; Bouvet, Philippe; Popoff, Michel R.

    2016-01-01

    In France, human botulism is mainly food-borne intoxication, whereas infant botulism is rare. A total of 99 group I and II Clostridium botulinum strains including 59 type A (12 historical isolates [1947–1961], 43 from France [1986–2013], 3 from other countries, and 1 collection strain), 31 type B (3 historical, 23 recent isolates, 4 from other countries, and 1 collection strain), and 9 type E (5 historical, 3 isolates, and 1 collection strain) were investigated by botulinum locus gene sequencing and multilocus sequence typing analysis. Historical C. botulinum A strains mainly belonged to subtype A1 and sequence type (ST) 1, whereas recent strains exhibited a wide genetic diversity: subtype A1 in orfX or ha locus, A1(B), A1(F), A2, A2b2, A5(B2′) A5(B3′), as well as the recently identified A7 and A8 subtypes, and were distributed into 25 STs. Clostridium botulinum A1(B) was the most frequent subtype from food-borne botulism and food. Group I C. botulinum type B in France were mainly subtype B2 (14 out of 20 historical and recent strains) and were divided into 19 STs. Food-borne botulism resulting from ham consumption during the recent period was due to group II C. botulinum B4. Type E botulism is rare in France, 5 historical and 1 recent strains were subtype E3. A subtype E12 was recently identified from an unusual ham contamination. Clostridium botulinum strains from human botulism in France showed a wide genetic diversity and seems to result not from a single evolutionary lineage but from multiple and independent genetic rearrangements. PMID:27189984

  5. Diversity of Group I and II Clostridium botulinum Strains from France Including Recently Identified Subtypes.

    PubMed

    Mazuet, Christelle; Legeay, Christine; Sautereau, Jean; Ma, Laurence; Bouchier, Christiane; Bouvet, Philippe; Popoff, Michel R

    2016-06-13

    In France, human botulism is mainly food-borne intoxication, whereas infant botulism is rare. A total of 99 group I and II Clostridium botulinum strains including 59 type A (12 historical isolates [1947-1961], 43 from France [1986-2013], 3 from other countries, and 1 collection strain), 31 type B (3 historical, 23 recent isolates, 4 from other countries, and 1 collection strain), and 9 type E (5 historical, 3 isolates, and 1 collection strain) were investigated by botulinum locus gene sequencing and multilocus sequence typing analysis. Historical C. botulinum A strains mainly belonged to subtype A1 and sequence type (ST) 1, whereas recent strains exhibited a wide genetic diversity: subtype A1 in orfX or ha locus, A1(B), A1(F), A2, A2b2, A5(B2') A5(B3'), as well as the recently identified A7 and A8 subtypes, and were distributed into 25 STs. Clostridium botulinum A1(B) was the most frequent subtype from food-borne botulism and food. Group I C. botulinum type B in France were mainly subtype B2 (14 out of 20 historical and recent strains) and were divided into 19 STs. Food-borne botulism resulting from ham consumption during the recent period was due to group II C. botulinum B4. Type E botulism is rare in France, 5 historical and 1 recent strains were subtype E3. A subtype E12 was recently identified from an unusual ham contamination. Clostridium botulinum strains from human botulism in France showed a wide genetic diversity and seems to result not from a single evolutionary lineage but from multiple and independent genetic rearrangements.

  6. Some environmental contaminants influence motor and feeding behaviors in the ornate wrasse (Thalassoma pavo) via distinct cerebral histamine receptor subtypes.

    PubMed

    Giusi, Giuseppina; Facciolo, Rosa Maria; Alò, Raffaella; Carelli, Antonio; Madeo, Maria; Brandmayr, Pietro; Canonaco, Marcello

    2005-11-01

    Common environmental contaminants such as heavy metals and pesticides pose serious risks to behavioral and neuroendocrine functions of many aquatic organisms. In the present study, we show that the heavy metal cadmium and the pesticide endosulfan produce such effects through an interaction of specific cerebral histamine receptor subtypes in the teleost ornate wrasse (Thalassoma pavo). Treatment of this teleost with toxic cadmium levels for 1 week was sufficient to induce abnormal swimming movements, whereas reduced feeding behaviors were provoked predominantly by elevated endosulfan concentrations. In the brain, these environmental contaminants caused neuronal degeneration in cerebral targets such as the mesencephalon and hypothalamus, damage that appeared to correlate with altered binding levels of the three major histamine receptors (subtypes 1, 2, and 3). Although cadmium accounted for reduced binding activity of all three subtypes in most brain regions, it was subtype 2 that seemed to be its main target, as shown by a very great (p < 0.001) down-regulation in mesencephalic areas such as the stratum griseum central layer. Conversely, endosulfan provided very great and great (p < 0.01) up-regulating effects of subtype 3 and 1 levels, respectively, in preoptic-hypothalamic areas such as the medial part of the lateral tuberal nucleus, and in the suprachiasmatic nucleus. These results suggest that the neurotoxicant-dependent abnormal motor and feeding behaviors may well be tightly linked to binding activities of distinct histamine subtypes in localized brain regions of the Thalassoma pavo.

  7. Identification and characterization of a new and distinct molecular subtype of human T-cell lymphotropic virus type 2.

    PubMed Central

    Eiraku, N; Novoa, P; da Costa Ferreira, M; Monken, C; Ishak, R; da Costa Ferreira, O; Zhu, S W; Lorenco, R; Ishak, M; Azvedo, V; Guerreiro, J; de Oliveira, M P; Loureiro, P; Hammerschlak, N; Ijichi, S; Hall, W M

    1996-01-01

    Molecular studies have demonstrated the existence of at least two major subtypes of human T-cell lymphotropic virus type 2 (HTLV-2), designated HTLV-2a and HTLV-2b. To further investigate the heterogeneity of this family of viruses, we have characterized the HTLV-2 subtypes present in several urban areas in Brazil. DNAs from peripheral blood mononuclear cells of a large number of infected individuals, the majority of whom were intravenous drug abusers, were analyzed by using PCR with restriction fragment length polymorphism and nucleotide sequencing analysis. Restriction fragment length polymorphism analysis of the env region suggested that all individuals were infected with the HTLV-2a subtype, and this was confirmed by nucleotide sequence analysis. In contrast, nucleotide sequence analysis of the long terminal repeat demonstrated that although the viruses were more related to the HTLV-2a than to the HTLV-2b subtype, they clustered in a distinct phylogenetic group, suggesting that they may represent a new and distinct molecular subtype of HTLV-2. This conclusion was supported by nucleotide sequence analysis of the pX region, which demonstrated that the Tax proteins of the Brazilian viruses differed from that of prototype HTLV-2a isolates but were more similar to that of HTLV-2b in that they would be expected to have an additional 25 amino acids at the carboxy terminus. In transient expression assays, the extended Tax protein of the prototype HTLV-2a subtype. The studies suggest that the Brazilian viruses analyzed in this study, while being phylogenetically related to the prototypic HTLV-2a seen in North America, are phenotypically more related to HTLV-2b and can be justifiably classified as a new molecular subtype, which has been tentatively designated HTLV-2c. PMID:8627666

  8. Genetically distinct genogroup IV norovirus strains identified in wastewater.

    PubMed

    Kitajima, Masaaki; Rachmadi, Andri T; Iker, Brandon C; Haramoto, Eiji; Gerba, Charles P

    2016-12-01

    We investigated the prevalence and genetic diversity of genogroup IV norovirus (GIV NoV) strains in wastewater in Arizona, United States, over a 13-month period. Among 50 wastewater samples tested, GIV NoVs were identified in 13 (26 %) of the samples. A total of 47 different GIV NoV strains were identified, which were classified into two genetically distinct clusters: the GIV.1 human cluster and a unique genetic cluster closely related to strains previously identified in Japanese wastewater. The results provide additional evidence of the considerable genetic diversity among GIV NoV strains through the analysis of wastewater containing virus strains shed from all populations.

  9. Identifying Subtypes of Peer Status by Combining Popularity and Preference: A Cohort-Sequential Approach

    ERIC Educational Resources Information Center

    van den Berg, Yvonne H. M.; Burk, William J.; Cillessen, Antonius H. N.

    2015-01-01

    The purpose of this study was to identify and validate subtypes of peer status by integrating preference and popularity into a single framework. Person-oriented analyses were performed among 3,630 children and adolescents of different cohorts in primary and secondary education. In the young age groups (Grade 3/4 to Grade 7), three clusters were…

  10. Identifying Subtypes of Peer Status by Combining Popularity and Preference: A Cohort-Sequential Approach

    ERIC Educational Resources Information Center

    van den Berg, Yvonne H. M.; Burk, William J.; Cillessen, Antonius H. N.

    2015-01-01

    The purpose of this study was to identify and validate subtypes of peer status by integrating preference and popularity into a single framework. Person-oriented analyses were performed among 3,630 children and adolescents of different cohorts in primary and secondary education. In the young age groups (Grade 3/4 to Grade 7), three clusters were…

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

    PubMed Central

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

    2017-01-01

    Background Parallel-polarized light (PPL) photography evaluates skin characteristics by analyzing light reflections from the skin surface. Objective 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. Methods 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. Results 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. Conclusion 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. PMID:28392643

  12. Different AMPA receptor subtypes mediate the distinct kinetic components of a biphasic EPSC in hippocampal interneurons

    PubMed Central

    Stincic, Todd L.; Frerking, Matthew E.

    2015-01-01

    CA1 hippocampal interneurons at the border between stratum radiatum (SR) and stratum lacunosum-moleculare (SLM) have AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) that consist of two distinct phases: a typical fast component (FC), and a highly unusual slow component (SC) that persists for hundreds of milliseconds. To determine whether these kinetically distinct components of the EPSC are mediated by distinct AMPAR subpopulations, we examined the relative contributions of GluA2-containing and—lacking AMPARs to the SC. GluA2-containing AMPARs mediated the majority of the FC whereas GluA2-lacking AMPARs preferentially generated the SC. When glutamate uptake through the glial glutamate transporter excitatory amino acid transporter (EAAT1) was inhibited, spill over-mediated AMPAR activation recruited an even slower third kinetic component that persisted for several seconds; however, this spillover-mediated current was mediated predominantly by GluA2-containing AMPARs and therefore was clearly distinct from the SC when uptake is intact. Thus, different AMPAR subpopulations that vary in GluA2 content mediate the distinct components of the AMPAR EPSC. The SC is developmentally downregulated in mice, declining after the second postnatal week. This downregulation affects both GluA2-containing and GluA2-lacking AMPARs mediating the SC, and is not accompanied by developmental changes in the GluA2 content of AMPARs underlying the FC. Thus, the downregulation of the SC appears to be independent of synaptic GluA2 expression, suggesting the involvement of another AMPAR subunit or an auxiliary protein. Our results therefore identify GluA2-dependent and GluA2-independent determinants of the SC: GluA2-lacking AMPARs preferentially contribute to the SC, while the developmental downregulation of the SC is independent of GluA2 content. PMID:26042027

  13. β-Sulfonamido Functionalized Aspartate Analogues as Excitatory Amino Acid Transporter Inhibitors: Distinct Subtype Selectivity Profiles Arising from Subtle Structural Differences.

    PubMed

    Hansen, Jacob C; Bjørn-Yoshimoto, Walden E; Bisballe, Niels; Nielsen, Birgitte; Jensen, Anders A; Bunch, Lennart

    2016-10-13

    In this study inspired by previous work on 3-substituted Asp analogues, we designed and synthesized a total of 32 β-sulfonamide Asp analogues and characterized their pharmacological properties at the excitatory amino acid transporter subtypes EAAT1, EAAT2, and EAAT3. In addition to several potent 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 that displayed an IC50 of 0.8 μM at EAAT1 with a 14- and 9-fold preference over EAAT2 and EAAT3, respectively. Conversely, the m-CF3-phenyl analogue 4r was a potent selective EAAT2-inhibitor (IC50 = 2.8 μM) exhibiting 30- and 50-fold selectivity over EAAT1 and EAAT3, respectively. In conclusion, even small structural differences in these β-sulfonamide Asp analogues provide analogues with diverse EAAT subtype selectivity profiles.

  14. Single-cell RNA sequencing identifies distinct mouse medial ganglionic eminence cell types

    PubMed Central

    Chen, Ying-Jiun J.; Friedman, Brad A.; Ha, Connie; Durinck, Steffen; Liu, Jinfeng; Rubenstein, John L.; Seshagiri, Somasekar; Modrusan, Zora

    2017-01-01

    Many subtypes of cortical interneurons (CINs) are found in adult mouse cortices, but the mechanism generating their diversity remains elusive. We performed single-cell RNA sequencing on the mouse embryonic medial ganglionic eminence (MGE), the major birthplace for CINs, and on MGE-like cells differentiated from embryonic stem cells. Two distinct cell types were identified as proliferating neural progenitors and immature neurons, both of which comprised sub-populations. Although lineage development of MGE progenitors was reconstructed and immature neurons were characterized as GABAergic, cells that might correspond to precursors of different CINs were not identified. A few non-neuronal cell types were detected, including microglia. In vitro MGE-like cells resembled bona fide MGE cells but expressed lower levels of Foxg1 and Epha4. Together, our data provide detailed understanding of the embryonic MGE developmental program and suggest how CINs are specified. PMID:28361918

  15. OCD in the perinatal period: is postpartum OCD (ppOCD) a distinct subtype? A review of the literature.

    PubMed

    McGuinness, Mary; Blissett, Jackie; Jones, Chris

    2011-05-01

    It has been suggested that the perinatal period is a period of increased risk for the development and/or exacerbation of OCD and that postpartum OCD (ppOCD) presents a distinct clinical picture. This raises the possibility that ppOCD might be a distinct subtype of OCD. This review examines this contention. A search using Ovid (Medline, PsycINFO and Embase), EBSCO, Cochrane Library, Web of Science (ISI), Pubmed databases and Google Scholar was carried out using the key words: "obsessive compulsive disorder" (and derivatives), "perinatal", "pregnancy", "postnatal", "postpartum", "mothers" (and derivatives), "anxiety disorders" and "subtypes." These articles and their references were reviewed. The majority of studies reviewed were retrospective, which makes it impossible to infer causality. Two prospective studies found a higher incidence of OCD in the postpartum period. These were carried out in Turkey and Brazil and, as such, may be limited in their applicability to other cultural groups. The concept of ppOCD as a specific subtype has not been robustly demonstrated. The evidence that OCD is more prevalent in the postpartum period is mixed. The evidence that OCD in the postpartum period presents a distinctive clinical picture with specific symptomatology and course is more compelling. In view of the impact of culture and religion on the expression of OCD, collaborative, international, prospective studies that take into account the methodological and definitional issues raised in this review are necessary to provide clarification. © British Association for Behavioural and Cognitive Psychotherapies 2011

  16. P16 and p53 play distinct roles in different subtypes of breast cancer.

    PubMed

    Shan, Ming; Zhang, Xianyu; Liu, Xiaolong; Qin, Yu; Liu, Tong; Liu, Yang; Wang, Ji; Zhong, Zhenbin; Zhang, Youxue; Geng, Jingshu; Pang, Da

    2013-01-01

    Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16(INK4a) and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up-regulated in the luminal-A of IDC (P<0.008). Triple-negative breast cancers were characterized by a correlation of p53 overexpression with a high level of p16 expression. Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction. Taken together, the present study suggest that p16 expression in luminal-A breast cancers is associated with their progression from DCIS to IDC, and both p53 and p16 expressions are important for the development of triple-negative breast cancers in DCIS and IDC.

  17. P16 and P53 Play Distinct Roles in Different Subtypes of Breast Cancer

    PubMed Central

    Liu, Xiaolong; Qin, Yu; Liu, Tong; Liu, Yang; Wang, Ji; Zhong, Zhenbin; Zhang, Youxue; Geng, Jingshu; Pang, Da

    2013-01-01

    Breast cancers are heterogeneous and complex diseases, and subtypes of breast cancers may involve unique molecular mechanisms. The p16INK4a and p53 pathways are two of the major pathways involved in control of the cell cycle. They also play key roles in tumorigenesis. However, whether the roles of these pathways differ in the subtypes of breast cancer is unclear. Therefore, p16 and p53 expression were investigated in different breast cancer subtypes to ascertain their contributions to these cancers. A total of 400 cases of non-invasive ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC), including the major molecular subtypes luminal-A, luminal-B, Her-2, and triple-negative subtypes, and 50 cases of normal controls were compared. Luminal-A cancers expressed the lowest level of p16 among the subtypes in DCIS, and the level of p16 expression was up-regulated in the luminal-A of IDC (P<0.008). Triple-negative breast cancers were characterized by a correlation of p53 overexpression with a high level of p16 expression. Luminal lesion types with high p16 expression in DCIS were found to be more likely to develop into aggressive breast cancers, possibly promoted by p53 dysfunction. Taken together, the present study suggest that p16 expression in luminal-A breast cancers is associated with their progression from DCIS to IDC, and both p53 and p16 expressions are important for the development of triple-negative breast cancers in DCIS and IDC. PMID:24146864

  18. Morphea subtypes are distinct autoimmune syndromes: A review of 245 adult and pediatric cases

    PubMed Central

    Leitenberger, Justin J.; Cayce, Rachael L.; Haley, Robert W.; Adams-Huet, Beverley; Bergstresser, Paul R.; Jacobe, Heidi T.

    2010-01-01

    Objective Morphea is associated with systemic manifestations and autoimmunity, but the prevalence of these findings remains unclear. With the goal of characterizing the frequency of these associations the prevalence of extra-cutaneous manifestations and autoimmunity in adult and pediatric morphea subjects was ascertained. Design A retrospective review of 245 morphea subjects. Settings The University of Texas Southwestern Medical Center Affiliated Institutions Patients or Other Participants Patients with clinical findings consistent with morphea. Intervention(s) None Main Outcome Measure(s) (a) prevalence of concomitant autoimmune diseases, (b) prevalence of familial autoimmune disease, (c) prevalence of extra-cutaneous manifestations, and (d) laboratory evidence of autoimmunity (ANA positivity). Secondary outcomes measures included demographic features. Results In this group, adults and children were affected nearly equally and African-Americans were affected less frequently than expected. The prevalence of concomitant autoimmunity in the generalized subtype of morphea was statistically significantly greater than that found in all other subtypes combined (P = 0.01). Frequency of a family history of autoimmune disease showed a trend in favor of generalized and mixed subgroups. The linear subtype showed a significant association with neurologic manifestations. While general systemic manifestations were most common in the generalized subtype. ANA positivity was most frequent in mixed and generalized subtypes. Conclusions High prevalence of concomitant and familial autoimmune disease, systemic manifestations, and ANA positivity in the generalized and possibly mixed subtypes suggest that these are systemic autoimmune syndromes and not skin only phenomena. This has implications for the management and treatment of these patients. PMID:19451498

  19. TCEB1-mutated Renal Cell Carcinoma: A Distinct Genomic and Morphologic Subtype

    PubMed Central

    Sarungbam, Judy; Sfakianos, John P; Sato, Yusuke; Morikawa, Teppei; Kume, Haruki; Fukayama, Masashi; Homma, Yukio; Chen, Ying-Bei; Sankin, Alexander; Mano, Roy; Coleman, Jonathan A; Russo, Paul; Ogawa, Seishi; Sander, Chris

    2014-01-01

    Integrated sequencing analysis identified a group of tumors among clear cell renal cell carcinomas characterized by hotspot mutations in TCEB1 (a gene that contributes to the VHL complex to ubiquitinate hypoxia inducible factor). We analyzed 11 tumors from two distinct cohorts with TCEB1 mutations along with an expanded cohort to assess whether these should be considered an entity distinct from clear cell renal cell carcinoma and clear cell papillary renal cell carcinoma. All tumors were characterized by hotspot mutations in TCEB1 Y79C/S/F/N or A100P. Morphologic and immunohistochemical characteristics of the tumors were assessed by two experienced genitourinary pathologists. Clinical and pathologic variables, copy number alterations, mutations and expression signatures were compared to a cohort of TCEB1 wild type tumors. All TCEB1 mutated tumors were VHL and PBRM1 wild type and contained distinct copy number profiles including loss of heterozygosity of chromosome 8, the location of TCEB1 (8q21.11). All tumors lacked the clear cell renal cell carcinoma signature 3p loss and contained distinct gene expression signatures. None of the clear cell papillary tumor harbored TCEB1 mutations. Pathologically, TCEB1-mutated tumors all shared characteristic features including thick fibromuscular bands transecting the tumor, pure clear cell cytology frequently with cells showing voluminous cytoplasm, clear cell renal cell carcinoma-like acinar areas associated with in-folding tubular and focally papillary architecture. The presence of voluminous cytoplasm, absence of luminal polarization of tumor nuclei and lack of extensive cup-like distribution of carbonic anhydrase IX expression distinguish it from clear cell papillary carcinoma. No patients had developed metastases at last follow-up (median 48 months). In sum, TCEB1-mutated renal cell carcinoma is a distinct entity with recurrent hotspot mutations, specific copy number alterations, pathway activation and characteristic

  20. Improved Methods to Identify Stable, Highly Heritable Subtypes of Opioid Use and Related Behaviors

    PubMed Central

    Sun, Jiangwen; Bi, Jinbo; Chan, Grace; Oslin, David; Farrer, Lindsay; Gelernter, Joel; Kranzler, Henry R.

    2012-01-01

    Although there is evidence that opioid dependence (OD) is heritable, efforts to identify genes contributing to risk for the disorder have been hampered by its complex etiology and variable clinical manifestations. Decomposition of a complex set of opioid users into homogeneous subgroups could enhance genetic analysis. We applied a series of data mining techniques, including multiple correspondence analysis, variable selection and cluster analysis, to 69 opioid-related measures from 5,390 subjects aggregated from family-based and case-control genetic studies to identify homogeneous subtypes and estimate their heritability. Novel aspects of this work include our use of 1) heritability estimates of specific clinical features of OD to enhance the heritability of the subtypes and 2) a k-medoids clustering method in combination with hierarchical clustering to yield replicable clusters that are less sensitive to noise than previous methods. We identified five homogeneous groups, including two large groups comprised of 762 and 1,353 heavy opioid users, with estimated heritability of 0.69 and 0.76, respectively. These methods represent a promising approach to the identification of highly heritable subtypes in complex, heterogeneous disorders. PMID:22694982

  1. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes

    PubMed Central

    Nakayama, Akiyoshi; Nakaoka, Hirofumi; Yamamoto, Ken; Sakiyama, Masayuki; Shaukat, Amara; Toyoda, Yu; Okada, Yukinori; Kamatani, Yoichiro; Nakamura, Takahiro; Takada, Tappei; Inoue, Katsuhisa; Yasujima, Tomoya; Yuasa, Hiroaki; Shirahama, Yuko; Nakashima, Hiroshi; Shimizu, Seiko; Higashino, Toshihide; Kawamura, Yusuke; Ogata, Hiraku; Kawaguchi, Makoto; Ohkawa, Yasuyuki; Danjoh, Inaho; Tokumasu, Atsumi; Ooyama, Keiko; Ito, Toshimitsu; Kondo, Takaaki; Wakai, Kenji; Stiburkova, Blanka; Pavelka, Karel; Stamp, Lisa K; Dalbeth, Nicola; Sakurai, Yutaka; Suzuki, Hiroshi; Hosoyamada, Makoto; Fujimori, Shin; Yokoo, Takashi; Hosoya, Tatsuo; Inoue, Ituro; Takahashi, Atsushi; Kubo, Michiaki; Ooyama, Hiroshi; Shimizu, Toru; Ichida, Kimiyoshi; Shinomiya, Nariyoshi; Merriman, Tony R; Matsuo, Hirotaka

    2017-01-01

    Objective A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Methods Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. Results In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10−8): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (pmeta=3.58×10−8). Conclusions Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia. PMID:27899376

  2. Subtypes of attention-deficit/hyperactivity disorder (ADHD): distinct or related disorders across measurement levels?

    PubMed

    Baeyens, Dieter; Roeyers, Herbert; Walle, Johan Vande

    2006-01-01

    The aim of this literature review is to assess the current state of knowledge regarding differences and similarities between the inattentive (IA) and combined (C) subtypes of Attention-Deficit/Hyperactivity Disorder (ADHD) in order to detail challenges concerning further conceptualization, diagnostics, and treatment. The literature on ADHD-IA and ADHD-C was reviewed and contrasted across genetic, neuroanatomical, neurophysiological/ neurochemical, neuro(psycho)logical, and clinical psychiatric measurement levels. It was found that the more fundamental the measurement level, the less unambiguous evidence is found for subtype differences. Only on the clinical psychiatric diagnostic level, do more or less clear-cut differences in cognitive, social, academic, and behavioural functioning emerge. In conclusion, fundamental research that compares ADHD-IA and ADHD-C is relatively rare. At this point, only irrefutable phenomenological evidence of subtype differences seems to be available, even in attention problems which are presumed to be identical. The question as to whether both subtypes should be considered as two independent disorders was not adequately resolved.

  3. New Stx2e monoclonal antibodies for immunological detection and distinction of Stx2 subtypes

    USDA-ARS?s Scientific Manuscript database

    Background Stx2e is a primary virulence factor in STEC strains that cause edema disease in neonatal piglets. Though Stx2a and Stx2e are similar, most antibody-based Stx detection kits are designed to detect Stx2a and do not recognize the Stx2e subtype. Methods and Findings Four monoclonal antibodie...

  4. COPD subtypes identified by network-based clustering of blood gene expression

    PubMed Central

    Chang, Yale; Glass, Kimberly; Liu, Yang-Yu; Silverman, Edwin K.; Crapo, James D.; Tal-Singer, Ruth; Bowler, Russ; Dy, Jennifer; Cho, Michael; Castaldi, Peter

    2016-01-01

    One of the most common smoking-related diseases, chronic obstructive pulmonary disease (COPD), results from a dysregulated, multi-tissue inflammatory response to cigarette smoke. We hypothesized that systemic inflammatory signals in genome-wide blood gene expression can identify clinically important COPD-related disease subtypes, and we leveraged pre-existing gene interaction networks to guide unsupervised clustering of blood microarray expression data. Using network-informed non-negative matrix factorization, we analyzed genome-wide blood gene expression from 229 former smokers in the ECLIPSE Study, and we identified novel, clinically relevant molecular subtypes of COPD. These network-informed clusters were more stable and more strongly associated with measures of lung structure and function than clusters derived from a network-naïve approach, and they were associated with subtype-specific enrichment for inflammatory and protein catabolic pathways. These clusters were successfully reproduced in an independent sample of 135 smokers from the COPDGene Study. PMID:26773458

  5. Identifying three different architectural subtypes of mammary ductal carcinoma in situ using multiphoton microscopy

    NASA Astrophysics Data System (ADS)

    Wu, Yan; Fu, Fangmeng; Lian, Yuane; Nie, Yuting; Zhuo, shuangmu; Wang, Chuan; Chen, Jianxin

    2015-10-01

    Ductal carcinoma in situ (DCIS) is often considered as the precursor of invasive breast cancer, and the risk of DCIS progression to IBC has been estimated based on the evaluation of pathological features, among which the architectural subtype is the most common one. In this study, multiphoton microscopy (MPM) is applied to identify three different architectural subtypes of DCIS (solid, cribriform and comedo). It is found that MPM has the capability to visualize the proliferating pattern of tumor cells, the presence of intraluminal necrosis and the morphology of basement membrane, which are all taken into account in subtyping DCIS. In addition, MPM also can be used to quantify the cellular metabolism, for quantitatively identifying tumor staging during tumor progression. This result highlights the potential of MPM as an advanced technique to assess the pathological characters of the breast tumor in real-time and reflect the degree of tumor progression in vivo, by integrating into the intra-fiberoptic ductoscopy or transdermal biopsy needle.

  6. TP53 mutation spectrum in breast cancer is subtype specific and has distinct prognostic relevance.

    PubMed

    Silwal-Pandit, Laxmi; Vollan, Hans Kristian Moen; Chin, Suet-Feung; Rueda, Oscar M; McKinney, Steven; Osako, Tomo; Quigley, David A; Kristensen, Vessela N; Aparicio, Samuel; Børresen-Dale, Anne-Lise; Caldas, Carlos; Langerød, Anita

    2014-07-01

    In breast cancer, the TP53 gene is frequently mutated and the mutations have been associated with poor prognosis. The prognostic impact of the different types of TP53 mutations across the different molecular subtypes is still poorly understood. Here, we characterize the spectrum and prognostic significance of TP53 mutations with respect to the PAM50 subtypes and integrative clusters (IC). TP53 mutation status was obtained for 1,420 tumor samples from the METABRIC cohort by sequencing all coding exons using the Sanger method. TP53 mutations were found in 28.3% of the tumors, conferring a worse overall and breast cancer-specific survival [HR = 2.03; 95% confidence interval (CI), 1.65-2.48, P < 0.001], and were also found to be an independent marker of poor prognosis in estrogen receptor-positive cases (HR = 1.86; 95% CI, 1.39-2.49, P < 0.001). The mutation spectrum of TP53 varied between the breast cancer subtypes, and individual alterations showed subtype-specific association. TP53 mutations were associated with increased mortality in patients with luminal B, HER2-enriched, and normal-like tumors, but not in patients with luminal A and basal-like tumors. Similar observations were made in ICs, where mutation associated with poorer outcome in IC1, IC4, and IC5. The combined effect of TP53 mutation, TP53 LOH, and MDM2 amplification on mortality was additive. This study reveals that TP53 mutations have different clinical relevance in molecular subtypes of breast cancer, and suggests diverse roles for TP53 in the biology underlying breast cancer development. ©2014 American Association for Cancer Research.

  7. Different disease subtypes with distinct clinical expression in familial Mediterranean fever: results of a cluster analysis.

    PubMed

    Akar, Servet; Solmaz, Dilek; Kasifoglu, Timucin; Bilge, Sule Yasar; Sari, Ismail; Gumus, Zeynep Zehra; Tunca, Mehmet

    2016-02-01

    The aim of this study was to evaluate whether there are clinical subgroups that may have different prognoses among FMF patients. The cumulative clinical features of a large group of FMF patients [1168 patients, 593 (50.8%) male, mean age 35.3 years (s.d. 12.4)] were studied. To analyse our data and identify groups of FMF patients with similar clinical characteristics, a two-step cluster analysis using log-likelihood distance measures was performed. For clustering the FMF patients, we evaluated the following variables: gender, current age, age at symptom onset, age at diagnosis, presence of major clinical features, variables related with therapy and family history for FMF, renal failure and carriage of M694V. Three distinct groups of FMF patients were identified. Cluster 1 was characterized by a high prevalence of arthritis, pleuritis, erysipelas-like erythema (ELE) and febrile myalgia. The dosage of colchicine and the frequency of amyloidosis were lower in cluster 1. Patients in cluster 2 had an earlier age of disease onset and diagnosis. M694V carriage and amyloidosis prevalence were the highest in cluster 2. This group of patients was using the highest dose of colchicine. Patients in cluster 3 had the lowest prevalence of arthritis, ELE and febrile myalgia. The frequencies of M694V carriage and amyloidosis were lower in cluster 3 than the overall FMF patients. Non-response to colchicine was also slightly lower in cluster 3. Patients with FMF can be clustered into distinct patterns of clinical and genetic manifestations and these patterns may have different prognostic significance. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  8. Modeling distinct osteosarcoma subtypes in vivo using Cre:lox and lineage-restricted transgenic shRNA.

    PubMed

    Mutsaers, Anthony J; Ng, Alvin J M; Baker, Emma K; Russell, Megan R; Chalk, Alistair M; Wall, Meaghan; Liddicoat, Brain J J; Ho, Patricia W M; Slavin, John L; Goradia, Ankita; Martin, T John; Purton, Louise E; Dickins, Ross A; Walkley, Carl R

    2013-07-01

    Osteosarcoma is the most common primary cancer of bone and one that predominantly affects children and adolescents. Osteoblastic osteosarcoma represents the major subtype of this tumor, with approximately equal representation of fibroblastic and chondroblastic subtypes. We and others have previously described murine models of osteosarcoma based on osteoblast-restricted Cre:lox deletion of Trp53 (p53) and Rb1 (Rb), resulting in a phenotype most similar to fibroblastic osteosarcoma in humans. We now report a model of the most prevalent form of human osteosarcoma, the osteoblastic subtype. In contrast to other osteosarcoma models that have used Cre:lox mediated gene deletion, this model was generated through shRNA-based knockdown of p53. As is the case with the human disease the shRNA tumors most frequently present in the long bones and preferentially disseminate to the lungs; feature less consistently modeled using Cre:lox approaches. Our approach allowed direct comparison of the in vivo consequences of targeting the same genetic drivers using two different technologies, Cre:lox and shRNA. This demonstrated that the effects of Cre:lox and shRNA mediated knock-down are qualitatively different, at least in the context of osteosarcoma, and yielded distinct subtypes of osteosarcoma. Through the use of complementary genetic modification strategies we have established a model of the most common clinical subtype of osteosarcoma that was not previously represented and more fully recapitulated the clinical spectrum of this cancer. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2

    PubMed Central

    Poirier, John T.; Gardner, Eric E.; Connis, Nick; Moreira, Andre L.; de Stanchina, Elisa; Hann, Christine L.; Rudin, Charles M.

    2015-01-01

    Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy, and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDXs) and cell lines at single nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, while PDXs maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth. PMID:25746006

  10. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2.

    PubMed

    Poirier, J T; Gardner, E E; Connis, N; Moreira, A L; de Stanchina, E; Hann, C L; Rudin, C M

    2015-11-26

    Small cell lung cancer (SCLC) is an aggressive malignancy characterized by early metastasis, rapid development of resistance to chemotherapy and genetic instability. This study profiles DNA methylation in SCLC, patient-derived xenografts (PDX) and cell lines at single-nucleotide resolution. DNA methylation patterns of primary samples are distinct from those of cell lines, whereas PDX maintain a pattern closely consistent with primary samples. Clustering of DNA methylation and gene expression of primary SCLC revealed distinct disease subtypes among histologically indistinguishable primary patient samples with similar genetic alterations. SCLC is notable for dense clustering of high-level methylation in discrete promoter CpG islands, in a pattern clearly distinct from other lung cancers and strongly correlated with high expression of the E2F target and histone methyltransferase gene EZH2. Pharmacologic inhibition of EZH2 in a SCLC PDX markedly inhibited tumor growth.

  11. A Three-Gene Model to Robustly Identify Breast Cancer Molecular Subtypes

    PubMed Central

    Desmedt, Christine; Loi, Sherene; Culhane, Aedin C.; Bontempi, Gianluca; Quackenbush, John; Sotiriou, Christos

    2012-01-01

    Background Single sample predictors (SSPs) and Subtype classification models (SCMs) are gene expression–based classifiers used to identify the four primary molecular subtypes of breast cancer (basal-like, HER2-enriched, luminal A, and luminal B). SSPs use hierarchical clustering, followed by nearest centroid classification, based on large sets of tumor-intrinsic genes. SCMs use a mixture of Gaussian distributions based on sets of genes with expression specifically correlated with three key breast cancer genes (estrogen receptor [ER], HER2, and aurora kinase A [AURKA]). The aim of this study was to compare the robustness, classification concordance, and prognostic value of these classifiers with those of a simplified three-gene SCM in a large compendium of microarray datasets. Methods Thirty-six publicly available breast cancer datasets (n = 5715) were subjected to molecular subtyping using five published classifiers (three SSPs and two SCMs) and SCMGENE, the new three-gene (ER, HER2, and AURKA) SCM. We used the prediction strength statistic to estimate robustness of the classification models, defined as the capacity of a classifier to assign the same tumors to the same subtypes independently of the dataset used to fit it. We used Cohen κ and Cramer V coefficients to assess concordance between the subtype classifiers and association with clinical variables, respectively. We used Kaplan–Meier survival curves and cross-validated partial likelihood to compare prognostic value of the resulting classifications. All statistical tests were two-sided. Results SCMs were statistically significantly more robust than SSPs, with SCMGENE being the most robust because of its simplicity. SCMGENE was statistically significantly concordant with published SCMs (κ = 0.65–0.70) and SSPs (κ = 0.34–0.59), statistically significantly associated with ER (V = 0.64), HER2 (V = 0.52) status, and histological grade (V = 0.55), and yielded similar strong prognostic value. Conclusion

  12. Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex.

    PubMed

    Luo, Chongyuan; Keown, Christopher L; Kurihara, Laurie; Zhou, Jingtian; He, Yupeng; Li, Junhao; Castanon, Rosa; Lucero, Jacinta; Nery, Joseph R; Sandoval, Justin P; Bui, Brian; Sejnowski, Terrence J; Harkins, Timothy T; Mukamel, Eran A; Behrens, M Margarita; Ecker, Joseph R

    2017-08-11

    The mammalian brain contains diverse neuronal types, yet we lack single-cell epigenomic assays that are able to identify and characterize them. DNA methylation is a stable epigenetic mark that distinguishes cell types and marks regulatory elements. We generated >6000 methylomes from single neuronal nuclei and used them to identify 16 mouse and 21 human neuronal subpopulations in the frontal cortex. CG and non-CG methylation exhibited cell type-specific distributions, and we identified regulatory elements with differential methylation across neuron types. Methylation signatures identified a layer 6 excitatory neuron subtype and a unique human parvalbumin-expressing inhibitory neuron subtype. We observed stronger cross-species conservation of regulatory elements in inhibitory neurons than in excitatory neurons. Single-nucleus methylomes expand the atlas of brain cell types and identify regulatory elements that drive conserved brain cell diversity. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  13. New Stx2e Monoclonal Antibodies for Immunological Detection and Distinction of Stx2 Subtypes

    PubMed Central

    Skinner, Craig; Patfield, Stephanie; Hernlem, Bradley J.; He, Xiaohua

    2015-01-01

    Background Stx2e is a primary virulence factor in STEC strains that cause edema disease in neonatal piglets. Though Stx2a and Stx2e are similar, many antibody-based Stx detection kits are designed to detect Stx2a and do not recognize the Stx2e subtype. Methods and Findings Four monoclonal antibodies against Stx2e were developed and characterized. Two of these mAbs recognize the B subunit of Stx2e, Stx2f, and to a lesser extent, Stx2b, Stx2c, and Stx2d. The other two mAbs recognize the A subunit of Stx2e, and cross-react with all Stx2 subtypes except Stx2f. The most sensitive sandwich ELISA using these mAbs has a limit of detection for Stx2e of 11.8 pg/mL. The ability of the neutralizing antibody Stx2e-2 to block Stx2e-receptor binding in Vero cells was visualized using immunofluorescence. Combinations of these and previously developed mAbs permit ELISA-based differentiation between closely related Stx2a, Stx2c, and Stx2d (using mAbs Stx2-5/2-1, Stx2-5/2e-2, and Stx2e-3/2e-2, respectively). Conclusions The sensitive immunoassays developed in this study should augment our capacity to detect Stx2e in porcine environments and biological samples. Moreover, immunoassays that can distinguish between the closely related Stx2a, Stx2c, and Stx2d subtypes can be useful in quickly analyzing Stx subtypes in samples containing more than one strain of STEC. PMID:26192407

  14. Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration

    PubMed Central

    Peng, Yu-Ching; Levine, Charles M.; Zahid, Sarwar; Wilson, E. Lynette; Joyner, Alexandra L.

    2013-01-01

    The adult mouse prostate has a seemingly endless capacity for regeneration, and sonic hedgehog (SHH) signaling has been implicated in this stem cell-driven process. However, it is not clear whether SHH acts on the epithelium or stromal cells that secrete factors required for epithelial expansion. Because little is known about stromal stem cells compared with their epithelial counterparts, we used in vivo mouse genetics tools to characterize four prostate stromal subtypes and their stem cells. Using knockin reporter alleles, we uncovered that SHH signals from prostate basal epithelial cells to adjacent stromal cells. Furthermore, the SHH target gene Gli1 is preferentially expressed in subepithelial fibroblast-like cells, one of four prostate stromal subtypes and the subtype closest to the epithelial source of SHH. Using Genetic Inducible Fate Mapping to mark adult Gli1- or Smooth muscle actin-expressing cells and follow their fate during regeneration, we uncovered that Gli1-expressing cells exhibit long-term self-renewal capacity during multiple rounds of androgen-mediated regeneration after castration-induced involution, and depleted smooth muscle cells are mainly replenished by preexisting smooth muscle cells. Based on our Genetic Inducible Fate Mapping studies, we propose a model where SHH signals to multiple stromal stem cells, which are largely unipotent in vivo. PMID:24218555

  15. Ctip1 regulates the balance between specification of distinct projection neuron subtypes in deep cortical layers

    PubMed Central

    Woodworth, Mollie B.; Greig, Luciano C.; Liu, Kevin X.; Ippolito, Gregory C.; Tucker, Haley O.; Macklis, Jeffrey D.

    2016-01-01

    SUMMARY The molecular linkage between neocortical projection neuron subtype and area development, which enables the establishment of functional areas by projection neuron populations appropriate for specific sensory and motor functions, is poorly understood. Here, we report that Ctip1 controls precision of neocortical development by regulating subtype identity in deep-layer projection neurons. Ctip1 is expressed by postmitotic callosal and corticothalamic projection neurons, but is excluded over embryonic development from corticospinal motor neurons, which instead express its close relative, Ctip2. Loss of Ctip1 function results in a striking bias in favor of subcerebral projection neuron development in sensory cortex at the expense of corticothalamic and deep-layer callosal development, while misexpression of Ctip1 in vivo represses subcerebral gene expression and projections. As we report in a paired paper, Ctip1 also controls acquisition of sensory area identity. Therefore, Ctip1 couples subtype and area specification, enabling specific functional areas to organize precise ratios of appropriate output projections. PMID:27117402

  16. Intimate partner violence perpetration by court-ordered men: distinctions among subtypes of physical violence, sexual violence, psychological abuse, and stalking.

    PubMed

    Hall, Jeffrey E; Walters, Mikel L; Basile, Kathleen C

    2012-05-01

    This study continues previous work documenting the structure of violence perpetrated by males against their female intimate partners. It assesses the construct validity of a measurement model depicting associations among eight subtypes of perpetration: moderate physical violence, severe physical violence, forced or coerced sexual violence, sexual violence where consent was not possible, emotional/verbal psychological abuse, dominance/isolation psychological abuse, interactional contacts/surveillance related stalking, and stalking involving mediated contacts. Data were obtained from a sample of 340 men arrested for physical assault of a female spouse or partner, and court ordered into batterer intervention programs. Men were surveyed before starting the intervention. Confirmatory factor analyses (CFA) supported the validity of model as evidenced by good model to data fit and satisfaction of requirements for fit statistics. In addition, the eight factor solution was characterized by a slightly better model to data fit than a four factor higher order solution described in the author's previous work. Latent variable correlations across the broader categories of intimate partner violence (IPV) revealed that the violence subtypes were mostly moderately positively correlated and ranged from .381 (emotional/verbal psychological abuse with interactional contacts/surveillance related stalking) to .795 (dominance/isolation psychological with abuse with forced sex). Future studies should determine whether there are distinct risk factors and health outcomes associated with each of the eight IPV perpetration subtypes and identify possible patterns of co-occurrence.

  17. Differential expression of neurogenes among breast cancer subtypes identifies high risk patients

    PubMed Central

    Fernández-Nogueira, Patricia; Bragado, Paloma; Almendro, Vanessa; Ametller, Elisabet; Rios, Jose; Choudhury, Sibgat

    2016-01-01

    The nervous system is now recognized to be a relevant component of the tumor microenvironment. Receptors for neuropeptides and neurotransmitters have been identified in breast cancer. However, very little is known about the role of neurogenes in regulating breast cancer progression. Our purpose was to identify neurogenes associated with breast cancer tumorigenesis with a potential to be used as biomarker and/or targets for treatment. We used three databases of human genes: GeneGo, GeneCards and Eugenes to generate a list of 1266 relevant neurogenes. Then we used bioinformatics tools to interrogate two published breast cancer databases SAGE and MicMa (n=96) and generated a list of 7 neurogenes that are differentially express among breast cancer subtypes. The clinical potential was further investigated using the GOBO database (n=1881). We identified 6 neurogenes that are differentially expressed among breast cancer subtypes and whose expression correlates with prognosis. Histamine receptor1 (HRH1), neuropilin2 (NRP2), ephrin-B1 (EFNB1), neural growth factor receptor (NGFR) and amyloid precursor protein (APP) were differentially overexpressed in basal and HER2-enriched tumor samples and syntaxin 1A (STX1A) was overexpressed in HER2-enriched and luminal B tumors. Analysis of HRH1, NRP2, and STX1A expression using the GOBO database showed that their expression significantly correlated with a shorter overall survival (p < 0.0001) and distant metastasis-free survival (p < 0.0001). In contrast, elevated co-expression of NGFR, EFNB1 and APP was associated with longer overall (p < 0.0001) and metastasis-free survival (p < 0.0001). We propose that HRH1, NRP2, and STX1A can be used as prognostic biomarkers and therapeutic targets for basal and HER2-enriched breast cancer subtypes. PMID:26673618

  18. Parkinson's Disease Subtypes Identified from Cluster Analysis of Motor and Non-motor Symptoms.

    PubMed

    Mu, Jesse; Chaudhuri, Kallol R; Bielza, Concha; de Pedro-Cuesta, Jesus; Larrañaga, Pedro; Martinez-Martin, Pablo

    2017-01-01

    Parkinson's disease is now considered a complex, multi-peptide, central, and peripheral nervous system disorder with considerable clinical heterogeneity. Non-motor symptoms play a key role in the trajectory of Parkinson's disease, from prodromal premotor to end stages. To understand the clinical heterogeneity of Parkinson's disease, this study used cluster analysis to search for subtypes from a large, multi-center, international, and well-characterized cohort of Parkinson's disease patients across all motor stages, using a combination of cardinal motor features (bradykinesia, rigidity, tremor, axial signs) and, for the first time, specific validated rater-based non-motor symptom scales. Two independent international cohort studies were used: (a) the validation study of the Non-Motor Symptoms Scale (n = 411) and (b) baseline data from the global Non-Motor International Longitudinal Study (n = 540). k-means cluster analyses were performed on the non-motor and motor domains (domains clustering) and the 30 individual non-motor symptoms alone (symptoms clustering), and hierarchical agglomerative clustering was performed to group symptoms together. Four clusters are identified from the domains clustering supporting previous studies: mild, non-motor dominant, motor-dominant, and severe. In addition, six new smaller clusters are identified from the symptoms clustering, each characterized by clinically-relevant non-motor symptoms. The clusters identified in this study present statistical confirmation of the increasingly important role of non-motor symptoms (NMS) in Parkinson's disease heterogeneity and take steps toward subtype-specific treatment packages.

  19. GWAS of clinically defined gout and subtypes identifies multiple susceptibility loci that include urate transporter genes.

    PubMed

    Nakayama, Akiyoshi; Nakaoka, Hirofumi; Yamamoto, Ken; Sakiyama, Masayuki; Shaukat, Amara; Toyoda, Yu; Okada, Yukinori; Kamatani, Yoichiro; Nakamura, Takahiro; Takada, Tappei; Inoue, Katsuhisa; Yasujima, Tomoya; Yuasa, Hiroaki; Shirahama, Yuko; Nakashima, Hiroshi; Shimizu, Seiko; Higashino, Toshihide; Kawamura, Yusuke; Ogata, Hiraku; Kawaguchi, Makoto; Ohkawa, Yasuyuki; Danjoh, Inaho; Tokumasu, Atsumi; Ooyama, Keiko; Ito, Toshimitsu; Kondo, Takaaki; Wakai, Kenji; Stiburkova, Blanka; Pavelka, Karel; Stamp, Lisa K; Dalbeth, Nicola; Sakurai, Yutaka; Suzuki, Hiroshi; Hosoyamada, Makoto; Fujimori, Shin; Yokoo, Takashi; Hosoya, Tatsuo; Inoue, Ituro; Takahashi, Atsushi; Kubo, Michiaki; Ooyama, Hiroshi; Shimizu, Toru; Ichida, Kimiyoshi; Shinomiya, Nariyoshi; Merriman, Tony R; Matsuo, Hirotaka

    2017-05-01

    A genome-wide association study (GWAS) of gout and its subtypes was performed to identify novel gout loci, including those that are subtype-specific. Putative causal association signals from a GWAS of 945 clinically defined gout cases and 1213 controls from Japanese males were replicated with 1396 cases and 1268 controls using a custom chip of 1961 single nucleotide polymorphisms (SNPs). We also first conducted GWASs of gout subtypes. Replication with Caucasian and New Zealand Polynesian samples was done to further validate the loci identified in this study. In addition to the five loci we reported previously, further susceptibility loci were identified at a genome-wide significance level (p<5.0×10(-8)): urate transporter genes (SLC22A12 and SLC17A1) and HIST1H2BF-HIST1H4E for all gout cases, and NIPAL1 and FAM35A for the renal underexcretion gout subtype. While NIPAL1 encodes a magnesium transporter, functional analysis did not detect urate transport via NIPAL1, suggesting an indirect association with urate handling. Localisation analysis in the human kidney revealed expression of NIPAL1 and FAM35A mainly in the distal tubules, which suggests the involvement of the distal nephron in urate handling in humans. Clinically ascertained male patients with gout and controls of Caucasian and Polynesian ancestries were also genotyped, and FAM35A was associated with gout in all cases. A meta-analysis of the three populations revealed FAM35A to be associated with gout at a genome-wide level of significance (p meta =3.58×10(-8)). Our findings including novel gout risk loci provide further understanding of the molecular pathogenesis of gout and lead to a novel concept for the therapeutic target of gout/hyperuricaemia. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Tubulocystic carcinoma of the kidney: clinicopathologic analysis of 31 cases of a distinctive rare subtype of renal cell carcinoma.

    PubMed

    Amin, Mahul B; MacLennan, Gregory T; Gupta, Ruta; Grignon, David; Paraf, Francois; Vieillefond, Annick; Paner, Gladell P; Stovsky, Mark; Young, Andrew N; Srigley, John R; Cheville, John C

    2009-03-01

    A distinctive tumor described under the terms Bellini duct carcinoma and low-grade collecting duct carcinoma has been referred to by us and others as tubulocystic carcinoma. This renal cell carcinoma subtype is not recognized in the World Health Organization 2004 classification. Herein, we present a detailed study of 31 cases to further characterize this rare subtype of renal cell carcinoma. The tumor occurred in adults (mean age, 54 years) with a strong male predominance (7:1). Grossly, the tumors ranged from 0.7 to 17 cm, and exhibited a spongy or "bubble wrap" appearance reflecting the microscopic presence of variably sized cystically dilated tubules lined by a single layer of epithelium. The lining varied with a cuboidal, flat, and hobnail cell appearance, and the neoplastic cells had abundant eosinophilic cytoplasm and enlarged nuclei with prominent nucleoli. The cysts were closely spaced with an intervening variably fibrotic stroma. Immunohistochemistry and ultrastructural examination showed features of proximal convoluted tubules (Pax 2 immunoreactivity and short microvilli with brush border organization) and distal nephron (kidney-specific cadherin immunoreactivity and cytoplasmic interdigitation). Gene expression profiling showed that tubulocystic carcinoma displayed a unique molecular signature. Twenty-four tumors were stage pT1, 4 stage pT2, and 3 stage pT3. Disease progression (median follow-up of 56 months) occurred in 3 patients; 1 with local recurrence, and 2 with distant metastasis to bone and liver. In light of the distinctive clinicopathologic features and a low but definite metastatic potential, this unique subtype of renal cell carcinoma deserves formal recognition in the contemporary classification of renal neoplasms.

  1. Genomic analysis of hepatoblastoma identifies distinct molecular and prognostic subgroups.

    PubMed

    Sumazin, Pavel; Chen, Yidong; Treviño, Lisa R; Sarabia, Stephen F; Hampton, Oliver A; Patel, Kayuri; Mistretta, Toni-Ann; Zorman, Barry; Thompson, Patrick; Heczey, Andras; Comerford, Sarah; Wheeler, David A; Chintagumpala, Murali; Meyers, Rebecka; Rakheja, Dinesh; Finegold, Milton J; Tomlinson, Gail; Parsons, D Williams; López-Terrada, Dolores

    2017-01-01

    Despite being the most common liver cancer in children, hepatoblastoma (HB) is a rare neoplasm. Consequently, few pretreatment tumors have been molecularly profiled, and there are no validated prognostic or therapeutic biomarkers for HB patients. We report on the first large-scale effort to profile pretreatment HBs at diagnosis. Our analysis of 88 clinically annotated HBs revealed three risk-stratifying molecular subtypes that are characterized by differential activation of hepatic progenitor cell markers and metabolic pathways: high-risk tumors were characterized by up-regulated nuclear factor, erythroid 2-like 2 activity; high lin-28 homolog B, high mobility group AT-hook 2, spalt-like transcription factor 4, and alpha-fetoprotein expression; and high coordinated expression of oncofetal proteins and stem-cell markers, while low-risk tumors had low lin-28 homolog B and lethal-7 expression and high hepatic nuclear factor 1 alpha activity.

  2. Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach

    PubMed Central

    Scott, Milcah C.; Sarver, Aaron L.; Gavin, Katherine J.; Thayanithy, Venugopal; Getzy, David M.; Newman, Robert A.; Cutter, Gary R.; Lindblad-Toh, Kerstin; Kisseberth, William C.; Hunter, Lawrence E.; Subramanian, Subbaya; Breen, Matthew; Modiano, Jaime F.

    2011-01-01

    The heterogeneous and chaotic nature of osteosarcoma has confounded accurate molecular classification, prognosis, and prediction for this tumor. The occurrence of spontaneous osteosarcoma is largely confined to humans and dogs. While the clinical features are remarkably similar in both species, the organization of dogs into defined breeds provides a more homogeneous genetic background that may increase the likelihood to uncover molecular subtypes for this complex disease. We thus hypothesized that molecular profiles derived from canine osteosarcoma would aid in molecular subclassification of this disease when applied to humans. To test the hypothesis, we performed genome wide gene expression profiling in a cohort of dogs with osteosarcoma, primarily from high-risk breeds. To further reduce inter-sample heterogeneity, we assessed tumor-intrinsic properties through use of an extensive panel of osteosarcoma-derived cell lines. We observed strong differential gene expression that segregated samples into two groups with differential survival probabilities. Groupings were characterized by the inversely correlated expression of genes associated with G2/M transition and DNA damage checkpoint and microenvironment-interaction categories. This signature was preserved in data from whole tumor samples of three independent dog osteosarcoma cohorts, with stratification into the two expected groups. Significantly, this restricted signature partially overlapped a previously defined, predictive signature for soft tissue sarcomas, and it unmasked orthologous molecular subtypes and their corresponding natural histories in five independent data sets from human patients with osteosarcoma. Our results indicate that the narrower genetic diversity of dogs can be utilized to group complex human osteosarcoma into biologically and clinically relevant molecular subtypes. This in turn may enhance prognosis and prediction, and identify relevant therapeutic targets. PMID:21621658

  3. Activity of distinct growth factor receptor network components in breast tumors uncovers two biologically relevant subtypes.

    PubMed

    Rahman, Mumtahena; MacNeil, Shelley M; Jenkins, David F; Shrestha, Gajendra; Wyatt, Sydney R; McQuerry, Jasmine A; Piccolo, Stephen R; Heiser, Laura M; Gray, Joe W; Johnson, W Evan; Bild, Andrea H

    2017-04-26

    The growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns. Novel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection and InteGratioN (ASSIGN) was used to estimate pathway activity for GFRN components in 1119 breast tumors from The Cancer Genome Atlas (TCGA) and across 55 breast cancer cell lines from the Integrative Cancer Biology Program (ICBP43). These signatures were investigated for their relationship to pro- and anti-apoptotic protein expression and drug response in breast cancer cell lines. Application of these signatures to breast tumor gene expression data identified two novel discrete phenotypes characterized by concordant, aberrant activation of either the HER2, IGF1R, and AKT pathways ("the survival phenotype") or the EGFR, KRAS (G12V), RAF1, and BAD pathways ("the growth phenotype"). These phenotypes described a significant amount of the variability in the total expression data across breast cancer tumors and characterized distinctive patterns in apoptosis evasion and drug response. The growth phenotype expressed lower levels of BIM and higher levels of MCL-1 proteins. Further, the growth phenotype was more sensitive to common chemotherapies and targeted therapies directed at EGFR and MEK. Alternatively, the survival phenotype was more sensitive to drugs inhibiting HER2, PI3K, AKT, and mTOR, but more resistant to chemotherapies. Gene expression profiling revealed a bifurcation pattern

  4. The oxytocin/vasopressin receptor family has at least five members in the gnathostome lineage, inclucing two distinct V2 subtypes.

    PubMed

    Ocampo Daza, Daniel; Lewicka, Michalina; Larhammar, Dan

    2012-01-01

    The vertebrate oxytocin and vasopressin receptors form a family of G-protein-coupled receptors (GPCRs) that mediate a large variety of functions, including social behavior and the regulation of blood pressure, water balance and reproduction. In mammals four family members have been identified, three of which respond to vasopressin (VP) named V1A, V1B and V2, and one of which is activated by oxytocin (OT), called the OT receptor. Four receptors have been identified in chicken as well, but these have received different names. Until recently only V1-type receptors have been described in several species of teleost fishes. We have identified family members in several gnathostome genomes and performed phylogenetic analyses to classify OT/VP-receptors across species and determine orthology relationships. Our phylogenetic tree identifies five distinct ancestral gnathostome receptor subtypes in the OT/VP receptor family: V1A, V1B, V2A, V2B and OT receptors. The existence of distinct V2A and V2B receptors has not been previously recognized. We have found these two subtypes in all examined teleost genomes as well as in available frog and lizard genomes and conclude that the V2A-type is orthologous to mammalian V2 receptors whereas the V2B-type is orthologous to avian V2 receptors. Some teleost fishes have acquired additional and more recent gene duplicates with up to eight receptor family members. Thus, this analysis reveals an unprecedented complexity in the gnathostome repertoire of OT/VP receptors, opening interesting research avenues regarding functions such as regulation of water balance, reproduction and behavior, particularly in reptiles, amphibians, teleost fishes and cartilaginous fishes. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. New avian influenza A virus subtype combination H5N7 identified in Danish mallard ducks.

    PubMed

    Bragstad, K; Jørgensen, P H; Handberg, K J; Mellergaard, S; Corbet, S; Fomsgaard, A

    2005-05-01

    During the past years increasing incidences of influenza A zoonosis have made it of uppermost importance to possess methods for rapid and precise identification and characterisation of influenza A viruses. We present here a convenient one-step RT-PCR method that will amplify full-length haemagglutinin (HA) and neuraminidase (NA) directly from clinical samples and from all known subtypes of influenza A. We applied the method on samples collected in September 2003 from a Danish flock of mallards with general health problems and by this a previously undescribed influenza A subtype combination, H5N7, was identified. The HA gene showed great sequence similarity to the highly pathogenic avian influenza A virus (HPAIV) A/Chicken/Italy/312/97 (H5N2); however, the cleavage site sequence between HA1 and HA2 had a motif typical for low pathogenic avian influenza viruses (LPAIV). The full-length NA sequence was most closely related to the HPAIV A/Chicken/Netherlands/01/03 (H7N7) that infected chickens and humans in the Netherlands in 2003. Ten persons with direct or indirect contact with the Danish mallard ducks showed signs of influenza-like illness 2-3 days following the killing of the ducks, but no evidence of influence infections was detected. To our knowledge this is the first report of an H5N7 influenza A virus.

  6. Integration of electrophysiological recordings with single-cell RNA-seq data identifies neuronal subtypes.

    PubMed

    Fuzik, János; Zeisel, Amit; Máté, Zoltán; Calvigioni, Daniela; Yanagawa, Yuchio; Szabó, Gábor; Linnarsson, Sten; Harkany, Tibor

    2016-02-01

    Traditionally, neuroscientists have defined the identity of neurons by the cells' location, morphology, connectivity and excitability. However, the direct relationship between these parameters and the molecular phenotypes has remained largely unexplored. Here, we present a method for obtaining full transcriptome data from single neocortical pyramidal cells and interneurons after whole-cell patch-clamp recordings in mouse brain slices. In our approach, termed Patch-seq, a patch-clamp stimulus protocol is followed by the aspiration of the entire somatic compartment into the recording pipette, reverse transcription of RNA including addition of unique molecular identifiers, cDNA amplification, Illumina library preparation and sequencing. We show that Patch-seq reveals a close link between electrophysiological characteristics, responses to acute chemical challenges and RNA expression of neurotransmitter receptors and channels. Moreover, it distinguishes neuronal subpopulations that correspond to both well-established and, to our knowledge, hitherto undescribed neuronal subtypes. Our findings demonstrate the ability of Patch-seq to precisely map neuronal subtypes and predict their network contributions in the brain.

  7. Quantitative Classification of Somatostatin-Positive Neocortical Interneurons Identifies Three Interneuron Subtypes

    PubMed Central

    McGarry, Laura M.; Packer, Adam M.; Fino, Elodie; Nikolenko, Volodymyr; Sippy, Tanya; Yuste, Rafael

    2010-01-01

    Deciphering the circuitry of the neocortex requires knowledge of its components, making a systematic classification of neocortical neurons necessary. GABAergic interneurons contribute most of the morphological, electrophysiological and molecular diversity of the cortex, yet interneuron subtypes are still not well defined. To quantitatively identify classes of interneurons, 59 GFP-positive interneurons from a somatostatin-positive mouse line were characterized by whole-cell recordings and anatomical reconstructions. For each neuron, we measured a series of physiological and morphological variables and analyzed these data using unsupervised classification methods. PCA and cluster analysis of morphological variables revealed three groups of cells: one comprised of Martinotti cells, and two other groups of interneurons with short asymmetric axons targeting layers 2/3 and bending medially. PCA and cluster analysis of electrophysiological variables also revealed the existence of these three groups of neurons, particularly with respect to action potential time course. These different morphological and electrophysiological characteristics could make each of these three interneuron subtypes particularly suited for a different function within the cortical circuit. PMID:20617186

  8. Quantification of the methylation at the GNAS locus identifies subtypes of sporadic pseudohypoparathyroidism type Ib.

    PubMed

    Maupetit-Méhouas, Stéphanie; Mariot, Virginie; Reynès, Christelle; Bertrand, Guylène; Feillet, Francois; Carel, Jean-Claude; Simon, Dominique; Bihan, Hélène; Gajdos, Vincent; Devouge, Eve; Shenoy, Savitha; Agbo-Kpati, Placide; Ronan, Anne; Naud-Saudreau, Catherine; Lienhardt, Anne; Silve, Caroline; Linglart, Agnès

    2011-01-01

    Pseudohypoparathyroidism type Ib (PHP-Ib) is due to epigenetic changes at the imprinted GNAS locus, including loss of methylation at the A/B differentially methylated region (DMR) and sometimes at the XL and AS DMRs and gain of methylation at the NESP DMR. To investigate if quantitative measurement of the methylation at the GNAS DMRs identifies subtypes of PHP-Ib. In 19 patients with PHP-Ib and 7 controls, methylation was characterised at the four GNAS DMRs through combined bisulfite restriction analysis and quantified through cytosine specific real-time PCR in blood lymphocyte DNA. A principal component analysis using the per cent of methylation at seven cytosines of the GNAS locus provided three clusters of subjects (controls n=7, autosomal dominant PHP-Ib with loss of methylation restricted to the A/B DMR n=3, and sporadic PHP-Ib with broad GNAS methylation changes n=16) that matched perfectly the combined bisulfite restriction analysis classification. Furthermore, three sub-clusters of patients with sporadic PHP-Ib, that displayed different patterns of methylation, were identified: incomplete changes at all DMRs compatible with somatic mosaicism (n=5), profound epigenetic changes at all DMRs (n=8), and unmodified methylation at XL in contrast with the other DMRs (n=3). Interestingly, parathyroid hormone concentration at the time of diagnosis correlated with the per cent of methylation at the A/B DMR. Quantitative assessment of the methylation in blood lymphocyte DNA is of clinical relevance, allows the diagnosis of PHP-Ib, and identifies subtypes of PHP-Ib. These epigenetic findings suggest mosaicism at least in some patients.

  9. Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles.

    PubMed

    Marincevic-Zuniga, Yanara; Dahlberg, Johan; Nilsson, Sara; Raine, Amanda; Nystedt, Sara; Lindqvist, Carl Mårten; Berglund, Eva C; Abrahamsson, Jonas; Cavelier, Lucia; Forestier, Erik; Heyman, Mats; Lönnerholm, Gudmar; Nordlund, Jessica; Syvänen, Ann-Christine

    2017-08-14

    Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.

  10. M3 muscarinic acetylcholine receptor expression confers differential cholinergic modulation to neurochemically distinct hippocampal basket cell subtypes

    PubMed Central

    Cea-del Rio, Christian A.; Lawrence, J. Josh; Tricoire, Ludovic; Erdelyi, Ferenc; Szabo, Gabor; McBain, Chris J.

    2010-01-01

    Cholinergic neuromodulation of hippocampal circuitry promotes network oscillations and facilitates learning and memory through cellular actions on both excitatory and inhibitory circuits. Despite widespread recognition that neurochemical content discriminates between functionally distinct interneuron populations, there has been no systematic examination of whether neurochemically distinct interneuron classes undergo differential cholinergic neuromodulation in the hippocampus. Using GFP transgenic mice that enable the visualization of perisomatically targeting parvalbumin-positive (PV+) or cholecystokinin-positive (CCK+) basket cells (BCs), we tested the hypothesis that neurochemically distinct interneuron populations are differentially engaged by muscarinic acetylcholine receptor (mAChR) activation. Cholinergic fiber activation revealed that CCK BCs were more sensitive to synaptic release of ACh than PV BCs. In response to depolarizing current steps, mAChR activation of PV BCs and CCK BCs also elicited distinct cholinergic response profiles, differing in mAChR-induced changes in action potential (AP) waveform, firing frequency, and intrinsic excitability. In contrast to PV BCs, CCK BCs exhibited a mAChR-induced afterdepolarization (mADP) that was frequency and activity-dependent. Pharmacological, molecular, and loss-of-function data converged on the presence of M3 mAChRs in distinguishing CCK BCs from PV BCs. Firing frequency of CCK BCs was controlled through M3 mAChRs but PV BC excitability was altered solely through M1 mAChRs. Finally, upon mAChR activation, glutamatergic transmission enhanced cellular excitability preferentially in CCK BCs but not in PV BCs. Our findings demonstrate that cell-type specific cholinergic specializations are present on neurochemically distinct interneuron subtypes in the hippocampus, revealing an organizing principle that cholinergic neuromodulation depends critically on neurochemical identity. PMID:20427660

  11. Identifying significant microRNA-mRNA pairs associated with breast cancer subtypes.

    PubMed

    Bhattacharyya, Malay; Nath, Joyshree; Bandyopadhyay, Sanghamitra

    2016-07-01

    MicroRNAs (miRNAs) are small non-coding RNAs that help in post-transcriptional gene silencing. These endogenous RNAs develop a post-transcriptional gene-regulatory network by binding to complementary sequences of target mRNAs and essentially degrade them. Cancer is a class of diseases that is caused by the uncontrolled cell growth, thereby resulting into a gradual degradation of cell structure. Earlier researches have shown that miRNAs have significant biological involvement in cancer. Prolonged research in this genre has led to the identification of the functions of numerous miRNAs in cancer development. Studying the differential expression profiles of miRNAs and mRNAs together could help us in recognizing the significant miRNA-mRNA pairs from cancer samples. In this paper, we have analyzed the simultaneous over-expression of miRNAs and under-expression of mRNAs and vice versa to establish their association with cancer. This study focuses on breast tumor samples and the miRNA-mRNA target pairs that have a visible signature in such breast tumor samples. We have been able to identify the differentially expressed miRNAs and mRNAs, and further established relations between them to extract the miRNA-mRNA pairs that might be significant in the breast cancer types. This gives us the clue about the potential biomarkers for the breast cancer subtypes that can further help in understanding the progression of each of the subtypes separately. This might be helpful for the joint miRNA-mRNA biomarker identification.

  12. Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project.

    PubMed

    Sohn, Bo Hwa; Hwang, Jun-Eul; Jang, Hee-Jin; Lee, Hyun-Sung; Oh, Sang Cheul; Shim, Jae-Jun; Lee, Keun-Wook; Kim, Eui Hyun; Yim, Sun Young; Lee, Sang Ho; Cheong, Jae-Ho; Jeong, Woojin; Cho, Jae Yong; Kim, Joohee; Chae, Jungsoo; Lee, Jeeyun; Kang, Won Ki; Kim, Sung; Noh, Sung Hoon; Ajani, Jaffer A; Lee, Ju-Seog

    2017-07-26

    Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein-Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer.Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed.Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2-1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16-0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36-1.89; P = 0.65).Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 1-9. ©2017 AACR. ©2017 American Association for Cancer Research.

  13. Distinct and overlapping sarcoma subtypes initiated from muscle stem and progenitor cells.

    PubMed

    Blum, Jordan M; Añó, Leonor; Li, Zhizhong; Van Mater, David; Bennett, Brian D; Sachdeva, Mohit; Lagutina, Irina; Zhang, Minsi; Mito, Jeffrey K; Dodd, Leslie G; Cardona, Diana M; Dodd, Rebecca D; Williams, Nerissa; Ma, Yan; Lepper, Christoph; Linardic, Corinne M; Mukherjee, Sayan; Grosveld, Gerard C; Fan, Chen-Ming; Kirsch, David G

    2013-11-27

    Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, whereas undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue sarcomas diagnosed in adults. To investigate the myogenic cell(s) of origin of these sarcomas, we used Pax7-CreER and MyoD-CreER mice to transform Pax7(+) and MyoD(+) myogenic progenitors by expressing oncogenic Kras(G12D) and deleting Trp53 in vivo. Pax7-CreER mice developed RMS and UPS, whereas MyoD-CreER mice developed UPS. Using gene set enrichment analysis, RMS and UPS each clustered specifically within their human counterparts. These results suggest that RMS and UPS have distinct and overlapping cells of origin within the muscle lineage. Taking them together, we have established mouse models of soft tissue sarcoma from muscle stem and progenitor cells.

  14. Constructing taxonomies to identify distinctive forms of primary healthcare organizations.

    PubMed

    Borgès Da Silva, Roxane; Pineault, Raynald; Hamel, Marjolaine; Levesque, Jean-Frédéric; Roberge, Danièle; Lamarche, Paul

    2013-01-01

    Background. Primary healthcare (PHC) renewal gives rise to important challenges for policy makers, managers, and researchers in most countries. Evaluating new emerging forms of organizations is therefore of prime importance in assessing the impact of these policies. This paper presents a set of methods related to the configurational approach and an organizational taxonomy derived from our analysis. Methods. In 2005, we carried out a study on PHC in two health and social services regions of Quebec that included urban, suburban, and rural areas. An organizational survey was conducted in 473 PHC practices. We used multidimensional nonparametric statistical methods, namely, multiple correspondence and principal component analyses, and an ascending hierarchical classification method to construct a taxonomy of organizations. Results. PHC organizations were classified into five distinct models: four professional and one community. Study findings indicate that the professional integrated coordination and the community model have great potential for organizational development since they are closest to the ideal type promoted by current reforms. Conclusion. Results showed that the configurational approach is useful to assess complex phenomena such as the organization of PHC. The analysis highlights the most promising organizational models. Our study enhances our understanding of organizational change in health services organizations.

  15. Constructing Taxonomies to Identify Distinctive Forms of Primary Healthcare Organizations

    PubMed Central

    Borgès Da Silva, Roxane; Pineault, Raynald; Hamel, Marjolaine; Levesque, Jean-Frédéric; Roberge, Danièle; Lamarche, Paul

    2013-01-01

    Background. Primary healthcare (PHC) renewal gives rise to important challenges for policy makers, managers, and researchers in most countries. Evaluating new emerging forms of organizations is therefore of prime importance in assessing the impact of these policies. This paper presents a set of methods related to the configurational approach and an organizational taxonomy derived from our analysis. Methods. In 2005, we carried out a study on PHC in two health and social services regions of Quebec that included urban, suburban, and rural areas. An organizational survey was conducted in 473 PHC practices. We used multidimensional nonparametric statistical methods, namely, multiple correspondence and principal component analyses, and an ascending hierarchical classification method to construct a taxonomy of organizations. Results. PHC organizations were classified into five distinct models: four professional and one community. Study findings indicate that the professional integrated coordination and the community model have great potential for organizational development since they are closest to the ideal type promoted by current reforms. Conclusion. Results showed that the configurational approach is useful to assess complex phenomena such as the organization of PHC. The analysis highlights the most promising organizational models. Our study enhances our understanding of organizational change in health services organizations. PMID:24959575

  16. Distinct subtypes of basolateral amygdala taste neurons reflect palatability and reward

    PubMed Central

    Fontanini, Alfredo; Grossman, Stephen E.; Figueroa, Joshua A.; Katz, Donald B.

    2009-01-01

    The amygdala processes multiple, dissociable properties of sensory stimuli. Given its central location within a dense network of reciprocally connected regions, it is reasonable to expect that basolateral amygdala (BLA) neurons should produce a rich repertoire of dynamical responses to taste stimuli. Here, we examined single BLA neuron taste responses in awake rats, and report the existence of two distinct subgroups of BLA taste neurons operating simultaneously during perceptual processing. One neuron type produced long, protracted responses with dynamics that were strikingly similar to those previously observed in gustatory cortex. These responses reflect co-operation between amygdala and cortex for the purposes of processing palatability. A second type of BLA taste neuron may be part of the system often described as being responsible for reward learning: these neurons produced very brief, short-latency responses to rewarding stimuli; when the rat participated in procuring the taste by pressing a lever in response to a tone, however, those phasic taste responses vanished, phasic responses to the tone appearing instead. Our data provide strong evidence that the neural handling of taste is actually a distributed set of processes, and that BLA is a nexus of these multiple processes. These results offer new insights into how amygdala imbues naturalistic sensory stimuli with value. PMID:19244523

  17. Beta-adrenergic receptors are differentially expressed in distinct interneuron subtypes in the rat hippocampus.

    PubMed

    Cox, David J; Racca, Claudia; LeBeau, Fiona E N

    2008-08-20

    Noradrenaline (NA) acting via beta-adrenergic receptors (betaARs) plays an important role in the modulation of memory in the hippocampus. betaARs have been shown to be expressed in principal cells, but their distribution across different interneuron classes is unknown. We have used specific interneuron markers including calcium binding proteins (parvalbumin, calbindin, and calretinin) and neuropeptides (somatostatin, neuropeptide Y, and cholecystokinin) together with either beta1AR or beta2AR to determine the distribution of these receptors in all major subfields of the hippocampus. We found that beta1AR-expressing interneurons were more prevalent in the CA3 and CA1 regions of the hippocampus than in the dentate gyrus, where they were relatively sparse. beta2AR-expressing interneurons were more uniformly distributed between all three regions of the hippocampus. A high proportion of neuropeptide Y-containing interneurons in the dentate gyrus co-expressed beta2AR. beta1AR labeling was common in interneurons expressing somatostatin and parvalbumin in the CA3 and CA1 regions, particularly in the stratum oriens of these regions. beta2AR labeling was more likely to be found than beta1AR labeling in cholecystokinin-expressing interneurons. In contrast, calretinin-containing interneurons were virtually devoid of beta1AR or beta2AR labeling. These regional and interneuron type-specific differences suggest functionally distinct roles for NA in modulating hippocampal activity via activation of betaARs.

  18. Anxiety disorders among offenders with antisocial personality disorders: a distinct subtype?

    PubMed

    Hodgins, Sheilagh; De Brito, Stephane A; Chhabra, Preeti; Côté, Gilles

    2010-12-01

    about 50% of men with antisocial personality disorder (APD) present a comorbid anxiety disorder. Historically, it was thought that anxiety limited criminal activity and the development of APD, but recent evidence suggests that heightened responsiveness to threat may lead to persistent violent behaviour. Our study aimed to determine the prevalence of APD comorbid with anxiety disorders among offenders and the association of these comorbid disorders with violent offending. a random sample of 495 male penitentiary inmates completed an interview using the Diagnostic Interview Schedule. After excluding men with psychotic disorders, 279 with APD were retained. All authorized access to their criminal records. two-thirds of the prisoners with APD presented a lifetime anxiety disorder. Among them, one-half had the onset of their anxiety disorder before they were aged 16 years. Among the offenders with APD, those with, compared with those without, anxiety disorders presented significantly more symptoms of APD, were more likely to have begun their criminal careers before they were aged 15 years, to have diagnoses of alcohol and (or) drug abuse and (or) dependence, and to have experienced suicidal ideas and attempts. While there were no differences in the mean number of convictions for violent offences between APD prisoners with and without anxiety disorders, more of those with anxiety disorders had been convicted of serious crimes involving interpersonal violence. among men with APD, a substantial subgroup present life-long anxiety disorders. This pattern of comorbidity may reflect a distinct mechanism underlying violent behaviour and signalling the need for specific treatments.

  19. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes

    PubMed Central

    Matsuo, Hirotaka; Yamamoto, Ken; Nakaoka, Hirofumi; Nakayama, Akiyoshi; Sakiyama, Masayuki; Chiba, Toshinori; Takahashi, Atsushi; Nakamura, Takahiro; Nakashima, Hiroshi; Takada, Yuzo; Danjoh, Inaho; Shimizu, Seiko; Abe, Junko; Kawamura, Yusuke; Terashige, Sho; Ogata, Hiraku; Tatsukawa, Seishiro; Yin, Guang; Okada, Rieko; Morita, Emi; Naito, Mariko; Tokumasu, Atsumi; Onoue, Hiroyuki; Iwaya, Keiichi; Ito, Toshimitsu; Takada, Tappei; Inoue, Katsuhisa; Kato, Yukio; Nakamura, Yukio; Sakurai, Yutaka; Suzuki, Hiroshi; Kanai, Yoshikatsu; Hosoya, Tatsuo; Hamajima, Nobuyuki; Inoue, Ituro; Kubo, Michiaki; Ichida, Kimiyoshi; Ooyama, Hiroshi; Shimizu, Toru; Shinomiya, Nariyoshi

    2016-01-01

    Objective Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. Methods A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Results Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10−8), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10−12; OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10−23; OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10−9; OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case–control ORs for two distinct types of gout (r=0.96 [p=4.8×10−4] for urate clearance and r=0.96 [p=5.0×10−4] for urinary urate excretion). Conclusions Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics. PMID:25646370

  20. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes.

    PubMed

    Matsuo, Hirotaka; Yamamoto, Ken; Nakaoka, Hirofumi; Nakayama, Akiyoshi; Sakiyama, Masayuki; Chiba, Toshinori; Takahashi, Atsushi; Nakamura, Takahiro; Nakashima, Hiroshi; Takada, Yuzo; Danjoh, Inaho; Shimizu, Seiko; Abe, Junko; Kawamura, Yusuke; Terashige, Sho; Ogata, Hiraku; Tatsukawa, Seishiro; Yin, Guang; Okada, Rieko; Morita, Emi; Naito, Mariko; Tokumasu, Atsumi; Onoue, Hiroyuki; Iwaya, Keiichi; Ito, Toshimitsu; Takada, Tappei; Inoue, Katsuhisa; Kato, Yukio; Nakamura, Yukio; Sakurai, Yutaka; Suzuki, Hiroshi; Kanai, Yoshikatsu; Hosoya, Tatsuo; Hamajima, Nobuyuki; Inoue, Ituro; Kubo, Michiaki; Ichida, Kimiyoshi; Ooyama, Hiroshi; Shimizu, Toru; Shinomiya, Nariyoshi

    2016-04-01

    Gout, caused by hyperuricaemia, is a multifactorial disease. Although genome-wide association studies (GWASs) of gout have been reported, they included self-reported gout cases in which clinical information was insufficient. Therefore, the relationship between genetic variation and clinical subtypes of gout remains unclear. Here, we first performed a GWAS of clinically defined gout cases only. A GWAS was conducted with 945 patients with clinically defined gout and 1213 controls in a Japanese male population, followed by replication study of 1048 clinically defined cases and 1334 controls. Five gout susceptibility loci were identified at the genome-wide significance level (p<5.0×10(-8)), which contained well-known urate transporter genes (ABCG2 and SLC2A9) and additional genes: rs1260326 (p=1.9×10(-12); OR=1.36) of GCKR (a gene for glucose and lipid metabolism), rs2188380 (p=1.6×10(-23); OR=1.75) of MYL2-CUX2 (genes associated with cholesterol and diabetes mellitus) and rs4073582 (p=6.4×10(-9); OR=1.66) of CNIH-2 (a gene for regulation of glutamate signalling). The latter two are identified as novel gout loci. Furthermore, among the identified single-nucleotide polymorphisms (SNPs), we demonstrated that the SNPs of ABCG2 and SLC2A9 were differentially associated with types of gout and clinical parameters underlying specific subtypes (renal underexcretion type and renal overload type). The effect of the risk allele of each SNP on clinical parameters showed significant linear relationships with the ratio of the case-control ORs for two distinct types of gout (r=0.96 [p=4.8×10(-4)] for urate clearance and r=0.96 [p=5.0×10(-4)] for urinary urate excretion). Our findings provide clues to better understand the pathogenesis of gout and will be useful for development of companion diagnostics. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  1. Distinct and Overlapping Sarcoma Subtypes Initiated from Muscle Stem and Progenitor Cells

    PubMed Central

    Blum, Jordan M.; Añó, Leonor; Li, Zhizhong; Van Mater, David; Bennett, Brian D.; Sachdeva, Mohit; Lagutina, Irina; Zhang, Minsi; Mito, Jeffrey K.; Dodd, Leslie G.; Cardona, Diana M.; Dodd, Rebecca D.; Williams, Nerissa; Ma, Yan; Lepper, Christoph; Linardic, Corinne M.; Mukherjee, Sayan; Grosveld, Gerard C.; Fan, Chen-Ming; Kirsch, David G.

    2013-01-01

    SUMMARY Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children, while undifferentiated pleomorphic sarcoma (UPS) is one of the most common soft tissue sarcomas diagnosed in adults. To investigate the myogenic cell(s) of origin of these sarcomas, we used Pax7-CreER and MyoD-CreER mice to transform Pax7+ and MyoD+ myogenic progenitors by expressing oncogenic KrasG12D and deleting p53 in vivo. Pax7-CreER mice developed RMS and UPS, while MyoD-CreER mice developed UPS. Using gene set enrichment analysis, RMS and UPS each clustered specifically within their human counterparts. These results suggest that RMS and UPS have distinct and overlapping cells of origin within the muscle lineage. Taken together, we have established novel mouse models of soft tissue sarcoma from muscle stem and progenitor cells. SIGNIFICANCE Although muscle stem cells have been presumed to be a cell of origin for RMS, studies with constitutive Cre drivers expressed in Myf6-expressing cells or adipocyte P2-expressing cells suggest that cells of origin for RMS can be differentiated myofibers or adipogenic precursors, respectively. However, recent studies have demonstrated that Myf6 is expressed in muscle stem cell precursors, revealing a potential limitation of utilizing constitutive Cre drivers for cell of origin studies. Here, using inducible CreER mice, we mutate genes relevant to human RMS specifically in Pax7-expressing or MyoD-expressing cells. Our results suggest that RMS can be initiated in muscle stem cells, while UPS can be initiated in activated (Pax7+MyoD+) satellite cells. PMID:24239359

  2. Identifying risk factors of highly pathogenic avian influenza (H5N1 subtype) in Indonesia

    PubMed Central

    Leo, Loth; Marius, Gilbert; Jianmei, Wu; Christina, Czarnecki; Muhammad, Hidayat; Xiangming, Xiao

    2016-01-01

    Highly pathogenic avian influenza (HPAI), subtype H5N1, was first officially reported in Indonesia in 2004. Since then the disease has spread and is now endemic in large parts of the country. This study investigated the statistical relationship between a set of risk factors and the presence or absence of HPAI in Indonesia during 2006 and 2007. HPAI was evaluated through participatory disease surveillance (PDS) in backyard village chickens (the study population), and risk factors included descriptors of people and poultry distribution (separating chickens, ducks and production sectors), poultry movement patterns and agro-ecological conditions. The study showed that the risk factors “elevation”, “human population density” and “rice cropping” were significant in accounting for the spatial variation of the PDS-defined HPAI cases. These findings were consistent with earlier studies in Thailand and Vietnam. In addition “commercial poultry population”, and two indicators of market locations and transport; “human settlements” and “road length”, were identified as significant risk factors in the models. In contrast to several previous studies carried out in Southeast Asia, domestic backyard ducks were not found to be a significant risk factor in Indonesia. The study used surrogate estimates of market locations and marketing chains and further work should focus on the actual location of the live bird markets, and on the flow of live poultry and poultry products between them, so that patterns of possible transmission, and regions of particular risk could be better inferred. PMID:21813198

  3. Identifying subtypes among offenders with antisocial personality disorder: a cluster-analytic study.

    PubMed

    Poythress, Norman G; Edens, John F; Skeem, Jennifer L; Lilienfeld, Scott O; Douglas, Kevin S; Frick, Paul J; Patrick, Christopher J; Epstein, Monica; Wang, Tao

    2010-05-01

    The question of whether antisocial personality disorder (ASPD) and psychopathy are largely similar or fundamentally different constructs remains unresolved. In the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994), many of the personality features of psychopathy are cast as associated features of ASPD, although the DSM-IV offers no guidance as to how, or the extent to which, these features relate to ASPD. In a sample of 691 offenders who met DSM-IV criteria for ASPD, we used model-based clustering to identify subgroups of individuals with relatively homogeneous profiles on measures of associated features (psychopathic personality traits) and other constructs with potential etiological significance for subtypes of ASPD. Two emergent groups displayed profiles that conformed broadly to theoretical descriptions of primary psychopathy and Karpman's (1941) variant of secondary psychopathy. As expected, a third group (nonpsychopathic ASPD) lacked substantial associated features. A fourth group exhibited elevated psychopathic features as well as a highly fearful temperament, a profile not clearly predicted by extant models. Planned comparisons revealed theoretically informative differences between primary and secondary groups in multiple domains, including self-report measures, passive avoidance learning, clinical ratings, and official records. Our results inform ongoing debates about the overlap between psychopathy and ASPD and raise questions about the wisdom of placing most individuals who habitually violate social norms and laws into a single diagnostic category.

  4. Characteristics of the old and homeless: identifying distinct service needs.

    PubMed

    Kimbler, Kristopher J; DeWees, Mari A; Harris, Ashley N

    2017-02-01

    Research suggests that being older and homeless is associated with unique characteristics and potential barriers to improved living conditions. Additional research is needed to better understand the vulnerabilities associated with this population. The purpose of this study was to identify characteristics related to aging and homelessness. It was hypothesized that older adults would exhibit more vulnerability compared to other age groups related to health, social support proximity, occupational perceptions, and recent living conditions prior to seeking assistance at an emergency shelter. It was also hypothesized that these age-related characteristics would predict the amount of time that individuals resided in the emergency shelter. A cross-sectional sample of young, middle-aged, and older homeless adults seeking shelter at two emergency homeless shelters was utilized for this study. Data included information obtained during a structured interview after participants arrived at the shelter and the number of days that were spent at the shelter. Older adults were more likely to exhibit several characteristics (i.e., poorer health, being further from social support, longer durations of homelessness, lack of employment area, prior residence types, and mental health treatment) potentially contributing to and/or recovering from homelessness. Duration of homelessness, reports of having no career area, and age were predictive of the amount of time spent at the shelter. The various characteristics that differentiate older homeless populations (e.g., health, social support, homelessness duration, and employment) could create potential barriers to overcoming homelessness that should be considered when serving this population.

  5. Variation of types of alcoholism: review and subtypes identified in Han Chinese.

    PubMed

    Lee, Sheng-Yu; Chen, Shiou-Lan; Chang, Yun-Hsuan; Lu, Ru-Band

    2014-01-03

    Alcoholism, as it has been hypothesized, is caused by a highly heterogeneous genetic load. Since 1960, many reports have used the bio-psycho-social approach to subtype alcoholism; however, no subtypes have been genetically validated. We reviewed and compared the major single-gene, multiple-gene, and gene-to-gene interaction studies on alcoholism published during the past quarter-century, including many recent studies that have made contributions to the subtyping of alcoholism. Four subtypes of alcoholism have been reported: [1] pure alcoholism, [2] anxiety/depression alcoholism, [3] antisocial alcoholism, and [4] mixed alcoholism. Most of the important studies focused on three genes: DRD2, MAOA, and ALDH2. Therefore, our review focuses on these three genes. © 2013.

  6. Systematic discovery of molecular probes targeting multiple non-orthosteric and spatially distinct sites in the botulinum neurotoxin subtype A (BoNT/A).

    PubMed

    Dadgar, Saedeh; Floriano, Wely B

    2015-06-01

    The development of molecular probes targeting proteins has traditionally relied on labeling compounds already known to bind to the protein of interest. These known ligands bind to orthosteric or allosteric sites in their target protein as a way to control their activity. Binding pockets other than known orthosteric or allosteric sites may exist that are large enough to accommodate a ligand without significantly disrupting protein activity. Such sites may provide opportunities to discriminate between subtypes or other closely related proteins, since they are under less evolutionary pressure to be conserved. The Protein Scanning with Virtual Ligand Screening (PSVLS) approach was previously used to identify a novel inhibitor and a fluorescent probe against the catalytic site of the botulinum neurotoxin subtype A (BoNT/A). PSVLS screens compound databases against multiple sites within a target protein, and the results for all the sites probed against BoNT/A, not only the catalytic site, are available online. Here, we analyze the PSVLS data for multiple sites in order to identify molecular probes with affinity for binding pockets other than the catalytic site of BoNT/A. BoNT/A is a large protein with a light (LC) and a heavy (HC) chain that can be assayed separately. We used scintillation proximity assay (SPA) to test experimentally 5 probe candidates predicted computationally to have affinity for different non-orthosteric binding regions within the HC and LC, and one compound predicted not to have affinity for either domain. The binding profiles obtained experimentally confirmed the targeting of multiple and spatially distinct pockets within BoNT/A. Moreover, inhibition assay results indicate that some of these probes do not significantly interfere with the catalytic activity of BoNT/A.

  7. Estrogen Receptor Subtypes Mediate Distinct Microvascular Dilation and Reduction in [Ca2+]i in Mesenteric Microvessels of Female Rat

    PubMed Central

    Mazzuca, Marc Q.; Mata, Karina M.; Li, Wei; Rangan, Sridhar S.

    2015-01-01

    Estrogen interacts with estrogen receptors (ERs) to induce vasodilation, but the ER subtype and post-ER relaxation pathways are unclear. We tested if ER subtypes mediate distinct vasodilator and intracellular free Ca2+ concentration ([Ca2+]i) responses via specific relaxation pathways in the endothelium and vascular smooth muscle (VSM). Pressurized mesenteric microvessels from female Sprague-Dawley rats were loaded with fura-2, and the changes in diameter and [Ca2+]i in response to 17β-estradiol (E2) (all ERs), PPT (4,4′,4′′-[4-propyl-(1H)-pyrazole-1,3,5-triyl]-tris-phenol) (ERα), diarylpropionitrile (DPN) (ERβ), and G1 [(±)-1-[(3aR*,4S*,9bS*)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro:3H-cyclopenta(c)quinolin-8-yl]-ethanon] (GPR30) were measured. In microvessels preconstricted with phenylephrine, ER agonists caused relaxation and decrease in [Ca2+]i that were with E2 = PPT > DPN > G1, suggesting that E2-induced vasodilation involves ERα > ERβ > GPR30. Acetylcholine caused vasodilation and decreased [Ca2+]i, which were abolished by endothelium removal or treatment with the nitric oxide synthase blocker Nω-nitro-l-arginine methyl ester (L-NAME) and the K+ channel blockers tetraethylammonium (nonspecific) or apamin (small conductance Ca2+-activated K+ channel) plus TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole) (intermediate conductance Ca2+-activated K+ channel), suggesting endothelium-derived hyperpolarizing factor–dependent activation of KCa channels. E2-, PPT-, DPN-, and G1-induced vasodilation and decreased [Ca2+]i were not blocked by L-NAME, TEA, apamin plus TRAM-34, iberiotoxin (large conductance Ca2+- and voltage-activated K+ channel), 4-aminopyridine (voltage-dependent K+ channel), glibenclamide (ATP-sensitive K+ channel), or endothelium removal, suggesting an endothelium- and K+ channel–independent mechanism. In endothelium-denuded vessels preconstricted with phenylephrine, high KCl, or the Ca2+ channel activator Bay K

  8. The Common p.R114W HNF4A Mutation Causes a Distinct Clinical Subtype of Monogenic Diabetes.

    PubMed

    Laver, Thomas W; Colclough, Kevin; Shepherd, Maggie; Patel, Kashyap; Houghton, Jayne A L; Dusatkova, Petra; Pruhova, Stepanka; Morris, Andrew D; Palmer, Colin N; McCarthy, Mark I; Ellard, Sian; Hattersley, Andrew T; Weedon, Michael N

    2016-10-01

    HNF4A mutations cause increased birth weight, transient neonatal hypoglycemia, and maturity onset diabetes of the young (MODY). The most frequently reported HNF4A mutation is p.R114W (previously p.R127W), but functional studies have shown inconsistent results; there is a lack of cosegregation in some pedigrees and an unexpectedly high frequency in public variant databases. We confirm that p.R114W is a pathogenic mutation with an odds ratio of 30.4 (95% CI 9.79-125, P = 2 × 10(-21)) for diabetes in our MODY cohort compared with control subjects. p.R114W heterozygotes did not have the increased birth weight of patients with other HNF4A mutations (3,476 g vs. 4,147 g, P = 0.0004), and fewer patients responded to sulfonylurea treatment (48% vs. 73%, P = 0.038). p.R114W has reduced penetrance; only 54% of heterozygotes developed diabetes by age 30 years compared with 71% for other HNF4A mutations. We redefine p.R114W as a pathogenic mutation that causes a distinct clinical subtype of HNF4A MODY with reduced penetrance, reduced sensitivity to sulfonylurea treatment, and no effect on birth weight. This has implications for diabetes treatment, management of pregnancy, and predictive testing of at-risk relatives. The increasing availability of large-scale sequence data is likely to reveal similar examples of rare, low-penetrance MODY mutations.

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

    PubMed

    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.

  10. Structural Brain Alterations Associated With Schizophrenia Preceded by Conduct Disorder: A Common and Distinct Subtype of Schizophrenia?

    PubMed Central

    Schiffer, Boris

    2013-01-01

    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. PMID:23015687

  11. Identifying personality subtypes based on the five-factor model dimensions in male prisoners: implications for psychopathy and criminal offending.

    PubMed

    Claes, Laurence; Tavernier, Geert; Roose, Annelore; Bijttebier, Patricia; Smith, Sarah Francis; Lilienfeld, Scott O

    2014-01-01

    The current study was designed to identify personality subtypes on the basis of the five-factor model dimensions in male prisoners. Participants included 110 Flemish male prisoners assessed by means of the Neuroticism, Extraversion, Openness Five Factor Inventory and different symptom, personality, and coping measures. We found two clusters: an emotionally stable/resilient cluster and an aggressive/undercontrolled cluster. Prisoners within the aggressive/undercontrolled cluster scored significantly higher on almost all Minnesota Multiphasic Personality Inventory-2 basic scales, (in)direct aggression measures, and depressive coping scales compared with resilients. They also scored higher on drug abuse and committed more sexual offenses than resilient prisoners. These two personality subtypes bear theoretically and practically important implications for psychopathy subtypes and different pathways to criminal offenses.

  12. Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation.

    PubMed

    Roode, Sarah C; Rotroff, Daniel; Avery, Anne C; Suter, Steven E; Bienzle, Dorothee; Schiffman, Joshua D; Motsinger-Reif, Alison; Breen, Matthew

    2015-12-01

    Leukemia in dogs is a heterogeneous disease with survival ranging from days to years, depending on the subtype. Strides have been made in both human and canine leukemia to improve classification and understanding of pathogenesis through immunophenotyping, yet classification and choosing appropriate therapy remains challenging. In this study, we assessed 123 cases of canine leukemia (28 ALLs, 24 AMLs, 25 B-CLLs, and 46 T-CLLs) using high-resolution oligonucleotide array comparative genomic hybridization (oaCGH) to detect DNA copy number alterations (CNAs). For the first time, such data were used to identify recurrent CNAs and inclusive genes that may be potential drivers of subtype-specific pathogenesis. We performed predictive modeling to identify CNAs that could reliably differentiate acute subtypes (ALL vs. AML) and chronic subtypes (B-CLL vs. T-CLL) and used this model to differentiate cases with up to 83.3 and 95.8 % precision, respectively, based on CNAs at only one to three genomic regions. In addition, CGH datasets for canine and human leukemia were compared to reveal evolutionarily conserved copy number changes between species, including the shared gain of HSA 21q in ALL and ∼25 Mb of shared gain of HSA 12 and loss of HSA 13q14 in CLL. These findings support the use of canine leukemia as a relevant in vivo model for human leukemia and justify the need to further explore the conserved genomic regions of interest for their clinical impact.

  13. Subtypes of primary angiitis of the CNS identified by MRI patterns reflect the size of affected vessels.

    PubMed

    Schuster, Simon; Bachmann, Henrike; Thom, Vivien; Kaufmann-Buehler, Ann-Katrin; Matschke, Jakob; Siemonsen, Susanne; Glatzel, Markus; Fiehler, Jens; Gerloff, Christian; Magnus, Tim; Thomalla, Götz

    2017-09-01

    To describe patterns of diagnostic findings, and identify subgroups of primary angiitis of the central nervous system (PACNS). We retrospectively analysed 31 patients with PACNS. Cases were selected by predetermined diagnostic criteria and stratified into biopsy-proven and imaging-based PACNS. We compared clinical characteristics, cerebrospinal fluid (CSF) findings and imaging results including high-resolution vessel wall MRI between groups. There were 31 cases of PACNS (mean age 45.6 years, 58.1% female), of whom 17 (55%) were biopsy-proven, 14 (45%) were based on imaging findings. Patients with a positive biopsy had fewer infarcts (29.4% vs 85.7%, p=0.003), were more likely to have meningeal and parenchymal contrast enhancement (76.5% vs 28.6%, p=0.012), were less likely to have abnormal MR angiography (11.8% vs 100%, p<0.001) and did not show vessel wall enhancement at the time of diagnosis (0% vs 76.9%, p<0.001). In contrast, patients with imaging-based diagnosis showed more frequently multiple infarcts and vessel abnormalities, with vessel wall enhancement in most of the cases. Clinical characteristics and CSF analysis did not reveal marked differences between groups. Multi-parametric MRI distinguishes two subtypes of PACNS that most likely differ concerning the affected vessel size. Biopsy-proven PACNS primarily involves smaller vessels beyond the resolution of vascular imaging, while imaging-based PACNS affects predominantly medium-sized vessels leading to false-negative biopsy results. Using distinct MRI patterns may be helpful for selecting patients for appropriate invasive diagnostic modalities. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  14. Sequencing and Phylogenetic Analysis of Near Full-Length HIV-1 Subtypes A, B, G and Unique Recombinant AC and AD Viral Strains Identified in South Africa

    PubMed Central

    Wilkinson, Eduan; Holzmayer, Vera; Jacobs, Graeme B.; de Oliveira, Tulio; Brennan, Catherine A.; Hackett, John; van Rensburg, Estrelita Janse

    2015-01-01

    Abstract By the end of 2012, more than 6.1 million people were infected with HIV-1 in South Africa. Subtype C was responsible for the majority of these infections and more than 300 near full-length genomes (NFLGs) have been published. Currently very few non-subtype C isolates have been identified and characterized within the country, particularly full genome non-C isolates. Seven patients from the Tygerberg Virology (TV) cohort were previously identified as possible non-C subtypes and were selected for further analyses. RNA was isolated from five individuals (TV047, TV096, TV101, TV218, and TV546) and DNA from TV016 and TV1057. The NFLGs of these samples were amplified in overlapping fragments and sequenced. Online subtyping tools REGA version 3 and jpHMM were used to screen for subtypes and recombinants. Maximum likelihood (ML) phylogenetic analysis (phyML) was used to infer subtypes and SimPlot was used to confirm possible intersubtype recombinants. We identified three subtype B (TV016, TV047, and TV1057) isolates, one subtype A1 (TV096), one subtype G (TV546), one unique AD (TV101), and one unique AC (TV218) recombinant form. This is the first NFLG of subtype G that has been described in South Africa. The subtype B sequences described also increased the NFLG subtype B sequences in Africa from three to six. There is a need for more NFLG sequences, as partial HIV-1 sequences may underrepresent viral recombinant forms. It is also necessary to continue monitoring the evolution and spread of HIV-1 in South Africa, because understanding viral diversity may play an important role in HIV-1 prevention strategies. PMID:25492033

  15. Sequencing and phylogenetic analysis of near full-length HIV-1 subtypes A, B, G and unique recombinant AC and AD viral strains identified in South Africa.

    PubMed

    Wilkinson, Eduan; Holzmayer, Vera; Jacobs, Graeme B; de Oliveira, Tulio; Brennan, Catherine A; Hackett, John; van Rensburg, Estrelita Janse; Engelbrecht, Susan

    2015-04-01

    By the end of 2012, more than 6.1 million people were infected with HIV-1 in South Africa. Subtype C was responsible for the majority of these infections and more than 300 near full-length genomes (NFLGs) have been published. Currently very few non-subtype C isolates have been identified and characterized within the country, particularly full genome non-C isolates. Seven patients from the Tygerberg Virology (TV) cohort were previously identified as possible non-C subtypes and were selected for further analyses. RNA was isolated from five individuals (TV047, TV096, TV101, TV218, and TV546) and DNA from TV016 and TV1057. The NFLGs of these samples were amplified in overlapping fragments and sequenced. Online subtyping tools REGA version 3 and jpHMM were used to screen for subtypes and recombinants. Maximum likelihood (ML) phylogenetic analysis (phyML) was used to infer subtypes and SimPlot was used to confirm possible intersubtype recombinants. We identified three subtype B (TV016, TV047, and TV1057) isolates, one subtype A1 (TV096), one subtype G (TV546), one unique AD (TV101), and one unique AC (TV218) recombinant form. This is the first NFLG of subtype G that has been described in South Africa. The subtype B sequences described also increased the NFLG subtype B sequences in Africa from three to six. There is a need for more NFLG sequences, as partial HIV-1 sequences may underrepresent viral recombinant forms. It is also necessary to continue monitoring the evolution and spread of HIV-1 in South Africa, because understanding viral diversity may play an important role in HIV-1 prevention strategies.

  16. Distinct Abnormalities of Small Bowel and Regional Colonic Volumes in Subtypes of Irritable Bowel Syndrome Revealed by MRI.

    PubMed

    Lam, Ching; Chaddock, Gemma; Marciani Laurea, Luca; Costigan, Carolyn; Cox, Eleanor; Hoad, Caroline; Pritchard, Susan; Gowland, Penny; Spiller, Robin

    2017-02-01

    Non-invasive biomarkers which identify different mechanisms of disease in subgroups of irritable bowel syndrome (IBS) could be valuable. Our aim was to seek useful magnetic resonance imaging (MRI) parameters that could distinguish each IBS subtypes. 34 healthy volunteers (HV), 30 IBS with diarrhea (IBS-D), 16 IBS with constipation (IBS-C), and 11 IBS with mixed bowel habit (IBS-M) underwent whole-gut transit and small and large bowel volumes assessment with MRI scans from t=0 to t=360 min. Since the bowel frequency for IBS-M were similar to IBS-D, IBS-M and IBS-D were grouped together and labeled as IBS non-constipation group (IBS-nonC). Median (interquartile range): fasting small bowel water content in IBS-nonC was 21 (10-42), significantly less than HV at 44 ml (15-70), P<0.01 as was the postprandial area under the curve (AUC) P<0.01. The fasting transverse colon volumes in IBS-C were significantly larger at 253 (200-329) compared with HV, IBS-nonC whose values were 165 (117-255) and 198 (106-270) ml, respectively, P=0.02. Whole-gut transit time for IBS-C was prolonged at 69 (51-111), compared with HV at 34 (4-63) and IBS-D at 34 (17-78) h, P=0.03. Bloating score (VAS 0-10 cm) correlated with transverse colon volume at t=405 min, Spearman r=0.21, P=0.04. The constricted small bowel in IBS-nonC and the dilated transverse colon in IBS-C point to significant differences in underlying mechanisms of disease.

  17. Distinct Abnormalities of Small Bowel and Regional Colonic Volumes in Subtypes of Irritable Bowel Syndrome Revealed by MRI

    PubMed Central

    Lam, Ching; Chaddock, Gemma; Marciani Laurea, Luca; Costigan, Carolyn; Cox, Eleanor; Hoad, Caroline; Pritchard, Susan; Gowland, Penny; Spiller, Robin

    2017-01-01

    OBJECTIVES: Non-invasive biomarkers which identify different mechanisms of disease in subgroups of irritable bowel syndrome (IBS) could be valuable. Our aim was to seek useful magnetic resonance imaging (MRI) parameters that could distinguish each IBS subtypes. METHODS: 34 healthy volunteers (HV), 30 IBS with diarrhea (IBS-D), 16 IBS with constipation (IBS-C), and 11 IBS with mixed bowel habit (IBS-M) underwent whole-gut transit and small and large bowel volumes assessment with MRI scans from t=0 to t=360 min. Since the bowel frequency for IBS-M were similar to IBS-D, IBS-M and IBS-D were grouped together and labeled as IBS non-constipation group (IBS-nonC). RESULTS: Median (interquartile range): fasting small bowel water content in IBS-nonC was 21 (10–42), significantly less than HV at 44 ml (15–70), P<0.01 as was the postprandial area under the curve (AUC) P<0.01. The fasting transverse colon volumes in IBS-C were significantly larger at 253 (200–329) compared with HV, IBS-nonC whose values were 165 (117–255) and 198 (106–270) ml, respectively, P=0.02. Whole-gut transit time for IBS-C was prolonged at 69 (51–111), compared with HV at 34 (4–63) and IBS-D at 34 (17–78) h, P=0.03. Bloating score (VAS 0–10 cm) correlated with transverse colon volume at t=405 min, Spearman r=0.21, P=0.04. CONCLUSIONS: The constricted small bowel in IBS-nonC and the dilated transverse colon in IBS-C point to significant differences in underlying mechanisms of disease. PMID:27958282

  18. CSF Proteomics Identifies Specific and Shared Pathways for Multiple Sclerosis Clinical Subtypes

    PubMed Central

    Avsar, Timucin; Durası, İlknur Melis; Uygunoğlu, Uğur; Tütüncü, Melih; Demirci, Nuri Onat; Saip, Sabahattin; Sezerman, O. Uğur; Siva, Aksel; Tahir Turanlı, Eda

    2015-01-01

    Multiple sclerosis (MS) is an immune-mediated, neuro-inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS) with a heterogeneous clinical presentation and course. There is a remarkable phenotypic heterogeneity in MS, and the molecular mechanisms underlying it remain unknown. We aimed to investigate further the etiopathogenesis related molecular pathways in subclinical types of MS using proteomic and bioinformatics approaches in cerebrospinal fluids of patients with clinically isolated syndrome, relapsing remitting MS and progressive MS (n=179). Comparison of disease groups with controls revealed a total of 151 proteins that are differentially expressed in clinically different MS subtypes. KEGG analysis using PANOGA tool revealed the disease related pathways including aldosterone-regulated sodium reabsorption (p=8.02x10-5) which is important in the immune cell migration, renin-angiotensin (p=6.88x10-5) system that induces Th17 dependent immunity, notch signaling (p=1.83x10-10) pathway indicating the activated remyelination and vitamin digestion and absorption pathways (p=1.73x10-5). An emerging theme from our studies is that whilst all MS clinical forms share common biological pathways, there are also clinical subtypes specific and pathophysiology related pathways which may have further therapeutic implications. PMID:25942430

  19. Targeted next-generation sequencing and non-coding RNA expression analysis of clear cell papillary renal cell carcinoma suggests distinct pathological mechanisms from other renal tumour subtypes.

    PubMed

    Lawrie, Charles H; Larrea, Erika; Larrinaga, Gorka; Goicoechea, Ibai; Arestin, María; Fernandez-Mercado, Marta; Hes, Ondrej; Cáceres, Francisco; Manterola, Lorea; López, José I

    2014-01-01

    Clear cell tubulopapillary renal cell carcinoma (CCPRCC) is a recently described rare renal malignancy that displays characteristic gross, microscopic and immunohistochemical differences from other renal tumour types. However, CCPRCC remains a very poorly understood entity. We therefore sought to elucidate some of the molecular mechanisms involved in this neoplasm by carrying out targeted next-generation sequencing (NGS) to identify associated mutations, and in addition examined the expression of non-coding (nc) RNAs. We identified multiple somatic mutations in CCPRCC cases, including a recurrent [3/14 cases (21%)] non-synonymous T992I mutation in the MET proto-oncogene, a gene associated with epithelial-to-mesenchymal transition (EMT). Using a microarray approach, we found that the expression of mature (n = 1105) and pre-miRNAs (n = 1105), as well as snoRNA and scaRNAs (n = 2214), in CCPRCC cases differed from that of clear cell renal cell carcinoma (CCRCC) or papillary renal cell carcinoma (PRCC) tumours. Surprisingly, and unlike other renal tumour subtypes, we found that all five members of the miR-200 family were over-expressed in CCPRCC cases. As these miRNAs are intimately involved with EMT, we stained CCPRCC cases for E-cadherin, vimentin and β-catenin and found that the tumour cells of all cases were positive for all three markers, a combination rarely reported in other renal tumours that could have diagnostic implications. Taken together with the mutational analysis, these data suggest that EMT in CCPRCC tumour cells is incomplete or blocked, consistent with the indolent clinical course typical of this malignancy. In summary, as well as describing a novel pathological mechanism in renal carcinomas, this study adds to the mounting evidence that CCPRCC should be formally considered a distinct entity. Microarray data have been deposited in the GEO database [GEO accession number (GSE51554)]. Copyright © 2013 Pathological Society of Great Britain and Ireland

  20. AChBP-targeted α-conotoxin correlates distinct binding orientations with nAChR subtype selectivity

    PubMed Central

    Dutertre, Sébastien; Ulens, Chris; Büttner, Regina; Fish, Alexander; van Elk, René; Kendel, Yvonne; Hopping, Gene; Alewood, Paul F; Schroeder, Christina; Nicke, Annette; Smit, August B; Sixma, Titia K; Lewis, Richard J

    2007-01-01

    Neuronal nAChRs are a diverse family of pentameric ion channels with wide distribution throughout cells of the nervous and immune systems. However, the role of specific subtypes in normal and pathological states remains poorly understood due to the lack of selective probes. Here, we used a binding assay based on acetylcholine-binding protein (AChBP), a homolog of the nicotinic acetylcholine ligand-binding domain, to discover a novel α-conotoxin (α-TxIA) in the venom of Conus textile. α-TxIA bound with high affinity to AChBPs from different species and selectively targeted the α3β2 nAChR subtype. A co-crystal structure of Ac-AChBP with the enhanced potency analog TxIA(A10L), revealed a 20° backbone tilt compared to other AChBP–conotoxin complexes. This reorientation was coordinated by a key salt bridge formed between Arg5 (TxIA) and Asp195 (Ac-AChBP). Mutagenesis studies, biochemical assays and electrophysiological recordings directly correlated the interactions observed in the co-crystal structure to binding affinity at AChBP and different nAChR subtypes. Together, these results establish a new pharmacophore for the design of novel subtype-selective ligands with therapeutic potential in nAChR-related diseases. PMID:17660751

  1. Gene Set-Based Integrative Analysis Revealing Two Distinct Functional Regulation Patterns in Four Common Subtypes of Epithelial Ovarian Cancer.

    PubMed

    Chang, Chia-Ming; Chuang, Chi-Mu; Wang, Mong-Lien; Yang, Yi-Ping; Chuang, Jen-Hua; Yang, Ming-Jie; Yen, Ming-Shyen; Chiou, Shih-Hwa; Chang, Cheng-Chang

    2016-08-05

    Clear cell (CCC), endometrioid (EC), mucinous (MC) and high-grade serous carcinoma (SC) are the four most common subtypes of epithelial ovarian carcinoma (EOC). The widely accepted dualistic model of ovarian carcinogenesis divided EOCs into type I and II categories based on the molecular features. However, this hypothesis has not been experimentally demonstrated. We carried out a gene set-based analysis by integrating the microarray gene expression profiles downloaded from the publicly available databases. These quantified biological functions of EOCs were defined by 1454 Gene Ontology (GO) term and 674 Reactome pathway gene sets. The pathogenesis of the four EOC subtypes was investigated by hierarchical clustering and exploratory factor analysis. The patterns of functional regulation among the four subtypes containing 1316 cases could be accurately classified by machine learning. The results revealed that the ERBB and PI3K-related pathways played important roles in the carcinogenesis of CCC, EC and MC; while deregulation of cell cycle was more predominant in SC. The study revealed that two different functional regulation patterns exist among the four EOC subtypes, which were compatible with the type I and II classifications proposed by the dualistic model of ovarian carcinogenesis.

  2. The association between school exclusion, delinquency and subtypes of cyber- and F2F-victimizations: identifying and predicting risk profiles and subtypes using latent class analysis.

    PubMed

    Barboza, Gia Elise

    2015-01-01

    This purpose of this paper is to identify risk profiles of youth who are victimized by on- and offline harassment and to explore the consequences of victimization on school outcomes. Latent class analysis is used to explore the overlap and co-occurrence of different clusters of victims and to examine the relationship between class membership and school exclusion and delinquency. Participants were a random sample of youth between the ages of 12 and 18 selected for inclusion to participate in the 2011 National Crime Victimization Survey: School Supplement. The latent class analysis resulted in four categories of victims: approximately 3.1% of students were highly victimized by both bullying and cyberbullying behaviors; 11.6% of youth were classified as being victims of relational bullying, verbal bullying and cyberbullying; a third class of students were victims of relational bullying, verbal bullying and physical bullying but were not cyberbullied (8%); the fourth and final class, characteristic of the majority of students (77.3%), was comprised of non-victims. The inclusion of covariates to the latent class model indicated that gender, grade and race were significant predictors of at least one of the four victim classes. School delinquency measures were included as distal outcomes to test for both overall and pairwise associations between classes. With one exception, the results were indicative of a significant relationship between school delinquency and the victim subtypes. Implications for these findings are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  3. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy

    PubMed Central

    Choi, Woonyoung; Porten, Sima; Kim, Seungchan; Willis, Daniel; Plimack, Elizabeth R.; Hoffman-Censits, Jean; Roth, Beat; Cheng, Tiewei; Tran, Mai; Lee, I-Ling; Melquist, Jonathan; Bondaruk, Jolanta; Majewski, Tadeusz; Zhang, Shizhen; Pretzsch, Shanna; Baggerly, Keith; Siefker-Radtke, Arlene; Czerniak, Bogdan; Dinney, Colin P.N.; McConkey, David J.

    2014-01-01

    Summary Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered 3 molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor (ER) transcription and were enriched with activating FGFR3 mutations and potentially FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant MVAC chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy. PMID:24525232

  4. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy.

    PubMed

    Choi, Woonyoung; Porten, Sima; Kim, Seungchan; Willis, Daniel; Plimack, Elizabeth R; Hoffman-Censits, Jean; Roth, Beat; Cheng, Tiewei; Tran, Mai; Lee, I-Ling; Melquist, Jonathan; Bondaruk, Jolanta; Majewski, Tadeusz; Zhang, Shizhen; Pretzsch, Shanna; Baggerly, Keith; Siefker-Radtke, Arlene; Czerniak, Bogdan; Dinney, Colin P N; McConkey, David J

    2014-02-10

    Muscle-invasive bladder cancers (MIBCs) are biologically heterogeneous and have widely variable clinical outcomes and responses to conventional chemotherapy. We discovered three molecular subtypes of MIBC that resembled established molecular subtypes of breast cancer. Basal MIBCs shared biomarkers with basal breast cancers and were characterized by p63 activation, squamous differentiation, and more aggressive disease at presentation. Luminal MIBCs contained features of active PPARγ and estrogen receptor transcription and were enriched with activating FGFR3 mutations and potential FGFR inhibitor sensitivity. p53-like MIBCs were consistently resistant to neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy, and all chemoresistant tumors adopted a p53-like phenotype after therapy. Our observations have important implications for prognostication, the future clinical development of targeted agents, and disease management with conventional chemotherapy.

  5. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes.

    PubMed

    Walter, Vonn; Yin, Xiaoying; Wilkerson, Matthew D; Cabanski, Christopher R; Zhao, Ni; Du, Ying; Ang, Mei Kim; Hayward, Michele C; Salazar, Ashley H; Hoadley, Katherine A; Fritchie, Karen; Sailey, Charles J; Sailey, Charles G; Weissler, Mark C; Shockley, William W; Zanation, Adam M; Hackman, Trevor; Thorne, Leigh B; Funkhouser, William D; Muldrew, Kenneth L; Olshan, Andrew F; Randell, Scott H; Wright, Fred A; Shores, Carol G; Hayes, D Neil

    2013-01-01

    Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

  6. Molecular Subtypes in Head and Neck Cancer Exhibit Distinct Patterns of Chromosomal Gain and Loss of Canonical Cancer Genes

    PubMed Central

    Walter, Vonn; Yin, Xiaoying; Wilkerson, Matthew D.; Cabanski, Christopher R.; Zhao, Ni; Du, Ying; Ang, Mei Kim; Hayward, Michele C.; Salazar, Ashley H.; Hoadley, Katherine A.; Fritchie, Karen; Sailey, Charles G.; Weissler, Mark C.; Shockley, William W.; Zanation, Adam M.; Hackman, Trevor; Thorne, Leigh B.; Funkhouser, William D.; Muldrew, Kenneth L.; Olshan, Andrew F.; Randell, Scott H.; Wright, Fred A.; Shores, Carol G.; Hayes, D. Neil

    2013-01-01

    Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented. PMID:23451093

  7. Distinct muscarinic acetylcholine receptor subtypes contribute to stability and growth, but not compensatory plasticity, of neuromuscular synapses.

    PubMed

    Wright, Megan C; Potluri, Srilatha; Wang, Xueyong; Dentcheva, Eva; Gautam, Dinesh; Tessler, Alan; Wess, Jürgen; Rich, Mark M; Son, Young-Jin

    2009-11-25

    Muscarinic acetylcholine receptors (mAChRs) modulate synaptic function, but whether they influence synaptic structure remains unknown. At neuromuscular junctions (NMJs), mAChRs have been implicated in compensatory sprouting of axon terminals in paralyzed or denervated muscles. Here we used pharmacological and genetic inhibition and localization studies of mAChR subtypes at mouse NMJs to demonstrate their roles in synaptic stability and growth but not in compensatory sprouting. M(2) mAChRs were present solely in motor neurons, whereas M(1), M(3), and M(5) mAChRs were associated with Schwann cells and/or muscle fibers. Blockade of all five mAChR subtypes with atropine evoked pronounced effects, including terminal sprouting, terminal withdrawal, and muscle fiber atrophy. In contrast, methoctramine, an M(2/4)-preferring antagonist, induced terminal sprouting and terminal withdrawal, but no muscle fiber atrophy. Consistent with this observation, M(2)(-/-) but no other mAChR mutant mice exhibited spontaneous sprouting accompanied by extensive loss of parental terminal arbors. Terminal sprouting, however, seemed not to be the causative defect because partial loss of terminal branches was common even in the M(2)(-/-) NMJs without sprouting. Moreover, compensatory sprouting after paralysis or partial denervation was normal in mice deficient in M(2) or other mAChR subtypes. We also found that many NMJs of M(5)(-/-) mice were exceptionally small and reduced in proportion to the size of parental muscle fibers. These findings show that axon terminals are unstable without M(2) and that muscle fiber growth is defective without M(5). Subtype-specific muscarinic signaling provides a novel means for coordinating activity-dependent development and maintenance of the tripartite synapse.

  8. Neurocognitive and Behavioral Indexes for Identifying the Amnestic Subtypes of Mild Cognitive Impairment.

    PubMed

    Cid-Fernández, Susana; Lindín, Mónica; Díaz, Fernando

    2017-09-01

    Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer's disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants).

  9. Neurocognitive and Behavioral Indexes for Identifying the Amnestic Subtypes of Mild Cognitive Impairment

    PubMed Central

    Cid-Fernández, Susana; Lindín, Mónica; Díaz, Fernando

    2017-01-01

    Early identification of amnestic mild cognitive impairment (aMCI) subtypes is important for early diagnosis and prognosis of Alzheimer’s disease. Healthy, single-domain (sdaMCI) and multiple-domain aMCI (mdaMCI) participants performed an auditory-visual distraction-attention task. Event-related brain potentials (ERPs) were recorded while the participants performed the task to evaluate Go/NoGo N2 and P3 ERP components. The results showed the expected behavioral and cognitive decline in mdaMCI participants relative to controls (fewer hits, longer reaction times [RTs], slightly smaller Go-N2 and NoGo-N2 amplitudes), while sdaMCI participants showed some decline (slightly longer RTs, smaller Go- and NoGo-N2 amplitudes) along with some unexpected results (a late positive slow wave, PSW) and good levels of execution. In addition, some of these parameters proved to be useful markers. Thus, the number of hits was the best marker for diagnosing mdaMCI participants (distinguishing them from controls, from sdaMCI participants, and from both groups together), while the PSW amplitude was the best marker for diagnosing sdaMCI participants (distinguishing them from controls, and from control & mdaMCI participants). PMID:28869473

  10. Clinically relevant molecular subtypes in leiomyosarcoma

    PubMed Central

    Guo, Xiangqian; Jo, Vickie Young; Mills, Anne M.; Zhu, Shirley X.; Lee, Cheng-Han; Espinosa, Inigo; Nucci, Marisa Rose; Varma, Sushama; Forgó, Erna; Hastie, Trevor; Anderson, Sharon; Ganjoo, Kristen; Beck, Andrew H.; West, Robert B.; Fletcher, Christopher; van de Rijn, Matt

    2015-01-01

    Purpose Leiomyosarcoma (LMS) is a malignant neoplasm with smooth muscle differentiation. Little is known about its molecular heterogeneity and no targeted therapy currently exists for LMS. Recognition of different molecular subtypes is necessary to evaluate novel therapeutic options. In a previous study on 51 LMS, we identified three molecular subtypes in LMS. The current study was performed to determine whether the existence of these subtypes could be confirmed in independent cohorts. Experimental Design 99 cases of LMS were expression profiled with 3′end RNA-Sequencing (3SEQ). Consensus Clustering was conducted to determine the optimal number of subtypes. Results We identified 3 LMS molecular subtypes and confirmed this finding by analyzing publically available data on 82 LMS from The Cancer Genome Atlas (TCGA). We identified two new FFPE tissue-compatible diagnostic immunohistochemical markers; LMOD1 for subtype I LMS and ARL4C for subtype II LMS. An LMS tissue microarray with known clinical outcome was used to show that subtype I LMS is associated with good outcome in extrauterine LMS while subtype II LMS is associated with poor prognosis in both uterine and extrauterine LMS. The LMS subtypes showed significant differences in expression levels for genes for which novel targeted therapies are being developed, suggesting that LMS subtypes may respond differentially to these targeted therapies. Conclusion We confirm the existence of 3 molecular subtypes in LMS using two independent datasets and show that the different molecular subtypes are associated with distinct clinical outcomes. The findings offer an opportunity for treating LMS in a subtype-specific targeted approach. PMID:25896974

  11. Choline acetyltransferase-like immunoreactivity in a physiologically distinct subtype of olfactory nonspiking local interneurons in the cockroach (periplaneta americana).

    PubMed

    Fusca, Debora; Husch, Andreas; Baumann, Arnd; Kloppenburg, Peter

    2013-10-15

    Behavioral and physiological studies have shown that local interneurons are pivotal for processing odor information in the insect antennal lobe. They mediate inhibitory and excitatory interactions between the glomerular pathways and ultimately shape the tuning profile of projection neurons. To identify putative cholinergic local interneurons in the antennal lobe of Periplaneta americana, an antibody raised against the biosynthetic enzyme choline acetyltransferase (ChAT) was applied to individual morphologically and electrophysiologically characterized local interneurons. In nonspiking type IIa1 local interneurons, which were classified in this study, we found ChAT-like immunoreactivity suggesting that they are most likely excitatory. This is a well-defined population of neurons that generates Ca(2+) -driven spikelets upon depolarization and stimulation with odorants, but not Na(+) -driven action potentials, because they lack voltage-activated transient Na(+) currents. The nonspiking type IIa2 and type IIb local interneurons, in which Ca(2+) -driven spikelets were absent, had no ChAT-like immunoreactivity. The GABA-like immunoreactive, spiking type I local interneurons had no ChAT-like immunoreactivity. In addition, we showed that uniglomerular projection neurons with cell bodies located in the ventral portion of the ventrolateral somata group and projections along the inner antennocerebral tract exhibited ChAT-like immunoreactivity. Assigning potential transmitters and neuromodulators to distinct morphological and electrophysiological types of antennal lobe neurons is an important prerequisite for a detailed understanding of odor information processing in insects.

  12. An effective tool for identifying HIV-1 subtypes B, C, CRF01_AE, their recombinant forms, and dual infections in Southeast Asia by the multi-region subtype specific PCR (MSSP) assay.

    PubMed

    Sakkhachornphop, Supachai; Kijak, Gustavo H; Beyrer, Chris; Razak, Myat Htoo; Sanders-Buell, Eric; Jittiwutikarn, Jaroon; Suriyanon, Vinai; Robb, Merlin L; Kim, Jerome H; Celentano, David D; McCutchan, Francine E; Tovanabutra, Sodsai

    2015-06-01

    The RV144 Thai vaccine trial has been the only vaccine study to show efficacy in preventing HIV infection. Ongoing molecular surveillance of HIV-1 in Southeast Asia is vital for vaccine development and evaluation. In this study a novel tool, the multi-region subtype specific PCR (MSSP) assay, that was able to identify subtypes B, C, CRF01_AE for Thailand, other Southeast Asian countries, India and China is described. The MSSP assay is based on a nested PCR strategy and amplifies eight short regions distributed along the HIV-1 genome using subtype-specific primers. A panel of 41 clinical DNA samples obtained primarily from opiate users in northern Thailand was used to test the assay performance. The MSSP assay provided 73-100% sensitivity and 100% specificity for the three subtypes in each genome region. The assay was then field-tested on 337 sera from HIV infected northern Thai drug users collected between 1999 and 2002. Subtype distribution was CRF01_AE 77.4% (n=261), subtype B 3.3% (n=11), CRF01_AE/B recombinant 12.2% (n=41), CRF01_AE/C recombinant 0.6% (n=2), and non-typeable 6.5% (n=22). The MSSP assay is a simple, cost-effective, and accurate genotyping tool for laboratory settings with limited resources and is sensitive enough to capture the recombinant genomes and dual infections.

  13. Benzodiazepine-induced anxiolysis and reduction of conditioned fear are mediated by distinct GABAA receptor subtypes in mice.

    PubMed

    Smith, Kiersten S; Engin, Elif; Meloni, Edward G; Rudolph, Uwe

    2012-08-01

    GABA(A) receptor modulating drugs such as benzodiazepines (BZs) have been used to treat anxiety disorders for over five decades. In order to determine whether the same or different GABA(A) receptor subtypes are necessary for the anxiolytic-like action of BZs in unconditioned anxiety and conditioned fear models, we investigated the role of different GABA(A) receptor subtypes by challenging wild type, α1(H101R), α2(H101R) and α3(H126R) mice bred on the C57BL/6J background with diazepam or chlordiazepoxide in the elevated plus maze and the fear-potentiated startle paradigms. Both drugs significantly increased open arm exploration in the elevated plus maze in wild type, α1(H101R) and α3(H126R), but this effect was abolished in α2(H101R) mice; these were expected results based on previous published results. In contrast, while administration of diazepam and chlordiazepoxide significantly attenuated fear-potentiated startle (FPS) in wild type mice and α3(H126R) mice, the fear-reducing effects of these drugs were absent in both α1(H101R) and α2(H101R) point mutants, indicating that both α1- and α2-containing GABA(A) receptors are necessary for BZs to exert their effects on conditioned fear responses. Our findings illustrate both an overlap and a divergence between the GABA(A) receptor subtype requirements for the impact of BZs, specifically that both α1- and α2-containing GABA(A) receptors are necessary for BZs to reduce conditioned fear whereas only α2-containing GABA(A) receptors are needed for BZ-induced anxiolysis in unconditioned tests of anxiety. This raises the possibility that GABAergic pharmacological interventions for specific anxiety disorders can be differentially tailored. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Distinctive Patterns of Three-Dimensional Arterial Spin-Labeled Perfusion Magnetic Resonance Imaging in Subtypes of Acute Ischemic Stroke.

    PubMed

    Kohno, Naoto; Okada, Kazunori; Yamagata, Shingo; Takayoshi, Hiroyuki; Yamaguchi, Shuhei

    2016-07-01

    Ischemic penumbra in acute ischemic stroke (AIS) can be evaluated using arterial spin-labeled (ASL) perfusion magnetic resonance imaging (MRI). We used three-dimensional ASL-MRI to examine patients with different stroke subtypes and the clinical utility of the method within 24 hours of AIS onset. The 55 male and 48 female patients (mean age, 79.0 years) underwent diffusion-weighted imaging (DWI), fluid-attenuated inversion recovery imaging, magnetic resonance angiography, and pulsed continuous ASL perfusion imaging to determine stroke subtype, hypoperfused ASL area, and neurological deficit severity (National Institutes of Health Stroke Scale). Arterial transit artifacts, indicative of occlusive regions or collateral flow, and other stroke indices were compared. ASL hypoperfusion was detected in 3 of 9 patients with transient ischemic attack (TIA), 2 of 27 patients with lacunar infarction (LI), 19 of 31 patients with atherothrombotic infarction (AT), and 30 of 36 patients with cardiogenic embolic infarction (CE). ASL abnormalities were significantly less frequent in LI than in AT and CE, and more frequent in CE than in TIA. ASL abnormalities were more prevalent in patients with medium-to-large DWI-assessed lesions than in those with small lesions on DWI. Patients with medium-sized lesions following AT and CE had a high frequency of diffusion-perfusion mismatch. In 4 of the 5 patients who underwent intravenous thrombolytic therapy, ASL hypoperfusion and diffusion-perfusion mismatch were improved and the occluded arteries were recanalized. ASL perfusion studies may provide useful clinical information allowing diffusion-perfusion mismatch detection and treatment selection in AIS patients, depending on stroke subtype. Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  15. Subtypes of paranoia in a nonclinical sample.

    PubMed

    Combs, Dennis R; Penn, David L; Chadwick, Paul; Trower, Peter; Michael, Christopher O; Basso, Michael R

    2007-11-01

    Previous research has proposed that there may be subtypes of paranoia with different patterns of performance on symptom and clinical measures. However, there has been little empirical examination of whether distinct subtypes actually exist. Recent research has suggested that paranoia can be found in normal individuals and exists on a continuum. Thus, it is possible that evidence for subtypes of paranoia can be derived from nonclinical samples. From a total of 723 participants, we identified 114 college students who showed elevated levels of paranoia as determined by two measures of paranoid ideation. The remaining sample of 609 persons served as the nonparanoid control group. All participants completed measures of depression, self-esteem, and social anxiety. Scores from the high subclinical group was subjected to cluster analysis to derive homogeneous subtypes. Participants also completed a measure of attributional style, the IPSAQ, which was used to validate the subtypes and was not used in the cluster analysis. Based on the cluster analysis, three subtypes were derived. Each subtype showed a different pattern of scores on measures of depression, self-esteem, and anxiety. There were also additional differences on the externalising and personalising bias scores from the IPSAQ between the subtypes. We conclude that there is preliminary evidence for the presence of subtypes among nonclinical samples and discuss the patterns of performance in relation to previous research on subtypes of paranoia. The implications of these subtypes for the study of paranoia are discussed.

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

    PubMed

    Henry, C E; Emmanuel, C; Lambie, N; Loo, C; Kan, B; Kennedy, C J; de Fazio, A; Hacker, N F; Ford, C E

    2017-06-01

    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. To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. 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. 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. 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. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  17. Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain

    SciTech Connect

    Sumners, C.; Wei Tang; Zelezna, B.; Raizada, M.K. )

    1991-09-01

    Both neurons and astrocytes contain specific receptors for angiotensin II (AII). The authors used selective ligands for the AT{sub 1} and AT{sub 2} types of AII receptors to investigate the expression of functional receptor subtypes in astrocyte cultures and neuron cultures from 1-day-old (neonatal) rat brain. In astrocyte cultures, competition of {sup 125}I-labeled AII ({sup 125}I-AII) specific binding with AT{sub 1} (DuP753) or AT{sub 2} {l brace}PD123177, CGP42112A, (Phe(p-NH{sub 2}){sup 6})AII{r brace} selective receptor ligands revealed a potency series of AII > DuP753 > > > CGP42112A > (Phe(p-NH{sub 2}){sup 6})AII > PD123177. These results suggest a predominance of the AT{sub 1} receptor subtype in neonatal astrocytes. {sup 125}I-AII specific binding to neonate neuronal cultures was reduced 73-84% by 1 {mu} MPD123177, and the residual {sup 125}I-AII specific binding was eliminated by DuP753. The results suggest that astrocyte cultures from neonatal rat brains contain predominantly AT{sub 1} receptors that are coupled to a stimulation of inositophospholipid hydrolysis. In contrast, neuron cultures from neonatal rat brain contain mostly AT{sub 2} receptors that are coupled to a reduction in basal cGMP levels, but a smaller population of AT{sub 1} receptors is also present in these neurons.

  18. Cluster analysis for identifying sub-types of tinnitus: a positron emission tomography and voxel-based morphometry study.

    PubMed

    Schecklmann, Martin; Lehner, Astrid; Poeppl, Timm B; Kreuzer, Peter M; Hajak, Göran; Landgrebe, Michael; Langguth, Berthold

    2012-11-16

    Tinnitus is a heterogeneous disorder with respect to its etiology and phenotype. Thus, the identification of sub-types implicates high relevance for treatment recommendations. For this aim, we used cluster analysis of patients for which clinical data, positron-emission tomography (PET) data and voxel-based morphometry (VBM) data were available. 44 patients with chronic tinnitus were included in this analysis. On a phenotypical level, we used tinnitus distress, duration, and laterality for clustering. To correct PET and VBM data for age, gender, and hearing, we built up a design matrix including these variables as regressors and extracted the residuals. We applied Ward's clustering method and forced cluster analysis to divide the data into two groups for both imaging and phenotypical data. On a phenotypical level the clustered groups differed only in tinnitus laterality (uni- vs. bilateral tinnitus), but not in tinnitus duration, distress, age, gender, and hearing. For grey matter volume, groups differed mainly in frontal, cingulate, temporal, and thalamic areas. For glucose metabolism, groups differed in temporal and parietal areas. The correspondence of classification was near chance level for the interrelationship of all three data set clusters. Thus, we showed that clustering according to imaging data is feasible and might depict a new approach for identifying tinnitus sub-types. However, it remains an open question to what extent the phenotypical and imaging levels may be interrelated. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

  19. Identifying Clinically Distinct Subgroups of Self-Injurers among Young Adults: A Latent Class Analysis

    ERIC Educational Resources Information Center

    Klonsky, E. David; Olino, Thomas M.

    2008-01-01

    High rates of nonsuicidal self-injury (NSSI; 14%-17%) in adolescents and young adults suggest that some self-injurers may exhibit more or different psychiatric problems than others. In the present study, the authors utilized a latent class analysis to identify clinically distinct subgroups of self-injurers. Participants were 205 young adults with…

  20. Non-Ceruloplasmin Copper Distinguishes A Distinct Subtype of Alzheimer's Disease: A Study of EEG-Derived Brain Activity.

    PubMed

    Tecchio, Franca; Vecchio, Fabrizio; Ventriglia, Mariacarla; Porcaro, Camillo; Miraglia, Francesca; Siotto, Mariacristina; Rossini, Paolo M; Rongioletti, Mauro; Squitti, Rosanna

    2016-01-01

    Meta-analyses show that percentages of non-Cp-Cu-copper that is not bound to ceruloplasmin (also known as 'free' copper)-in serum are higher in Alzheimer's disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp-Cu cut-off sustains the existence of a copper AD metabolic subtype. Non-Cp-Cu abnormalities correlated with alterations of electroencephalographic rhythms (EEG). We aimed to determine whether an EEG-derived brain cortical rhythm's heterogeneity between two AD groups stratified on the basis of a copper marker. We assessed levels of copper, ceruloplasmin, Non-Cp-Cu, and the APOE4 genotype in 67 AD patients and compared resting EEG-derived eLORETA cortical rhythms between AD groups stratified in terms of 'Normal' and 'High' non-Cp-Cu. The High non-Cp-Cu group experienced a lower power in all bands (0.2-48 Hz) in the parietal cortices (p=0.019) and a more limited alpha band (8-13 Hz) power in the sensory lobes (temporal, occipital, and parietal p>0.05 consistently) than the Normal non-Cp-Cu AD group. When corrected for MMSE, the non-Cp-Cu levels correlated with a reduction of high-frequency brain activity (from high alpha to gamma, 10.5-48 Hz). This neurophysiological heterogeneity in EEG-derived brain cortical rhythms between the two AD groups sustains a copper AD metabolic subtype; Non-Cp-Cu is a marker of this copper AD.

  1. Functional genomics identifies neural stem cell sub-type expression profiles and genes regulating neuroblast homeostasis

    PubMed Central

    Carney, Travis D.; Miller, Michael R.; Robinson, Kristin J.; Bayraktar, Omer A.; Osterhout, Jessica A.; Doe, Chris Q.

    2014-01-01

    The Drosophila larval central brain contains about 10,000 differentiated neurons and 200 scattered neural progenitors (neuroblasts), which can be further subdivided into ~95 type I neuroblasts and eight type II neuroblasts per brain lobe. Only type II neuroblasts generate self-renewing intermediate neural progenitors (INPs), and consequently each contributes more neurons to the brain, including much of the central complex. We characterized six different mutant genotypes that lead to expansion of neuroblast numbers; some preferentially expand type II or type I neuroblasts. Transcriptional profiling of larval brains from these mutant genotypes versus wild-type allowed us to identify small clusters of transcripts enriched in type II or type I neuroblasts, and we validated these clusters by gene expression analysis. Unexpectedly, only a few genes were found to be differentially expressed between type I/II neuroblasts, suggesting that these genes play a large role in establishing the different cell types. We also identified a large group of genes predicted to be expressed in all neuroblasts but not neurons. We performed a neuroblast-specific, RNAi-based functional screen and identified 84 genes that are required to maintain proper neuroblast numbers; all have conserved mammalian orthologs. These genes are excellent candidates for regulating neural progenitor self-renewal in Drosophila and mammals. PMID:22061480

  2. An integrated genomics approach identifies drivers of proliferation in luminal-subtype human breast cancer.

    PubMed

    Gatza, Michael L; Silva, Grace O; Parker, Joel S; Fan, Cheng; Perou, Charles M

    2014-10-01

    Elucidating the molecular drivers of human breast cancers requires a strategy that is capable of integrating multiple forms of data and an ability to interpret the functional consequences of a given genetic aberration. Here we present an integrated genomic strategy based on the use of gene expression signatures of oncogenic pathway activity (n = 52) as a framework to analyze DNA copy number alterations in combination with data from a genome-wide RNA-mediated interference screen. We identify specific DNA amplifications and essential genes within these amplicons representing key genetic drivers, including known and new regulators of oncogenesis. The genes identified include eight that are essential for cell proliferation (FGD5, METTL6, CPT1A, DTX3, MRPS23, EIF2S2, EIF6 and SLC2A10) and are uniquely amplified in patients with highly proliferative luminal breast tumors, a clinical subset of patients for which few therapeutic options are effective. This general strategy has the potential to identify therapeutic targets within amplicons through an integrated use of genomic data sets.

  3. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1

    SciTech Connect

    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.

  4. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients

    PubMed Central

    van der Pouw Kraan, T C T M; Wijbrandts, C A; van Baarsen, L G M; Voskuyl, A E; Rustenburg, F; Baggen, J M; Ibrahim, S M; Fero, M; Dijkmans, B A C; Tak, P P; Verweij, C L

    2007-01-01

    Background Rheumatoid arthritis (RA) is a heterogeneous disease with unknown cause. Aim To identify peripheral blood (PB) gene expression profiles that may distinguish RA subtypes. Methods Large‐scale expression profiling by cDNA microarrays was performed on PB from 35 patients and 15 healthy individuals. Differential gene expression was analysed by significance analysis of microarrays (SAM), followed by gene ontology analysis of the significant genes. Gene set enrichment analysis was applied to identify pathways relevant to disease. Results A substantially raised expression of a spectrum of genes involved in immune defence was found in the PB of patients with RA compared with healthy individuals. SAM analysis revealed a highly significant elevated expression of interferon (IFN) type I regulated genes in patients with RA compared with healthy individuals, which was confirmed by gene ontology and pathway analysis, suggesting that this pathway was activated systemically in RA. A quantitative analysis revealed that increased expression of IFN‐response genes was characteristic of approximately half of the patients (IFNhigh patients). Application of pathway analysis revealed that the IFNhigh group was largely different from the controls, with evidence for upregulated pathways involved in coagulation and complement cascades, and fatty acid metabolism, while the IFNlow group was similar to the controls. Conclusion The IFN type I signature defines a subgroup of patients with RA, with a distinct biomolecular phenotype, characterised by increased activity of the innate defence system, coagulation and complement cascades, and fatty acid metabolism. PMID:17223656

  5. Non-Ceruloplasmin Copper Distincts Subtypes in Alzheimer's Disease: a Genetic Study of ATP7B Frequency.

    PubMed

    Squitti, Rosanna; Ventriglia, Mariacarla; Gennarelli, Massimo; Colabufo, Nicola A; El Idrissi, Imane Ghafir; Bucossi, Serena; Mariani, Stefania; Rongioletti, Mauro; Zanetti, Orazio; Congiu, Chiara; Rossini, Paolo M; Bonvicini, Cristian

    2017-01-01

    Meta-analyses show that serum copper non-bound-to-ceruloplasmin (non-Cp-Cu) is higher in patients with Alzheimer's disease (AD). ATP7B gene variants associate with AD, modulating the size of non-Cp-Cu pool. However, a dedicated genetic study comparing AD patients after stratification for a copper biomarker to demonstrate the existence of a copper subtype of AD has not yet been carried out. An independent patient sample of 287 AD patients was assessed for non-Cp-Cu serum concentrations, rs1801243, rs1061472, and rs732774 ATP7B genetic variants and the APOE4 genotype. Patients were stratified into two groups based on a non-Cp-Cu cutoff (1.9 μM). Single-locus and haplotype-group analyses were performed to define their frequencies in dependence of the non-Cp-Cu group. The two AD subgroups did not differ regarding age, sex, MMSE score, or APOE4 frequency allele, while they did differ regarding non-Cp-Cu concentrations in serum, allele, genotype, and haplotype frequencies of rs1061472 A > G and rs732774 C > T after multiple testing corrections. AD patients with a GG genotype had a 1.76-fold higher risk of having a non-Cp-Cu higher than 1.9 μmol/L (p = 0.029), and those with a TT genotype for rs732774 C > T of 1.8-fold (p = 0.018). After 100,000 permutations for multiple testing corrections, the haplotype containing the AC alleles appeared more frequently in AD patients with normal non-Cp-Cu [43 vs. 33 %; Pm = 0.03], while the haplotype containing the GT risk alleles appeared more frequently in the higher non-Cp-Cu AD (66 vs. 55 %; Pm = 0.01). Genetic heterogeneity sustains a copper AD metabolic subtype; non-Cp-Cu is a marker of this copper AD.

  6. IMP-27, a Unique Metallo-β-Lactamase Identified in Geographically Distinct Isolates of Proteus mirabilis.

    PubMed

    Dixon, Nyssa; Fowler, Randal C; Yoshizumi, A; Horiyama, Tsukasa; Ishii, Y; Harrison, Lucas; Geyer, Chelsie N; Moland, Ellen Smith; Thomson, Kenneth; Hanson, Nancy D

    2016-10-01

    A novel metallo-β-lactamase gene, blaIMP-27, was identified in unrelated Proteus mirabilis isolates from two geographically distinct locations in the United States. Both isolates harbor blaIMP-27 as part of the first gene cassette in a class 2 integron. Antimicrobial susceptibility testing indicated susceptibility to aztreonam, piperacillin-tazobactam, and ceftazidime but resistance to ertapenem. However, hydrolysis assays indicated that ceftazidime was a substrate for IMP-27. Copyright © 2016 Dixon et al.

  7. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods.

    PubMed

    Reese, Jessica A; Li, Xiaoning; Hauben, Manfred; Aster, Richard H; Bougie, Daniel W; Curtis, Brian R; George, James N; Vesely, Sara K

    2010-09-23

    Drug-induced immune thrombocytopenia (DITP) is often suspected in patients with acute thrombocytopenia unexplained by other causes, but documenting that a drug is the cause of thrombocytopenia can be challenging. To provide a resource for diagnosis of DITP and for drug safety surveillance, we analyzed 3 distinct methods for identifying drugs that may cause thrombocytopenia. (1) Published case reports of DITP have described 253 drugs suspected of causing thrombocytopenia; using defined clinical criteria, 87 (34%) were identified with evidence that the drug caused thrombocytopenia. (2) Serum samples from patients with suspected DITP were tested for 202 drugs; drug-dependent, platelet-reactive antibodies were identified for 67 drugs (33%). (3) The Food and Drug Administration's Adverse Event Reporting System database was searched for drugs associated with thrombocytopenia by use of data mining algorithms; 1444 drugs had at least 1 report associated with thrombocytopenia, and 573 (40%) drugs demonstrated a statistically distinctive reporting association with thrombocytopenia. Among 1468 drugs suspected of causing thrombocytopenia, 102 were evaluated by all 3 methods, and 23 of these 102 drugs had evidence for an association with thrombocytopenia by all 3 methods. Multiple methods, each with a distinct perspective, can contribute to the identification of drugs that can cause thrombocytopenia.

  8. Can IgG4 Levels Identify the Ulcerative Colitis Subtype of Inflammatory Bowel Disease?

    PubMed Central

    Faria, Ricardo Jacaranda; Clemente, Cintia Mendes; Carneiro, Fabiana P.; Santos-Neto, Leopoldo

    2015-01-01

    Background Pancreatitis and exocrine pancreatic insufficiency may occur as extraintestinal manifestations of inflammatory bowel disease. Recently, autoimmune pancreatitis and colitis have been described as presentations of IgG4-related disease. IgG4+ plasma cells have been identified in colon tissue from patients with refractory forms of inflammatory bowel disease. The presence of elevated serum/tissue levels of IgG4 and the frequency of exocrine pancreatic insufficiency in inflammatory bowel disease are still a source of controversy. Our aim was to investigate the meaning of elevated IgG4 levels in patients with inflammatory bowel disease. Methods A cross-sectional study analyzed 56 patients with a diagnosis of inflammatory bowel disease recruited by convenience sampling from two tertiary centers in Midwestern Brazil. All patients underwent fecal pancreatic elastase testing for detection of exocrine pancreatic insufficiency and serum IgG4 measurement. Findings were correlated with clinical and epidemiological data and disease activity. Results Elevated serum IgG4 levels were found in 10 patients, and were most frequent in ulcerative colitis (nine cases), with a prevalence ratio of 16.42 (95% CI: 3.32 - 79.58). Ten patients (10 of 56, 17.8%) were diagnosed with exocrine pancreatic insufficiency, which did not correlate with disease activity, and serum IgG4 levels. Conclusion Exocrine pancreatic insufficiency is prevalent in patients with inflammatory bowel disease, but it is not associated with elevated serum IgG4 levels. The high prevalence of elevated serum IgG4 in ulcerative colitis suggests that this parameter has potential for use as a diagnostic biomarker. PMID:27785293

  9. A Framework for Identifying Distinct Multipollutant Profiles in Air Pollution Data

    PubMed Central

    Austin, Elena; Coull, Brent; Thomas, Dylan; Koutrakis, Petros

    2013-01-01

    BACKGROUND The importance of describing, understanding and regulating multi-pollutant mixtures has been highlighted by the US National Academy of Science and the Environmental Protection Agency. Furthering our understanding of the health effects associated with exposure to mixtures of pollutants will lead to the development of new multi-pollutant National Air Quality Standards. OBJECTIVES Introduce a framework within which diagnostic methods that are based on our understanding of air pollution mixtures are used to validate the distinct air pollutant mixtures identified using cluster analysis. METHODS: S ix years of daily gaseous and particulate air pollution data collected in Boston, MA were classified solely on their concentration profiles. Classification was performed using k-means partitioning and hierarchical clustering. Diagnostic strategies were developed to identify the most optimal clustering. RESULTS The optimal solution used k-means analysis and contained five distinct groups of days. Pollutant concentrations and elemental ratios were computed in order to characterize the differences between clusters. Time-series regression confirmed that the groups differed in their chemical compositions. The mean values of meteorological parameters were estimated for each group and air mass origin between clusters was examined using back-trajectory analysis. This allowed us to link the distinct physico-chemical characteristics of each cluster to characteristic weather patterns and show that different clusters were associated with distinct air mass origins. CONCLUSIONS This analysis yielded a solution that was robust to outlier points and interpretable based on chemical, physical and meteorological characteristics. This novel method provides an exciting tool with which to identify and further investigate multi-pollutant mixtures and link them directly to health effects studies. PMID:22584082

  10. Genome-Wide Association Identifies Regulatory Loci Associated with Distinct Local Histogram Emphysema Patterns

    PubMed Central

    Cho, Michael H.; San José Estépar, Raúl; McDonald, Merry-Lynn N.; Laird, Nan; Beaty, Terri H.; Washko, George; Crapo, James D.; Silverman, Edwin K.

    2014-01-01

    Rationale: Emphysema is a heritable trait that occurs in smokers with and without chronic obstructive pulmonary disease. Emphysema occurs in distinct pathologic patterns, but the genetic determinants of these patterns are unknown. Objectives: To identify genetic loci associated with distinct patterns of emphysema in smokers and investigate the regulatory function of these loci. Methods: Quantitative measures of distinct emphysema patterns were generated from computed tomography scans from smokers in the COPDGene Study using the local histogram emphysema quantification method. Genome-wide association studies (GWAS) were performed in 9,614 subjects for five emphysema patterns, and the results were referenced against enhancer and DNase I hypersensitive regions from ENCODE and Roadmap Epigenomics cell lines. Measurements and Main Results: Genome-wide significant associations were identified for seven loci. Two are novel associations (top single-nucleotide polymorphism rs379123 in MYO1D and rs9590614 in VMA8) located within genes that function in cell-cell signaling and cell migration, and five are in loci previously associated with chronic obstructive pulmonary disease susceptibility (HHIP, IREB2/CHRNA3, CYP2A6/ADCK, TGFB2, and MMP12). Five of these seven loci lay within enhancer or DNase I hypersensitivity regions in lung fibroblasts or small airway epithelial cells, respectively. Enhancer enrichment analysis for top GWAS associations (single-nucleotide polymorphisms associated at P < 5 × 10−6) identified multiple cell lines with significant enhancer enrichment among top GWAS loci, including lung fibroblasts. Conclusions: This study demonstrates for the first time genetic associations with distinct patterns of pulmonary emphysema quantified by computed tomography scan. Enhancer regions are significantly enriched among these GWAS results, with pulmonary fibroblasts among the cell types showing the strongest enrichment. PMID:25006744

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

    PubMed

    Chang, Yeun-Chung; Huang, Yao-Sian; Huang, Chiun-Sheng; Chen, Jeon-Hor; Chang, Ruey-Feng

    2014-08-01

    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. 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. 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. 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. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

    PubMed

    McKay, James D; Hung, Rayjean J; Han, Younghun; Zong, Xuchen; Carreras-Torres, Robert; Christiani, David C; Caporaso, Neil E; Johansson, Mattias; Xiao, Xiangjun; Li, Yafang; Byun, Jinyoung; Dunning, Alison; Pooley, Karen A; Qian, David C; Ji, Xuemei; Liu, Geoffrey; Timofeeva, Maria N; Bojesen, Stig E; Wu, Xifeng; Le Marchand, Loic; Albanes, Demetrios; Bickeböller, Heike; Aldrich, Melinda C; Bush, William S; Tardon, Adonina; Rennert, Gad; Teare, M Dawn; Field, John K; Kiemeney, Lambertus A; Lazarus, Philip; Haugen, Aage; Lam, Stephen; Schabath, Matthew B; Andrew, Angeline S; Shen, Hongbing; Hong, Yun-Chul; Yuan, Jian-Min; Bertazzi, Pier Alberto; Pesatori, Angela C; Ye, Yuanqing; Diao, Nancy; Su, Li; Zhang, Ruyang; Brhane, Yonathan; Leighl, Natasha; Johansen, Jakob S; Mellemgaard, Anders; Saliba, Walid; Haiman, Christopher A; Wilkens, Lynne R; Fernandez-Somoano, Ana; Fernandez-Tardon, Guillermo; van der Heijden, Henricus F M; Kim, Jin Hee; Dai, Juncheng; Hu, Zhibin; Davies, Michael P A; Marcus, Michael W; Brunnström, Hans; Manjer, Jonas; Melander, Olle; Muller, David C; Overvad, Kim; Trichopoulou, Antonia; Tumino, Rosario; Doherty, Jennifer A; Barnett, Matt P; Chen, Chu; Goodman, Gary E; Cox, Angela; Taylor, Fiona; Woll, Penella; Brüske, Irene; Wichmann, H-Erich; Manz, Judith; Muley, Thomas R; Risch, Angela; Rosenberger, Albert; Grankvist, Kjell; Johansson, Mikael; Shepherd, Frances A; Tsao, Ming-Sound; Arnold, Susanne M; Haura, Eric B; Bolca, Ciprian; Holcatova, Ivana; Janout, Vladimir; Kontic, Milica; Lissowska, Jolanta; Mukeria, Anush; Ognjanovic, Simona; Orlowski, Tadeusz M; Scelo, Ghislaine; Swiatkowska, Beata; Zaridze, David; Bakke, Per; Skaug, Vidar; Zienolddiny, Shanbeh; Duell, Eric J; Butler, Lesley M; Koh, Woon-Puay; Gao, Yu-Tang; Houlston, Richard S; McLaughlin, John; Stevens, Victoria L; Joubert, Philippe; Lamontagne, Maxime; Nickle, David C; Obeidat, Ma'en; Timens, Wim; Zhu, Bin; Song, Lei; Kachuri, Linda; Artigas, María Soler; Tobin, Martin D; Wain, Louise V; Rafnar, Thorunn; Thorgeirsson, Thorgeir E; Reginsson, Gunnar W; Stefansson, Kari; Hancock, Dana B; Bierut, Laura J; Spitz, Margaret R; Gaddis, Nathan C; Lutz, Sharon M; Gu, Fangyi; Johnson, Eric O; Kamal, Ahsan; Pikielny, Claudio; Zhu, Dakai; Lindströem, Sara; Jiang, Xia; Tyndale, Rachel F; Chenevix-Trench, Georgia; Beesley, Jonathan; Bossé, Yohan; Chanock, Stephen; Brennan, Paul; Landi, Maria Teresa; Amos, Christopher I

    2017-07-01

    Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.

  13. Whole-genome screening identifies proteins localized to distinct nuclear bodies.

    PubMed

    Fong, Ka-Wing; Li, Yujing; Wang, Wenqi; Ma, Wenbin; Li, Kunpeng; Qi, Robert Z; Liu, Dan; Songyang, Zhou; Chen, Junjie

    2013-10-14

    The nucleus is a unique organelle that contains essential genetic materials in chromosome territories. The interchromatin space is composed of nuclear subcompartments, which are defined by several distinctive nuclear bodies believed to be factories of DNA or RNA processing and sites of transcriptional and/or posttranscriptional regulation. In this paper, we performed a genome-wide microscopy-based screening for proteins that form nuclear foci and characterized their localizations using markers of known nuclear bodies. In total, we identified 325 proteins localized to distinct nuclear bodies, including nucleoli (148), promyelocytic leukemia nuclear bodies (38), nuclear speckles (27), paraspeckles (24), Cajal bodies (17), Sam68 nuclear bodies (5), Polycomb bodies (2), and uncharacterized nuclear bodies (64). Functional validation revealed several proteins potentially involved in the assembly of Cajal bodies and paraspeckles. Together, these data establish the first atlas of human proteins in different nuclear bodies and provide key information for research on nuclear bodies.

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

    SciTech Connect

    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

    2012-09-10

    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.

  15. Identifying depressive subtypes in a large cohort study: results from the Netherlands Study of Depression and Anxiety (NESDA).

    PubMed

    Lamers, Femke; de Jonge, Peter; Nolen, Willem A; Smit, Johannes H; Zitman, Frans G; Beekman, Aartjan T F; Penninx, Brenda W J H

    2010-12-01

    The heterogeneity of depression in the current classification system remains a point of discussion in the psychiatric field, despite previous efforts to subclassify depressive disorders. Data-driven techniques may help to come to a more empirically based classification. This study aimed to identify depressive subtypes within a large cohort of subjects with depression. Baseline data from 818 persons with a DSM-IV diagnosis of current major depressive disorder or minor depression who participated in the Netherlands Study of Depression and Anxiety were used. Respondents were recruited in the community, in primary care, and in specialized mental health care from September 2004 through February 2007. Latent classes were derived from latent class analysis using 16 depressive symptoms from the Composite International Diagnostic Interview and the Inventory of Depressive Symptomatology. Classes were characterized using demographic, clinical psychiatric, psychosocial, and physical health descriptors. Three classes were identified: a severe melancholic class (prevalence, 46.3%), a severe atypical class (prevalence, 24.6%), and a class of moderate severity (prevalence, 29.1%). Both severe classes were characterized by more neuroticism (melancholic OR = 1.05 [95% CI, 1.01-1.10]; atypical OR = 1.07 [95% CI, 1.03-1.12]), more disability (melancholic OR = 1.07 [95% CI, 1.05-1.09]; atypical OR = 1.06 [95% CI, 1.04-1.07]), and less extraversion (melancholic OR = 0.95 [95% CI, 0.92-0.99]; atypical OR = 0.95 [95% CI, 0.92-0.99]) than the moderate class. Comparing the melancholic class with the atypical class revealed that the melancholic class had more smokers (atypical OR = 0.57 [95% CI, 0.39-0.84]) and more childhood trauma (atypical OR = 0.86 [95% CI, 0.74-1.00]), whereas the atypical class had more women (atypical OR = 1.52 [95% CI, 0.99-2.32]), a higher body mass index (atypical OR = 1.13 [95% CI, 1.09-1.17]), and more metabolic syndrome (atypical OR = 2.17 [95% CI, 1

  16. Does major depressive disorder with somatic delusions constitute a distinct subtype of major depressive disorder with psychotic features?

    PubMed

    Kamara, Taafoi S; Whyte, Ellen M; Mulsant, Benoit H; Peasley-Miklus, Catherine; Rothschild, Anthony J; Flint, Alastair J; Heo, Moonseong; Papademetriou, Eros; Mathis, Erin R; Meyers, Barnett S

    2009-01-01

    Among patients with major depression with psychotic features, little is known about the extent to which those with and without somatic delusions differ. The first 183 participants in the STOP-PD study were divided into two groups based on the presence or absence of somatic delusions and were compared on multiple demographic and clinical characteristics. In the multivariate analysis, those with somatic delusions reported more somatic symptoms, rated their health as worse, and were less likely to have persecutory delusions. Based on the methods we used, we could not detect meaningful differences between subjects with and without somatic delusions. This suggests that the presence of irrational somatic ideation does not define a distinct clinical subgroup among patients with psychotic depression. This finding needs to be replicated.

  17. Global DNA Methylation Analysis Identifies Two Discrete clusters of Pheochromocytoma with Distinct Genomic and Genetic Alterations

    PubMed Central

    Backman, Samuel; Maharjan, Rajani; Falk-Delgado, Alberto; Crona, Joakim; Cupisti, Kenko; Stålberg, Peter; Hellman, Per; Björklund, Peyman

    2017-01-01

    Pheochromocytomas and paragangliomas (PPGLs) are rare and frequently heritable neural-crest derived tumours arising from the adrenal medulla or extra-adrenal chromaffin cells respectively. The majority of PPGL tumours are benign and do not recur with distant metastases. However, a sizeable fraction of these tumours secrete vasoactive catecholamines into the circulation causing a variety of symptoms including hypertension, palpitations and diaphoresis. The genetic landscape of PPGL has been well characterized and more than a dozen genes have been described as recurrently mutated. Recent studies of DNA-methylation have revealed distinct clusters of PPGL that share DNA methylation patterns and driver mutations, as well as identified potential biomarkers for malignancy. However, these findings have not been adequately validated in independent cohorts. In this study we use an array-based genome-wide approach to study the methylome of 39 PPGL and 4 normal adrenal medullae. We identified two distinct clusters of tumours characterized by different methylation patterns and different driver mutations. Moreover, we identify genes that are differentially methylated between tumour subcategories, and between tumours and normal tissue. PMID:28327598

  18. Immunofluorescence identifies distinct subsets of endothelial cells in the human liver

    PubMed Central

    Strauss, Otto; Phillips, Anthony; Ruggiero, Katya; Bartlett, Adam; Dunbar, P. Rod

    2017-01-01

    As well as systemic vascular endothelial cells, the liver has specialised sinusoidal endothelial cells (LSEC). LSEC dysfunction has been documented in many diseased states yet their phenotype in normal human liver has not been comprehensively assessed. Our aim was to improve characterisation of subsets of endothelial cells and associated pericytes in the human liver. Immunofluorescence microscopy was performed on normal human liver tissue samples to assess endothelial and structural proteins in a minimum of three donors. LSEC are distributed in an acinar pattern and universally express CD36, but two distinctive subsets of LSEC can be identified in different acinar zones. Type 1 LSEC are CD36hiCD32−CD14−LYVE-1− and are located in acinar zone 1 of the lobule, while Type 2 LSEC are LYVE-1+CD32hiCD14+CD54+CD36mid-lo and are located in acinar zones 2 and 3 of the lobule. Portal tracts and central veins can be identified using markers for systemic vascular endothelia and pericytes, none of which are expressed by LSEC. In areas of low hydrostatic pressure LSEC are lined by stellate cells that express the pericyte marker CD146. Our findings identify distinctive populations of LSEC and distinguish these cells from adjacent stellate cells, systemic vasculature and pericytes in different zones of the liver acinus. PMID:28287163

  19. Distinct Host Tropism Protein Signatures to Identify Possible Zoonotic Influenza A Viruses.

    PubMed

    Eng, Christine L P; Tong, Joo Chuan; Tan, Tin Wee

    2016-01-01

    Zoonotic influenza A viruses constantly pose a health threat to humans as novel strains occasionally emerge from the avian population to cause human infections. Many past epidemic as well as pandemic strains have originated from avian species. While most viruses are restricted to their primary hosts, zoonotic strains can sometimes arise from mutations or reassortment, leading them to acquire the capability to escape host species barrier and successfully infect a new host. Phylogenetic analyses and genetic markers are useful in tracing the origins of zoonotic infections, but there are still no effective means to identify high risk strains prior to an outbreak. Here we show that distinct host tropism protein signatures can be used to identify possible zoonotic strains in avian species which have the potential to cause human infections. We have discovered that influenza A viruses can now be classified into avian, human, or zoonotic strains based on their host tropism protein signatures. Analysis of all influenza A viruses with complete proteome using the host tropism prediction system, based on machine learning classifications of avian and human viral proteins has uncovered distinct signatures of zoonotic strains as mosaics of avian and human viral proteins. This is in contrast with typical avian or human strains where they show mostly avian or human viral proteins in their signatures respectively. Moreover, we have found that zoonotic strains from the same influenza outbreaks carry similar host tropism protein signatures characteristic of a common ancestry. Our results demonstrate that the distinct host tropism protein signature in zoonotic strains may prove useful in influenza surveillance to rapidly identify potential high risk strains circulating in avian species, which may grant us the foresight in anticipating an impending influenza outbreak.

  20. Distinct Host Tropism Protein Signatures to Identify Possible Zoonotic Influenza A Viruses

    PubMed Central

    Eng, Christine L. P.; Tong, Joo Chuan; Tan, Tin Wee

    2016-01-01

    Zoonotic influenza A viruses constantly pose a health threat to humans as novel strains occasionally emerge from the avian population to cause human infections. Many past epidemic as well as pandemic strains have originated from avian species. While most viruses are restricted to their primary hosts, zoonotic strains can sometimes arise from mutations or reassortment, leading them to acquire the capability to escape host species barrier and successfully infect a new host. Phylogenetic analyses and genetic markers are useful in tracing the origins of zoonotic infections, but there are still no effective means to identify high risk strains prior to an outbreak. Here we show that distinct host tropism protein signatures can be used to identify possible zoonotic strains in avian species which have the potential to cause human infections. We have discovered that influenza A viruses can now be classified into avian, human, or zoonotic strains based on their host tropism protein signatures. Analysis of all influenza A viruses with complete proteome using the host tropism prediction system, based on machine learning classifications of avian and human viral proteins has uncovered distinct signatures of zoonotic strains as mosaics of avian and human viral proteins. This is in contrast with typical avian or human strains where they show mostly avian or human viral proteins in their signatures respectively. Moreover, we have found that zoonotic strains from the same influenza outbreaks carry similar host tropism protein signatures characteristic of a common ancestry. Our results demonstrate that the distinct host tropism protein signature in zoonotic strains may prove useful in influenza surveillance to rapidly identify potential high risk strains circulating in avian species, which may grant us the foresight in anticipating an impending influenza outbreak. PMID:26915079

  1. Functional Genetic Screen to Identify Interneurons Governing Behaviorally Distinct Aspects of Drosophila Larval Motor Programs.

    PubMed

    Clark, Matt Q; McCumsey, Stephanie J; Lopez-Darwin, Sereno; Heckscher, Ellie S; Doe, Chris Q

    2016-07-07

    Drosophila larval crawling is an attractive system to study rhythmic motor output at the level of animal behavior. Larval crawling consists of waves of muscle contractions generating forward or reverse locomotion. In addition, larvae undergo additional behaviors, including head casts, turning, and feeding. It is likely that some neurons (e.g., motor neurons) are used in all these behaviors, but the identity (or even existence) of neurons dedicated to specific aspects of behavior is unclear. To identify neurons that regulate specific aspects of larval locomotion, we performed a genetic screen to identify neurons that, when activated, could elicit distinct motor programs. We used 165 Janelia CRM-Gal4 lines-chosen for sparse neuronal expression-to ectopically express the warmth-inducible neuronal activator TrpA1, and screened for locomotor defects. The primary screen measured forward locomotion velocity, and we identified 63 lines that had locomotion velocities significantly slower than controls following TrpA1 activation (28°). A secondary screen was performed on these lines, revealing multiple discrete behavioral phenotypes, including slow forward locomotion, excessive reverse locomotion, excessive turning, excessive feeding, immobile, rigid paralysis, and delayed paralysis. While many of the Gal4 lines had motor, sensory, or muscle expression that may account for some or all of the phenotype, some lines showed specific expression in a sparse pattern of interneurons. Our results show that distinct motor programs utilize distinct subsets of interneurons, and provide an entry point for characterizing interneurons governing different elements of the larval motor program. Copyright © 2016 Clark et al.

  2. Functional Genetic Screen to Identify Interneurons Governing Behaviorally Distinct Aspects of Drosophila Larval Motor Programs

    PubMed Central

    Clark, Matt Q.; McCumsey, Stephanie J.; Lopez-Darwin, Sereno; Heckscher, Ellie S.; Doe, Chris Q.

    2016-01-01

    Drosophila larval crawling is an attractive system to study rhythmic motor output at the level of animal behavior. Larval crawling consists of waves of muscle contractions generating forward or reverse locomotion. In addition, larvae undergo additional behaviors, including head casts, turning, and feeding. It is likely that some neurons (e.g., motor neurons) are used in all these behaviors, but the identity (or even existence) of neurons dedicated to specific aspects of behavior is unclear. To identify neurons that regulate specific aspects of larval locomotion, we performed a genetic screen to identify neurons that, when activated, could elicit distinct motor programs. We used 165 Janelia CRM-Gal4 lines—chosen for sparse neuronal expression—to ectopically express the warmth-inducible neuronal activator TrpA1, and screened for locomotor defects. The primary screen measured forward locomotion velocity, and we identified 63 lines that had locomotion velocities significantly slower than controls following TrpA1 activation (28°). A secondary screen was performed on these lines, revealing multiple discrete behavioral phenotypes, including slow forward locomotion, excessive reverse locomotion, excessive turning, excessive feeding, immobile, rigid paralysis, and delayed paralysis. While many of the Gal4 lines had motor, sensory, or muscle expression that may account for some or all of the phenotype, some lines showed specific expression in a sparse pattern of interneurons. Our results show that distinct motor programs utilize distinct subsets of interneurons, and provide an entry point for characterizing interneurons governing different elements of the larval motor program. PMID:27172197

  3. Profiling of ARDS Pulmonary Edema Fluid Identifies a Metabolically Distinct Subset.

    PubMed

    Rogers, Angela J; Contrepois, Kevin; Wu, Manhong; Zheng, Ming; Peltz, Gary; Ware, Lorraine B; Matthay, Michael A

    2017-03-03

    There is considerable biologic and physiologic heterogeneity among patients who meet standard clinical criteria for acute respiratory distress syndrome (ARDS). In this study, we tested the hypothesis that there exists a sub-group of ARDS patients who exhibit a metabolically distinct profile. We examined undiluted pulmonary edema fluid obtained at the time of endotracheal intubation from 16 clinically phenotyped ARDS patients and 13 control patients with hydrostatic pulmonary edema. Non-targeted metabolic profiling was carried out on the undiluted edema fluid. Univariate and multivariate statistical analyses including principal components analysis (PCA) and partial least squares discriminant analysis (PLSDA) were conducted to find discriminant metabolites. 760 unique metabolites were identified in the pulmonary edema fluid of these 29 patients. We found that a subset of ARDS patients (6/16, 38%) presented a distinct metabolic profile with the overrepresentation of 235 metabolites compared to edema fluid from the other 10 ARDS patients, whose edema fluid metabolic profile was indistinguishable from those of the 13 control patients with hydrostatic edema. This "high metabolite" endotype was characterized by higher concentrations of metabolites belonging to all of the main metabolic classes including lipids, amino acids, and carbohydrates. This distinct group with high metabolite levels in the edema fluid was also associated with a higher mortality rate. Thus, metabolic profiling of the edema fluid of ARDS patients supports the hypothesis that there is considerable biologic heterogeneity among ARDS patients who meet standard clinical and physiologic criteria for ARDS.

  4. Antibody Responses to NY-ESO-1 in Primary Breast Cancer Identify a Subtype Target for Immunotherapy

    PubMed Central

    Hamaï, Ahmed; Duperrier-Amouriaux, Karine; Pignon, Pascale; Raimbaud, Isabelle; Memeo, Lorenzo; Colarossi, Cristina; Canzonieri, Vincenzo; Perin, Tiziana; Classe, Jean-Marc; Campone, Mario; Jézéquel, Pascal; Campion, Loïc

    2011-01-01

    The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)− invasive ductal carcinomas of high grade, including both HER2− and HER2+ tumors. In line with these results, we detected ESO expression in 20% of primary HR− BC, including both ESO Ab+ and Ab− patients, but not in HR+ BC. Interestingly, whereas expression levels in ESO+ BC were not significantly different between ESO Ab+ and Ab− patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR− (HER2− or HER2+) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy. PMID:21747904

  5. Antibody responses to NY-ESO-1 in primary breast cancer identify a subtype target for immunotherapy.

    PubMed

    Hamaï, Ahmed; Duperrier-Amouriaux, Karine; Pignon, Pascale; Raimbaud, Isabelle; Memeo, Lorenzo; Colarossi, Cristina; Canzonieri, Vincenzo; Perin, Tiziana; Classe, Jean-Marc; Campone, Mario; Jézéquel, Pascal; Campion, Loïc; Ayyoub, Maha; Valmori, Danila

    2011-01-01

    The highly immunogenic human tumor antigen NY-ESO-1 (ESO) is a target of choice for anti-cancer immune therapy. In this study, we assessed spontaneous antibody (Ab) responses to ESO in a large cohort of patients with primary breast cancer (BC) and addressed the correlation between the presence of anti-ESO Ab, the expression of ESO in the tumors and their characteristics. We found detectable Ab responses to ESO in 1% of the patients. Tumors from patients with circulating Ab to ESO exhibited common characteristics, being mainly hormone receptor (HR)⁻ invasive ductal carcinomas of high grade, including both HER2⁻ and HER2⁺ tumors. In line with these results, we detected ESO expression in 20% of primary HR⁻ BC, including both ESO Ab⁺ and Ab⁻ patients, but not in HR⁺ BC. Interestingly, whereas expression levels in ESO⁺ BC were not significantly different between ESO Ab⁺ and Ab⁻ patients, the former had, in average, significantly higher numbers of tumor-infiltrated lymph nodes, indicating that lymph node invasion may be required for the development of spontaneous anti-tumor immune responses. Thus, the presence of ESO Ab identifies a tumor subtype of HR⁻ (HER2⁻ or HER2⁺) primary BC with frequent ESO expression and, together with the assessment of antigen expression in the tumor, may be instrumental for the selection of patients for whom ESO-based immunotherapy may complement standard therapy.

  6. Differential activation of glutamate receptor subtypes on a single class of cells enables a neural oscillator to produce distinct behaviors.

    PubMed

    Spiro, J E

    1997-08-01

    Electric fish generate different types of abrupt modulations of their electric organ discharge (EOD) rhythm to convey specific social signals. Intracellular recordings were made from neurons of the medullary pacemaker nucleus, which generates and transmits the rhythm that drives the EOD, to study the neuronal basis of two such modulations of the regular EOD rhythm, sudden accelerations, and abrupt interruptions. Recordings were both in vivo, and in a new in vitro brain preparation of Hypopomus pinnicaudatus (order Gymnotiformes). In vivo recordings during triggered behaviors indicated that abrupt modulations of the EOD rhythm are generated in the medullary pacemaker nucleus at the level of the relay cells, which are the projection cells of the nucleus, and not the pacemaker cells. In the in vitro brain stem preparation, cells of the pacemaker nucleus were spontaneously and rhythmically active as in the intact animal. Distinct modulations of the pacemaker nucleus rhythm that closely resembled those seen during natural behaviors could be triggered by electrical stimulation of afferent fibers. Modulations of the rhythm also could be triggered by direct pharmacological activation of the relay cells. When non-N-methyl-D-aspartate (NMDA) receptors were activated, relay cells were transiently depolarized and generated bursts of synchronized action potentials. NMDA receptor activation, alternatively, initiated a prolonged depolarization in the relay cells, during which time they failed to relay the regular pacemaker rhythm. The two firing states of the relay cell directly correlate with sudden accelerations and abrupt interruptions of the EOD.

  7. Genetic profiling by single-nucleotide polymorphism-based array analysis defines three distinct subtypes of orbital meningioma.

    PubMed

    Ho, Cheng-Ying; Mosier, Stacy; Safneck, Janice; Salomao, Diva R; Miller, Neil R; Eberhart, Charles G; Gocke, Christopher D; Batista, Denise A S; Rodriguez, Fausto J

    2015-03-01

    Orbital meningiomas can be classified as primary optic nerve sheath (ON) meningiomas, primary intraorbital ectopic (Ob) meningiomas and spheno-orbital (Sph-Ob) meningiomas based on anatomic site. Single-nucleotide polymorphism (SNP)-based array analysis with the Illumina 300K platform was performed on formalin-fixed, paraffin-embedded tissue from 19 orbital meningiomas (5 ON, 4 Ob and 10 Sph-Ob meningiomas). Tumors were World Health Organization (WHO) grade I except for two grade II meningiomas, and one was NF2-associated. We found genomic alterations in 68% (13 of 19) of orbital meningiomas. Sph-Ob tumors frequently exhibited monosomy 22/22q loss (70%; 7/10) and deletion of chromosome 1p, 6q and 19p (50% each; 5/10). Among genetic alterations, loss of chromosome 1p and 6q were more frequent in clinically progressive tumors. Chromosome 22q loss also was detected in the majority of Ob meningiomas (75%; 3/4) but was infrequent in ON meningiomas (20%; 1/5). In general, Ob tumors had fewer chromosome alterations than Sph-Ob and ON tumors. Unlike Sph-Ob meningiomas, most of the Ob and ON meningiomas did not progress even after incomplete excision, although follow-up was limited in some cases. Our study suggests that ON, Ob and Sph-Ob meningiomas are three molecularly distinct entities. Our results also suggest that molecular subclassification may have prognostic implications.

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

    PubMed

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

    2014-05-07

    Traditional diagnoses of major depressive disorder (MDD) suggested that the presence or absence of stress prior to onset results in either 'reactive' or 'endogenous' subtypes of the disorder, respectively. Several lines of research suggest that the biological underpinnings of 'reactive' or 'endogenous' subtypes may also differ, resulting in differential response to treatment. We investigated this hypothesis by comparing the gene-expression profiles of three animal models of 'reactive' and 'endogenous' depression. We then translated these findings to clinical samples using a human post-mortem mRNA study. Affymetrix mouse whole-genome oligonucleotide arrays were used to measure gene expression from hippocampal tissues of 144 mice from the Genome-based Therapeutic Drugs for Depression (GENDEP) project. The study used four inbred mouse strains and two depressogenic 'stress' protocols (maternal separation and Unpredictable Chronic Mild Stress) to model 'reactive' depression. Stress-related mRNA differences in mouse were compared with a parallel mRNA study using Flinders Sensitive and Resistant rat lines as a model of 'endogenous' depression. Convergent genes differentially expressed across the animal studies were used to inform candidate gene selection in a human mRNA post-mortem case control study from the Stanley Brain Consortium. In the mouse 'reactive' model, the expression of 350 genes changed in response to early stresses and 370 in response to late stresses. A minimal genetic overlap (less than 8.8%) was detected in response to both stress protocols, but 30% of these genes (21) were also differentially regulated in the 'endogenous' rat study. This overlap is significantly greater than expected by chance. The VAMP-2 gene, differentially expressed across the rodent studies, was also significantly altered in the human study after correcting for multiple testing. Our results suggest that 'endogenous' and 'reactive' subtypes of depression are associated with largely

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

    PubMed Central

    2014-01-01

    that ‘endogenous’ and ‘reactive’ subtypes of depression are associated with largely 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. PMID:24886127

  10. Gastric crypt dysplasia: a distinct subtype of gastric dysplasia with characteristic endoscopic features and immunophenotypic and biological anomalies.

    PubMed

    Kim, Ahrong; Ahn, Sang-Jeong; Park, Do Youn; Lee, Bong-Eun; Song, Geum-Am; Kim, Gwang Ha; Lauwers, Gregory Y

    2016-05-01

    Previous reports have shown that gastric epithelial dysplasia (GED) limited to the crypt (gastric crypt dysplasia, GCD) is commonly identified at the periphery of gastric carcinoma. However, it is unknown whether GCD is endoscopically identifiable, and how it relates to classic GED lesions. We investigated 1196 consecutive endoscopic resections of GED lesions between January 2011 and December 2014. We also evaluated clinicopathological features of these lesions, as well as the immunohistochemical expression of mucin (Muc)2, Muc5AC, Muc6, CD10, Ki67 and p53. We found 51 (4.3%) lesions composed microscopically of GCD among 1196 GED lesions. Those were elevated mucosal lesions (66.7%) similar in colour and texture to the adjacent mucosa (68.6%). GCD was likely to have an antropyloric location and a higher grade than the adenomatous type, similar to the foveolar and hybrid types (P < 0.05). A gastric immunophenotype was more common in GCD compared to adenomatous GED (P < 0.05). Ki-67- and p53-positive cells were more evident in GCD compared to the adjacent gastric mucosa. Our results demonstrated that GCD can be an endoscopically identifiable lesion, sharing many similarities with foveolar and hybrid GED, for which it may represent a precursor lesion in the gastric carcinogenic sequence. © 2015 John Wiley & Sons Ltd.

  11. Sleep quality subtypes and obesity.

    PubMed

    Magee, Christopher A; Reddy, Prasuna; Robinson, Laura; McGregor, Alisha

    2016-12-01

    Poor sleep quality could be a risk factor for obesity. This article utilized a person-centered approach to investigate whether distinct sleep quality subtypes were associated with obesity directly, and indirectly via physical activity. The sample included 8,932 Australian employees who participated in the Household, Income and Labor Dynamics in Australia Survey. Structured interviews and self-report questionnaires collected information on sleep quality, obesity, and relevant demographic, health, and work-related variables. Latent class analysis identified distinct subtypes of sleep quality. General linear modeling examined the associations of sleep quality subtypes with body mass index (BMI) and waist circumference. Multicategorical mediation models examined indirect paths linking sleep quality classes with obesity via physical activity. Five distinct sleep quality subtypes were identified: Poor Sleepers (20.0%), Frequent Sleep Disturbances (19.2%), Minor Sleep Disturbances (24.5%), Long Sleepers (9.6%), and Good Sleepers (26.7%). BMI, waist circumference, and physical activity differed among the sleep quality subtypes, with similar results observed for males and females. For example, Poor Sleepers had the highest BMIs, followed by Frequent Sleep Disturbances and Minor Sleep Disturbances; Long Sleepers and Good Sleepers had the lowest BMIs. Mediation analyses indicated that low levels of physical activity linked the Poor Sleep, Frequent Sleep Disturbance, and Long Sleep classes with higher BMI. These results provide new insights into the nature of sleep quality in employees. In particular, distinct sleep quality patterns had differing associations with measures of obesity, suggesting the need for tailored workplace interventions. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

  12. Online discourse on fibromyalgia: text-mining to identify clinical distinction and patient concerns.

    PubMed

    Park, Jungsik; Ryu, Young Uk

    2014-10-07

    The purpose of this study was to evaluate the possibility of using text-mining to identify clinical distinctions and patient concerns in online memoires posted by patients with fibromyalgia (FM). A total of 399 memoirs were collected from an FM group website. The unstructured data of memoirs associated with FM were collected through a crawling process and converted into structured data with a concordance, parts of speech tagging, and word frequency. We also conducted a lexical analysis and phrase pattern identification. After examining the data, a set of FM-related keywords were obtained and phrase net relationships were set through a web-based visualization tool. The clinical distinction of FM was verified. Pain is the biggest issue to the FM patients. The pains were affecting body parts including 'muscles,' 'leg,' 'neck,' 'back,' 'joints,' and 'shoulders' with accompanying symptoms such as 'spasms,' 'stiffness,' and 'aching,' and were described as 'sever,' 'chronic,' and 'constant.' This study also demonstrated that it was possible to understand the interests and concerns of FM patients through text-mining. FM patients wanted to escape from the pain and symptoms, so they were interested in medical treatment and help. Also, they seemed to have interest in their work and occupation, and hope to continue to live life through the relationships with the people around them. This research shows the potential for extracting keywords to confirm the clinical distinction of a certain disease, and text-mining can help objectively understand the concerns of patients by generalizing their large number of subjective illness experiences. However, it is believed that there are limitations to the processes and methods for organizing and classifying large amounts of text, so these limits have to be considered when analyzing the results. The development of research methodology to overcome these limitations is greatly needed.

  13. Rat supraoptic magnocellular neurones show distinct large conductance, Ca2+-activated K+ channel subtypes in cell bodies versus nerve endings

    PubMed Central

    Dopico, Alejandro M; Widmer, Hélène; Wang, Gang; Lemos, José R; Treistman, Steven N

    1999-01-01

    Large conductance, Ca2+-activated K+ (BK) channels were identified in freshly dissociated rat supraoptic neurones using patch clamp techniques. The single channel conductance of cell body BK channels, recorded from inside-out patches in symmetric 145 mM K+, was 246.1 pS, compared with 213 pS in nerve ending BK channels (P < 0.01). At low open probability (Po), the reciprocal of the slope in the ln(NPo)-voltage relationship (N, number of available channels in the patch) for cell body and nerve ending channels were similar: 11 vs. 14 mVper e-fold change in NPo, respectively. At 40 mV, the [Ca2+]i producing half-maximal activation was 273 nM, as opposed to > 1.53 μM for the neurohypophysial channel, indicating the higher Ca2+ sensitivity of the cell body isochannel. Cell body BK channels showed fast kinetics (open time constant, 8.5 ms; fast closed time constant, 1.6 and slow closed time constant, 12.7 ms), identifying them as ‘type I’ isochannels, as opposed to the slow gating (type II) of neurohypophysial BK channels. Cell body BK activity was reduced by 10 nM charybdotoxin (NPo, 37 % of control), or 10 nM iberiotoxin (NPo, 5 % of control), whereas neurohypophysial BK channels are insensitive to charybdotoxin at concentrations as high as 360 nM. Whilst blockade of nerve ending BK channels markedly slowed the repolarization of evoked single spikes, blockade of cell body channels was without effect on repolarization of evoked single spikes. Ethanol reversibly increased neurohypophysial BK channel activity (EC50, 22 mM; maximal effect, 100 mM). In contrast, ethanol (up to 100 mM) failed to increase cell body BK channel activity. In conclusion, we have characterized BK channels in supraoptic neuronal cell bodies, and demonstrated that they display different electrophysiological and pharmacological properties from their counterparts in the nerve endings. PMID:10432342

  14. Gene expression profiling identifies distinct molecular subgroups of leiomyosarcoma with clinical relevance

    PubMed Central

    Lee, Yin-Fai; Roe, Toby; Mangham, D Chas; Fisher, Cyril; Grimer, Robert J; Judson, Ian

    2016-01-01

    Background: Soft tissue sarcomas are heterogeneous and a major complication in their management is that the existing classification scheme is not definitive and is still evolving. Leiomyosarcomas, a major histologic category of soft tissue sarcomas, are malignant tumours displaying smooth muscle differentiation. Although defined as a single group, they exhibit a wide range of clinical behaviour. We aimed to carry out molecular classification to identify new molecular subgroups with clinical relevance. Methods: We used gene expression profiling on 20 extra-uterine leiomyosarcomas and cross-study analyses for molecular classification of leiomyosarcomas. Clinical significance of the subgroupings was investigated. Results: We have identified two distinct molecular subgroups of leiomyosarcomas. One group was characterised by high expression of 26 genes that included many genes from the sub-classification gene cluster proposed by Nielsen et al. These sub-classification genes include genes that have importance structurally, as well as in cell signalling. Notably, we found a statistically significant association of the subgroupings with tumour grade. Further refinement led to a group of 15 genes that could recapitulate the tumour subgroupings in our data set and in a second independent sarcoma set. Remarkably, cross-study analyses suggested that these molecular subgroups could be found in four independent data sets, providing strong support for their existence. Conclusions: Our study strongly supported the existence of distinct leiomyosarcoma molecular subgroups, which have clinical association with tumour grade. Our findings will aid in advancing the classification of leiomyosarcomas and lead to more individualised and better management of the disease. PMID:27607470

  15. Distinct contributions by ionotropic purinoceptor subtypes to ATP-evoked calcium signals in mouse parotid acinar cells

    PubMed Central

    Bhattacharya, Sumit; Verrill, Douglas S; Carbone, Kristopher M; Brown, Stefanie; Yule, David I; Giovannucci, David R

    2012-01-01

    There is emerging consensus that P2X4 and P2X7 ionotropic purinoceptors (P2X4R and P2X7R) are critical players in regulating [Ca2+]i dynamics and fluid secretion in the salivary gland. In contrast, details regarding their compartmentalization and selective activation, contributions to the spatiotemporal properties of intracellular signals and roles in regulating protein exocytosis and ion channel activity have remained largely undefined. To address these concerns, we profiled mouse parotid acinar cells using live-cell imaging to follow the spatial and temporal features of ATP-evoked Ca2+ dynamics and exocytotic activity. Selective activation of P2X7Rs revealed an apical-to-basal [Ca2+]i signal that initiated at the sub-luminal border and propagated with a wave speed estimated at 17.3 ± 4.3 μm s−1 (n = 6). The evoked Ca2+ spike consisted of Ca2+ influx and Ca2+-induced Ca2+ release from intracellular Ca2+ channels. In contrast, selective activation of P2X4Rs induced a Ca2+ signal that initiated basally and propagated toward the lumen with a wave speed of 4.3 ± 0.2 μm s−1 (n = 8) that was largely independent of intracellular Ca2+ channel blockade. Consistent with these observations, P2X7R expression was enriched in the sub-luminal regions of acinar cells while P2X4R appeared localized to basal areas. In addition, we showed that P2X4R and P2X7R activation evokes exocytosis in parotid acinar cells. Our studies also demonstrate that the P2X4R-mediated [Ca2+]i rise and subsequent protein exocytosis was enhanced by ivermectin (IVR). Thus, in addition to furthering our understanding of salivary gland physiology, this study identifies P2X4R as a potential target for treatment of salivary hypofunction diseases. PMID:22451435

  16. MicroRNA profiles of healthy basal and luminal mammary epithelial cells are distinct and reflected in different breast cancer subtypes.

    PubMed

    Bockmeyer, Clemens L; Christgen, Matthias; Müller, Mirco; Fischer, Sebastian; Ahrens, Philipp; Länger, Florian; Kreipe, Hans; Lehmann, Ulrich

    2011-12-01

    In order to determine the microRNA expression pattern in normal basal and luminal breast epithelium and to analyze the relationship of this expression pattern to different breast cancer subtypes, laser-microdissected luminal and basal cells isolated from plastic surgery tissue samples were used for comprehensive expression profiling, measuring 664 microRNAs by low-density TaqMan arrays. In a test (n = 5) and validation set (n = 9) 10 differentially expressed microRNAs were identified by TaqMan RT-qPCR. These microRNAs were studied in laser-microdissected cells of luminal A (n = 5), luminal B (n = 5), basal-like subtypes of breast cancer (n = 10), and malignant myoepithelioma of the breast (n = 10). From 116 microRNAs unequivocally expressed in normal breast epithelial cells, we identified 8 basal microRNAs (let7c, miR-125b, miR-126, miR-127-3p, miR-143, miR-145, miR-146b-5p, and miR-199a-3p), preferentially expressed in normal basal cells, exceeding luminal cells by a factor from 4 to 1000. All of these microRNAs were also found to be significantly elevated in malignant myoepithelioma but not in basal-type of breast cancer. Two members of the miR-200 family (miR-200c and miR-429) were predominantly luminal. Both microRNAs were expressed in the luminal and basal type of breast cancer in contrast to malignant myoepithelioma, which revealed significantly lower levels potentially contributing to its mesenchymal phenotype. In conclusion, normal luminal and basal mammary epithelial cells exhibit a different microRNA expression profile. Malignant myoepithelioma seems to exhibit a basal pattern of microRNA expression, whereas the so-called basal-like breast cancer is clearly different and reveals a luminal type pattern.

  17. Identifying Subtypes among Children with Developmental Coordination Disorder and Mathematical Learning Disabilities, Using Model-Based Clustering

    ERIC Educational Resources Information Center

    Pieters, Stefanie; Roeyers, Herbert; Rosseel, Yves; Van Waelvelde, Hilde; Desoete, Annemie

    2015-01-01

    A relationship between motor and mathematical skills has been shown by previous research. However, the question of whether subtypes can be differentiated within developmental coordination disorder (DCD) and/or mathematical learning disability (MLD) remains unresolved. In a sample of children with and without DCD and/or MLD, a data-driven…

  18. Adolescent Adjustment in a Nationally Collected Sample: Identifying Group Differences by Adoption Status, Adoption Subtype, Developmental Stage and Gender

    ERIC Educational Resources Information Center

    Burrow, Anthony L.; Tubman, Jonathan G.; Finley, Gordon E.

    2004-01-01

    The current study investigated group differences in adolescent adjustment by adoption status and adoption subtype in a national sample, in contrast to group differences based on developmental stage or gender. Secondary analyses of the National Longitudinal Study of Adolescent Health were performed to describe group differences in a broad range of…

  19. Identifying Subtypes among Children with Developmental Coordination Disorder and Mathematical Learning Disabilities, Using Model-Based Clustering

    ERIC Educational Resources Information Center

    Pieters, Stefanie; Roeyers, Herbert; Rosseel, Yves; Van Waelvelde, Hilde; Desoete, Annemie

    2015-01-01

    A relationship between motor and mathematical skills has been shown by previous research. However, the question of whether subtypes can be differentiated within developmental coordination disorder (DCD) and/or mathematical learning disability (MLD) remains unresolved. In a sample of children with and without DCD and/or MLD, a data-driven…

  20. A Systematic Approach to Identify Markers of Distinctly Activated Human Macrophages

    PubMed Central

    Sudan, Bayan; Wacker, Mark A.; Wilson, Mary E.; Graff, Joel W.

    2015-01-01

    Polarization has been a useful concept for describing activated macrophage phenotypes and gene expression profiles. However, macrophage activation status within tumors and other settings are often inferred based on only a few markers. Complicating matters for relevance to human biology, many macrophage activation markers have been best characterized in mice and sometimes are not similarly regulated in human macrophages. To identify novel markers of activated human macrophages, gene expression profiles for human macrophages of a single donor subjected to 33 distinct activating conditions were obtained and a set of putative activation markers were subsequently evaluated in macrophages from multiple donors using integrated fluidic circuit (IFC)-based RT-PCR. Using unsupervised hierarchical clustering of the microarray screen, highly altered transcripts (>4-fold change in expression) sorted the macrophage transcription profiles into two major and 13 minor clusters. Among the 1874 highly altered transcripts, over 100 were uniquely altered in one major or two related minor clusters. IFC PCR-derived data confirmed the microarray results and determined the kinetics of expression of potential macrophage activation markers. Transcripts encoding chemokines, cytokines, and cell surface were prominent in our analyses. The activation markers identified by this study could be used to better characterize tumor-associated macrophages from biopsies as well as other macrophage populations collected from human clinical samples. PMID:26074920

  1. Distinct clinical characteristics of Tuberous Sclerosis Complex patients with no mutation identified

    PubMed Central

    Camposano, Susana; Greenberg, Erica; Kwiatkowski, David; Thiele, Elizabeth A.

    2009-01-01

    Tuberous Sclerosis Complex (TSC) is a multi-system disorder that is highly variable in its clinical presentation. Current molecular diagnostic methods permit identification of mutations in either TSC1 or TSC2 in 75–85% of TSC patients. Here we examine the clinical characteristics of those TSC patients who have no mutation identified (NMI). A retrospective review of our patient population that had comprehensive testing for mutations in TSC1/TSC2 identified 23/157 (15 %) that were NMI. NMI patients had a lower incidence of brain findings on imaging studies, neurological features, and renal findings than those with TSC2 mutations. In contrast, NMI patients had a lower incidence of seizures than TSC patients with TSC1 mutations, but had a higher incidence of both renal angiomyolipomas and pulmonary lymphangioleiomyomatosis. This distinct constellation of findings suggest that NMI patients may have a unique molecular pathogenesis, different from that seen in TSC patients with the usual mutations in TSC1 and TSC2. We suggest that the mechanisms of disease in these patients include both mosaicism for a TSC2 mutation, and unusual non-coding region mutations in TSC2. PMID:19133941

  2. Distinct myeloid progenitor differentiation pathways identified through single cell RNA sequencing

    PubMed Central

    Drissen, Roy; Buza-Vidas, Natalija; Woll, Petter; Thongjuea, Supat; Gambardella, Adriana; Giustacchini, Alice; Mancini, Elena; Zriwil, Alya; Lutteropp, Michael; Grover, Amit; Mead, Adam; Sitnicka, Ewa

    2016-01-01

    According to current models for hematopoiesis, lymphoid-primed multi-potent progenitors (LMPPs; Lin−Sca-1+c-Kit+CD34+Flt3hi) and common myeloid progenitors (CMPs; Lin−Sca-1+c-Kit+CD34+CD41hi) establish an early branch point for separate lineage commitment pathways from hematopoietic stem cells, with the notable exception that both pathways are proposed to generate all myeloid innate immune cell types through the same myeloid-restricted pre-granulocyte-macrophage progenitor (pre-GM; Lin−Sca-1−c-Kit+CD41−FcγRII/III−CD150−CD105−). By single cell transcriptome profiling of pre-GMs we identify distinct myeloid differentiation pathways: a Gata1-expressing pathway generates mast cells, eosinophils, megakaryocytes and erythroid cells, and a Gata1-negative pathway that generates monocytes, neutrophils and lymphocytes. These results identify an early hematopoietic lineage bifurcation, separating the myeloid lineages prior to their segregation from other hematopoietic lineage potentials. PMID:27043410

  3. Online Discourse on Fibromyalgia: Text-Mining to Identify Clinical Distinction and Patient Concerns

    PubMed Central

    Park, Jungsik; Ryu, Young Uk

    2014-01-01

    Background The purpose of this study was to evaluate the possibility of using text-mining to identify clinical distinctions and patient concerns in online memoires posted by patients with fibromyalgia (FM). Material/Methods A total of 399 memoirs were collected from an FM group website. The unstructured data of memoirs associated with FM were collected through a crawling process and converted into structured data with a concordance, parts of speech tagging, and word frequency. We also conducted a lexical analysis and phrase pattern identification. After examining the data, a set of FM-related keywords were obtained and phrase net relationships were set through a web-based visualization tool. Results The clinical distinction of FM was verified. Pain is the biggest issue to the FM patients. The pains were affecting body parts including ‘muscles,’ ‘leg,’ ‘neck,’ ‘back,’ ‘joints,’ and ‘shoulders’ with accompanying symptoms such as ‘spasms,’ ‘stiffness,’ and ‘aching,’ and were described as ‘sever,’ ‘chronic,’ and ‘constant.’ This study also demonstrated that it was possible to understand the interests and concerns of FM patients through text-mining. FM patients wanted to escape from the pain and symptoms, so they were interested in medical treatment and help. Also, they seemed to have interest in their work and occupation, and hope to continue to live life through the relationships with the people around them. Conclusions This research shows the potential for extracting keywords to confirm the clinical distinction of a certain disease, and text-mining can help objectively understand the concerns of patients by generalizing their large number of subjective illness experiences. However, it is believed that there are limitations to the processes and methods for organizing and classifying large amounts of text, so these limits have to be considered when analyzing the results. The development of research methodology to overcome

  4. Integrated Proteomic and Transcriptomic-Based Approaches to Identifying Signature Biomarkers and Pathways for Elucidation of Daoy and UW228 Subtypes.

    PubMed

    Higdon, Roger; Kala, Jessie; Wilkins, Devan; Yan, Julia Fangfei; Sethi, Manveen K; Lin, Liang; Liu, Siqi; Montague, Elizabeth; Janko, Imre; Choiniere, John; Kolker, Natali; Hancock, William S; Kolker, Eugene; Fanayan, Susan

    2017-02-03

    Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Patient survival has remained largely the same for the past 20 years, with therapies causing significant health, cognitive, behavioral and developmental complications for those who survive the tumor. In this study, we profiled the total transcriptome and proteome of two established MB cell lines, Daoy and UW228, using high-throughput RNA sequencing (RNA-Seq) and label-free nano-LC-MS/MS-based quantitative proteomics, coupled with advanced pathway analysis. While Daoy has been suggested to belong to the sonic hedgehog (SHH) subtype, the exact UW228 subtype is not yet clearly established. Thus, a goal of this study was to identify protein markers and pathways that would help elucidate their subtype classification. A number of differentially expressed genes and proteins, including a number of adhesion, cytoskeletal and signaling molecules, were observed between the two cell lines. While several cancer-associated genes/proteins exhibited similar expression across the two cell lines, upregulation of a number of signature proteins and enrichment of key components of SHH and WNT signaling pathways were uniquely observed in Daoy and UW228, respectively. The novel information on differentially expressed genes/proteins and enriched pathways provide insights into the biology of MB, which could help elucidate their subtype classification.

  5. Integrated Proteomic and Transcriptomic-Based Approaches to Identifying Signature Biomarkers and Pathways for Elucidation of Daoy and UW228 Subtypes

    PubMed Central

    Higdon, Roger; Kala, Jessie; Wilkins, Devan; Yan, Julia Fangfei; Sethi, Manveen K.; Lin, Liang; Liu, Siqi; Montague, Elizabeth; Janko, Imre; Choiniere, John; Kolker, Natali; Hancock, William S.; Kolker, Eugene; Fanayan, Susan

    2017-01-01

    Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Patient survival has remained largely the same for the past 20 years, with therapies causing significant health, cognitive, behavioral and developmental complications for those who survive the tumor. In this study, we profiled the total transcriptome and proteome of two established MB cell lines, Daoy and UW228, using high-throughput RNA sequencing (RNA-Seq) and label-free nano-LC-MS/MS-based quantitative proteomics, coupled with advanced pathway analysis. While Daoy has been suggested to belong to the sonic hedgehog (SHH) subtype, the exact UW228 subtype is not yet clearly established. Thus, a goal of this study was to identify protein markers and pathways that would help elucidate their subtype classification. A number of differentially expressed genes and proteins, including a number of adhesion, cytoskeletal and signaling molecules, were observed between the two cell lines. While several cancer-associated genes/proteins exhibited similar expression across the two cell lines, upregulation of a number of signature proteins and enrichment of key components of SHH and WNT signaling pathways were uniquely observed in Daoy and UW228, respectively. The novel information on differentially expressed genes/proteins and enriched pathways provide insights into the biology of MB, which could help elucidate their subtype classification. PMID:28248256

  6. Longitudinal Stability of Phonological and Surface Subtypes of Developmental Dyslexia

    PubMed Central

    Peterson, Robin L.; Pennington, Bruce F.; Olson, Richard K.; Wadsworth, Sally

    2014-01-01

    Limited evidence supports the external validity of the distinction between developmental phonological and surface dyslexia. We previously identified children age 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 stability of subtype membership was fair and appeared stronger for phonological than surface dyslexia. Phonological dyslexia was associated with a pronounced phonological awareness deficit, but subgroups otherwise had similar cognitive profiles. Subtype did not inform prognosis. Results provide modest evidence for the validity of the distinction, although not for its clinical utility. PMID:25429194

  7. In vitro culture of stress erythroid progenitors identifies distinct progenitor populations and analogous human progenitors

    PubMed Central

    Xiang, Jie; Wu, Dai-Chen; Chen, Yuanting

    2015-01-01

    Tissue hypoxia induces a systemic response designed to increase oxygen delivery to tissues. One component of this response is increased erythropoiesis. Steady-state erythropoiesis is primarily homeostatic, producing new erythrocytes to replace old erythrocytes removed from circulation by the spleen. In response to anemia, the situation is different. New erythrocytes must be rapidly made to increase hemoglobin levels. At these times, stress erythropoiesis predominates. Stress erythropoiesis is best characterized in the mouse, where it is extramedullary and utilizes progenitors and signals that are distinct from steady-state erythropoiesis. In this report, we use an in vitro culture system that recapitulates the in vivo development of stress erythroid progenitors. We identify cell-surface markers that delineate a series of stress erythroid progenitors with increasing maturity. In addition, we use this in vitro culture system to expand human stress erythroid progenitor cells that express analogous cell-surface markers. Consistent with previous suggestions that human stress erythropoiesis is similar to fetal erythropoiesis, we demonstrate that human stress erythroid progenitors express fetal hemoglobin upon differentiation. These data demonstrate that similar to murine bone marrow, human bone marrow contains cells that can generate BMP4-dependent stress erythroid burst-forming units when cultured under stress erythropoiesis conditions. PMID:25608563

  8. Distinct forms of the. beta. subunit of GTP-binding regulatory proteins identified by molecular cloning

    SciTech Connect

    Fong, H.K.W.; Amatruda, T.T. III; Birren, B.W.; Simon, M.I.

    1987-06-01

    Two distinct ..beta.. subunits of guanine nucleotide-binding regulatory proteins have been identified by cDNA cloning and are referred to as ..beta../sub 1/ and ..beta../sub 1/ subunits. The bovine transducin ..beta.. subunit (..beta../sub 1/) has been cloned previously. The author now isolated and analyzed cDNA clones that encode the ..beta../sub 2/ subunit from bovine adrenal, bovine brain, and a human myeloid leukemia cell line, HL-60. The 340-residue M/sub r/ 37,329 BETA/sub 2/ protein is 90% identical with ..beta../sub 1/ in predicted amino acid sequence, and it is also organized as a series of repetitive homologous segments. The major mRNA that encodes the bovine ..beta../sub 2/ subunit is 1.7 kilobases in length. It is expressed at lower levels than ..beta../sub 1/ subunit mRNA in all tissues examined. The ..beta../sub 1/ and ..beta../sub 2/ messages are expressed in cloned human cell lines. Hybridization of cDNA probes to bovine DNA showed that ..beta../sub 1/ and ..beta../sub 2/ are encoded by separate genes. The amino acid sequences for the bovine and human ..beta../sub 2/ subunit are identical, as are the amino acid sequences for the bovine and human ..beta../sub 1/ subunit. This evolutionary conservation suggests that the two ..beta.. subunits have different roles in the signal transduction process.

  9. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing.

    PubMed

    Sifrim, Alejandro; Hitz, Marc-Phillip; Wilsdon, Anna; Breckpot, Jeroen; Turki, Saeed H Al; Thienpont, Bernard; McRae, Jeremy; Fitzgerald, Tomas W; Singh, Tarjinder; Swaminathan, Ganesh Jawahar; Prigmore, Elena; Rajan, Diana; Abdul-Khaliq, Hashim; Banka, Siddharth; Bauer, Ulrike M M; Bentham, Jamie; Berger, Felix; Bhattacharya, Shoumo; Bu'Lock, Frances; Canham, Natalie; Colgiu, Irina-Gabriela; Cosgrove, Catherine; Cox, Helen; Daehnert, Ingo; Daly, Allan; Danesh, John; Fryer, Alan; Gewillig, Marc; Hobson, Emma; Hoff, Kirstin; Homfray, Tessa; Kahlert, Anne-Karin; Ketley, Ami; Kramer, Hans-Heiner; Lachlan, Katherine; Lampe, Anne Katrin; Louw, Jacoba J; Manickara, Ashok Kumar; Manase, Dorin; McCarthy, Karen P; Metcalfe, Kay; Moore, Carmel; Newbury-Ecob, Ruth; Omer, Seham Osman; Ouwehand, Willem H; Park, Soo-Mi; Parker, Michael J; Pickardt, Thomas; Pollard, Martin O; Robert, Leema; Roberts, David J; Sambrook, Jennifer; Setchfield, Kerry; Stiller, Brigitte; Thornborough, Chris; Toka, Okan; Watkins, Hugh; Williams, Denise; Wright, Michael; Mital, Seema; Daubeney, Piers E F; Keavney, Bernard; Goodship, Judith; Abu-Sulaiman, Riyadh Mahdi; Klaassen, Sabine; Wright, Caroline F; Firth, Helen V; Barrett, Jeffrey C; Devriendt, Koenraad; FitzPatrick, David R; Brook, J David; Hurles, Matthew E

    2016-09-01

    Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

  10. Functionally distinct amygdala subregions identified using DTI and high-resolution fMRI

    PubMed Central

    Balderston, Nicholas L.; Schultz, Douglas H.; Hopkins, Lauren

    2015-01-01

    Although the amygdala is often directly linked with fear and emotion, amygdala neurons are activated by a wide variety of emotional and non-emotional stimuli. Different subregions within the amygdala may be engaged preferentially by different aspects of emotional and non-emotional tasks. To test this hypothesis, we measured and compared the effects of novelty and fear on amygdala activity. We used high-resolution blood oxygenation level-dependent (BOLD) imaging and streamline tractography to subdivide the amygdala into three distinct functional subunits. We identified a laterobasal subregion connected with the visual cortex that responds generally to visual stimuli, a non-projecting region that responds to salient visual stimuli, and a centromedial subregion connected with the diencephalon that responds only when a visual stimulus predicts an aversive outcome. We provide anatomical and functional support for a model of amygdala function where information enters through the laterobasal subregion, is processed by intrinsic circuits in the interspersed tissue, and is then passed to the centromedial subregion, where activation leads to behavioral output. PMID:25969533

  11. Multilocus sequence typing identifies evidence for recombination and two distinct lineages of Corynebacterium diphtheriae.

    PubMed

    Bolt, Frances; Cassiday, Pamela; Tondella, Maria Lucia; Dezoysa, Aruni; Efstratiou, Androulla; Sing, Andreas; Zasada, Aleksandra; Bernard, Kathryn; Guiso, Nicole; Badell, Edgar; Rosso, Marie-Laure; Baldwin, Adam; Dowson, Christopher

    2010-11-01

    We describe the development of a multilocus sequence typing (MLST) scheme for Corynebacterium diphtheriae, the causative agent of the potentially fatal upper respiratory disease diphtheria. Global changes in diphtheria epidemiology are highlighted by the recent epidemic in the former Soviet Union (FSU) and also by the emergence of nontoxigenic strains causing atypical disease. Although numerous techniques have been developed to characterize C. diphtheriae, their use is hindered by limited portability and, in some instances, poor reproducibility. One hundred fifty isolates from 18 countries and encompassing a period of 50 years were analyzed by multilocus sequence typing (MLST). Strain discrimination was in accordance with previous ribotyping data, and clonal complexes associated with disease outbreaks were clearly identified by MLST. The data produced are portable, reproducible, and unambiguous. The MLST scheme described provides a valuable tool for monitoring and characterizing endemic and epidemic C. diphtheriae strains. Furthermore, multilocus sequence analysis of the nucleotide data reveals two distinct lineages within the population of C. diphtheriae examined, one of which is composed exclusively of biotype belfanti isolates and the other of multiple biotypes.

  12. A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing.

    PubMed

    Poulter, James A; Smith, Claire E L; Murrillo, Gina; Silva, Sandra; Feather, Sally; Howell, Marianella; Crinnion, Laura; Bonthron, David T; Carr, Ian M; Watson, Christopher M; Inglehearn, Chris F; Mighell, Alan J

    2015-11-01

    Biallelic FAM20A mutations cause two conditions where Amelogenesis Imperfecta (AI) is the presenting feature: Amelogenesis Imperfecta and Gingival Fibromatosis Syndrome; and Enamel Renal Syndrome. A distinctive oral phenotype is shared in both conditions. On Sanger sequencing of FAM20A in cases with that phenotype, we identified two probands with single, likely pathogenic heterozygous mutations. Given the recessive inheritance pattern seen in all previous FAM20A mutation-positive families and the potential for renal disease, further screening was carried out to look for a second pathogenic allele. Reverse transcriptase-PCR on cDNA was used to determine transcript levels. CNVseq was used to screen for genomic insertions and deletions. In one family, FAM20A cDNA screening revealed only a single mutated FAM20A allele with the wild-type allele not transcribed. In the second family, CNV detection by whole genome sequencing (CNVseq) revealed a heterozygous 54.7 kb duplication encompassing exons 1 to 4 of FAM20A. This study confirms the link between biallelic FAM20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care.

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

    PubMed

    Taïbi, Khaled; Del Campo, Antonio D; Vilagrosa, Alberto; Bellés, José M; López-Gresa, María Pilar; Pla, Davinia; Calvete, Juan J; López-Nicolás, José M; Mulet, José M

    2017-01-01

    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.

  14. Distinct Cytokine Patterns Identified from Multiplex Profiles of Murine DSS and TNBS-Induced Colitis

    PubMed Central

    Alex, Philip; Zachos, Nicholas C.; Nguyen, Thuan; Gonzales, Liberty; Chen, Tian E.; Conklin, Laurie S.; Centola, Michael; Li, Xuhang

    2008-01-01

    The cytokine network in inflammatory bowel disease (IBD) is a complex, dynamic system that plays an important role in regulating mucosal innate and adaptive immune responses. While several studies have been done to evaluate immunomodulatory profiles in murine IBD, they have been limited to a relatively small number of cytokines that do not take into account its dependency of the interplay of multiple factors, and therefore the diagnostic potential of their cytokine profiles have been inconclusive. Herein we demonstrate a novel approach of comprehensive serum multiplex cytokine profiling to describe the modulation of 16 Th1, Th2, Th17 cytokines and chemokines in both acute and chronic murine models of DSS and TNBS-induced colitis. Distinctive disease-specific cytokine profiles were identified with significant correlations to disease activity and duration of disease. TNBS colitis exhibits heightened Th1-Th17 response (increased IL-12 and IL-17) as the disease becomes chronic. In contrast, DSS colitis switches from a Th1-Th17-mediated acute inflammation (increased TNFα, IL6, IL-17 and KC) to a predominant Th2-mediated inflammatory response (increase in IL-4 and IL-10 and concomitant decrease in TNFα, IL6, IL-17 and KC) in the chronic state. Profiles of multiple cytokines seen systemically were also validated locally in colonic mucosa. Moreover, advanced multivariate analyses identified discriminatory cytokine profiles that can be sufficiently used to distinguish unaffected controls from diseases, and one disease type from another. IL-6 and IL-12 stratified gender-associated disease activity in chronic colitis. Our studies provide insight into disease immunopathogenesis and illustrate the significant potential of utilizing multiplex cytokine profiles and bioinformatics as diagnostic tools in IBD. PMID:18942757

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

    PubMed Central

    Taïbi, Khaled; del Campo, Antonio D.; Vilagrosa, Alberto; Bellés, José M.; López-Gresa, María Pilar; Pla, Davinia; Calvete, Juan J.; López-Nicolás, José M.; Mulet, José M.

    2017-01-01

    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. PMID:28791030

  16. Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer.

    PubMed

    Silva, Grace O; He, Xiaping; Parker, Joel S; Gatza, Michael L; Carey, Lisa A; Hou, Jack P; Moulder, Stacy L; Marcom, Paul K; Ma, Jian; Rosen, Jeffrey M; Perou, Charles M

    2015-07-01

    A large number of DNA copy number alterations (CNAs) exist in human breast cancers, and thus characterizing the most frequent CNAs is key to advancing therapeutics because it is likely that these regions contain breast tumor 'drivers' (i.e., cancer causal genes). This study aims to characterize the genomic landscape of breast cancer CNAs and identify potential subtype-specific drivers using a large set of human breast tumors and genetically engineered mouse (GEM) mammary tumors. Using a novel method called SWITCHplus, we identified subtype-specific DNA CNAs occurring at a 15% or greater frequency, which excluded many well-known breast cancer-related drivers such as amplification of ERBB2, and deletions of TP53 and RB1. A comparison of CNAs between mouse and human breast tumors identified regions with shared subtype-specific CNAs. Additional criteria that included gene expression-to-copy number correlation, a DawnRank network analysis, and RNA interference functional studies highlighted candidate driver genes that fulfilled these multiple criteria. Numerous regions of shared CNAs were observed between human breast tumors and GEM mammary tumor models that shared similar gene expression features. Specifically, we identified chromosome 1q21-23 as a Basal-like subtype-enriched region with multiple potential driver genes including PI4KB, SHC1, and NCSTN. This step-wise computational approach based on a cross-species comparison is applicable to any tumor type for which sufficient human and model system DNA copy number data exist, and in this instance, highlights that a single region of amplification may in fact harbor multiple driver genes.

  17. Absence of an Orphan Mitochondrial Protein, C19orf12, Causes a Distinct Clinical Subtype of Neurodegeneration with Brain Iron Accumulation

    PubMed Central

    Hartig, Monika B.; Iuso, Arcangela; Haack, Tobias; Kmiec, Tomasz; Jurkiewicz, Elzbieta; Heim, Katharina; Roeber, Sigrun; Tarabin, Victoria; Dusi, Sabrina; Krajewska-Walasek, Malgorzata; Jozwiak, Sergiusz; Hempel, Maja; Winkelmann, Juliane; Elstner, Matthias; Oexle, Konrad; Klopstock, Thomas; Mueller-Felber, Wolfgang; Gasser, Thomas; Trenkwalder, Claudia; Tiranti, Valeria; Kretzschmar, Hans; Schmitz, Gerd; Strom, Tim M.; Meitinger, Thomas; Prokisch, Holger

    2011-01-01

    The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders. PMID:21981780

  18. MM2-thalamic Creutzfeldt-Jakob disease: neuropathological, biochemical and transmission studies identify a distinctive prion strain.

    PubMed

    Moda, Fabio; Suardi, Silvia; Di Fede, Giuseppe; Indaco, Antonio; Limido, Lucia; Vimercati, Chiara; Ruggerone, Margherita; Campagnani, Ilaria; Langeveld, Jan; Terruzzi, Alessandro; Brambilla, Antonio; Zerbi, Pietro; Fociani, Paolo; Bishop, Matthew T; Will, Robert G; Manson, Jean C; Giaccone, Giorgio; Tagliavini, Fabrizio

    2012-09-01

    In Creutzfeldt-Jakob disease (CJD), molecular typing based on the size of the protease resistant core of the disease-associated prion protein (PrP(Sc) ) and the M/V polymorphism at codon 129 of the PRNP gene correlates with the clinico-pathologic subtypes. Approximately 95% of the sporadic 129MM CJD patients are characterized by cerebral deposition of type 1 PrP(Sc) and correspond to the classic clinical CJD phenotype. The rare 129MM CJD patients with type 2 PrP(Sc) are further subdivided in a cortical and a thalamic form also indicated as sporadic fatal insomnia. We observed two young patients with MM2-thalamic CJD. Main neuropathological features were diffuse, synaptic PrP immunoreactivity in the cerebral cortex and severe neuronal loss and gliosis in the thalamus and olivary nucleus. Western blot analysis showed the presence of type 2A PrP(Sc) . Challenge of transgenic mice expressing 129MM human PrP showed that MM2-thalamic sporadic CJD (sCJD) was able to transmit the disease, at variance with MM2-cortical sCJD. The affected mice showed deposition of type 2A PrP(Sc) , a scenario that is unprecedented in this mouse line. These data indicate that MM2-thalamic sCJD is caused by a prion strain distinct from the other sCJD subtypes including the MM2-cortical form.

  19. A Case-Control Study to Identify Risk Factors Associated with Avian Influenza Subtype H9N2 on Commercial Poultry Farms in Pakistan

    PubMed Central

    Chaudhry, Mamoona; Rashid, Hamad B.; Thrusfield, Michael; Welburn, Sue; Bronsvoort, Barend MdeC.

    2015-01-01

    A 1:1 matched case-control study was conducted to identify risk factors for avian influenza subtype H9N2 infection on commercial poultry farms in 16 districts of Punjab, and 1 administrative unit of Pakistan. One hundred and thirty-three laboratory confirmed positive case farms were matched on the date of sample submission with 133 negative control farms. The association between a series of farm-level characteristics and the presence or absence of H9N2 was assessed by univariable analysis. Characteristics associated with H9N2 risk that passed the initial screening were included in a multivariable conditional logistic regression model. Manual and automated approaches were used, which produced similar models. Key risk factors from all approaches included selling of eggs/birds directly to live bird retail stalls, being near case/infected farms, a previous history of infectious bursal disease (IBD) on the farm and having cover on the water storage tanks. The findings of current study are in line with results of many other studies conducted in various countries to identify similar risk factors for AI subtype H9N2 infection. Enhancing protective measures and controlling risks identified in this study could reduce spread of AI subtype H9N2 and other AI viruses between poultry farms in Pakistan. PMID:25774768

  20. A case-control study to identify risk factors associated with avian influenza subtype H9N2 on commercial poultry farms in Pakistan.

    PubMed

    Chaudhry, Mamoona; Rashid, Hamad B; Thrusfield, Michael; Welburn, Sue; Bronsvoort, Barend MdeC

    2015-01-01

    A 1:1 matched case-control study was conducted to identify risk factors for avian influenza subtype H9N2 infection on commercial poultry farms in 16 districts of Punjab, and 1 administrative unit of Pakistan. One hundred and thirty-three laboratory confirmed positive case farms were matched on the date of sample submission with 133 negative control farms. The association between a series of farm-level characteristics and the presence or absence of H9N2 was assessed by univariable analysis. Characteristics associated with H9N2 risk that passed the initial screening were included in a multivariable conditional logistic regression model. Manual and automated approaches were used, which produced similar models. Key risk factors from all approaches included selling of eggs/birds directly to live bird retail stalls, being near case/infected farms, a previous history of infectious bursal disease (IBD) on the farm and having cover on the water storage tanks. The findings of current study are in line with results of many other studies conducted in various countries to identify similar risk factors for AI subtype H9N2 infection. Enhancing protective measures and controlling risks identified in this study could reduce spread of AI subtype H9N2 and other AI viruses between poultry farms in Pakistan.

  1. Effects of the xenoestrogen bisphenol A in diencephalic regions of the teleost fish Coris julis occur preferentially via distinct somatostatin receptor subtypes.

    PubMed

    Alo', Raffaella; Facciolo, Rosa Maria; Madeo, Maria; Giusi, Giuseppina; Carelli, Antonio; Canonaco, Marcello

    2005-04-15

    The xenoestrogen bisphenol A, a contaminant used in the manufacturing of polymers for many consumer products, has been shown to mimic estrogenic actions. This xenoestrogen regulates secretion and expression of pituitary lactotrophs plus morphological and structural features of estrogen target tissues in rodents. Recently, ecological hazards produced by bisphenol A have drawn interests towards the effects of this environmental chemical on neurobiological functions of aquatic vertebrates of which little is known. In this study, the effects of bisphenol A on the distribution of the biologically more active somatostatin receptor subtypes in diencephalic regions of the teleost fish Coris julis were assessed using nonpeptide agonists (L-779, 976 and L-817, 818) that are highly selective for subtype(2) and subtype(5), respectively. Bisphenol A proved to be responsible for highly significant increased binding levels of subtype(2) in hypothalamic areas, while markedly decreased levels of subtype(5) were found in these diencephalic areas, as well as in the medial preglomerular nucleus. The extensive distribution of somatostatin receptor subtype(2) and subtype(5) in the teleost diencephalic areas suggests that, like in mammals, this receptor system may not only be involved in enhanced hypophysiotropic neurohormonal functions but might also promote neuroplasticity events.

  2. Incidence and risk factors for breast cancer subtypes in three distinct South-East Asian ethnic groups: Chinese, Malay and natives of Sarawak, Malaysia.

    PubMed

    Devi, C R Beena; Tang, Tieng Swee; Corbex, Marilys

    2012-12-15

    We determined the incidences of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) subtypes among breast cancer cases in Sarawak, Malaysia and their correlation with various risk factors in the three ethnic groups: Chinese, Malay and native. Subtype status was ascertained for 1,034 cases of female breast cancer (93% of all cases diagnosed since 2003), and the age-standardized incidence rates (ASRs) of each subtype were inferred. Case-case comparisons across subtypes were performed for reproductive risk factors. We found 48% luminal A (ER+/PR+/HER2-), 29% triple-negative (ER-/PR-/HER2-), 12% triple-positive (ER+/PR+/HER2+) and 11% HER2-overexpressing (ER-/PR-/HER2+) subtypes, with ASRs of 10.6, 6.0, 2.8 and 2.8 per 100,000, respectively. The proportions of subtypes and ASRs differed significantly by ethnic groups: HER2-positive cases were more frequent in Malays (29%; 95% CI [23;35]) than Chinese (22%; [19;26] and natives (21%; [16;26]); triple-negative cases were less frequent among Chinese (23%; [20;27]) than Malays (33%; [27;39]) and natives (37%; [31;43]). The results of the case-case comparison were in accordance with those observed in western case series. Some uncommon associations, such as between triple-negative subtype and older age at menopause (OR, 1.59; p < 0.05), were found. The triple-negative and HER2+ subtypes predominate in our region, with significant differences among ethnic groups. Our results support the idea that the risk factors for different subtypes vary markedly. Westernized populations are more likely to have factors that increase the risk for the luminal A type, while risk factors for the triple-negative type are more frequent in local populations. Copyright © 2012 UICC.

  3. Expression of CD8alpha identifies a distinct subset of effector memory CD4+ T lymphocytes.

    PubMed

    Macchia, Iole; Gauduin, Marie-Claire; Kaur, Amitinder; Johnson, R Paul

    2006-10-01

    Circulating CD4+ CD8+ T lymphocytes have been described in the peripheral blood of humans and several animal species. However, the origin and functional properties of these cells remain poorly understood. In the present study, we evaluated the frequency, phenotype and function of peripheral CD4+ CD8+ T cells in rhesus macaques. Two distinct populations of CD4+ CD8+ T cells were identified: the dominant one was CD4hi CD8lo and expressed the CD8alphaalpha homodimer, while the minor population was CD4lo CD8hi and expressed the CD8alphabeta heterodimer. The majority of CD4hi CD8alphalo T cells exhibited an activated effector/memory phenotype (CCR5lo CD7- CD28- HLA-DR+) and expressed relatively high levels of granzyme B. Intracellular cytokine staining assays demonstrated that the frequency of cytomegalovirus-specific T cells was enriched five-fold in CD4hi CD8alphalo T cells compared to single-positive CD4+ T cells, whereas no consistent enrichment was observed for simian immunodeficiency virus (SIV)-specific T cells. Cross-sectional studies of SIV-infected animals demonstrated that the frequency of CD4hi CD8alphalo T cells was lower in wild-type SIV-infected animals compared to uninfected controls, although prospective studies of SIV-infected animals demonstrated depletion of CD4hi CD8alphalo lymphocytes only in a subset of animals. Taken together, these data suggest that CD4+ T cells expressing CD8alpha represent an effector/memory subset of CD4+ T cells and that this cell population can be depleted during the course of SIV infection.

  4. Distinct Phenotypes of Cigarette Smokers Identified by Cluster Analysis of Patients with Severe Asthma.

    PubMed

    Konno, Satoshi; Taniguchi, Natsuko; Makita, Hironi; Nakamaru, Yuji; Shimizu, Kaoruko; Shijubo, Noriharu; Fuke, Satoshi; Takeyabu, Kimihiro; Oguri, Mitsuru; Kimura, Hirokazu; Maeda, Yukiko; Suzuki, Masaru; Nagai, Katsura; Ito, Yoichi M; Wenzel, Sally E; Nishimura, Masaharu

    2015-12-01

    Smoking may have multifactorial effects on asthma phenotypes, particularly in severe asthma. Cluster analysis has been applied to explore novel phenotypes, which are not based on any a priori hypotheses. To explore novel severe asthma phenotypes by cluster analysis when including cigarette smokers. We recruited a total of 127 subjects with severe asthma, including 59 current or ex-smokers, from our university hospital and its 29 affiliated hospitals/pulmonary clinics. Twelve clinical variables obtained during a 2-day hospital stay were used for cluster analysis. After clustering using clinical variables, the sputum levels of 14 molecules were measured to biologically characterize the clinical clusters. Five clinical clusters were identified, including two characterized by high pack-year exposure to cigarette smoking and low FEV1/FVC. There were marked differences between the two clusters of cigarette smokers. One had high levels of circulating eosinophils, high IgE levels, and a high sinus disease score. The other was characterized by low levels of the same parameters. Sputum analysis revealed increased levels of IL-5 in the former cluster and increased levels of IL-6 and osteopontin in the latter. The other three clusters were similar to those previously reported: young onset/atopic, nonsmoker/less eosinophilic, and female/obese. Key clinical variables were confirmed to be stable and consistent 1 year later. This study reveals two distinct phenotypes of severe asthma in current and former cigarette smokers with potentially different biological pathways contributing to fixed airflow limitation. Clinical trial registered with www.umin.ac.jp (000003254).

  5. Cluster analysis of the national weight control registry to identify distinct subgroups maintaining successful weight loss.

    PubMed

    Ogden, Lorraine G; Stroebele, Nanette; Wyatt, Holly R; Catenacci, Victoria A; Peters, John C; Stuht, Jennifer; Wing, Rena R; Hill, James O

    2012-10-01

    The National Weight Control Registry (NWCR) is the largest ongoing study of individuals successful at maintaining weight loss; the registry enrolls individuals maintaining a weight loss of at least 13.6 kg (30 lb) for a minimum of 1 year. The current report uses multivariate latent class cluster analysis to identify unique clusters of individuals within the NWCR that have distinct experiences, strategies, and attitudes with respect to weight loss and weight loss maintenance. The cluster analysis considers weight and health history, weight control behaviors and strategies, effort and satisfaction with maintaining weight, and psychological and demographic characteristics. The analysis includes 2,228 participants enrolled between 1998 and 2002. Cluster 1 (50.5%) represents a weight-stable, healthy, exercise conscious group who are very satisfied with their current weight. Cluster 2 (26.9%) has continuously struggled with weight since childhood; they rely on the greatest number of resources and strategies to lose and maintain weight, and report higher levels of stress and depression. Cluster 3 (12.7%) represents a group successful at weight reduction on the first attempt; they were least likely to be overweight as children, are maintaining the longest duration of weight loss, and report the least difficulty maintaining weight. Cluster 4 (9.9%) represents a group less likely to use exercise to control weight; they tend to be older, eat fewer meals, and report more health problems. Further exploration of the unique characteristics of these clusters could be useful for tailoring future weight loss and weight maintenance programs to the specific characteristics of an individual.

  6. Tryptophan Scanning Mutagenesis Identifies the Molecular Determinants of Distinct Barttin Functions*

    PubMed Central

    Wojciechowski, Daniel; Fischer, Martin; Fahlke, Christoph

    2015-01-01

    CLC-K chloride channels are expressed in the kidney and in the inner ear and require the accessory subunit barttin for proper function and membrane insertion. Barttin exerts multiple functions on CLC-proteins: it modifies protein stability and intracellular trafficking as well as channel activity, ion conduction, and gating. So far, the molecular determinants of these distinct barttin functions have remained elusive. Here we performed serial perturbation mutagenesis to identify the sequence determinants of barttin function. Barttin consists of two transmembrane helices followed by a long intracellular carboxyl terminus, and earlier work demonstrated that the transmembrane core of barttin suffices for most effects on the α-subunit. We individually substituted every amino acid of the predicted transmembrane core (amino acids 9–26 and 35–55) with tryptophan, co-expressed mutant barttin with hClC-Ka or V166E rClC-K1, and characterized CLC-K/barttin channels by patch clamp techniques, biochemistry, and confocal microscopy. The majority of mutations left the chaperone function of barttin, i.e. the effects on endoplasmic reticulum exit and surface membrane insertion, unaffected. In contrast, tryptophan insertion at multiple positions resulted in impaired activity of hClC-Ka/barttin and changes in gating of V166E rClC-K1/barttin. These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit. Whereas tight interaction is necessary for functional modification, even impaired association of barttin and CLC-K suffices for normal intracellular trafficking. Our findings allow definition of a likely interaction surface and clarify the mechanisms underlying CLC-K channel modification by barttin. PMID:26063802

  7. Affinity-Based Screening of Tetravalent Peptides Identifies Subtype-Selective Neutralizers of Shiga Toxin 2d, a Highly Virulent Subtype, by Targeting a Unique Amino Acid Involved in Its Receptor Recognition

    PubMed Central

    Mitsui, Takaaki; Watanabe-Takahashi, Miho; Shimizu, Eiko; Zhang, Baihao; Funamoto, Satoru; Yamasaki, Shinji

    2016-01-01

    Shiga toxin (Stx), a major virulence factor of enterohemorrhagic Escherichia coli (EHEC), can be classified into two subgroups, Stx1 and Stx2, each consisting of various closely related subtypes. Stx2 subtypes Stx2a and Stx2d are highly virulent and linked with serious human disorders, such as acute encephalopathy and hemolytic-uremic syndrome. Through affinity-based screening of a tetravalent peptide library, we previously developed peptide neutralizers of Stx2a in which the structure was optimized to bind to the B-subunit pentamer. In this study, we identified Stx2d-selective neutralizers by targeting Asn16 of the B subunit, an amino acid unique to Stx2d that plays an essential role in receptor binding. We synthesized a series of tetravalent peptides on a cellulose membrane in which the core structure was exactly the same as that of peptides in the tetravalent library. A total of nine candidate motifs were selected to synthesize tetravalent forms of the peptides by screening two series of the tetravalent peptides. Five of the tetravalent peptides effectively inhibited the cytotoxicity of Stx2a and Stx2d, and notably, two of the peptides selectively inhibited Stx2d. These two tetravalent peptides bound to the Stx2d B subunit with high affinity dependent on Asn16. The mechanism of binding to the Stx2d B subunit differed from that of binding to Stx2a in that the peptides covered a relatively wide region of the receptor-binding surface. Thus, this highly optimized screening technique enables the development of subtype-selective neutralizers, which may lead to more sophisticated treatments of infections by Stx-producing EHEC. PMID:27382021

  8. Comprehensive N-glycome profiling of cultured human epithelial breast cells identifies unique secretome N-glycosylation signatures enabling tumorigenic subtype classification.

    PubMed

    Lee, Ling Y; Thaysen-Andersen, Morten; Baker, Mark S; Packer, Nicolle H; Hancock, William S; Fanayan, Susan

    2014-11-07

    The secreted cellular sub-proteome (secretome) is a rich source of biologically active glycoproteins. N-Glycan profiling of secretomes of cultured cancer cells provides an opportunity to investigate the link between protein N-glycosylation and tumorigenesis. Utilizing carbon-LC-ESI-CID-MS/MS of protein released native N-glycans, we accurately profiled the secretome N-glycosylation of six human epithelial breast cells including normal mammary epithelial cells (HMEC) and breast cancer cells belonging to luminal A subtype (MCF7), HER2-overexpressing subtype (SKBR3), and basal B subtype (MDA-MB157, MDA-MB231, HS578T). On the basis of intact molecular mass, LC retention time, and MS/MS fragmentation, a total of 74 N-glycans were confidently identified and quantified. The secretomes comprised significant levels of highly sialylated and fucosylated complex type N-glycans, which were elevated in all cancer cells relative to HMEC (57.7-87.2% vs 24.9%, p < 0.0001 and 57.1-78.0% vs 38.4%, p < 0.0001-0.001, respectively). Similarly, other glycan features were found to be altered in breast cancer secretomes including paucimannose and complex type N-glycans containing bisecting β1,4-GlcNAc and LacdiNAc determinants. Subtype-specific glycosylation were observed, including the preferential expression of α2,3-sialylation in the basal B breast cancer cells. Pathway analysis indicated that the regulated N-glycans were biosynthetically related. Tight clustering of the breast cancer subtypes based on N-glycome signatures supported the involvement of N-glycosylation in cancer. In conclusion, we are the first to report on the secretome N-glycosylation of a panel of breast epithelial cell lines representing different subtypes. Complementing proteome and lipid profiling, N-glycome mapping yields important pieces of structural information to help understand the biomolecular deregulation in breast cancer development and progression, knowledge that may facilitate the discovery of candidate

  9. Subtypes of anorgasmia via mathematical taxonomy.

    PubMed

    Derogatis, L R; Schmidt, C W; Fagan, P J; Wise, T N

    1989-01-01

    Seventy-six women who presented with a principal complaint of anorgasmia were partitioned into four distinct subtypes on the basis of psychosexual and psychological symptoms using hierarchical cluster analysis, a mathematical taxonomic method. The classification was accomplished with data from the Derogatis Sexual Functioning Inventory (DSFI) and the Brief Symptom Inventory (BSI). Comparisons involving age, race, marital status, and social class demonstrated no significant differences between the four subtypes; however, statistical analyses of psychosexual, psychological symptom, and chart-review variables (including psychiatric diagnosis) revealed very significant distinctions between the four groups. From the resulting typology, anorgasmic subtypes were presumptively identified as "low desire" (n = 21), "histrionic/marital conflict" (n = 20) "psychiatric disorder" (n = 12) and "constitutional" (n = 16). Implications of the typology for etiologic and optimal treatment decisions concerning anorgasmia are discussed.

  10. Molecular epidemiology of 58 new African human T-cell leukemia virus type 1 (HTLV-1) strains: identification of a new and distinct HTLV-1 molecular subtype in Central Africa and in Pygmies.

    PubMed Central

    Mahieux, R; Ibrahim, F; Mauclere, P; Herve, V; Michel, P; Tekaia, F; Chappey, C; Garin, B; Van Der Ryst, E; Guillemain, B; Ledru, E; Delaporte, E; de The, G; Gessain, A

    1997-01-01

    To gain new insights on the origin, evolution, and modes of dissemination of human T-cell leukemia virus type I (HTLV-1), we performed a molecular analysis of 58 new African HTLV-1 strains (18 from West Africa, 36 from Central Africa, and 4 from South Africa) originating from 13 countries. Of particular interest were eight strains from Pygmies of remote areas of Cameroon and the Central African Republic (CAR), considered to be the oldest inhabitants of these regions. Eight long-term activated T-cell lines producing HTLV-1 gag and env antigens were established from peripheral blood mononuclear cell cultures of HTLV-1 seropositive individuals, including three from Pygmies. A fragment of the env gene encompassing most of the gp21 transmembrane region was sequenced for the 58 new strains, while the complete long terminal repeat (LTR) region was sequenced for 9 strains, including 4 from Pygmies. Comparative sequence analyses and phylogenetic studies performed on both the env and LTR regions by the neighbor-joining and DNA parsimony methods demonstrated that all 22 strains from West and South Africa belong to the widespread cosmopolitan subtype (also called HTLV-1 subtype A). Within or alongside the previously described Zairian cluster (HTLV-1 subtype B), we discovered a number of new HTLV-1 variants forming different subgroups corresponding mainly to the geographical origins of the infected persons, Cameroon, Gabon, and Zaire. Six of the eight Pygmy strains clustered together within this Central African subtype, suggesting a common origin. Furthermore, three new strains (two originating from Pygmies from Cameroon and the CAR, respectively, and one from a Gabonese individual) were particularly divergent and formed a distinct new phylogenetic cluster, characterized by specific mutations and occupying in most analyses a unique phylogenetic position between the large Central African genotype (HTLV-1 subtype B) and the Melanesian subtype (HTLV-1 subtype C). We have

  11. Striatal muscarinic receptors promote activity-dependence of dopamine transmission via distinct receptor subtypes on cholinergic interneurons in ventral versus dorsal striatum

    PubMed Central

    Threlfell, Sarah; Clements, Michael A.; Khodai, Tansi; Pienaar, Ilse S.; Exley, Richard; Wess, Jürgen; Cragg, Stephanie J.

    2010-01-01

    Striatal dopamine (DA) and acetylcholine (ACh) regulate motivated behaviors and striatal plasticity. Interactions between these neurotransmitters may be important, through synchronous changes in parent neuron activities and reciprocal presynaptic regulation of release. How DA signalling is regulated by striatal muscarinic receptors (mAChRs) is unresolved; contradictory reports indicate suppression or facilitation, implicating several mAChR-subtypes on various neurons. We investigated whether mAChR regulation of DA signaling varies with presynaptic activity, and identified the mAChRs responsible in sensorimotor- versus limbic-associated striatum. We detected DA in real-time at carbon-fiber microelectrodes in mouse striatal slices. Broad-spectrum mAChR agonists (oxotremorine-M, APET) decreased DA release evoked by low-frequency stimuli (1–10 Hz, 4 pulses) but increased the sensitivity of DA release to presynaptic activity, even enhancing release by high frequencies (e.g. >25 Hz for 4 pulses). These bidirectional effects depended upon ACh input to striatal nicotinic receptors (nAChRs) on DA axons but not GABA- or glutamate-input. In caudate-putamen (CPu), knockout of M2- or M4-mAChRs (not M5) prevented mAChR control of DA indicating that M2- and M4-mAChRs are required. In nucleus accumbens (NAc) core or shell, mAChR function was prevented in M4-knockouts, but not M2- or M5-knockouts. These data indicate that striatal mAChRs, by inhibiting ACh release from cholinergic interneurons and thus modifying nAChR activity, offer variable control of DA release probability that promotes how DA release reflects activation of dopaminergic axons. Furthermore, different coupling of striatal M2-/M4-mAChRs to the control of DA release in CPu versus NAc suggests targets to influence DA/ACh function differentially between striatal domains. PMID:20203199

  12. Distinct populations of quiescent and proliferative pancreatic β-cells identified by HOTcre mediated labeling

    PubMed Central

    Hesselson, Daniel; Anderson, Ryan M.; Beinat, Marine; Stainier, Didier Y. R.

    2009-01-01

    Pancreatic β-cells are critical regulators of glucose homeostasis, and they vary dramatically in their glucose stimulated metabolic response and levels of insulin secretion. It is unclear whether these parameters are influenced by the developmental origin of individual β-cells. Using HOTcre, a Cre-based genetic switch that uses heat-induction to precisely control the temporal expression of transgenes, we labeled two populations of β-cells within the developing zebrafish pancreas. These populations originate in distinct pancreatic buds and exhibit gene expression profiles suggesting distinct functions during development. We find that the dorsal bud derived β-cells are quiescent and exhibit a marked decrease in insulin expression postembryonically. In contrast, ventral bud derived β-cells proliferate actively, and maintain high levels of insulin expression compared with dorsal bud derived β-cells. Therapeutic strategies to regulate β-cell proliferation and function are required to cure pathological states that result from excessive β-cell proliferation (e.g., insulinoma) or insufficient β-cell mass (e.g., diabetes mellitus). Our data reveal the existence of distinct populations of β-cells in vivo and should help develop better strategies to regulate β-cell differentiation and proliferation. PMID:19706417

  13. Genetic approach identifies distinct asthma pathways in overweight vs normal weight children.

    PubMed

    Butsch Kovacic, M; Martin, L J; Biagini Myers, J M; He, H; Lindsey, M; Mersha, T B; Khurana Hershey, G K

    2015-08-01

    The pathogenesis of asthma in the context of excess body weight may be distinct from asthma that develops in normal weight children. The study's objective was to explore the biology of asthma in the context of obesity and normal weight status using genetic methodologies. Associations between asthma and SNPs in 49 genes were assessed, as well as, interactions between SNPs and overweight status in child participants of the Greater Cincinnati Pediatric Clinic Repository. Asthma was significantly associated with weight (OR = 1.38; P = 0.037). The number of genes and the magnitude of their associations with asthma were notably greater when considering overweight children alone vs normal weight and overweight children together. When considering weight, distinct sets of asthma-associated genes were observed, many times with opposing effects. We demonstrated that the underlying heterogeneity of asthma is likely due in part to distinct pathogenetic pathways that depend on preceding/comorbid overweight and/or allergy. It is therefore important to consider both obesity and asthma when conducting studies of asthma.

  14. Intimate Partner Violence Perpetration by Court-Ordered Men: Distinctions among Subtypes of Physical Violence, Sexual Violence, Psychological Abuse, and Stalking

    ERIC Educational Resources Information Center

    Hall, Jeffrey E.; Walters, Mikel L.; Basile, Kathleen C.

    2012-01-01

    This study continues previous work documenting the structure of violence perpetrated by males against their female intimate partners. It assesses the construct validity of a measurement model depicting associations among eight subtypes of perpetration: moderate physical violence, severe physical violence, forced or coerced sexual violence, sexual…

  15. Intimate Partner Violence Perpetration by Court-Ordered Men: Distinctions among Subtypes of Physical Violence, Sexual Violence, Psychological Abuse, and Stalking

    ERIC Educational Resources Information Center

    Hall, Jeffrey E.; Walters, Mikel L.; Basile, Kathleen C.

    2012-01-01

    This study continues previous work documenting the structure of violence perpetrated by males against their female intimate partners. It assesses the construct validity of a measurement model depicting associations among eight subtypes of perpetration: moderate physical violence, severe physical violence, forced or coerced sexual violence, sexual…

  16. Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles

    PubMed Central

    Nandi, Tannistha; Holden, Matthew T.G.; Didelot, Xavier; Mehershahi, Kurosh; Boddey, Justin A.; Beacham, Ifor; Peak, Ian; Harting, John; Baybayan, Primo; Guo, Yan; Wang, Susana; How, Lee Chee; Sim, Bernice; Essex-Lopresti, Angela; Sarkar-Tyson, Mitali; Nelson, Michelle; Smither, Sophie; Ong, Catherine; Aw, Lay Tin; Hoon, Chua Hui; Michell, Stephen; Studholme, David J.; Titball, Richard; Chen, Swaine L.; Parkhill, Julian

    2015-01-01

    Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity. PMID:25236617

  17. Burkholderia pseudomallei sequencing identifies genomic clades with distinct recombination, accessory, and epigenetic profiles.

    PubMed

    Nandi, Tannistha; Holden, Matthew T G; Holden, Mathew T G; Didelot, Xavier; Mehershahi, Kurosh; Boddey, Justin A; Beacham, Ifor; Peak, Ian; Harting, John; Baybayan, Primo; Guo, Yan; Wang, Susana; How, Lee Chee; Sim, Bernice; Essex-Lopresti, Angela; Sarkar-Tyson, Mitali; Nelson, Michelle; Smither, Sophie; Ong, Catherine; Aw, Lay Tin; Hoon, Chua Hui; Michell, Stephen; Studholme, David J; Titball, Richard; Chen, Swaine L; Parkhill, Julian; Tan, Patrick

    2015-01-01

    Burkholderia pseudomallei (Bp) is the causative agent of the infectious disease melioidosis. To investigate population diversity, recombination, and horizontal gene transfer in closely related Bp isolates, we performed whole-genome sequencing (WGS) on 106 clinical, animal, and environmental strains from a restricted Asian locale. Whole-genome phylogenies resolved multiple genomic clades of Bp, largely congruent with multilocus sequence typing (MLST). We discovered widespread recombination in the Bp core genome, involving hundreds of regions associated with multiple haplotypes. Highly recombinant regions exhibited functional enrichments that may contribute to virulence. We observed clade-specific patterns of recombination and accessory gene exchange, and provide evidence that this is likely due to ongoing recombination between clade members. Reciprocally, interclade exchanges were rarely observed, suggesting mechanisms restricting gene flow between clades. Interrogation of accessory elements revealed that each clade harbored a distinct complement of restriction-modification (RM) systems, predicted to cause clade-specific patterns of DNA methylation. Using methylome sequencing, we confirmed that representative strains from separate clades indeed exhibit distinct methylation profiles. Finally, using an E. coli system, we demonstrate that Bp RM systems can inhibit uptake of non-self DNA. Our data suggest that RM systems borne on mobile elements, besides preventing foreign DNA invasion, may also contribute to limiting exchanges of genetic material between individuals of the same species. Genomic clades may thus represent functional units of genetic isolation in Bp, modulating intraspecies genetic diversity.

  18. Integrative Analysis of Prognosis Data on Multiple Cancer Subtypes

    PubMed Central

    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

  19. Identifying Two Groups of Entitled Individuals: Cluster Analysis Reveals Emotional Stability and Self-Esteem Distinction.

    PubMed

    Crowe, Michael L; LoPilato, Alexander C; Campbell, W Keith; Miller, Joshua D

    2016-12-01

    The present study hypothesized that there exist two distinct groups of entitled individuals: grandiose-entitled, and vulnerable-entitled. Self-report scores of entitlement were collected for 916 individuals using an online platform. Model-based cluster analyses were conducted on the individuals with scores one standard deviation above mean (n = 159) using the five-factor model dimensions as clustering variables. The results support the existence of two groups of entitled individuals categorized as emotionally stable and emotionally vulnerable. The emotionally stable cluster reported emotional stability, high self-esteem, more positive affect, and antisocial behavior. The emotionally vulnerable cluster reported low self-esteem and high levels of neuroticism, disinhibition, conventionality, psychopathy, negative affect, childhood abuse, intrusive parenting, and attachment difficulties. Compared to the control group, both clusters reported being more antagonistic, extraverted, Machiavellian, and narcissistic. These results suggest important differences are missed when simply examining the linear relationships between entitlement and various aspects of its nomological network.

  20. Spectral clustering using Nyström approximation for the accurate identification of cancer molecular subtypes.

    PubMed

    Shi, Mingguang; Xu, Guofu

    2017-07-07

    A major challenge in clinical cancer research is the identification of accurate molecular subtype. While unsupervised clustering methods have been applied for class discovery, this clustering method remains a bottleneck in developing accurate method for molecular subtype discovery. In this analysis, we hypothesize that spectral clustering method could identify molecular subtypes in correlation with survival outcomes. We propose an accurate subtype identification method, Cancer Subtype Identification with Spectral Clustering using Nyström approximation (CSISCN), for the discovery of molecular subtypes, based on spectral clustering method. CSISCN could be used to improve gene expression-based identification of breast cancer molecular subtypes. We demonstrated that CSISCN identified the molecular subtypes with distinct clinical outcomes and was valid for the number of molecular subtypes. Furthermore, CSISCN identified molecular subtypes for improving clinical and molecular relevance which significantly outperformed consensus clustering and spectral clustering methods. To test the general applicability of the CSISCN, we further applied it on human CRC datasets and AML datasets and demonstrated superior performance as compared to consensus clustering method. In summary, CSISCN demonstrated the great potential in gene expression-based subtype identification.

  1. Subtyping adolescents with bulimia nervosa.

    PubMed

    Chen, Eunice Y; Le Grange, Daniel

    2007-12-01

    Cluster analyses of eating disorder patients have yielded a "dietary-depressive" subtype, typified by greater negative affect, and a "dietary" subtype, typified by dietary restraint. This study aimed to replicate these findings in an adolescent sample with bulimia nervosa (BN) from a randomized controlled trial and to examine the validity and reliability of this methodology. In the sample of BN adolescents (N=80), cluster analysis revealed a "dietary-depressive" subtype (37.5%) and a "dietary" subtype (62.5%) using the Beck Depression Inventory, Rosenberg Self-Esteem Scale and Eating Disorder Examination Restraint subscale. The "dietary-depressive" subtype compared to the "dietary" subtype was significantly more likely to: (1) report co-occurring disorders, (2) greater eating and weight concerns, and (3) less vomiting abstinence at post-treatment (all p's<.05). The cluster analysis based on "dietary" and "dietary-depressive" subtypes appeared to have concurrent validity, yielding more distinct groups than subtyping by vomiting frequency. In order to assess the reliability of the subtyping scheme, a larger sample of adolescents with mixed eating and weight disorders in an outpatient eating disorder clinic (N=149) was subtyped, yielding similar subtypes. These results support the validity and reliability of the subtyping strategy in two adolescent samples.

  2. Bacterially-Associated Transcriptional Remodelling in a Distinct Genomic Subtype of Colorectal Cancer Provides a Plausible Molecular Basis for Disease Development

    PubMed Central

    Goosen, Ryan W.

    2016-01-01

    The relevance of specific microbial colonisation to colorectal cancer (CRC) disease pathogenesis is increasingly recognised, but our understanding of possible underlying molecular mechanisms that may link colonisation to disease in vivo remains limited. Here, we investigate the relationships between the most commonly studied CRC-associated bacteria (Enterotoxigenic Bacteroides fragilis, pks+ Escherichia coli, Fusobacterium spp., afaC+ E. coli, Enterococcus faecalis & Enteropathogenic E. coli) and altered transcriptomic and methylation profiles of CRC patients, in order to gain insight into the potential contribution of these bacteria in the aetiopathogenesis of CRC. We show that colonisation by E. faecalis and high levels of Fusobacterium is associated with a specific transcriptomic subtype of CRC that is characterised by CpG island methylation, microsatellite instability and a significant increase in inflammatory and DNA damage pathways. Analysis of the significant, bacterially-associated changes in host gene expression, both at the level of individual genes as well as pathways, revealed a transcriptional remodeling that provides a plausible mechanistic link between specific bacterial colonisation and colorectal cancer disease development and progression in this subtype; these included upregulation of REG3A, REG1A and REG1P in the case of high-level colonization by Fusobacterium, and CXCL10 and BMI1 in the case of colonisation by E. faecalis. The enrichment of both E. faecalis and Fusobacterium in this CRC subtype suggests that polymicrobial colonisation of the colonic epithelium may well be an important aspect of colonic tumourigenesis. PMID:27846243

  3. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model.

    PubMed

    Silva-Santos, Sara; van Woerden, Geeske M; Bruinsma, Caroline F; Mientjes, Edwin; Jolfaei, Mehrnoush Aghadavoud; Distel, Ben; Kushner, Steven A; Elgersma, Ype

    2015-05-01

    Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design.

  4. Ube3a reinstatement identifies distinct developmental windows in a murine Angelman syndrome model

    PubMed Central

    Silva-Santos, Sara; van Woerden, Geeske M.; Bruinsma, Caroline F.; Mientjes, Edwin; Jolfaei, Mehrnoush Aghadavoud; Distel, Ben; Kushner, Steven A.; Elgersma, Ype

    2015-01-01

    Angelman syndrome (AS) is a severe neurodevelopmental disorder that results from loss of function of the maternal ubiquitin protein ligase E3A (UBE3A) allele. Due to neuron-specific imprinting, the paternal UBE3A copy is silenced. Previous studies in murine models have demonstrated that strategies to activate the paternal Ube3a allele are feasible; however, a recent study showed that pharmacological Ube3a gene reactivation in adulthood failed to rescue the majority of neurocognitive phenotypes in a murine AS model. Here, we performed a systematic study to investigate the possibility that neurocognitive rescue can be achieved by reinstating Ube3a during earlier neurodevelopmental windows. We developed an AS model that allows for temporally controlled Cre-dependent induction of the maternal Ube3a allele and determined that there are distinct neurodevelopmental windows during which Ube3a restoration can rescue AS-relevant phenotypes. Motor deficits were rescued by Ube3a reinstatement in adolescent mice, whereas anxiety, repetitive behavior, and epilepsy were only rescued when Ube3a was reinstated during early development. In contrast, hippocampal synaptic plasticity could be restored at any age. Together, these findings suggest that Ube3a reinstatement early in development may be necessary to prevent or rescue most AS-associated phenotypes and should be considered in future clinical trial design. PMID:25866966

  5. Neurocognitive subtypes of schizophrenia.

    PubMed

    Rangel, Andrés; Muñoz, Claudia; Ocampo, María V; Quintero, Claudia; Escobar, Marcela; Botero, Sonia; Marín, Catalina; Jaramillo, Luis E; Sánchez, Ricardo; Rodríguez-Losada, Jorge; Ospina-Duque, Jorge; Palacio, Carlos; C Arango, Juan; Valencia, Ana V; Aguirre-Acevedo, Daniel C; García, Jenny

    2015-01-01

    To empirically identify schizophrenia neurocognitive subtypes and establish their association with clinical characteristics. Sustained attention, executive function, facial emotion recognition, verbal learning, and working memory tests were applied to 253 subjects with schizophrenia. We identified neurocognitive subtypes by a latent class analysis of the tests results. After, we made a search for the association of these subtypes with clinic characteristics. We identified four neurocognitive subtypes: 1) “Global cognitive deficit”, 2) “Memory and executive function deficit”, 3) “Memory and facial emotion recognition deficit,” and 4) “Without cognitive deficit.” In comparison with the subtype “without cognitive deficit,” we found that the “memory and executive function deficit subtype” and the “global cognitive deficit subtype” had a higher frequency of male, unemployed, severe impairment, and adherence to treatment participants. However, in the “global cognitive deficit subtype” the differences were higher and there was also a lower frequency of past major depressive episodes (OR 0.39; 95%CI: 0.16 to 0.97). The “memory and facial recognition deficit subtype” had a higher probability of severe impairment (OR 5.52; 95%CI: 1.89 to 16.14) and unemployed (OR 2.43; 95%CI: 1.06 to 5.55) participants, but also a lower probability of past depressive episodes (OR 0.21; 95%CI: 0.07 to 0.66). Our results suggest the existence of four neurocognitive subtypes in schizophrenia with a spectrum of dysfunction and severity. We found higher dysfunction in those with worse cognitive dysfunction, and higher affective psychopathology and less treatment adherence in those with less cognitive dysfunction.

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

    PubMed

    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.

  7. CD15 Expression Does Not Identify a Phenotypically or Genetically Distinct Glioblastoma Population.

    PubMed

    Kenney-Herbert, Emma; Al-Mayhani, Talal; Piccirillo, Sara G M; Fowler, Joanna; Spiteri, Inmaculada; Jones, Philip; Watts, Colin

    2015-07-01

    : Recent research has focused on the hypothesis that the growth and regeneration of glioblastoma (GB) is sustained by a subpopulation of self-renewing stem-like cells. This has led to the prediction that molecular markers for cancer stem cells in GB may provide a treatment target. One candidate marker is CD15: we wanted to determine if CD15 represented a credible stem cell marker in GB. We first demonstrated that CD15-positive (CD15+) cells were less proliferative than their CD15-negative (CD15-) counterparts in 10 patient GB tumors. Next we compared the proliferative activity of CD15+ and CD15- cells in vitro using tumor-initiating primary GB cell lines (TICs) and found no difference in proliferative behavior. Furthermore, TICs sorted for CD15+ and CD15- were not significantly different cytogenetically or in terms of gene expression profile. Sorted single CD15+ and CD15- cells were equally capable of reconstituting a heterogeneous population containing both CD15+ and CD15- cells over time, and both CD15+ and CD15- cells were able to generate tumors in vivo. No difference was found in the phenotypic or genomic behavior of CD15+ cells compared with CD15- cells from the same patient. Moreover, we found that in vitro, cells were able to interconvert between the CD15+ and CD15- states. Our data challenge the utility of CD15 as a cancer stem cell marker. The data from this study contribute to the ongoing debate about the role of cancer stem cells in gliomagenesis. Results showed that CD15, a marker previously thought to be a cancer stem-like marker in glioblastoma, could not isolate a phenotypically or genetically distinct population. Moreover, isolated CD15-positive and -negative cells were able to generate mixed populations of glioblastoma cells in vitro. ©AlphaMed Press.

  8. CD15 Expression Does Not Identify a Phenotypically or Genetically Distinct Glioblastoma Population

    PubMed Central

    Al-Mayhani, Talal; Piccirillo, Sara G.M.; Fowler, Joanna; Spiteri, Inmaculada; Jones, Philip

    2015-01-01

    Recent research has focused on the hypothesis that the growth and regeneration of glioblastoma (GB) is sustained by a subpopulation of self-renewing stem-like cells. This has led to the prediction that molecular markers for cancer stem cells in GB may provide a treatment target. One candidate marker is CD15: we wanted to determine if CD15 represented a credible stem cell marker in GB. We first demonstrated that CD15-positive (CD15+) cells were less proliferative than their CD15-negative (CD15−) counterparts in 10 patient GB tumors. Next we compared the proliferative activity of CD15+ and CD15− cells in vitro using tumor-initiating primary GB cell lines (TICs) and found no difference in proliferative behavior. Furthermore, TICs sorted for CD15+ and CD15− were not significantly different cytogenetically or in terms of gene expression profile. Sorted single CD15+ and CD15− cells were equally capable of reconstituting a heterogeneous population containing both CD15+ and CD15− cells over time, and both CD15+ and CD15− cells were able to generate tumors in vivo. No difference was found in the phenotypic or genomic behavior of CD15+ cells compared with CD15− cells from the same patient. Moreover, we found that in vitro, cells were able to interconvert between the CD15+ and CD15− states. Our data challenge the utility of CD15 as a cancer stem cell marker. Significance The data from this study contribute to the ongoing debate about the role of cancer stem cells in gliomagenesis. Results showed that CD15, a marker previously thought to be a cancer stem-like marker in glioblastoma, could not isolate a phenotypically or genetically distinct population. Moreover, isolated CD15-positive and -negative cells were able to generate mixed populations of glioblastoma cells in vitro. PMID:26019225

  9. Identifying the distinct phases of THz waves from K-valley electrons in graphite

    SciTech Connect

    Irfan, Muhammad; Yim, Jong-Hyuk Jho, Young-Dahl; Kim, Changyoung

    2013-12-04

    The polarity change of THz electromagnetic waves radiated from single-crystalline graphite and polycrystalline graphite films has been studied to identify the main generation mechanism in conventional reflective THz time-domain spectroscopy scheme. The excitation wavelength variation around the K-valley produces no significant changes in THz field strength. We further found that THz waves become fully dispersed without polarity change in lateral detection geometry.

  10. Comparative genomic analysis of Helicobacter pylori from Malaysia identifies three distinct lineages suggestive of differential evolution

    PubMed Central

    Kumar, Narender; Mariappan, Vanitha; Baddam, Ramani; Lankapalli, Aditya K.; Shaik, Sabiha; Goh, Khean-Lee; Loke, Mun Fai; Perkins, Tim; Benghezal, Mohammed; Hasnain, Seyed E.; Vadivelu, Jamuna; Marshall, Barry J.; Ahmed, Niyaz

    2015-01-01

    The discordant prevalence of Helicobacter pylori and its related diseases, for a long time, fostered certain enigmatic situations observed in the countries of the southern world. Variation in H. pylori infection rates and disease outcomes among different populations in multi-ethnic Malaysia provides a unique opportunity to understand dynamics of host–pathogen interaction and genome evolution. In this study, we extensively analyzed and compared genomes of 27 Malaysian H. pylori isolates and identified three major phylogeographic lineages: hspEastAsia, hpEurope and hpSouthIndia. The analysis of the virulence genes within the core genome, however, revealed a comparable pathogenic potential of the strains. In addition, we identified four genes limited to strains of East-Asian lineage. Our analyses identified a few strain-specific genes encoding restriction modification systems and outlined 311 core genes possibly under differential evolutionary constraints, among the strains representing different ethnic groups. The cagA and vacA genes also showed variations in accordance with the host genetic background of the strains. Moreover, restriction modification genes were found to be significantly enriched in East-Asian strains. An understanding of these variations in the genome content would provide significant insights into various adaptive and host modulation strategies harnessed by H. pylori to effectively persist in a host-specific manner. PMID:25452339

  11. Nuclear Morphometry Identifies a Distinct Aggressive Cellular Phenotype in Cutaneous Squamous Cell Carcinoma

    PubMed Central

    Glazer, Evan S.; Bartels, Peter H.; Prasad, Anil R.; Yozwiak, Michael L.; Bartels, Hubert G.; Einspahr, Janine G.; Alberts, David S.; Krouse, Robert S.

    2011-01-01

    By identifying aggressive cutaneous squamous cell carcinoma (cSCC) in patients who are at high risk for recurrences or second primaries after resection, intensive surveillance and therapy may decrease morbidity and mortality. We investigated the role of nuclear morphometry (karyometry) in differentiating between aggressive and nonaggressive cSCC. We retrospectively analyzed cSCC lesions from 40 male patients. 22 patients had evidence of aggressive cSCC (local/regional recurrence or a second primary cSCC), and 18 patients were identified with similar ages and sites of disease as control patients with nonaggressive cSCC (no evidence of recurrence, metastasis, or second primary). We performed karyometric analysis to identify nuclear features that discriminate between aggressive and nonaggressive cSCC nuclei. We used statistically significant differences (Kruskal-Wallis test P < 0.0001) to compose a quantitative aggressive classification score (proportion of aggressive nuclei from 0% to 100%). For comparisons, we used Fisher’s exact test or Student t test. The mean age was 79 ± 7 years for aggressive cSCC and 80 ± 9 years for nonaggressive cSCC (P = 0.66). We analyzed a mean of 96 nuclei in each group. The mean classification score for aggressive cSCC was significantly higher (69% ± 6%) than for nonaggressive cSCC (28% ± 5%, P = 0.00002). Overall, the classification score accurately categorized 80% of our patients (P = 0.0004). In most patients, karyometry differentiated between aggressive and nonaggressive cSCC. We found that classification scores, which provide information on individual lesions, could be used for risk stratification. PMID:21636541

  12. Nuclear morphometry identifies a distinct aggressive cellular phenotype in cutaneous squamous cell carcinoma.

    PubMed

    Glazer, Evan S; Bartels, Peter H; Prasad, Anil R; Yozwiak, Michael L; Bartels, Hubert G; Einspahr, Janine G; Alberts, David S; Krouse, Robert S

    2011-11-01

    By identifying aggressive cutaneous squamous cell carcinoma (cSCC) in patients who are at high risk for recurrences or second primaries after resection, intensive surveillance and therapy may decrease morbidity and mortality. We investigated the role of nuclear morphometry (karyometry) in differentiating between aggressive and nonaggressive cSCC. We retrospectively analyzed cSCC lesions from 40 male patients. Twenty-two patients had evidence of aggressive cSCC (local/regional recurrence or a second primary cSCC), and 18 patients were identified with similar ages and sites of disease as control patients with nonaggressive cSCC (no evidence of recurrence, metastasis, or second primary). We carried out karyometric analysis to identify nuclear features that discriminate between aggressive and nonaggressive cSCC nuclei. We used statistically significant differences (Kruskal-Wallis test, P < 0.0001) to compose a quantitative aggressive classification score (proportion of aggressive nuclei from 0% to 100%). For comparisons, we used Fisher's exact test or Student's t test. The mean age was 79 ± 7 years for aggressive cSCC and 80 ± 9 years for nonaggressive cSCC (P = 0.66). We analyzed a mean of 96 nuclei in each group. The mean classification score for aggressive cSCC was significantly higher (69% ± 6%) than for nonaggressive cSCC (28% ± 5%, P = 0.00002). Overall, the classification score accurately categorized 80% of our patients (P = 0.0004). In most patients, karyometry differentiated between aggressive and nonaggressive cSCC. We found that classification scores, which provide information on individual lesions, could be used for risk stratification.

  13. Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1.

    PubMed

    Park, Chul-Kyu; Xu, Zhen-Zhong; Liu, Tong; Lü, Ning; Serhan, Charles N; Ji, Ru-Rong

    2011-12-14

    Inflammatory pain such as arthritic pain is typically treated with opioids and cyclo-oxygenase-2 inhibitors with well known side effects. Transient receptor potential subtype vanilloid 1 (TRPV1) and TRP ankyryn 1 (TRPA1) contribute importantly to the genesis of inflammatory pain via both peripheral mechanisms (peripheral sensitization) and spinal cord mechanisms (central sensitization). Although these TRP channels have been intensively studied, little is known about their endogenous inhibitors. Recent studies have demonstrated that the endogenous lipid mediators resolvins (RvE1 and RvD1), derived from ω-3 unsaturated fatty acids, are potent inhibitors for inflammatory pain, without noticeable side effects. However, the molecular mechanisms underlying resolvins' distinct analgesic actions in mice are unclear. RvD2 is a novel family member of resolvins. Here we report that RvD2 is a remarkably potent inhibitor of TRPV1 (IC(50) = 0.1 nm) and TRPA1 (IC(50) = 2 nm) in primary sensory neurons, whereas RvE1 and RvD1 selectively inhibited TRPV1 (IC(50) = 1 nm) and TRPA1 (IC(50) = 9 nm), respectively. Accordingly, RvD2, RvE1, and RvD1 differentially regulated TRPV1 and TRPA1 agonist-elicited acute pain and spinal cord synaptic plasticity [spontaneous EPSC (sEPSC) frequency increase]. RvD2 also abolished inflammation-induced sEPSC increases (frequency and amplitude), without affecting basal synaptic transmission. Intrathecal administration of RvD2 at very low doses (0.01-1 ng) prevented formalin-induced spontaneous pain. Intrathecal RvD2 also reversed adjuvant-induced inflammatory pain without altering baseline pain and motor function. Finally, intrathecal RvD2 reversed C-fiber stimulation-evoked long-term potentiation in the spinal cord. Our findings suggest distinct roles of resolvins in regulating TRP channels and identify RvD2 as a potent endogenous inhibitor for TRPV1/TRPA1 and inflammatory pain.

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

    PubMed

    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.

  15. Identification of sepsis subtypes in critically ill adults using gene expression profiling.

    PubMed

    Maslove, David M; Tang, Benjamin M; McLean, Anthony S

    2012-10-04

    Sepsis is a syndromic illness that has traditionally been defined by a set of broad, highly sensitive clinical parameters. As a result, numerous distinct pathophysiologic states may meet diagnostic criteria for sepsis, leading to syndrome heterogeneity. The existence of biologically distinct sepsis subtypes may in part explain the lack of actionable evidence from clinical trials of sepsis therapies. We used microarray-based gene expression data from adult patients with sepsis in order to identify molecularly distinct sepsis subtypes. We used partitioning around medoids (PAM) and hierarchical clustering of gene expression profiles from neutrophils taken from a cohort of septic patients in order to identify distinct subtypes. Using the medoids learned from this cohort, we then clustered a second independent cohort of septic patients, and used the resulting class labels to evaluate differences in clinical parameters, as well as the expression of relevant pharmacogenes. We identified two sepsis subtypes based on gene expression patterns. Subtype 1 was characterized by increased expression of genes involved in inflammatory and Toll receptor mediated signaling pathways, as well as a higher prevalence of severe sepsis. There were differences between subtypes in the expression of pharmacogenes related to hydrocortisone, vasopressin, norepinephrine, and drotrecogin alpha. Sepsis subtypes can be identified based on different gene expression patterns. These patterns may generate hypotheses about the underlying pathophysiology of sepsis and suggest new ways of classifying septic patients both in clinical practice, and in the design of clinical trials.

  16. Two distinct subpopulations of neurons in the thalamic intergeniculate leaflet identified by subthreshold currents.

    PubMed

    Chrobok, Lukasz; Palus, Katarzyna; Lewandowski, Marian Henryk

    2016-08-04

    The intergeniculate leaflet (IGL) is a flat retinorecipient thalamic structure implicated in orchestrating circadian rhythm, historically considered to be a subdivision of the neighboring ventrolateral geniculate nucleus (VLG). IGL consists of two main neuronal subpopulations: enkephalinergic and neuropeptide Y (NPY)-synthesizing cells. These cell types have different functions, connectivity and firing pattern in vivo, which suggest that they have different membrane currents to support their functional differences. We therefore performed patch-clamp experiments combined with immunohistochemical staining to clarify possible differences in the subthreshold currents of IGL neurons. Our results suggest that IGL neurons can be divided into two subpopulations based on two ionic currents. A T-type calcium current (IT) was identified in neurons that do not synthesise NPY, whereas all NPY-positive neurons were found to express a marked A-type potassium current (IA). Due to the fact that the clear electrophysiological discriminants between IGL and VLG are lacking, we decided to compare the amplitudes of the identified currents between those two structures. Our data suggest that VLG neurons can be characterized by a high amplitude IT and a low IA. Finally, we compared both currents with WAG/Rij rats, a well-established model of absence epilepsy, with co-occurring retinal pathologies, sleep-onset disturbances, and seizures exhibiting circadian rhythmicity. Data presented in this study uncovered pathologies in the IT exhibiting neurons of the IGL and VLG. In conclusion, the data presented here suggest that different subthreshold current expression supports the functional differences of thalamic nuclei. Those differences are promising for possible pharmacological manipulations of specified cell types in pathophysiologies including absence epilepsy. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  17. Pathological Gambling Subtypes

    ERIC Educational Resources Information Center

    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…

  18. Pathological Gambling Subtypes

    ERIC Educational Resources Information Center

    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…

  19. Integrated Genome-wide DNA Copy Number and Expression Analysis Identifies Distinct Mechanisms of Primary Chemo-resistance in Ovarian Carcinomas

    PubMed Central

    Etemadmoghadam, Dariush; deFazio, Anna; Beroukhim, Rameen; Mermel, Craig; George, Joshy; Getz, Gaddy; Tothill, Richard; Okamoto, Aikou; Raeder, Maria B; Harnett, Paul; Lade, Stephen; Akslen, Lars A; Tinker, Anna; Locandro, Bianca; Alsop, Kathryn; Chiew, Yoke-Eng; Traficante, Nadia; Fereday, Sian; Johnson, Daryl; Fox, Stephen; Sellers, William; Urashima, Mitsuyoshi; Salvesen, Helga B; Meyerson, Matthew; Bowtell, David

    2009-01-01

    Purpose A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-taxol based treatment. We analyzed somatic DNA copy number variation (CNV) and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers. Experimental Design Genome-wide CNV was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate CNV to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of twelve candidate genes as independent validation of previously reported associations with clinical outcome. Likely CNV targets and tumor molecular subtypes were further characterized by gene expression profiling. Results Amplification of 19q12, containing Cyclin E (CCNE1) and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor co-activator NCOA3, were significantly associated with poor response to primary treatment. Other genes previously associated with CNV and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too were a subset of treatment responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification over expressed genes involved in extracellular matrix deposition. Conclusions We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer. PMID:19193619

  20. Genetic profiling identifies two classes of soft-tissue leiomyosarcomas with distinct clinical characteristics.

    PubMed

    Italiano, Antoine; Lagarde, Pauline; Brulard, Céline; Terrier, Philippe; Laë, Marick; Marques, Bernard; Ranchere-Vince, Dominique; Michels, Jean-Jacques; Trassard, Martine; Cioffi, Angela; Piperno-Neumann, Sophie; Chevreau, Christine; Blay, Jean-Yves; Delcambre, Corinne; Isambert, Nicolas; Penel, Nicolas; Bay, Jacques-Olivier; Bonvalot, Sylvie; Le Cesne, Axel; Coindre, Jean-Michel; Chibon, Frédéric

    2013-03-01

    Data about the prognostic factors of soft-tissue leiomyosarcomas and their correlation with molecular profile are limited. From 1990 to 2010, 586 adult patients with a primary soft-tissue leiomyosarcoma were included in the French Sarcoma Group (GSF) database after surgery of the primary tumor. Multivariate analyses were conducted by Cox regression model in a backward stepwise procedure. Genetic profiling was conducted for 73 cases. Median age was 59 years (range, 21-98 years). The median follow-up of patients alive was 46 months. The 5-year metastasis-free survival (MFS) rate was 51% (95% location and grade > I were independent adverse prognostic factors for MFS). The 5-year overall survival (OS) rate was 63% [95% confidence interval (CI), 59-67]. On multivariate analysis, age ≥ 60 years old, tumor size > 5 cm, deep location, and grade > I were independent adverse prognostic factors for OS. Molecular profiling identified specific clusters with activation of different biologic pathways: retroperitoneal leiomyosarcomas are characterized by overexpression of genes involved in muscle differentiation and nonretroperitoneal leiomyosarcomas characterized by overexpression of genes mainly involved in extracellular matrix, wounding, and adhesion pathways. The CINSARC signature but not comparative genomic hybridization (CGH) profiling was predictive of outcome. Soft-tissue leiomyosarcomas represent a heterogeneous group of tumors with at least two categories, retroperitoneal and extremities leiomyosarcomas, having specific clinical outcome and molecular features. Future clinical trials should consider this heterogeneity for a better stratification of patients. ©2013 AACR.

  1. Development of a multiplex RT-PCR-ELISA to identify four distinct species of tospovirus.

    PubMed

    Charoenvilaisiri, Saengsoon; Seepiban, Channarong; Bhunchoth, Anjana; Warin, Nuchnard; Luxananil, Plearnpis; Gajanandana, Oraprapai

    2014-06-01

    In this study, a multiplex RT-PCR-ELISA was developed to detect and differentiate four tospovirus species found in Thailand, namely Capsicum chlorosis virus (CaCV), Melon yellow spot virus (MYSV), Tomato necrotic ringspot virus (TNRV), and Watermelon silver mottle virus (WSMoV). In this system, nucleocapsid (N) gene fragments of four tospoviruses were simultaneously amplified and labeled with digoxigenin (DIG) in a single RT-PCR reaction using a pair of degenerate primers binding to the same conserved regions in all four tospovirus N genes. The DIG-labeled amplicons were distinguished into species by four parallel hybridizations to species-specific biotinylated probes in streptavidin-coated microtiter wells followed by ELISA detection using a peroxidase-conjugated anti-DIG antibody. Results indicated that the multiplex RT-PCR-ELISA assay could specifically identify each of these four tospoviruses without cross-reactivity between species or reactivity to healthy plant negative controls. Assay sensitivity was 10- to 1000-fold higher than conventional RT-PCR. When applied to naturally infected plants, all samples yielded concordant results between RT-PCR-ELISA and the reference RT-PCR. In conclusion, the multiplex RT-PCR-ELISA developed in this study has superior specificity, sensitivity, and high-throughput capacity compared to conventional RT-PCR and is an attractive alternative for the identification of different tospovirus species.

  2. Novel application of the published kinase inhibitor set to identify therapeutic targets and pathways in triple negative breast cancer subtypes

    PubMed Central

    Phamduy, Theresa B.; Chrisey, Douglas B.

    2017-01-01

    Triple negative breast cancers (TNBCs) have high recurrence and metastasis rates. Acquisition of a mesenchymal morphology and phenotype in addition to driving migration is a consequential process that promotes metastasis. Although some kinases are known to regulate a mesenchymal phenotype, the role for a substantial portion of the human kinome remains uncharacterized. Here we evaluated the Published Kinase Inhibitor Set (PKIS) and screened a panel of TNBC cell lines to evaluate the compounds’ effects on a mesenchymal phenotype. Our screen identified 36 hits representative of twelve kinase inhibitor chemotypes based on reversal of the mesenchymal cell morphology, which was then prioritized to twelve compounds based on gene expression and migratory behavior analyses. We selected the most active compound and confirmed mesenchymal reversal on transcript and protein levels with qRT-PCR and Western Blot. Finally, we utilized a kinase array to identify candidate kinases responsible for the EMT reversal. This investigation shows the novel application to identify previously unrecognized kinase pathways and targets in acquisition of a mesenchymal TNBC phenotype that warrant further investigation. Future studies will examine specific roles of the kinases in mechanisms responsible for acquisition of the mesenchymal and/or migratory phenotype. PMID:28771473

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

    PubMed

    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.

  4. Identified motor terminals in Drosophila larvae show distinct differences in morphology and physiology

    NASA Technical Reports Server (NTRS)

    Lnenicka, G. A.; Keshishian, H.

    2000-01-01

    In Drosophila, the type I motor terminals innervating the larval ventral longitudinal muscle fibers 6 and 7 have been the most popular preparation for combining synaptic studies with genetics. We have further characterized the normal morphological and physiological properties of these motor terminals and the influence of muscle size on terminal morphology. Using dye-injection and physiological techniques, we show that the two axons supplying these terminals have different innervation patterns: axon 1 innervates only muscle fibers 6 and 7, whereas axon 2 innervates all of the ventral longitudinal muscle fibers. This difference in innervation pattern allows the two axons to be reliably identified. The terminals formed by axons 1 and 2 on muscle fibers 6 and 7 have the same number of branches; however, axon 2 terminals are approximately 30% longer than axon 1 terminals, resulting in a corresponding greater number of boutons for axon 2. The axon 1 boutons are approximately 30% wider than the axon 2 boutons. The excitatory postsynaptic potential (EPSP) produced by axon 1 is generally smaller than that produced by axon 2, although the size distributions show considerable overlap. Consistent with vertebrate studies, there is a correlation between muscle fiber size and terminal size. For a single axon, terminal area and length, the number of terminal branches, and the number of boutons are all correlated with muscle fiber size, but bouton size is not. During prolonged repetitive stimulation, axon 2 motor terminals show synaptic depression, whereas axon 1 EPSPs facilitate. The response to repetitive stimulation appears to be similar at all motor terminals of an axon. Copyright 2000 John Wiley & Sons, Inc.

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

    PubMed Central

    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. PMID:27200087

  6. Nucleotide sequence variation of the envelope protein gene identifies two distinct genotypes of yellow fever virus.

    PubMed

    Chang, G J; Cropp, B C; Kinney, R M; Trent, D W; Gubler, D J

    1995-09-01

    The evolution of yellow fever virus over 67 years was investigated by comparing the nucleotide sequences of the envelope (E) protein genes of 20 viruses isolated in Africa, the Caribbean, and South America. Uniformly weighted parsimony algorithm analysis defined two major evolutionary yellow fever virus lineages designated E genotypes I and II. E genotype I contained viruses isolated from East and Central Africa. E genotype II viruses were divided into two sublineages: IIA viruses from West Africa and IIB viruses from America, except for a 1979 virus isolated from Trinidad (TRINID79A). Unique signature patterns were identified at 111 nucleotide and 12 amino acid positions within the yellow fever virus E gene by signature pattern analysis. Yellow fever viruses from East and Central Africa contained unique signatures at 60 nucleotide and five amino acid positions, those from West Africa contained unique signatures at 25 nucleotide and two amino acid positions, and viruses from America contained such signatures at 30 nucleotide and five amino acid positions in the E gene. The dissemination of yellow fever viruses from Africa to the Americas is supported by the close genetic relatedness of genotype IIA and IIB viruses and genetic evidence of a possible second introduction of yellow fever virus from West Africa, as illustrated by the TRINID79A virus isolate. The E protein genes of American IIB yellow fever viruses had higher frequencies of amino acid substitutions than did genes of yellow fever viruses of genotypes I and IIA on the basis of comparisons with a consensus amino acid sequence for the yellow fever E gene. The great variation in the E proteins of American yellow fever virus probably results from positive selection imposed by virus interaction with different species of mosquitoes or nonhuman primates in the Americas.

  7. Nucleotide sequence variation of the envelope protein gene identifies two distinct genotypes of yellow fever virus.

    PubMed Central

    Chang, G J; Cropp, B C; Kinney, R M; Trent, D W; Gubler, D J

    1995-01-01

    The evolution of yellow fever virus over 67 years was investigated by comparing the nucleotide sequences of the envelope (E) protein genes of 20 viruses isolated in Africa, the Caribbean, and South America. Uniformly weighted parsimony algorithm analysis defined two major evolutionary yellow fever virus lineages designated E genotypes I and II. E genotype I contained viruses isolated from East and Central Africa. E genotype II viruses were divided into two sublineages: IIA viruses from West Africa and IIB viruses from America, except for a 1979 virus isolated from Trinidad (TRINID79A). Unique signature patterns were identified at 111 nucleotide and 12 amino acid positions within the yellow fever virus E gene by signature pattern analysis. Yellow fever viruses from East and Central Africa contained unique signatures at 60 nucleotide and five amino acid positions, those from West Africa contained unique signatures at 25 nucleotide and two amino acid positions, and viruses from America contained such signatures at 30 nucleotide and five amino acid positions in the E gene. The dissemination of yellow fever viruses from Africa to the Americas is supported by the close genetic relatedness of genotype IIA and IIB viruses and genetic evidence of a possible second introduction of yellow fever virus from West Africa, as illustrated by the TRINID79A virus isolate. The E protein genes of American IIB yellow fever viruses had higher frequencies of amino acid substitutions than did genes of yellow fever viruses of genotypes I and IIA on the basis of comparisons with a consensus amino acid sequence for the yellow fever E gene. The great variation in the E proteins of American yellow fever virus probably results from positive selection imposed by virus interaction with different species of mosquitoes or nonhuman primates in the Americas. PMID:7637022

  8. Identified motor terminals in Drosophila larvae show distinct differences in morphology and physiology

    NASA Technical Reports Server (NTRS)

    Lnenicka, G. A.; Keshishian, H.

    2000-01-01

    In Drosophila, the type I motor terminals innervating the larval ventral longitudinal muscle fibers 6 and 7 have been the most popular preparation for combining synaptic studies with genetics. We have further characterized the normal morphological and physiological properties of these motor terminals and the influence of muscle size on terminal morphology. Using dye-injection and physiological techniques, we show that the two axons supplying these terminals have different innervation patterns: axon 1 innervates only muscle fibers 6 and 7, whereas axon 2 innervates all of the ventral longitudinal muscle fibers. This difference in innervation pattern allows the two axons to be reliably identified. The terminals formed by axons 1 and 2 on muscle fibers 6 and 7 have the same number of branches; however, axon 2 terminals are approximately 30% longer than axon 1 terminals, resulting in a corresponding greater number of boutons for axon 2. The axon 1 boutons are approximately 30% wider than the axon 2 boutons. The excitatory postsynaptic potential (EPSP) produced by axon 1 is generally smaller than that produced by axon 2, although the size distributions show considerable overlap. Consistent with vertebrate studies, there is a correlation between muscle fiber size and terminal size. For a single axon, terminal area and length, the number of terminal branches, and the number of boutons are all correlated with muscle fiber size, but bouton size is not. During prolonged repetitive stimulation, axon 2 motor terminals show synaptic depression, whereas axon 1 EPSPs facilitate. The response to repetitive stimulation appears to be similar at all motor terminals of an axon. Copyright 2000 John Wiley & Sons, Inc.

  9. Analysis of the nucleoprotein gene identifies three distinct lineages of viral haemorrhagic septicemia virus (VHSV) within the European marine environment

    USGS Publications Warehouse

    Snow, M.; Cunningham, C.O.; Melvin, W.T.; Kurath, G.

    1999-01-01

    A ribonuclease (RNase) protection assay (RPA) has been used to detect nucleotide sequence variation within the nucleoprotein gene of 39 viral haemorrhagic septicaemia virus (VHSV) isolates of European marine origin. The classification of VHSV isolates based on RPA cleavage patterns permitted the identification of ten distinct groups of viruses based on differences at the molecular level. The nucleotide sequence of representatives of each of these groupings was determined and subjected to phylogenetic analysis. This revealed grouping of the European marine isolates of VHSV into three genotypes circulating within distinct geographic areas. A fourth genotype was identified comprising isolates originating from North America. Phylogenetic analyses indicated that VHSV isolates recovered from wild caught fish around the British Isles were genetically related to isolates responsible for losses in farmed turbot. Furthermore, a relationship between naturally occurring marine isolates and VHSV isolates causing mortality among rainbow trout in continental Europe was demonstrated. Analysis of the nucleoprotein gene identifies distinct lineages of viral haemorrhagic septicaemia virus within the European marine environment. Virus Res. 63, 35-44. Available from: 

  10. Cancer in silico drug discovery: a systems biology tool for identifying candidate drugs to target specific molecular tumor subtypes.

    PubMed

    San Lucas, F Anthony; Fowler, Jerry; Chang, Kyle; Kopetz, Scott; Vilar, Eduardo; Scheet, Paul

    2014-12-01

    Large-scale cancer datasets such as The Cancer Genome Atlas (TCGA) allow researchers to profile tumors based on a wide range of clinical and molecular characteristics. Subsequently, TCGA-derived gene expression profiles can be analyzed with the Connectivity Map (CMap) to find candidate drugs to target tumors with specific clinical phenotypes or molecular characteristics. This represents a powerful computational approach for candidate drug identification, but due to the complexity of TCGA and technology differences between CMap and TCGA experiments, such analyses are challenging to conduct and reproduce. We present Cancer in silico Drug Discovery (CiDD; scheet.org/software), a computational drug discovery platform that addresses these challenges. CiDD integrates data from TCGA, CMap, and Cancer Cell Line Encyclopedia (CCLE) to perform computational drug discovery experiments, generating hypotheses for the following three general problems: (i) determining whether specific clinical phenotypes or molecular characteristics are associated with unique gene expression signatures; (ii) finding candidate drugs to repress these expression signatures; and (iii) identifying cell lines that resemble the tumors being studied for subsequent in vitro experiments. The primary input to CiDD is a clinical or molecular characteristic. The output is a biologically annotated list of candidate drugs and a list of cell lines for in vitro experimentation. We applied CiDD to identify candidate drugs to treat colorectal cancers harboring mutations in BRAF. CiDD identified EGFR and proteasome inhibitors, while proposing five cell lines for in vitro testing. CiDD facilitates phenotype-driven, systematic drug discovery based on clinical and molecular data from TCGA.

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

    PubMed

    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. The differential expression of low-threshold K+ currents generates distinct firing patterns in different subtypes of adult mouse trigeminal ganglion neurones.

    PubMed

    Catacuzzeno, Luigi; Fioretti, Bernard; Pietrobon, Daniela; Franciolini, Fabio

    2008-11-01

    In adult mouse trigeminal ganglion (TG) neurones we identified three neuronal subpopulations, defined in terms of their firing response to protracted depolarizations, namely MF neurones, characterized by a multiple tonic firing; DMF neurones, characterized by a delay before the beginning of repetitive firing; and SS neurones, characterized by a strongly adapting response. The three subpopulations also differed in several other properties important for defining their functional role in vivo, namely soma size, action potential (AP) shape and capsaicin sensitivity. MF neurones had small soma, markedly long AP and mostly responded to capsaicin, properties typical of a subgroup of C-type nociceptors. SS neurones had large soma, short AP duration and were mostly capsaicin insensitive, suggesting that most of them have functions other than nociception. DMF neurones were all capsaicin insensitive, had a small soma size and intermediate AP duration, making them functionally distinct from both MF and SS neurones. We investigated the ionic basis underlying the delay to the generation of the first AP of DMF neurones, and the strong adaptation of SS neurones. We found that the expression of a fast-inactivating, 4-AP- and CP-339,818-sensitive K+ current (I(A)) in DMF neurones plays a critical role in the generation of the delay, whereas a DTX-sensitive K+ current (I(DTX)) selectively expressed in SS neurones appeared to be determinant for their strong firing adaptation. A minimal theoretical model of TG neuronal excitability confirmed that I(A) and I(DTX) have properties congruent with their suggested role.

  13. SOX11 expression is highly specific for mantle cell lymphoma and identifies the cyclin D1-negative subtype

    PubMed Central

    Mozos, Ana; Royo, Cristina; Hartmann, Elena; De Jong, Daphne; Baró, Cristina; Valera, Alexandra; Fu, Kai; Weisenburger, Dennis D.; Delabie, Jan; Chuang, Shih-Sung; Jaffe, Elaine S.; Ruiz-Marcellan, Carmen; Dave, Sandeep; Rimsza, Lisa; Braziel, Rita; Gascoyne, Randy D.; Solé, Francisco; López-Guillermo, Armando; Colomer, Dolors; Staudt, Louis M.; Rosenwald, Andreas; Ott, German; Jares, Pedro; Campo, Elias

    2009-01-01

    Background Cyclin D1-negative mantle cell lymphoma is difficult to distinguish from other small B-cell lymphomas. The clinical and pathological characteristics of patients with this form of lymphoma have not been well defined. Overexpression of the transcription factor SOX11 has been observed in conventional mantle cell lymphoma. The aim of this study was to determine whether this gene is expressed in cyclin D1-negative mantle cell lymphoma and whether its detection may be useful to identify these tumors. Design and Methods The microarray database of 238 mature B-cell neoplasms was re-examined. SOX11 protein expression was investigated immunohistochemically in 12 cases of cyclin D1-negative mantle cell lymphoma, 54 cases of conventional mantle cell lymphoma, and 209 additional lymphoid neoplasms. Results SOX11 mRNA was highly expressed in conventional and cyclin D1-negative mantle cell lymphoma and in 33% of the cases of Burkitt’s lymphoma but not in any other mature lymphoid neoplasm. SOX11 nuclear protein was detected in 50 cases (93%) of conventional mantle cell lymphoma and also in the 12 cyclin D1-negative cases of mantle cell lymphoma, the six cases of lymphoblastic lymphomas, in two of eight cases of Burkitt’s lymphoma, and in two of three T-prolymphocytic leukemias but was negative in the remaining lymphoid neoplasms. Cyclin D2 and D3 mRNA levels were significantly higher in cyclin D1-negative mantle cell lymphoma than in conventional mantle cell lymphoma but the protein expression was not discriminative. The clinico-pathological features and outcomes of the patients with cyclin D1-negative mantle cell lymphoma identified by SOX11 expression were similar to those of patients with conventional mantle cell lymphoma. Conclusions SOX11 mRNA and nuclear protein expression is a highly specific marker for both cyclin D1-positive and negative mantle cell lymphoma. PMID:19880778

  14. Longitudinal Stability of Phonological and Surface Subtypes of Developmental Dyslexia

    ERIC Educational Resources Information Center

    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…

  15. Longitudinal Stability of Phonological and Surface Subtypes of Developmental Dyslexia

    ERIC Educational Resources Information Center

    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…

  16. Electrophysiological properties of genetically identified subtypes of layer 5 neocortical pyramidal neurons: Ca2+ dependence and differential modulation by norepinephrine

    PubMed Central

    Guan, Dongxu; Armstrong, William E.

    2015-01-01

    We studied neocortical pyramidal neurons from two lines of bacterial artificial chromosome mice (etv1 and glt; Gene Expression Nervous System Atlas: GENSAT project), each of which expresses enhanced green fluorescent protein (EGFP) in a different subpopulation of layer 5 pyramidal neurons. In barrel cortex, etv1 and glt pyramidal cells were previously reported to differ in terms of their laminar distribution, morphology, thalamic inputs, cellular targets, and receptive field size. In this study, we measured the laminar distribution of etv1 and glt cells. On average, glt cells were located more deeply; however, the distributions of etv1 and glt cells extensively overlap in layer 5. To test whether these two cell types differed in electrophysiological properties that influence firing behavior, we prepared acute brain slices from 2–4-wk-old mice, where EGFP-positive cells in somatosensory cortex were identified under epifluorescence and then studied using whole cell current- or voltage-clamp recordings. We studied the details of action potential parameters and repetitive firing, characterized by the larger slow afterhyperpolarizations (AHPs) in etv1 neurons and larger medium AHPs (mAHPS) in glt cells, and compared currents underlying the mAHP and slow AHP (sAHP) in etv1 and glt neurons. Etv1 cells exhibited lower dV/dt for spike polarization and repolarization and reduced direct current (DC) gain (lower f-I slope) for repetitive firing than glt cells. Most importantly, we found that 1) differences in the expression of Ca2+-dependent K+ conductances (small-conductance calcium-activated potassium channels and sAHP channels) determine major functional differences between etv1 and glt cells, and 2) there is differential modulation of etv1 and glt neurons by norepinephrine. PMID:25568159

  17. Comprehensive assessment of the expression of the SWI/SNF complex defines two distinct prognostic subtypes of ovarian clear cell carcinoma.

    PubMed

    Abou-Taleb, Hisham; Yamaguchi, Ken; Matsumura, Noriomi; Murakami, Ryusuke; Nakai, Hidekatsu; Higasa, Koichiro; Amano, Yasuaki; Abiko, Kaoru; Yoshioka, Yumiko; Hamanishi, Junzo; Koshiyama, Masafumi; Baba, Tsukasa; Yamada, Ryo; Matsuda, Fumihiko; Konishi, Ikuo; Mandai, Masaki

    2016-08-23

    Somatic mutations in the ARID1A tumor-suppressor gene have been frequently identified in ovarian clear cell carcinoma (CCC) cases. BAF250a encoded by ARID1A is a member of the SWI/SNF complex, but the expression and mutation status of other SWI/SNF subunits have not been explored. The current study aimed to elucidate the biological and clinical significance of the SWI/SNF complex subunits, by assessing the expression and mutation status of SWI/SNF subunits, and distinct genomic aberrations associated with their expression. Of 82 CCC specimens, 38 samples presented no BAF250a expression, and 50 samples exhibited the loss of at least one subunit of the SWI/SNF complex. Cases which lack at least one SWI/SNF complex component exhibited significantly more advanced stages, faster growth and stronger nuclear atypia compared with SWI/SNF-positive samples (p<0.05). Although BAF250a expression is not related to poor prognosis, the group presenting the loss of at least one SWI/SNF complex subunit exhibited significantly shorter overall and progression-free survivals (p<0.05). A multivariate analysis suggested that the expression status of the SWI/SNF complex serves as an independent prognostic factor (p<0.005). The cases positive for all SWI/SNF subunits demonstrated significantly greater DNA copy number alterations, such as amplification at chromosomes 8q.24.3 and 20q.13.2-20q.13.33 (including ZNF217) and deletion at chromosomes 13q12.11-13q14.3 (including RB1), 17p13.2-17p13.1 (including TP53) and 19p13.2-19p13.12. In conclusion, the CCCs exhibiting the loss of one or multiple SWI/SNF complex subunits demonstrated aggressive behaviors and poor prognosis, whereas the CCCs with positive expression for all SWI/SNF components presented more copy number alterations and a favorable prognosis.

  18. Comprehensive assessment of the expression of the SWI/SNF complex defines two distinct prognostic subtypes of ovarian clear cell carcinoma

    PubMed Central

    Abou-Taleb, Hisham; Yamaguchi, Ken; Matsumura, Noriomi; Murakami, Ryusuke; Nakai, Hidekatsu; Higasa, Koichiro; Amano, Yasuaki; Abiko, Kaoru; Yoshioka, Yumiko; Hamanishi, Junzo; Koshiyama, Masafumi; Baba, Tsukasa; Yamada, Ryo; Matsuda, Fumihiko; Konishi, Ikuo; Mandai, Masaki

    2016-01-01

    Somatic mutations in the ARID1A tumor-suppressor gene have been frequently identified in ovarian clear cell carcinoma (CCC) cases. BAF250a encoded by ARID1A is a member of the SWI/SNF complex, but the expression and mutation status of other SWI/SNF subunits have not been explored. The current study aimed to elucidate the biological and clinical significance of the SWI/SNF complex subunits, by assessing the expression and mutation status of SWI/SNF subunits, and distinct genomic aberrations associated with their expression. Of 82 CCC specimens, 38 samples presented no BAF250a expression, and 50 samples exhibited the loss of at least one subunit of the SWI/SNF complex. Cases which lack at least one SWI/SNF complex component exhibited significantly more advanced stages, faster growth and stronger nuclear atypia compared with SWI/SNF-positive samples (p<0.05). Although BAF250a expression is not related to poor prognosis, the group presenting the loss of at least one SWI/SNF complex subunit exhibited significantly shorter overall and progression-free survivals (p<0.05). A multivariate analysis suggested that the expression status of the SWI/SNF complex serves as an independent prognostic factor (p<0.005). The cases positive for all SWI/SNF subunits demonstrated significantly greater DNA copy number alterations, such as amplification at chromosomes 8q.24.3 and 20q.13.2-20q.13.33 (including ZNF217) and deletion at chromosomes 13q12.11-13q14.3 (including RB1), 17p13.2-17p13.1 (including TP53) and 19p13.2-19p13.12. In conclusion, the CCCs exhibiting the loss of one or multiple SWI/SNF complex subunits demonstrated aggressive behaviors and poor prognosis, whereas the CCCs with positive expression for all SWI/SNF components presented more copy number alterations and a favorable prognosis. PMID:27340867

  19. Data mining the NCI cancer cell line compound GI(50) values: identifying quinone subtypes effective against melanoma and leukemia cell classes.

    PubMed

    Marx, Kenneth A; O'Neil, Philip; Hoffman, Patrick; Ujwal, M L

    2003-01-01

    substituted p-quinones. Attempts to subclassify melanoma or leukemia cell lines based upon their clinical cancer subtype met with limited success. For example, using GI(50) values for the 30 compounds we identified as effective against all leukemia cell lines, we could subclassify acute lymphoblastic leukemia (ALL) origin cell lines from non-ALL leukemia origin cell lines without significant overlap from non-leukemia cell lines. Based upon clustering using GI(50) values for the 60 cancer cell lines laid out by the RadViz algorithm, these two compound subsets did not overlap with clusters containing any of the NCI's 92 compounds of known mechanism of action, a few of which are quinones. Given their structural patterns, the two p-quinone subtypes we identified would clearly be expected to possess different redox potentials/substrate specificities for enzymatic reduction in vivo. These two p-quinone subtypes represent valuable information that may be used in the elucidation of pharmacophores for the design of compounds to treat these two cancer tissue types in the clinic.

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

    PubMed Central

    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

  1. Admixture Mapping of African–American Women in the AMBER Consortium Identifies New Loci for Breast Cancer and Estrogen-Receptor Subtypes

    PubMed Central

    Ruiz-Narváez, Edward A.; Sucheston-Campbell, Lara; Bensen, Jeannette T.; Yao, Song; Haddad, Stephen; Haiman, Christopher A.; Bandera, Elisa V.; John, Esther M.; Bernstein, Leslie; Hu, Jennifer J.; Ziegler, Regina G.; Deming, Sandra L.; Olshan, Andrew F.; Ambrosone, Christine B.; Palmer, Julie R.; Lunetta, Kathryn L.

    2016-01-01

    Recent genetic admixture coupled with striking differences in incidence of estrogen receptor (ER) breast cancer subtypes, as well as severity, between women of African and European ancestry, provides an excellent rationale for performing admixture mapping in African American women with breast cancer risk. We performed the largest breast cancer admixture mapping study with in African American women to identify novel genomic regions associated with the disease. We conducted a genome-wide admixture scan using 2,624 autosomal ancestry informative markers (AIMs) in 3,629 breast cancer cases (including 1,968 ER-positive, 1093 ER-negative, and 601 triple-negative) and 4,658 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a collaborative study of four large geographically different epidemiological studies of breast cancer in African American women. We used an independent case-control study to test for SNP association in regions with genome-wide significant admixture signals. We found two novel genome-wide significant regions of excess African ancestry, 4p16.1 and 17q25.1, associated with ER-positive breast cancer. Two regions known to harbor breast cancer variants, 10q26 and 11q13, were also identified with excess of African ancestry. Fine-mapping of the identified genome-wide significant regions suggests the presence of significant genetic associations with ER-positive breast cancer in 4p16.1 and 11q13. In summary, we identified three novel genomic regions associated with breast cancer risk by ER status, suggesting that additional previously unidentified variants may contribute to the racial differences in breast cancer risk in the African American population. PMID:27708667

  2. Anti-MDA5 autoantibodies in juvenile dermatomyositis identify a distinct clinical phenotype: a prospective cohort study

    PubMed Central

    2014-01-01

    Introduction The aim of this study was to define the frequency and associated clinical phenotype of anti-MDA5 autoantibodies in a large UK based, predominantly Caucasian, cohort of patients with juvenile dermatomyositis (JDM). Methods Serum samples and clinical data were obtained from 285 patients with JDM recruited to the UK Juvenile Dermatomyositis Cohort and Biomarker Study. The presence of anti-MDA5 antibodies was determined by immunoprecipitation and confirmed by ELISA using recombinant MDA5 protein. Results were compared with matched clinical data, muscle biopsies (scored by an experienced paediatric neuropathologist) and chest imaging (reviewed by an experienced paediatric radiologist). Results Anti-MDA5 antibodies were identified in 7.4% of JDM patients and were associated with a distinct clinical phenotype including skin ulceration (P = 0.03) oral ulceration (P = 0.01), arthritis (P <0.01) and milder muscle disease both clinically (as determined by Childhood Myositis Assessment Score (P = 0.03)) and histologically (as determined by a lower JDM muscle biopsy score (P <0.01)) than patients who did not have anti-MDA5 antibodies. A greater proportion of children with anti-MDA5 autoantibodies achieved disease inactivity at two years post-diagnosis according to PRINTO criteria (P = 0.02). A total of 4 out of 21 children with anti-MDA5 had interstitial lung disease; none had rapidly progressive interstitial lung disease. Conclusions Anti-MDA5 antibodies can be identified in a small but significant proportion of patients with JDM and identify a distinctive clinical sub-group. Screening for anti-MDA5 autoantibodies at diagnosis would be useful to guide further investigation for lung disease, inform on prognosis and potentially confirm the diagnosis, as subtle biopsy changes could otherwise be missed. PMID:24989778

  3. Molecular characterization of HIV-1 infection in Northwest Spain (2009-2013): Investigation of the subtype F outbreak.

    PubMed

    Paraskevis, Dimitrios; Kostaki, Evangelia; Beloukas, Apostolos; Cañizares, Angelina; Aguilera, Antonio; Rodríguez, Javier; Grandal, Marta; Pernas, Berta; Castro-Iglesias, Angeles; Mena, Álvaro; Pedreira, José D; Poveda, Eva

    2015-03-01

    HIV-1 subtype B is the predominant one in European regions several, while other subtypes and recombinants are also circulating with high prevalence. A sub-epidemic of subtype F with specific characteristics and low response to treatment has been recently identified in Galicia. In this study we investigated the characteristics of the HIV-1 subtype F sub-epidemic in A Coruña and Santiago de Compostela in Northwest Spain. 420 newly HIV-1 diagnosed patients during 2009-2013 were enrolled in this study. HIV-1 subtyping was carried out using automated subtyping tools and phylogenetic analysis. Molecular epidemiology investigation of subtypes B and F was performed by means of phylogenetic analysis using fast maximum likelihood. Phylodynamic analysis was performed using Bayesian method as implemented in BEAST v1.8. Subtype B found to be the predominant (61.2% and 70.4%) followed by subtype F (25.6% and 12.0%) in both areas (A Coruña and Santiago de Compostela, respectively). The latter found to mainly spread among men having sex with men (MSM). The vast majority of subtype F lineages from both areas clustered monophyletically, while subtype B sequences clustered in several tree branches. The exponential growth of subtype F sub-epidemic dated back in 2008 by means of phylodynamic analysis. Most of new infections during 2009-2013 occurred within the subtype F transmission cluster. Subtype F circulates at high prevalence in A Coruña and Santiago de Compostela in Northwest Spain, suggesting that the HIV-1 epidemic in this region has distinct characteristics to the rest of Spain. Subtype F has being spreading among MSM and is currently the most actively spreading network. The single cluster spread of this local sub-epidemic might provide an explanation for the distinct characteristics and the low response to antiretroviral treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Comparative expression profiling for human endoplasmic reticulum-resident aminopeptidases 1 and 2 in normal kidney versus distinct renal cell carcinoma subtypes.

    PubMed

    Stoehr, Christine G; Buettner-Herold, Maike; Kamphausen, Esther; Bertz, Simone; Hartmann, Arndt; Seliger, Barbara

    2013-01-01

    Altered expression of the ER-resident aminopeptidases ERAP1 and ERAP2 might play an important role in shaping the MHC class I-presented peptide repertoire, but their function in tumors has not been determined in detail. Thus, the expression of ERAP1, ERAP2 and HLA class I heavy chain (HC) was analysed in various renal tumor types and corresponding kidney parenchyma by immunohistochemistry. Additionally, comparative expression profilings of untreated versus interferon (IFN)-γ-treated RCC cell lines were performed applying qRT-PCR, Western blot and/or flow cytometry. Normal kidney tissues showed strong ERAP1 staining in the proximal tubules of 57.4 % of cases, in the distal tubules of 94.3 % of cases and in the medulla of 88.6 % of cases, whereas high ERAP2 levels were observed in the medulla of 77.1 % of cases and in both, proximal and distal tubules of about 88 % of cases. Imbalanced, downregulated and RCC subtype-specific ERAP1 or ERAP2 expression was detected in 12.7 % or 43.8 % of samples analyzed, respectively. A coordinated downregulation of ERAPs was found in 4.8 %, an upregulation of ERAP1 or ERAP2 in 22.8 % or 2.0 % of RCC lesions. No association exists between ERAP and HLA class I HC expression for any tissue type. A heterogeneous constitutive ERAP expression pattern was also detected in RCC cell lines with lower ERAP2 than ERAP1 expression levels, which was in 11/17 RCC cell lines inducible by IFN-γ. Conclusively, ERAP1 and ERAP2 might be involved in the development of immune escape mechanisms of RCC.

  5. Novel and Distinct Metabolites Identified Following a Single Oral Dose of α- or γ-Hexabromocyclododecane in Mice

    PubMed Central

    Szabo, David T.; Huwe, Janice; Diliberto, Janet; Birnbaum, Linda S.

    2013-01-01

    The metabolism of α- and γ-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. α- or γ-[14C]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice were dosed and sacrificed 3 hours post-exposure to investigate tissue metabolite levels. Extractable and non-extractable HBCD metabolites were quantitated in liver, blood, fat, brain, bile, urine and feces and characterized by LC/MS (ESI-). Metabolites identified were distinct between the two stereoisomers. In mice exposed to α-HBCD, four hydroxylated metabolites were detected in fecal extracts, and one of these metabolite isomers was consistently characterized in liver, brain, and adipose tissue extracts. In contrast, mice exposed to γ-HBCD contained multiple isomers of monohydroxy-pentabromocyclododecene, dihydroxy-pentabromocyclododecene, and dihydroxy-pentabromocyclododecadiene in the feces while only a single monohydroxy-pentabromocyclododecane metabolite was measured in liver and adipose tissue. Both stereoisomers were transformed to metabolites which formed covalent bonds to proteins and/or lipids in the gut as evidenced by high fecal non-extractables. Although the potential toxicity of these free and bound metabolites remains to be determined, the presence of distinct metabolic products from the two main HBCD stereoisomers should allow biomarkers to be selected that may aid in characterizing sources of HBCD exposure. PMID:23171393

  6. GATA-3 expression identifies a high-risk subset of PTCL, NOS with distinct molecular and clinical features.

    PubMed

    Wang, Tianjiao; Feldman, Andrew L; Wada, David A; Lu, Ye; Polk, Avery; Briski, Robert; Ristow, Kay; Habermann, Thomas M; Thomas, Dafydd; Ziesmer, Steven C; Wellik, Linda E; Lanigan, Thomas M; Witzig, Thomas E; Pittelkow, Mark R; Bailey, Nathanael G; Hristov, Alexandra C; Lim, Megan S; Ansell, Stephen M; Wilcox, Ryan A

    2014-05-08

    The cell of origin and the tumor microenvironment's role remain elusive for the most common peripheral T-cell lymphomas (PTCLs). As macrophages promote the growth and survival of malignant T cells and are abundant constituents of the tumor microenvironment, their functional polarization was examined in T-cell lymphoproliferative disorders. Cytokines that are abundant within the tumor microenvironment, particularly interleukin (IL)-10, were observed to promote alternative macrophage polarization. Macrophage polarization was signal transducer and activator of transcription 3 dependent and was impaired by the Janus kinase inhibitor ruxolitinib. In conventional T cells, the production of T helper (Th)2-associated cytokines and IL-10, both of which promote alternative macrophage polarization, is regulated by the T-cell transcription factor GATA-binding protein 3 (GATA-3). Therefore, its role in the T-cell lymphomas was examined. GATA-3 expression was observed in 45% of PTCLs, not otherwise specified (PTCL, NOS) and was associated with distinct molecular features, including the production of Th2-associated cytokines. In addition, GATA-3 expression identified a subset of PTCL, NOS with distinct clinical features, including inferior progression-free and overall survival. Collectively, these data suggest that further understanding the cell of origin and lymphocyte ontogeny among the T-cell lymphomas may improve our understanding of the tumor microenvironment's pathogenic role in these aggressive lymphomas.

  7. A formal method for identifying distinct states of variability in time-varying sources: SGR A* as an example

    SciTech Connect

    Meyer, L.; Witzel, G.; Ghez, A. M.; Longstaff, F. A.

    2014-08-10

    Continuously time variable sources are often characterized by their power spectral density and flux distribution. These quantities can undergo dramatic changes over time if the underlying physical processes change. However, some changes can be subtle and not distinguishable using standard statistical approaches. Here, we report a methodology that aims to identify distinct but similar states of time variability. We apply this method to the Galactic supermassive black hole, where 2.2 μm flux is observed from a source associated with Sgr A* and where two distinct states have recently been suggested. Our approach is taken from mathematical finance and works with conditional flux density distributions that depend on the previous flux value. The discrete, unobserved (hidden) state variable is modeled as a stochastic process and the transition probabilities are inferred from the flux density time series. Using the most comprehensive data set to date, in which all Keck and a majority of the publicly available Very Large Telescope data have been merged, we show that Sgr A* is sufficiently described by a single intrinsic state. However, the observed flux densities exhibit two states: noise dominated and source dominated. Our methodology reported here will prove extremely useful to assess the effects of the putative gas cloud G2 that is on its way toward the black hole and might create a new state of variability.

  8. Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression.

    PubMed

    Stricker, Thomas P; Brown, Christopher D; Bandlamudi, Chaitanya; McNerney, Megan; Kittler, Ralf; Montoya, Vanessa; Peterson, April; Grossman, Robert; White, Kevin P

    2017-03-01

    Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease with multiple different subtypes. These subtypes carry important implications for prognosis and therapy. Interestingly, it is known that these different subtypes not only have different biological behaviors, but also have distinct gene expression profiles. However, it has not been rigorously explored whether particular transcriptional isoforms are also differentially expressed among breast cancer subtypes, or whether transcript isoforms from the same sets of genes can be used to differentiate subtypes. To address these questions, we analyzed the patterns of transcript isoform expression using a small set of RNA-sequencing data for eleven Estrogen Receptor positive (ER+) subtype and fourteen triple negative (TN) subtype tumors. We identified specific sets of isoforms that distinguish these tumor subtypes with higher fidelity than standard mRNA expression profiles. We found that alternate promoter usage, alternative splicing, and alternate 3'UTR usage are differentially regulated in breast cancer subtypes. Profiling of isoform expression in a second, independent cohort of 68 tumors confirmed that expression of splice isoforms differentiates breast cancer subtypes. Furthermore, analysis of RNAseq data from 594 cases from the TCGA cohort confirmed the ability of isoform usage to distinguish breast cancer subtypes. Also using our expression data, we identified several RNA processing factors that were differentially expressed between tumor subtypes and/or regulated by estrogen receptor, including YBX1, YBX2, MAGOH, MAGOHB, and PCBP2. RNAi knock-down of these RNA processing factors in MCF7 cells altered isoform expression. These results indicate that global dysregulation of splicing in breast cancer occurs in a subtype-specific and reproducible manner and is driven by specific differentially expressed RNA processing factors.

  9. Robust stratification of breast cancer subtypes using differential patterns of transcript isoform expression

    PubMed Central

    Stricker, Thomas P.; Bandlamudi, Chaitanya; Kittler, Ralf; Montoya, Vanessa; Peterson, April; Grossman, Robert

    2017-01-01

    Breast cancer, the second leading cause of cancer death of women worldwide, is a heterogenous disease with multiple different subtypes. These subtypes carry important implications for prognosis and therapy. Interestingly, it is known that these different subtypes not only have different biological behaviors, but also have distinct gene expression profiles. However, it has not been rigorously explored whether particular transcriptional isoforms are also differentially expressed among breast cancer subtypes, or whether transcript isoforms from the same sets of genes can be used to differentiate subtypes. To address these questions, we analyzed the patterns of transcript isoform expression using a small set of RNA-sequencing data for eleven Estrogen Receptor positive (ER+) subtype and fourteen triple negative (TN) subtype tumors. We identified specific sets of isoforms that distinguish these tumor subtypes with higher fidelity than standard mRNA expression profiles. We found that alternate promoter usage, alternative splicing, and alternate 3’UTR usage are differentially regulated in breast cancer subtypes. Profiling of isoform expression in a second, independent cohort of 68 tumors confirmed that expression of splice isoforms differentiates breast cancer subtypes. Furthermore, analysis of RNAseq data from 594 cases from the TCGA cohort confirmed the ability of isoform usage to distinguish breast cancer subtypes. Also using our expression data, we identified several RNA processing factors that were differentially expressed between tumor subtypes and/or regulated by estrogen receptor, including YBX1, YBX2, MAGOH, MAGOHB, and PCBP2. RNAi knock-down of these RNA processing factors in MCF7 cells altered isoform expression. These results indicate that global dysregulation of splicing in breast cancer occurs in a subtype-specific and reproducible manner and is driven by specific differentially expressed RNA processing factors. PMID:28263985

  10. A digital signal processing-based bioinformatics approach to identifying the origins of HIV-1 non B subtypes infecting US Army personnel serving abroad.

    PubMed

    Nwankwo, Norbert

    2013-06-01

    Two HIV-1 non B isolates, 98US_MSC5007 and 98US_MSC5016, which have been identified amongst the US Army personnel serving abroad, are known to have originated from other nations. Notwithstanding, they are categorized as American strains. This is because their countries of origin are unknown. American isolates are basically B subtype. 98US_MSC5007 belongs to Circulating Recombinant Form (CRF02_AG) while 98US_MSC5016 is of the C clade. Both sub-groups are recognized to have originated from African and Asian continents. It has become necessary to properly determine the countries of origin of microbes and viruses. This is because diversity and cross-subtyping have been found to mitigate the designing and development of vaccine and therapeutic interventions. The aim of this study therefore is to identify the countries of origin of the two American isolates found amongst US Army personnel serving abroad. A Digital Signal Processing-based Bioinformatics technique called Informational Spectrum Method (ISM) has been engaged. ISM entails translating the amino acids sequences of the protein into numerical sequences (signals) by means of one biological parameter (Amino Acids Scale). The signals are then processed using Discrete Fourier Transform (DFT) in order to uncover and present the embedded biological information as Informational Spectra (IS). Spectral Position of Maximum Binding Interaction (SPMBI) is used. Several approaches including Phylogeny have preliminarily been employed in the determination of evolutionary trends of organisms and viruses. SPMBI has preliminarily been used to re-establish the semblance and common originality that exist between human and Chimpanzee, evolutionary roadmaps in the Influenza and HIV viruses. The results disclosed that 98US_MSC5007 shared same semblance and originality with a Nigeria isolate (92NG083) while 98US_MSC5016 with the Zairian isolates (ELI, MAL, and Z2/CDC-34). These results appear to demonstrate that the American soldiers

  11. Distinct Kv channel subtypes contribute to differences in spike signaling properties in the axon initial segment and presynaptic boutons of cerebellar interneurons.

    PubMed

    Rowan, Matthew J M; Tranquil, Elizabeth; Christie, Jason M

    2014-05-07

    The discrete arrangement of voltage-gated K(+) (Kv) channels in axons may impart functional advantages in action potential (AP) signaling yet, in compact cell types, the organization of Kv channels is poorly understood. We find that in cerebellar stellate cell interneurons of mice, the composition and influence of Kv channels populating the axon is diverse and depends on location allowing axonal compartments to differentially control APs in a local manner. Kv1 channels determine AP repolarization at the spike initiation site but not at more distal sites, limiting the expression of use-dependent spike broadening to the most proximal axon region, likely a key attribute informing spiking phenotype. Local control of AP repolarization at presynaptic boutons depends on Kv3 channels keeping APs brief, thus limiting Ca(2+) influx and synaptic strength. These observations suggest that AP repolarization is tuned by the local influence of distinct Kv channel types, and this organization enhances the functional segregation of axonal compartments.

  12. Novel Human Embryonic Stem Cell Regulators Identified by Conserved and Distinct CpG Island Methylation State

    PubMed Central

    Pells, Steve; Koutsouraki, Eirini; Morfopoulou, Sofia; Valencia-Cadavid, Sara; Tomlinson, Simon R.; Kalathur, Ravi; Futschik, Matthias E.; De Sousa, Paul A.

    2015-01-01

    Human embryonic stem cells (hESCs) undergo epigenetic changes in vitro which may compromise function, so an epigenetic pluripotency “signature” would be invaluable for line validation. We assessed Cytosine-phosphate-Guanine Island (CGI) methylation in hESCs by genomic DNA hybridisation to a CGI array, and saw substantial variation in CGI methylation between lines. Comparison of hESC CGI methylation profiles to corresponding somatic tissue data and hESC mRNA expression profiles identified a conserved hESC-specific methylation pattern associated with expressed genes. Transcriptional repressors and activators were over-represented amongst genes whose associated CGIs were methylated or unmethylated specifically in hESCs, respectively. Knockdown of candidate transcriptional regulators (HMGA1, GLIS2, PFDN5) induced differentiation in hESCs, whereas ectopic expression in fibroblasts modulated iPSC colony formation. Chromatin immunoprecipitation confirmed interaction between the candidates and the core pluripotency transcription factor network. We thus identify novel pluripotency genes on the basis of a conserved and distinct epigenetic configuration in human stem cells. PMID:26151932

  13. Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits

    PubMed Central

    Palmer, Cameron D.; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E.; Launer, Lenore J.; Nalls, Michael A.; Clark, Jeanne M.; Mitchell, Braxton D.; Shuldiner, Alan R.; Butler, Johannah L.; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M.; O'Donnell, Christopher J.; Sahani, Dushyant V.; Salomaa, Veikko; Schadt, Eric E.; Schwartz, Stephen M.; Siscovick, David S.; Voight, Benjamin F.; Carr, J. Jeffrey; Feitosa, Mary F.; Harris, Tamara B.; Fox, Caroline S.

    2011-01-01

    Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%–27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10−8) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT–assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits. PMID:21423719

  14. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.

    PubMed

    Speliotes, Elizabeth K; Yerges-Armstrong, Laura M; Wu, Jun; Hernaez, Ruben; Kim, Lauren J; Palmer, Cameron D; Gudnason, Vilmundur; Eiriksdottir, Gudny; Garcia, Melissa E; Launer, Lenore J; Nalls, Michael A; Clark, Jeanne M; Mitchell, Braxton D; Shuldiner, Alan R; Butler, Johannah L; Tomas, Marta; Hoffmann, Udo; Hwang, Shih-Jen; Massaro, Joseph M; O'Donnell, Christopher J; Sahani, Dushyant V; Salomaa, Veikko; Schadt, Eric E; Schwartz, Stephen M; Siscovick, David S; Voight, Benjamin F; Carr, J Jeffrey; Feitosa, Mary F; Harris, Tamara B; Fox, Caroline S; Smith, Albert V; Kao, W H Linda; Hirschhorn, Joel N; Borecki, Ingrid B

    2011-03-01

    Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.

  15. A Newly Identified Extrinsic Input Triggers a Distinct Gastric Mill Rhythm via Activation of Modulatory Projection Neurons

    PubMed Central

    Blitz, Dawn M.; White, Rachel S.; Saideman, Shari R.; Cook, Aaron; Christie, Andrew E.; Nadim, Farzan; Nusbaum, Michael P.

    2008-01-01

    Neuronal network flexibility enables animals to respond appropriately to changes in their internal and external states. We are using the isolated crab stomatogastric nervous system to determine how extrinsic inputs contribute to network flexibility. The stomatogastric system includes the well-characterized gastric mill (chewing) and pyloric (filtering of chewed food) motor circuits in the stomatogastric ganglion. Projection neurons with somata in the commissural ganglia (CoGs) regulate these rhythms. Previous work characterized a unique gastric mill rhythm that occurred spontaneously in some preparations, but whose origin remained undetermined. This rhythm includes a distinct protractor phase activity pattern, during which all active gastric mill circuit and projection neurons fire in a pyloric rhythm-timed activity pattern instead of the tonic firing pattern exhibited by these neurons during previously studied gastric mill rhythms. Here we identify a new extrinsic input, the post-oesophageal commissure (POC) neurons, relatively brief stimulation (30 sec) of which triggers a long-lasting (tens of minutes) activation of this novel gastric mill rhythm at least in part via its lasting activation of CoG projection neurons, including the previously identified MCN1 and CPN2. Immunocytochemical and electrophysiological data suggest that the POC neurons excite MCN1 and CPN2 by release of the neuropeptide Cancer borealis tachykinin-related peptide Ia (CabTRP Ia). These data further suggest that the CoG arborization of the POC neurons comprises the previously identified anterior commissural organ (ACO), a CabTRP Ia-containing neurohemal organ. This endocrine pathway thus appears to also have paracrine actions that include activation of a novel and lasting gastric mill rhythm. PMID:18310125

  16. HIV-1 subtypes in Yugoslavia.

    PubMed

    Stanojevic, Maja; Papa, Anna; Papadimitriou, Evagelia; Zerjav, Sonja; Jevtovic, Djordje; Salemovic, Dubravka; Jovanovic, Tanja; Antoniadis, Antonis

    2002-05-01

    To gain insight concerning the genetic diversity of HIV-1 viruses associated with the HIV-1 epidemic in Yugoslavia, 45 specimens from HIV-1-infected individuals were classified into subtypes by sequence-based phylogenetic analysis of the polymerase (pol) region of the viral genome. Forty-one of 45 specimens (91.2%) were identified as pol subtype B, 2 of 45 as subtype C (4.4%), 1 of 45 as CRF01_AE (2.2%), and 1 as CRF02_AG recombinant (2.2%). Nucleotide divergence among subtype B sequences was 4.8%. Results of this study show that among HIV-1-infected patients in Yugoslavia subtype B predominates (91.5%), whereas non-B subtypes are present at a low percentage, mostly related to travel abroad.

  17. Distinct APC subtypes drive spatially segregated CD4+ and CD8+ T-cell effector activity during skin infection with HSV-1.

    PubMed

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

    2014-08-01

    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).

  18. A Global Genomic Characterization of Nairoviruses Identifies Nine Discrete Genogroups with Distinctive Structural Characteristics and Host-Vector Associations

    PubMed Central

    Walker, Peter J.; Widen, Steven G.; Wood, Thomas G.; Guzman, Hilda; Tesh, Robert B.; Vasilakis, Nikolaos

    2016-01-01

    Nairoviruses are primarily tick-borne bunyaviruses, some of which are known to cause mild-to-severe febrile illness in humans or livestock. We describe the genome sequences of 11 poorly characterized nairoviruses that have ecological associations with either birds (Farallon, Punta Salinas, Sapphire II, Zirqa, Avalon, Clo Mor, Taggert, and Abu Hammad viruses), rodents (Qalyub and Bandia viruses), or camels (Dera Ghazi Khan virus). Global phylogenetic analyses of proteins encoded in the L, M, and S RNA segments of these and 20 other available nairovirus genomes identified nine well-supported genogroups (Nairobi sheep disease, Thiafora, Sakhalin, Keterah, Qalyub, Kasokero, Dera Ghazi Khan, Hughes, and Tamdy). Genogroup-specific structural variations were evident, particularly in the M segment encoding a polyprotein from which virion envelope glycoproteins (Gn and Gc) are generated by proteolytic processing. Structural variations include the extension, abbreviation, or absence sequences encoding an O-glycosylated mucin-like protein in the N-terminal domain, distinctive patterns of conserved cysteine residues in the GP38-like domain, insertion of sequences encoding a double-membrane-spanning protein (NSm) between the Gn and Gc domains, and the presence of an alternative long open reading frame encoding a viroporin-like transmembrane protein (Gx). We also observed strong genogroup-specific associations with categories of hosts and tick vectors. PMID:26903607

  19. Natural diversity in the model legume Medicago truncatula allows identifying distinct genetic mechanisms conferring partial resistance to Verticillium wilt.

    PubMed

    Ben, Cécile; Toueni, Maoulida; Montanari, Sara; Tardin, Marie-Claire; Fervel, Magalie; Negahi, Azam; Saint-Pierre, Laure; Mathieu, Guillaume; Gras, Marie-Christine; Noël, Dominique; Prospéri, Jean-Marie; Pilet-Nayel, Marie-Laure; Baranger, Alain; Huguet, Thierry; Julier, Bernadette; Rickauer, Martina; Gentzbittel, Laurent

    2013-01-01

    Verticillium wilt is a major threat to alfalfa (Medicago sativa) and many other crops. The model legume Medicago truncatula was used as a host for studying resistance and susceptibility to Verticillium albo-atrum. In addition to presenting well-established genetic resources, this wild plant species enables to investigate biodiversity of the response to the pathogen and putative crosstalk between disease and symbiosis. Symptom scoring after root inoculation and modelling of disease curves allowed assessing susceptibility levels in recombinant lines of three crosses between susceptible and resistant lines, in a core collection of 32 lines, and in mutants affected in symbiosis with rhizobia. A GFP-expressing V. albo-atrum strain was used to study colonization of susceptible plants. Symptoms and colonization pattern in infected M. truncatula plants were typical of Verticillium wilt. Three distinct major quantitative trait loci were identified using a multicross, multisite design, suggesting that simple genetic mechanisms appear to control Verticillium wilt resistance in M. truncatula lines A17 and DZA45.5. The disease functional parameters varied largely in lines of the core collection. This biodiversity with regard to disease response encourages the development of association genetics and ecological approaches. Several mutants of the resistant line, impaired in different steps of rhizobial symbiosis, were affected in their response to V. albo-atrum, which suggests that mechanisms involved in the establishment of symbiosis or disease might have some common regulatory control points.

  20. Two novel AGXT mutations identified in primary hyperoxaluria type-1 and distinct morphological and structural difference in kidney stones

    PubMed Central

    Wang, Cui; Lu, Jingru; Lang, Yanhua; Liu, Ting; Wang, Xiaoling; Zhao, Xiangzhong; Shao, Leping

    2016-01-01

    Primary hyperoxaluria type 1 (PH1) is a rare genetic disease characterized by excessive oxalate accumulation in plasma and urine, resulting in various phenotypes because of allelic and clinical heterogeneity. This study aimed to detect disease-associated genetic mutations in three PH1 patients in a Chinese family. All AGXT exons and 3 common polymorphisms which might synergistically interact with mutations, including P11L, I340 M and IVSI+74 bp were analyzed by direct sequencing in all family members. It demonstrated that in each of three patients, a previously reported nonsense mutation p.R333* was in cis with a novel missense mutation p.M49L in the minor allele characterized by the polymorphism of 74-bp duplication in intron 1, while the other novel missense mutation p.N72I was in trans with both p.R333* and P.M49L in the major allele. Kidney stones from two sibling patients were also observed though stereomicroscopic examination and scanning electron microscopy. Distinct morphological and inner-structure differences in calculi were noticed, suggesting clinical heterozygosity of PH1 to a certain extent. In brief, two novel missense mutations were identified probably in association with PH1, a finding which should provide an accurate tool for prenatal diagnosis, genetic counseling and screening for potential presymptomatic individuals. PMID:27644547

  1. Natural diversity in the model legume Medicago truncatula allows identifying distinct genetic mechanisms conferring partial resistance to Verticillium wilt

    PubMed Central

    Gentzbittel, Laurent

    2013-01-01

    Verticillium wilt is a major threat to alfalfa (Medicago sativa) and many other crops. The model legume Medicago truncatula was used as a host for studying resistance and susceptibility to Verticillium albo-atrum. In addition to presenting well-established genetic resources, this wild plant species enables to investigate biodiversity of the response to the pathogen and putative crosstalk between disease and symbiosis. Symptom scoring after root inoculation and modelling of disease curves allowed assessing susceptibility levels in recombinant lines of three crosses between susceptible and resistant lines, in a core collection of 32 lines, and in mutants affected in symbiosis with rhizobia. A GFP-expressing V. albo-atrum strain was used to study colonization of susceptible plants. Symptoms and colonization pattern in infected M. truncatula plants were typical of Verticillium wilt. Three distinct major quantitative trait loci were identified using a multicross, multisite design, suggesting that simple genetic mechanisms appear to control Verticillium wilt resistance in M. truncatula lines A17 and DZA45.5. The disease functional parameters varied largely in lines of the core collection. This biodiversity with regard to disease response encourages the development of association genetics and ecological approaches. Several mutants of the resistant line, impaired in different steps of rhizobial symbiosis, were affected in their response to V. albo-atrum, which suggests that mechanisms involved in the establishment of symbiosis or disease might have some common regulatory control points. PMID:23213135

  2. Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes

    PubMed Central

    Lindqvist, C. Mårten; Lundmark, Anders; Nordlund, Jessica; Freyhult, Eva; Ekman, Diana; Almlöf, Jonas Carlsson; Raine, Amanda; Övernäs, Elin; Abrahamsson, Jonas; Frost, Britt-Marie; Grandér, Dan; Heyman, Mats; Palle, Josefine; Forestier, Erik; Lönnerholm, Gudmar

    2016-01-01

    To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency. PMID:27590521

  3. Subtyping Stuttering II

    PubMed Central

    Seery, Carol Hubbard; Watkins, Ruth V.; Mangelsdorf, Sarah C.; Shigeto, Aya

    2007-01-01

    This paper is the second in a series of two articles exploring subtypes of stuttering, and it addresses the question of whether and how language ability and temperament variables may be relevant to the study of subtypes within the larger population of children who stutter. Despite observations of varied profiles among young children who stutter, efforts to identify and characterize subtypes of stuttering have had limited influence on theoretical or clinical understanding of the disorder. This manuscript briefly highlights research on language and temperament in young children who stutter, and considers whether the results can provide guidance for efforts to more effectively investigate and elucidate subtypes in childhood stuttering. Issues from the literature that appear relevant to research on stuttering subtypes include: (a) the question of whether stuttering is best characterized as categorical or continuous; (b) interpretation of individual differences in skills and profiles; and (c) the fact that, during the preschool years, the interaction among domains such as language and temperament are changing very rapidly, resulting in large differences in developmental profiles within relatively brief chronological age periods. PMID:17825669

  4. Colocalization of allatotropin and tachykinin-related peptides with classical transmitters in physiologically distinct subtypes of olfactory local interneurons in the cockroach (Periplaneta americana).

    PubMed

    Fusca, Debora; Schachtner, Joachim; Kloppenburg, Peter

    2015-07-01

    In the insect antennal lobe different types of local interneurons mediate complex excitatory and inhibitory interactions between the glomerular pathways to structure the spatiotemporal representation of odors. Mass spectrometric and immunohistochemical studies have shown that in local interneurons classical neurotransmitters are likely to colocalize with a variety of substances that can potentially act as cotransmitters or neuromodulators. In the antennal lobe of the cockroach Periplaneta americana, gamma-aminobutyric acid (GABA) has been identified as the potential inhibitory transmitter of spiking type I local interneurons, whereas acetylcholine is most likely the excitatory transmitter of nonspiking type IIa1 local interneurons. This study used whole-cell patch clamp recordings combined with single-cell labeling and immunohistochemistry to test if the GABAergic type I local interneurons and the cholinergic type IIa1 local interneurons express allatotropin and tachykinin-related neuropeptides (TKRPs). These are two of the most abundant types of peptides in the insect antennal lobe. GABA-like and choline acetyltransferase (ChAT)-like immunoreactivity were used as markers for GABAergic and cholinergic neurons, respectively. About 50% of the GABA-like immunoreactive (-lir) spiking type I local interneurons were allatotropin-lir, and ∼ 40% of these neurons were TKRP-lir. About 20% of nonspiking ChAT-lir type IIa1 local interneurons were TKRP-lir. Our results suggest that in subpopulations of GABAergic and cholinergic local interneurons, allatotropin and TKRPs might act as cotransmitters or neuromodulators. To unequivocally assign neurotransmitters, cotransmitters, and neuromodulators to identified classes of antennal lobe neurons is an important step to deepen our understanding of information processing in the insect olfactory system.

  5. Neural networks and Fuzzy clustering methods for assessing the efficacy of microarray based intrinsic gene signatures in breast cancer classification and the character and relations of identified subtypes.

    PubMed

    Samarasinghe, Sandhya; Chaiboonchoe, Amphun

    2015-01-01

    In the classification of breast cancer subtypes using microarray data, hierarchical clustering is commonly used. Although this form of clustering shows basic cluster patterns, more needs to be done to investigate the accuracy of clusters as well as to extract meaningful cluster characteristics and their relations to increase our confidence in their use in a clinical setting. In this study, an in-depth investigation of the efficacy of three reported gene subsets in distinguishing breast cancer subtypes was performed using four advanced computational intelligence methods-Self-Organizing Maps (SOM), Emergent Self-Organizing Maps (ESOM), Fuzzy Clustering by Local Approximation of Memberships (FLAME), and Fuzzy C-means (FCM)-each differing in the way they view data in terms of distance measures and fuzzy or crisp clustering. The gene subsets consisted of 71, 93, and 71 genes reported in the literature from three comprehensive experimental studies for distinguishing Luminal (A and B), Basal, Normal breast-like, and HER2 subtypes. Given the costly procedures involved in clinical studies, the proposed 93-gene set can be used for preliminary classification of breast cancer. Then, as a decision aid, SOM can be used to map the gene signature of a new patient to locate them with respect to all subtypes to get a comprehensive view of the classification. These can be followed by a deeper investigation in the light of the observations made in this study regarding overlapping subtypes. Results from the study could be used as the base for further refining the gene signatures from later experiments and from new experiments designed to separate overlapping clusters as well as to maximally separate all clusters.

  6. Depression and anxiety related subtypes in Parkinson's disease.

    PubMed

    Brown, Richard G; Landau, Sabine; Hindle, John V; Playfer, Jeremy; Samuel, Michael; Wilson, Kenneth C; Hurt, Catherine S; Anderson, Rachel J; Carnell, Joanna; Dickinson, Lucy; Gibson, Grant; van Schaick, Rachel; Sellwood, Katie; Thomas, Bonnita A; Burn, David J

    2011-07-01

    Depression and anxiety are common in Parkinson's disease (PD) and although clinically important remain poorly understood and managed. To date, research has tended to treat depression and anxiety as distinct phenomena. There is growing evidence for heterogeneity in PD in the motor and cognitive domains, with implications for pathophysiology and outcome. Similar heterogeneity may exist in the domain of depression and anxiety. To identify the main anxiety and depression related subtype(s) in PD and their associated demographic and clinical features. A sample of 513 patients with PD received a detailed assessment of depression and anxiety related symptomatology. Latent Class Analysis (LCA) was used to identify putative depression and anxiety related subtypes. Results LCA identified four classes, two interpretable as 'anxiety related': one anxiety alone (22.0%) and the other anxiety coexisting with prominent depressive symptoms (8.6%). A third subtype (9%) showed a prominent depressive profile only without significant anxiety. The final class (60.4%) showed a low probability of prominent affective symptoms. The validity of the four classes was supported by distinct patterns of association with important demographic and clinical variables. Depression in PD may manifest in two clinical phenotypes, one 'anxious-depressed' and the other 'depressed'. However, a further large proportion of patients can have relatively isolated anxiety. Further study of these putative phenotypes may identify important differences in pathophysiology and other aetiologically important factors and focus research on developing more targeted and effective treatment.

  7. Personality subtypes of suicidal adults.

    PubMed

    Ortigo, Kile M; Westen, Drew; Bradley, Bekh

    2009-09-01

    Research into personality factors related to suicidality suggests substantial variability among suicide attempters. A potentially useful approach that accounts for this complexity is personality subtyping. As part of a large sample looking at personality pathology, this study used Q-factor analysis to identify subtypes of 311 adult suicide attempters using Shedler-Westen Assessment Procedure-II personality profiles. Identified subtypes included internalizing, emotionally dysregulated, dependent, hostile-isolated, psychopathic, and anxious somatizing. Subtypes differed in hypothesized ways on criterion variables that address their construct validity, including adaptive functioning, Axis I and II comorbidity, and etiology-related variables (e.g., history of abuse). Furthermore, dimensional ratings of the subtypes predicted adaptive functioning above DSM-based diagnoses and symptoms.

  8. Distinguishing subtypes of extrinsic motivation among people with mild to borderline intellectual disability.

    PubMed

    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.

  9. Transcriptional Profiling of Plasmodium falciparum Parasites from Patients with Severe Malaria Identifies Distinct Low vs. High Parasitemic Clusters

    PubMed Central

    Krupka, Malkie; Williams, Chris; Seydel, Karl; Taylor, Terrie E.; Van de Peer, Yves; Regev, Aviv; Wirth, Dyann

    2012-01-01

    Background In the past decade, estimates of malaria infections have dropped from 500 million to 225 million per year; likewise, mortality rates have dropped from 3 million to 791,000 per year. However, approximately 90% of these deaths continue to occur in sub-Saharan Africa, and 85% involve children less than 5 years of age. Malaria mortality in children generally results from one or more of the following clinical syndromes: severe anemia, acidosis, and cerebral malaria. Although much is known about the clinical and pathological manifestations of CM, insights into the biology of the malaria parasite, specifically transcription during this manifestation of severe infection, are lacking. Methods and Findings We collected peripheral blood from children meeting the clinical case definition of cerebral malaria from a cohort in Malawi, examined the patients for the presence or absence of malaria retinopathy, and performed whole genome transcriptional profiling for Plasmodium falciparum using a custom designed Affymetrix array. We identified two distinct physiological states that showed highly significant association with the level of parasitemia. We compared both groups of Malawi expression profiles with our previously acquired ex vivo expression profiles of parasites derived from infected patients with mild disease; a large collection of in vitro Plasmodium falciparum life cycle gene expression profiles; and an extensively annotated compendium of expression data from Saccharomyces cerevisiae. The high parasitemia patient group demonstrated a unique biology with elevated expression of Hrd1, a member of endoplasmic reticulum-associated protein degradation system. Conclusions The presence of a unique high parasitemia state may be indicative of the parasite biology of the clinically recognized hyperparasitemic severe disease syndrome. PMID:22815802

  10. A family inheriting different subtypes of acute myelogenous leukemia identifies a gene common to the differentation of multiple hematopoetic lineages and acting early in leukemogenesis

    SciTech Connect

    Horwitz, M.S.; Radich, J.; Sabath, D.E.

    1994-09-01

    The initial steps promoting carcinogenesis in the hematologic malignancies remain poorly understood. We report on a family with an incompletely penetrant, autosomal dominant syndrome of acute myelogenous leukemia, affecting at least eight adults from three generations. The affected individuals have developed leukemias differing in morphologic subtype, tumor cytogenetics, and abruptness of presentation. Within this family are found subtypes affecting the granulocytic, monocytic, and megakaryocytic lineages. At least one individual has a normal tumor karyotype while another has complex rearrangements including monsomy 7, trisomy 8 and translocation 1;7. Some have presented with acute onset and others with a protracted myelodysplasia syndrome. One person at fifty percent risk of inheriting this gene developed disseminated atypical mycobacterium infection in the absence of leukemia, but also without apparent causes for acquired deficiencies in cellular immunity. Features common to affected family members, including the individual with mycobacterium infection, are the early presence in bone marrow of red cell and platelet maturation defects. A search for mutations in diseased marrows fails to detect abnormalities of p53 exons 5, 6, 7 and 8 or N-ras codons 12, 13 and 61. We conclude that there is a gene in this family that probably acts early in hematopoetic differentiation and confers susceptibility to a wide range of leukemia subtypes spanning the maturation of the myeloid series.

  11. Three-Dimensional Gene Map of Cancer Cell Types: Structural Entropy Minimisation Principle for Defining Tumour Subtypes

    NASA Astrophysics Data System (ADS)

    Li, Angsheng; Yin, Xianchen; Pan, Yicheng

    2016-02-01

    In this study, we propose a method for constructing cell sample networks from gene expression profiles, and a structural entropy minimisation principle for detecting natural structure of networks and for identifying cancer cell subtypes. Our method establishes a three-dimensional gene map of cancer cell types and subtypes. The identified subtypes are defined by a unique gene expression pattern, and a three-dimensional gene map is established by defining the unique gene expression pattern for each identified subtype for cancers, including acute leukaemia, lymphoma, multi-tissue, lung cancer and healthy tissue. Our three-dimensional gene map demonstrates that a true tumour type may be divided into subtypes, each defined by a unique gene expression pattern. Clinical data analyses demonstrate that most cell samples of an identified subtype share similar survival times, survival indicators and International Prognostic Index (IPI) scores and indicate that distinct subtypes identified by our algorithms exhibit different overall survival times, survival ratios and IPI scores. Our three-dimensional gene map establishes a high-definition, one-to-one map between the biologically and medically meaningful tumour subtypes and the gene expression patterns, and identifies remarkable cells that form singleton submodules.

  12. Three-Dimensional Gene Map of Cancer Cell Types: Structural Entropy Minimisation Principle for Defining Tumour Subtypes.

    PubMed

    Li, Angsheng; Yin, Xianchen; Pan, Yicheng

    2016-02-04

    In this study, we propose a method for constructing cell sample networks from gene expression profiles, and a structural entropy minimisation principle for detecting natural structure of networks and for identifying cancer cell subtypes. Our method establishes a three-dimensional gene map of cancer cell types and subtypes. The identified subtypes are defined by a unique gene expression pattern, and a three-dimensional gene map is established by defining the unique gene expression pattern for each identified subtype for cancers, including acute leukaemia, lymphoma, multi-tissue, lung cancer and healthy tissue. Our three-dimensional gene map demonstrates that a true tumour type may be divided into subtypes, each defined by a unique gene expression pattern. Clinical data analyses demonstrate that most cell samples of an identified subtype share similar survival times, survival indicators and International Prognostic Index (IPI) scores and indicate that distinct subtypes identified by our algorithms exhibit different overall survival times, survival ratios and IPI scores. Our three-dimensional gene map establishes a high-definition, one-to-one map between the biologically and medically meaningful tumour subtypes and the gene expression patterns, and identifies remarkable cells that form singleton submodules.

  13. Three-Dimensional Gene Map of Cancer Cell Types: Structural Entropy Minimisation Principle for Defining Tumour Subtypes

    PubMed Central

    Li, Angsheng; Yin, Xianchen; Pan, Yicheng

    2016-01-01

    In this study, we propose a method for constructing cell sample networks from gene expression profiles, and a structural entropy minimisation principle for detecting natural structure of networks and for identifying cancer cell subtypes. Our method establishes a three-dimensional gene map of cancer cell types and subtypes. The identified subtypes are defined by a unique gene expression pattern, and a three-dimensional gene map is established by defining the unique gene expression pattern for each identified subtype for cancers, including acute leukaemia, lymphoma, multi-tissue, lung cancer and healthy tissue. Our three-dimensional gene map demonstrates that a true tumour type may be divided into subtypes, each defined by a unique gene expression pattern. Clinical data analyses demonstrate that most cell samples of an identified subtype share similar survival times, survival indicators and International Prognostic Index (IPI) scores and indicate that distinct subtypes identified by our algorithms exhibit different overall survival times, survival ratios and IPI scores. Our three-dimensional gene map establishes a high-definition, one-to-one map between the biologically and medically meaningful tumour subtypes and the gene expression patterns, and identifies remarkable cells that form singleton submodules. PMID:26842724

  14. Neuroanatomical profiles of alexithymia dimensions and subtypes.

    PubMed

    Goerlich-Dobre, Katharina Sophia; Votinov, Mikhail; Habel, Ute; Pripfl, Juergen; Lamm, Claus

    2015-10-01

    Alexithymia, a major risk factor for a range of psychiatric and neurological disorders, has been recognized to comprise two dimensions, a cognitive dimension (difficulties identifying, analyzing, and verbalizing feelings) and an affective one (difficulties emotionalizing and fantasizing). Based on these dimensions, the existence of four distinct alexithymia subtypes has been proposed, but never empirically tested. In this study, 125 participants were assigned to four groups corresponding to the proposed alexithymia subtypes: Type I (impairment on both dimensions), Type II (impairment on the cognitive, but not the affective dimension), Type III (impairment on the affective, but not the cognitive dimension), and Lexithymics (no impairment on either dimension). By means of voxel-based morphometry, associations of the alexithymia dimensions and subtypes with gray and white matter volumes were analyzed. Type I and Type II alexithymia were characterized by gray matter volume reductions in the left amygdala and the thalamus. The cognitive dimension was further linked to volume reductions in the right amygdala, left posterior insula, precuneus, caudate, hippocampus, and parahippocampus. Type III alexithymia was marked by volume reduction in the MCC only, and the affective dimension was further characterized by larger sgACC volume. Moreover, individuals with the intermediate alexithymia Types II and III showed gray matter volume reductions in distinct regions, and had larger corpus callosum volumes compared to Lexithymics. These results substantiate the notion of a differential impact of the cognitive and affective alexithymia dimensions on brain morphology and provide evidence for separable neuroanatomical representations of the different alexithymia subtypes. © 2015 Wiley Periodicals, Inc.

  15. Catatonia in Autism: A Distinct Subtype?

    ERIC Educational Resources Information Center

    Ghaziuddin, M.; Quinlan, P.; Ghaziuddin, N.

    2005-01-01

    Catatonia is a life-threatening disorder characterized by motor abnormalities, mutism, and disturbances of behaviour, which is increasingly being diagnosed in persons with autism. In this report, we describe the presentation and course of catatonia in an adolescent with autism who responded to electroconvulsive therapy (ECT). The illness started…

  16. Catatonia in Autism: A Distinct Subtype?

    ERIC Educational Resources Information Center

    Ghaziuddin, M.; Quinlan, P.; Ghaziuddin, N.

    2005-01-01

    Catatonia is a life-threatening disorder characterized by motor abnormalities, mutism, and disturbances of behaviour, which is increasingly being diagnosed in persons with autism. In this report, we describe the presentation and course of catatonia in an adolescent with autism who responded to electroconvulsive therapy (ECT). The illness started…

  17. HIV type 1 V3 serotyping of Tanzanian samples: probable reasons for mismatching with genetic subtyping.

    PubMed

    Hoelscher, M; Hanker, S; Barin, F; Cheingsong-Popov, R; Dietrich, U; Jordan-Harder, B; Olaleye, D; Nägele, E; Markuzzi, A; Mwakagile, D; Minja, F; Weber, J; Gürtler, L; Von Sonnenburg, F

    1998-01-20

    HIV-1 V3 serotyping is used to classify immunodeficiency viruses on the basis of antibody binding to V3 peptides derived from env genetic subtypes. Although it shows a reasonable overlap, it has been reported to be distinct from viral genetic subtypes. The aim of this study is to determine the feasibility of HIV-1 serotyping to predict genetic subtypes in an East African setting, where multiple HIV-1 subtypes have coexisted for many years. HIV-1 genetic subtypes of 86 AIDS patients in Mbeya Town, southwest Tanzania, were determined, using env nucleic acid sequencing as the basis for comparison. Those data were compared with V3 serotyping results obtained by four different methodologies. Four HIV-1 genetic subtypes were identified, including A (25, 29%), C (47, 55%), D (13, 15%), and G (1, 1%). The sensitivity and specificity of those serotyping assays varied considerably: sensitivity for genetic subtype A (40-48%), C (52-96%), and D (9-31%); and specificity for genetic subtype A (77-95%), C (46-63%), and D (97-100%). We further tried to identify reasons for the discrepancies between serotyping results and genetic subtypes. By means of logistic regression analysis three amino acid residues within the V3 loop (positions 12, 13, and 19; V, H, and A for serotype A, I, R, and T for serotype C) were found to be most important for antibody binding; a deviation from the subtype-specific amino acids was highly related to mismatched results. In addition, we have shown that phenetic analysis of V3 amino acid sequence data could be used to predict the majority of V3 serotypes (93-94%). Our data demonstrated that for the majority of specimens HIV-1 V3 serotyping results closely match the subtype of the analyzed sample as revealed by the V3 loop amino acid sequence. However, our data demonstrate that HIV-1 serotyping is not sufficiently accurate to predict genetic subtypes in Tanzania, where subtypes A, C, D, and G are circulating. This was due to highly similar amino acid

  18. Etiologic Heterogeneity Among Non-Hodgkin Lymphoma Subtypes: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

    PubMed Central

    Morton, Lindsay M.; Slager, Susan L.; Cerhan, James R.; Wang, Sophia S.; Vajdic, Claire M.; Skibola, Christine F.; Bracci, Paige M.; de Sanjosé, Silvia; Smedby, Karin E.; Chiu, Brian C. H.; Zhang, Yawei; Mbulaiteye, Sam M.; Monnereau, Alain; Turner, Jennifer J.; Clavel, Jacqueline; Adami, Hans-Olov; Chang, Ellen T.; Glimelius, Bengt; Hjalgrim, Henrik; Melbye, Mads; Crosignani, Paolo; di Lollo, Simonetta; Miligi, Lucia; Nanni, Oriana; Ramazzotti, Valerio; Rodella, Stefania; Costantini, Adele Seniori; Stagnaro, Emanuele; Tumino, Rosario; Vindigni, Carla; Vineis, Paolo; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Cocco, Pierluigi; Foretova, Lenka; Maynadié, Marc; Nieters, Alexandra; Staines, Anthony; Colt, Joanne S.; Cozen, Wendy; Davis, Scott; de Roos, Anneclaire J.; Hartge, Patricia; Rothman, Nathaniel; Severson, Richard K.; Holly, Elizabeth A.; Call, Timothy G.; Feldman, Andrew L.; Habermann, Thomas M.; Liebow, Mark; Blair, Aaron; Cantor, Kenneth P.; Kane, Eleanor V.; Lightfoot, Tracy; Roman, Eve; Smith, Alex; Brooks-Wilson, Angela; Connors, Joseph M.; Gascoyne, Randy D.; Spinelli, John J.; Armstrong, Bruce K.; Kricker, Anne; Holford, Theodore R.; Lan, Qing; Zheng, Tongzhang; Orsi, Laurent; Dal Maso, Luigino; Franceschi, Silvia; La Vecchia, Carlo; Negri, Eva; Serraino, Diego; Bernstein, Leslie; Levine, Alexandra; Friedberg, Jonathan W.; Kelly, Jennifer L.; Berndt, Sonja I.; Birmann, Brenda M.; Clarke, Christina A.; Flowers, Christopher R.; Foran, James M.; Kadin, Marshall E.; Paltiel, Ora; Weisenburger, Dennis D.; Linet, Martha S.; Sampson, Joshua N.

    2014-01-01

    teacher generally were restricted to marginal zone lymphoma, Burkitt/Burkitt-like lymphoma/leukemia, diffuse large B-cell lymphoma, and/or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia. Conclusions Using a novel approach to investigate etiologic heterogeneity among NHL subtypes, we identified risk factors that were common among subtypes as well as risk factors that appeared to be distinct among individual or a few subtypes, suggesting both subtype-specific and shared underlying mechanisms. Further research is needed to test putative mechanisms, investigate other risk factors (eg, other infections, environmental exposures, and diet), and evaluate potential joint effects with genetic susceptibility. PMID:25174034

  19. Diagnosis and subtypes of adolescent antisocial personality disorder.

    PubMed

    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.

  20. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors.

    PubMed

    Melin, Beatrice S; Barnholtz-Sloan, Jill S; Wrensch, Margaret R; Johansen, Christoffer; Il'yasova, Dora; Kinnersley, Ben; Ostrom, Quinn T; Labreche, Karim; Chen, Yanwen; Armstrong, Georgina; Liu, Yanhong; Eckel-Passow, Jeanette E; Decker, Paul A; Labussière, Marianne; Idbaih, Ahmed; Hoang-Xuan, Khe; Di Stefano, Anna-Luisa; Mokhtari, Karima; Delattre, Jean-Yves; Broderick, Peter; Galan, Pilar; Gousias, Konstantinos; Schramm, Johannes; Schoemaker, Minouk J; Fleming, Sarah J; Herms, Stefan; Heilmann, Stefanie; Nöthen, Markus M; Wichmann, Heinz-Erich; Schreiber, Stefan; Swerdlow, Anthony; Lathrop, Mark; Simon, Matthias; Sanson, Marc; Andersson, Ulrika; Rajaraman, Preetha; Chanock, Stephen; Linet, Martha; Wang, Zhaoming; Yeager, Meredith; Wiencke, John K; Hansen, Helen; McCoy, Lucie; Rice, Terri; Kosel, Matthew L; Sicotte, Hugues; Amos, Christopher I; Bernstein, Jonine L; Davis, Faith; Lachance, Dan; Lau, Ching; Merrell, Ryan T; Shildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Scheurer, Michael; Shete, Sanjay; Lai, Rose K; Claus, Elizabeth B; Olson, Sara H; Jenkins, Robert B; Houlston, Richard S; Bondy, Melissa L

    2017-03-27

    Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10(-9), odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10(-10), OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10(-8), OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10(-11), OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10(-10), OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10(-9), OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10(-10), OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10(-10), OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10(-9), OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10(-8), OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10(-10), OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10(-11), OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10(-9), OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

  1. European surveillance network for influenza in pigs: surveillance programs, diagnostic tools and Swine influenza virus subtypes identified in 14 European countries from 2010 to 2013.

    PubMed

    Simon, Gaëlle; Larsen, Lars E; Dürrwald, Ralf; Foni, Emanuela; Harder, Timm; Van Reeth, Kristien; Markowska-Daniel, Iwona; Reid, Scott M; Dan, Adam; Maldonado, Jaime; Huovilainen, Anita; Billinis, Charalambos; Davidson, Irit; Agüero, Montserrat; Vila, Thaïs; Hervé, Séverine; Breum, Solvej Østergaard; Chiapponi, Chiara; Urbaniak, Kinga; Kyriakis, Constantinos S; Brown, Ian H; Loeffen, Willie

    2014-01-01

    Swine influenza causes concern for global veterinary and public health officials. In continuing two previous networks that initiated the surveillance of swine influenza viruses (SIVs) circulating in European pigs between 2001 and 2008, a third European Surveillance Network for Influenza in Pigs (ESNIP3, 2010-2013) aimed to expand widely the knowledge of the epidemiology of European SIVs. ESNIP3 stimulated programs of harmonized SIV surveillance in European countries and supported the coordination of appropriate diagnostic tools and subtyping methods. Thus, an extensive virological monitoring, mainly conducted through passive surveillance programs, resulted in the examination of more than 9 000 herds in 17 countries. Influenza A viruses were detected in 31% of herds examined from which 1887 viruses were preliminary characterized. The dominating subtypes were the three European enzootic SIVs: avian-like swine H1N1 (53.6%), human-like reassortant swine H1N2 (13%) and human-like reassortant swine H3N2 (9.1%), as well as pandemic A/H1N1 2009 (H1N1pdm) virus (10.3%). Viruses from these four lineages co-circulated in several countries but with very different relative levels of incidence. For instance, the H3N2 subtype was not detected at all in some geographic areas whereas it was still prevalent in other parts of Europe. Interestingly, H3N2-free areas were those that exhibited highest frequencies of circulating H1N2 viruses. H1N1pdm viruses were isolated at an increasing incidence in some countries from 2010 to 2013, indicating that this subtype has become established in the European pig population. Finally, 13.9% of the viruses represented reassortants between these four lineages, especially between previous enzootic SIVs and H1N1pdm. These novel viruses were detected at the same time in several countries, with increasing prevalence. Some of them might become established in pig herds, causing implications for zoonotic infections.

  2. European Surveillance Network for Influenza in Pigs: Surveillance Programs, Diagnostic Tools and Swine Influenza Virus Subtypes Identified in 14 European Countries from 2010 to 2013

    PubMed Central

    Simon, Gaëlle; Larsen, Lars E.; Dürrwald, Ralf; Foni, Emanuela; Harder, Timm; Van Reeth, Kristien; Markowska-Daniel, Iwona; Reid, Scott M.; Dan, Adam; Maldonado, Jaime; Huovilainen, Anita; Billinis, Charalambos; Davidson, Irit; Agüero, Montserrat; Vila, Thaïs; Hervé, Séverine; Breum, Solvej Østergaard; Chiapponi, Chiara; Urbaniak, Kinga; Kyriakis, Constantinos S.; Brown, Ian H.; Loeffen, Willie

    2014-01-01

    Swine influenza causes concern for global veterinary and public health officials. In continuing two previous networks that initiated the surveillance of swine influenza viruses (SIVs) circulating in European pigs between 2001 and 2008, a third European Surveillance Network for Influenza in Pigs (ESNIP3, 2010–2013) aimed to expand widely the knowledge of the epidemiology of European SIVs. ESNIP3 stimulated programs of harmonized SIV surveillance in European countries and supported the coordination of appropriate diagnostic tools and subtyping methods. Thus, an extensive virological monitoring, mainly conducted through passive surveillance programs, resulted in the examination of more than 9 000 herds in 17 countries. Influenza A viruses were detected in 31% of herds examined from which 1887 viruses were preliminary characterized. The dominating subtypes were the three European enzootic SIVs: avian-like swine H1N1 (53.6%), human-like reassortant swine H1N2 (13%) and human-like reassortant swine H3N2 (9.1%), as well as pandemic A/H1N1 2009 (H1N1pdm) virus (10.3%). Viruses from these four lineages co-circulated in several countries but with very different relative levels of incidence. For instance, the H3N2 subtype was not detected at all in some geographic areas whereas it was still prevalent in other parts of Europe. Interestingly, H3N2-free areas were those that exhibited highest frequencies of circulating H1N2 viruses. H1N1pdm viruses were isolated at an increasing incidence in some countries from 2010 to 2013, indicating that this subtype has become established in the European pig population. Finally, 13.9% of the viruses represented reassortants between these four lineages, especially between previous enzootic SIVs and H1N1pdm. These novel viruses were detected at the same time in several countries, with increasing prevalence. Some of them might become established in pig herds, causing implications for zoonotic infections. PMID:25542013

  3. α-Conotoxins Identify the α3β4* Subtype as the Predominant Nicotinic Acetylcholine Receptor Expressed in Human Adrenal Chromaffin Cells.

    PubMed

    Hone, Arik J; McIntosh, J Michael; Azam, Layla; Lindstrom, Jon; Lucero, Linda; Whiteaker, Paul; Passas, Juan; Blázquez, Jesús; Albillos, Almudena

    2015-11-01

    Ligands that selectively inhibit human α3β2 and α6β2 nicotinic acetylcholine receptor (nAChRs) and not the closely related α3β4 and α6β4 subtypes are lacking. Current α-conotoxins (α-Ctxs) that discriminate among these nAChR subtypes in rat fail to discriminate among the human receptor homologs. In this study, we describe the development of α-Ctx LvIA(N9R,V10A) that is 3000-fold more potent on oocyte-expressed human α3β2 than α3β4 and 165-fold more potent on human α6/α3β2β3 than α6/α3β4 nAChRs. This analog was used in conjuction with three other α-Ctx analogs and patch-clamp electrophysiology to characterize the nAChR subtypes expressed by human adrenal chromaffin cells. LvIA(N9R,V10A) showed little effect on the acetylcholine-evoked currents in these cells at concentrations expected to inhibit nAChRs with β2 ligand-binding sites. In contrast, the β4-selective α-Ctx BuIA(T5A,P6O) inhibited >98% of the acetylcholine-evoked current, indicating that most of the heteromeric receptors contained β4 ligand-binding sites. Additional studies using the α6-selective α-Ctx PeIA(A7V,S9H,V10A,N11R,E14A) indicated that the predominant heteromeric nAChR expressed by human adrenal chromaffin cells is the α3β4* subtype (asterisk indicates the possible presence of additional subunits). This conclusion was supported by polymerase chain reaction experiments of human adrenal medulla gland and of cultured human adrenal chromaffin cells that demonstrated prominent expression of RNAs for α3, α5, α7, β2, and β4 subunits and a low abundance of RNAs for α2, α4, α6, and α10 subunits.

  4. α-Conotoxins Identify the α3β4* Subtype as the Predominant Nicotinic Acetylcholine Receptor Expressed in Human Adrenal Chromaffin Cells

    PubMed Central

    Hone, Arik J.; McIntosh, J. Michael; Azam, Layla; Lindstrom, Jon; Lucero, Linda; Whiteaker, Paul; Passas, Juan; Blázquez, Jesús

    2015-01-01

    Ligands that selectively inhibit human α3β2 and α6β2 nicotinic acetylcholine receptor (nAChRs) and not the closely related α3β4 and α6β4 subtypes are lacking. Current α-conotoxins (α-Ctxs) that discriminate among these nAChR subtypes in rat fail to discriminate among the human receptor homologs. In this study, we describe the development of α-Ctx LvIA(N9R,V10A) that is 3000-fold more potent on oocyte-expressed human α3β2 than α3β4 and 165-fold more potent on human α6/α3β2β3 than α6/α3β4 nAChRs. This analog was used in conjuction with three other α-Ctx analogs and patch-clamp electrophysiology to characterize the nAChR subtypes expressed by human adrenal chromaffin cells. LvIA(N9R,V10A) showed little effect on the acetylcholine-evoked currents in these cells at concentrations expected to inhibit nAChRs with β2 ligand-binding sites. In contrast, the β4-selective α-Ctx BuIA(T5A,P6O) inhibited >98% of the acetylcholine-evoked current, indicating that most of the heteromeric receptors contained β4 ligand-binding sites. Additional studies using the α6-selective α-Ctx PeIA(A7V,S9H,V10A,N11R,E14A) indicated that the predominant heteromeric nAChR expressed by human adrenal chromaffin cells is the α3β4* subtype (asterisk indicates the possible presence of additional subunits). This conclusion was supported by polymerase chain reaction experiments of human adrenal medulla gland and of cultured human adrenal chromaffin cells that demonstrated prominent expression of RNAs for α3, α5, α7, β2, and β4 subunits and a low abundance of RNAs for α2, α4, α6, and α10 subunits. PMID:26330550

  5. Epidemiological risk factors associated with inflammatory breast cancer subtypes.

    PubMed

    Atkinson, Rachel L; El-Zein, Randa; Valero, Vicente; Lucci, Anthony; Bevers, Therese B; Fouad, Tamer; Liao, Weiqin; Ueno, Naoto T; Woodward, Wendy A; Brewster, Abenaa M

    2016-03-01

    In this single-institution case-control study, we identified risk factors associated with inflammatory breast cancer (IBC) subtypes based on staining of estrogen receptor (ER), progesterone receptor (PR) and expression of human epidermal growth factor 2 (HER2neu) to determine distinct etiologic pathways. We identified 224 women with IBC and 396 cancer-free women seen at the MD Anderson Cancer Center. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between breast cancer risk factors and the IBC tumor subtypes: luminal (ER+ and/or PR+/HER2neu-), HER2neu+ (any ER and PR, HER2neu+), and triple-negative (ER-/PR-/HER2neu-). In multivariable analysis, compared with women age ≥26 at first pregnancy, women age <26 had a higher risk of triple-negative IBC (OR 3.32, 95% CI 1.37-8.05). Women with a history of breast-feeding had a lower risk of triple-negative (OR 0.30; 95% CI 0.15-0.62) and luminal IBC (OR 0.35, 95% CI 0.18-0.68). A history of smoking was associated with an increased risk of luminal IBC (OR 2.37; 95% CI 1.24-4.52). Compared with normal-weight women, those who were overweight or obese (body mass index ≥25 kg/m(2)) had a higher risk of all three tumor subtypes (p < 0.01 for all subtypes). Overweight or obese status is important modifiable risk factor for IBC of any subtype. Modifiable risk factors, age at first pregnancy (≥26), breast-feeding, and smoking may be associated with specific IBC subtypes. These results highlight the importance of evaluating epidemiologic risk factors for IBC for the identification of subtype-specific prevention strategies.

  6. A coupling of homology modeling with multiple molecular dynamics simulation for identifying representative conformation of GPCR structures: a case study on human bombesin receptor subtype-3.

    PubMed

    Nowroozi, Amin; Shahlaei, Mohsen

    2017-02-01

    In this study, a computational pipeline was therefore devised to overcome homology modeling (HM) bottlenecks. The coupling of HM with molecular dynamics (MD) simulation is useful in that it tackles the sampling deficiency of dynamics simulations by providing good-quality initial guesses for the native structure. Indeed, HM also relaxes the severe requirement of force fields to explore the huge conformational space of protein structures. In this study, the interaction between the human bombesin receptor subtype-3 and MK-5046 was investigated integrating HM, molecular docking, and MD simulations. To improve conformational sampling in typical MD simulations of GPCRs, as in other biomolecules, multiple trajectories with different initial conditions can be employed rather than a single long trajectory. Multiple MD simulations of human bombesin receptor subtype-3 with different initial atomic velocities are applied to sample conformations in the vicinity of the structure generated by HM. The backbone atom conformational space distribution of replicates is analyzed employing principal components analysis. As a result, the averages of structural and dynamic properties over the twenty-one trajectories differ significantly from those obtained from individual trajectories.

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

    PubMed Central

    2014-01-01

    Background 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. Results 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. Conclusions 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. PMID:25521965

  8. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology.

    PubMed

    Damrauer, Jeffrey S; Hoadley, Katherine A; Chism, David D; Fan, Cheng; Tiganelli, Christopher J; Wobker, Sara E; Yeh, Jen Jen; Milowsky, Matthew I; Iyer, Gopa; Parker, Joel S; Kim, William Y

    2014-02-25

    We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.

  9. An Integrated Bioinformatics Approach Identifies Elevated Cyclin E2 Expression and E2F Activity as Distinct Features of Tamoxifen Resistant Breast Tumors

    PubMed Central

    Huang, Lei; Zhao, Shuangping; Frasor, Jonna M.; Dai, Yang

    2011-01-01

    Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers. PMID:21789246

  10. An integrated bioinformatics approach identifies elevated cyclin E2 expression and E2F activity as distinct features of tamoxifen resistant breast tumors.

    PubMed

    Huang, Lei; Zhao, Shuangping; Frasor, Jonna M; Dai, Yang

    2011-01-01

    Approximately half of estrogen receptor (ER) positive breast tumors will fail to respond to endocrine therapy. Here we used an integrative bioinformatics approach to analyze three gene expression profiling data sets from breast tumors in an attempt to uncover underlying mechanisms contributing to the development of resistance and potential therapeutic strategies to counteract these mechanisms. Genes that are differentially expressed in tamoxifen resistant vs. sensitive breast tumors were identified from three different publically available microarray datasets. These differentially expressed (DE) genes were analyzed using gene function and gene set enrichment and examined in intrinsic subtypes of breast tumors. The Connectivity Map analysis was utilized to link gene expression profiles of tamoxifen resistant tumors to small molecules and validation studies were carried out in a tamoxifen resistant cell line. Despite little overlap in genes that are differentially expressed in tamoxifen resistant vs. sensitive tumors, a high degree of functional similarity was observed among the three datasets. Tamoxifen resistant tumors displayed enriched expression of genes related to cell cycle and proliferation, as well as elevated activity of E2F transcription factors, and were highly correlated with a Luminal intrinsic subtype. A number of small molecules, including phenothiazines, were found that induced a gene signature in breast cancer cell lines opposite to that found in tamoxifen resistant vs. sensitive tumors and the ability of phenothiazines to down-regulate cyclin E2 and inhibit proliferation of tamoxifen resistant breast cancer cells was validated. Our findings demonstrate that an integrated bioinformatics approach to analyze gene expression profiles from multiple breast tumor datasets can identify important biological pathways and potentially novel therapeutic options for tamoxifen-resistant breast cancers.

  11. Single-molecule spectroscopy of LHCSR1 protein dynamics identifies two distinct states responsible for multi-timescale photosynthetic photoprotection

    NASA Astrophysics Data System (ADS)

    Kondo, Toru; Pinnola, Alberta; Chen, Wei Jia; Dall'Osto, Luca; Bassi, Roberto; Schlau-Cohen, Gabriela S.

    2017-08-01

    In oxygenic photosynthesis, light harvesting is regulated to safely dissipate excess energy and prevent the formation of harmful photoproducts. Regulation is known to be necessary for fitness, but the molecular mechanisms are not understood. One challenge has been that ensemble experiments average over active and dissipative behaviours, preventing identification of distinct states. Here, we use single-molecule spectroscopy to uncover the photoprotective states and dynamics of the light-harvesting complex stress-related 1 (LHCSR1) protein, which is responsible for dissipation in green algae and moss. We discover the existence of two dissipative states. We find that one of these states is activated by pH and the other by carotenoid composition, and that distinct protein dynamics regulate these states. Together, these two states enable the organism to respond to two types of intermittency in solar intensity—step changes (clouds and shadows) and ramp changes (sunrise), respectively. Our findings reveal key control mechanisms underlying photoprotective dissipation, with implications for increasing biomass yields and developing robust solar energy devices.

  12. Single-molecule spectroscopy of LHCSR1 protein dynamics identifies two distinct states responsible for multi-timescale photosynthetic photoprotection.

    PubMed

    Kondo, Toru; Pinnola, Alberta; Chen, Wei Jia; Dall'Osto, Luca; Bassi, Roberto; Schlau-Cohen, Gabriela S

    2017-08-01

    In oxygenic photosynthesis, light harvesting is regulated to safely dissipate excess energy and prevent the formation of harmful photoproducts. Regulation is known to be necessary for fitness, but the molecular mechanisms are not understood. One challenge has been that ensemble experiments average over active and dissipative behaviours, preventing identification of distinct states. Here, we use single-molecule spectroscopy to uncover the photoprotective states and dynamics of the light-harvesting complex stress-related 1 (LHCSR1) protein, which is responsible for dissipation in green algae and moss. We discover the existence of two dissipative states. We find that one of these states is activated by pH and the other by carotenoid composition, and that distinct protein dynamics regulate these states. Together, these two states enable the organism to respond to two types of intermittency in solar intensity-step changes (clouds and shadows) and ramp changes (sunrise), respectively. Our findings reveal key control mechanisms underlying photoprotective dissipation, with implications for increasing biomass yields and developing robust solar energy devices.

  13. Transient activation and delayed inhibition of Na+,K+,Cl- cotransport in ATP-treated C11-MDCK cells involve distinct P2Y receptor subtypes and signaling mechanisms.

    PubMed

    Akimova, Olga A; Grygorczyk, Alexandra; Bundey, Richard A; Bourcier, Nathalie; Gekle, Michael; Insel, Paul A; Orlov, Sergei N

    2006-10-20

    In C11-MDCK cells, which resemble intercalated cells from collecting ducts of the canine kidney, P2Y agonists promote transient activation of the Na+,K+,Cl- cotransporter (NKCC), followed by its sustained inhibition. We designed this study to identify P2Y receptor subtypes involved in dual regulation of this carrier. Real time polymerase chain reaction analysis demonstrated that C11-MDCK cells express abundant P2Y1 and P2Y2 mRNA compared with that of other P2Y receptor subtypes. The rank order of potency of agents (ATP approximately UTP > 2-(methylthio)-ATP (2MeSATP); adenosine 5'-[beta-thio]diphosphate (ADPbetaS) inactive) indicated that P2Y2 rather than P2Y1 receptors mediate a 3-4-fold activation of NKCC within the first 5-10 min of nucleotide addition. NKCC activation in ATP-treated cells was abolished by the intracellular calcium chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, calmodulin (CaM) antagonists trifluoroperazine and W-7, and KN-62, an inhibitor of Ca2+/CaM-dependent protein kinase II. By contrast with the transient activation, 30-min incubation with nucleotides produced up to 4-5-fold inhibition of NKCC, and this inhibition exhibited a rank order of potency (2MeSATP > ADPbetaS > ATP > UTP) typical of P2Y1 receptors. Unlike the early response, delayed inhibition of NKCC occurred in 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-loaded cells and was completely abolished by the P2Y1 antagonists MRS2179 and MRS2500. Transient activation and delayed inhibition of NKCC in C11 cell monolayers were observed after the addition of ATP to mucosal and serosal solutions, respectively. NKCC inhibition triggered by basolateral application of ADPbetaS was abolished by MRS2500. Our results thus show that transient activation and delayed inhibition of NKCC in ATP-treated C11-MDCK cells is mediated by Ca2+/CaM-dependent protein kinase II- and Ca2+-independent signaling triggered by apical P2Y2 and basolateral P2Y1 receptors, respectively.

  14. Severe and anxious depression: combining definitions of clinical sub-types to identify patients differentially responsive to selective serotonin reuptake inhibitors.

    PubMed

    Papakostas, George I; Fan, Hua; Tedeschini, Enrico

    2012-05-01

    Patients with severe major depressive disorder are more likely than those with mild/moderate depression to experience the relative benefits of antidepressant therapy versus placebo. Several studies have, unexpectedly, failed to show a similar antidepressant-placebo discrepancy between patients with versus without anxious depression, although patients with anxious depression are more likely to meet criteria for severe depression than those without. The aim of this study was to confirm the absence of treatment moderating effects for anxious depression in a general clinical trial population, and to examine for the presence of treatment moderating effects in severe depression. Patient-level outcome data from all randomized, double-blind, placebo-controlled trials involving the use of the selective serotonin reuptake inhibitor escitalopram for adults with major depressive disorder sponsored by H. Lundbeck A/S or Forest Laboratories were pooled. Studies focusing on patients with a specific axis-I or -III co-morbidity were excluded. Data from five trials were pooled. Anxious depression was not found to serve as a treatment moderator for selective serotonin reuptake inhibitor therapy versus placebo. However, when patients with severe depression were analyzed separately, anxious depression significantly influenced the relative degree of symptom reduction with selective serotonin reuptake inhibitors versus placebo (p=0.0094). In fact, the numbers needed to treat for remission for these two sub-types were the largest and smallest reported to date from analyses of large datasets of antidepressants (22 for severe anxious versus 4 for severe non-anxious depression). Subdividing patients with severe major depressive disorder into those with versus without anxious depression results in the characterization of sub-types that are particularly "responsive" (severe non-anxious) and "unresponsive" (severe anxious) to selective serotonin reuptake inhibitor therapy (relative to placebo

  15. Histopathological and clinical analysis of chronic rhinosinusitis by subtype.

    PubMed

    Czerny, Mary S; Namin, Arya; Gratton, Michael Anne; Antisdel, Jastin L

    2014-06-01

    Chronic rhinosinusitis (CRS) encompasses diverse phenotypic expression. Clinical and histological differences suggest 4 CRS subtypes: eosinophilic CRS with and without nasal polyps (eCRSwNP, eCRSsNP, respectively) and non-eosinophilic CRS with and without nasal polyps (neCRSwNP, neCRSsNP, respectively). The mucosal basement membrane (BM) and cilia are believed to play roles in CRS pathogenesis by impacting mucociliary clearance and immune barriers. This study aimed to identify clinical, surgical, and histopathological subtype differences to further elucidate disease mechanisms. Ethmoid tissue from 33 adult CRS patients and 7 controls was obtained during endoscopic sinus or other sinonasal surgery (controls) and analyzed by light and transmission electron microscopy for BM thickness and presence of cilia. CRS patients were categorized into the 4 subtypes, and 22-item Sinonasal Outcome Test (SNOT-22) score, endoscopy, computed tomography (CT), and surgical data were compared and analyzed for association with histopathology measures. CRS subtypes could be distinguished by CT score and surgical data, with eCRSwNP patients exhibiting greatest disease severity. Whereas eosinophilia was associated with absence of cilia, nasal polyposis showed no association with surgical or histopathological measures. No significant difference in BM thickness was found between controls and CRS subtypes, but distinctions were found regarding cilia, which were less common in eosinophilic subgroups compared to controls and neCRSsNP patients. CRS subtypes exhibit some differentiating histopathological and surgical features. The absence of cilia appears to have an important role in the eosinophilic subgroups. Further histologic evaluation is warranted to evaluate for possible subtype-specific treatment targets or prognostic markers. © 2014 ARS-AAOA, LLC.

  16. Statistical support for subtypes in posttraumatic stress disorder: the how and why of subtype analysis.

    PubMed

    Dalenberg, Constance J; Glaser, Dale; Alhassoon, Omar M

    2012-08-01

    A number of researchers have argued for the existence of different subtypes of posttraumatic stress disorder (PTSD). In the current paper we present criteria by which to assess these putative subtypes, clarify potential pitfalls of the statistical methods employed to determine them, and propose alternative methods for such determinations. Specifically, three PTSD subtypes are examined: (1) complex PTSD, (2) externalizing/internalizing PTSD, and (3) dissociative/nondissociative PTSD. In addition, three criteria are proposed for subtype evaluation, these are the need for (1) reliability and clarity of definition, (2) distinctions between subtypes either structurally or by mechanism, and (3) clinical meaningfulness. Common statistical evidence for subtyping, such as statistical mean difference and cluster analysis, are presented and evaluated. Finally, more robust statistical methods are suggested for future research on PTSD subtyping. © 2012 Wiley Periodicals, Inc.

  17. Genetic Alterations of the Retinoblastoma-Related Gene RB2/p130 Identify Different Pathogenetic Mechanisms in and among Burkitt’s Lymphoma Subtypes

    PubMed Central

    Cinti, Caterina; Leoncini, Lorenzo; Nyongo, Aggrey; Ferrari, Filomena; Lazzi, Stefano; Bellan, Cristiana; Vatti, Rosella; Zamparelli, Alessandra; Cevenini, Gabriele; osi, Gian Marco T; Claudio, Pier Paolo; Maraldi, Nadir M.; Tosi, Piero; Giordano, Antonio

    2000-01-01

    Alterations of cell cycle-associated genes probably contribute to the pathogenesis of Burkitt’s Lymphoma (BL), in addition to c-myc translocation. Mutations disrupting the nuclear localization signal of the retinoblastoma-related gene RB2/p130 have been documented recently in BL cell lines and primary tumors. Given the importance of the RB2/p130 gene in controlling cell growth, mutations of this gene may result in uncontrolled cell proliferation. We tested the expression and genomic organization of the RB2/p130 gene in relation to the proliferative features of a series of BL samples collected from the endemic and sporadic regions, regardless of whether the samples were acquired immune deficiency syndrome (AIDS)-related. The expression of the Rb2/p130, p107, and cell proliferation-related proteins (cyclin A and B) was determined by immunohistochemistry. The structures of exons 19 through 22 of the RB2/p130 gene, encoding for the B domain and C terminus, were analyzed by polymerase chain reaction (PCR) analysis and single-strand conformation polymorphism (SSCP) technique. The direct PCR products were sequenced to identify the actual mutations. Our results suggest that BL is composed of a mixture of molecular types with distinct genetic and phenotypic patterns, probably resulting from different pathogenetic mechanisms. In endemic BL, the RB2/p130 gene is mutated in most of the cases, and the protein is restricted to the cytoplasm. In AIDS-related BL, high levels of nuclear expression of the wild-type pRb2/p130, p107, and cell proliferation-related proteins were detected. This finding is in line with the molecular mechanisms observed in virus-linked oncogenesis. Sporadic BLs were mainly characterized by the low nuclear values of the wild-type pRb2/p130 and, conversely, the high values of p107. The increased cell proliferation due to different alterations of cell growth control by Rb-related proteins may be the first step in lymphomagenesis, during which additional

  18. Distinct photoluminescence and Raman spectroscopy signatures for identifying highly crystalline WS2 monolayers produced by different growth methods

    DOE PAGES

    McCreary, Amber; Berkdemir, Ayse; Wang, Junjie; ...

    2016-03-08

    We report that transition metal dichalcogenides (TMDs) such as WS2 show exciting promise in electronic and optoelectronic applications. Significant variations in the transport, Raman, and photoluminescence (PL) can be found in the literature, yet it is rarely addressed why this is. In this report, Raman and PL of monolayered WS2 produced via different methods are studied and distinct features that indicate the degree of crystallinity of the material are observed. While the intensity of the LA(M) Raman mode is found to be a useful indicator to assess the crystallinity, PL is drastically more sensitive to the quality of the materialmore » than Raman spectroscopy. We also show that even exfoliated crystals, which are usually regarded as the most pristine material, can contain large amounts of defects that would not be apparent without Raman and PL measurements. Ultimately, these findings can be applied to the understanding of other two-dimensional heterostructured systems.« less

  19. Distinct photoluminescence and Raman spectroscopy signatures for identifying highly crystalline WS2 monolayers produced by different growth methods

    SciTech Connect

    McCreary, Amber; Berkdemir, Ayse; Wang, Junjie; Nguyen, Minh An; Elías, Ana Laura; Perea-López, Néstor; Fujisawa, Kazunori; Kabius, Bernd; Carozo, Victor; Cullen, David A.; Mallouk, Thomas E.; Zhu, J.; Terrones, Mauricio

    2016-03-08

    We report that transition metal dichalcogenides (TMDs) such as WS2 show exciting promise in electronic and optoelectronic applications. Significant variations in the transport, Raman, and photoluminescence (PL) can be found in the literature, yet it is rarely addressed why this is. In this report, Raman and PL of monolayered WS2 produced via different methods are studied and distinct features that indicate the degree of crystallinity of the material are observed. While the intensity of the LA(M) Raman mode is found to be a useful indicator to assess the crystallinity, PL is drastically more sensitive to the quality of the material than Raman spectroscopy. We also show that even exfoliated crystals, which are usually regarded as the most pristine material, can contain large amounts of defects that would not be apparent without Raman and PL measurements. Ultimately, these findings can be applied to the understanding of other two-dimensional heterostructured systems.

  20. Insulin-like growth factor I messenger RNA and protein are expressed in the human lymph node and distinctly confined to subtypes of macrophages, antigen-presenting cells, lymphocytes and endothelial cells.

    PubMed

    Oberlin, Dominique; Fellbaum, Christian; Eppler, Elisabeth

    2009-11-01

    Insulin-like growth factor I (IGF-I) is a potent hormone that stimulates growth and differentiation and inhibits apoptosis in numerous tissues. Preliminary evidence suggests that IGF-I exerts differentiating, mitogenic and restoring activities in the immune system but the sites of synthesis of local IGF-I are unknown. Identification of these sites would allow the functional role of local IGF-I to be clarified. The presence of IGF-I in non-immune cells suggests that it acts as a trophic factor, while its occurrence in subtypes of lymphocytes or antigen-presenting cells indicates paracrine/autocrine direct regulatory involvement of IGF-I in the human immune response. The present study investigated the location of IGF-I messenger RNA and protein on archival human lymph node samples by in situ hybridization, immunohistochemistry and double immunofluorescence staining using an IGF-I probe and antisera specific for human IGF-I and CD3 (T lymphocytes), CD20 (B lymphocytes), CD68 (macrophages), CD21 (follicular dendritic cells), S100 (interdigitating dendritic cells) and podoplanin (fibroblastic reticular cells). Numerous cells within the B- and T-cell compartments expressed the IGF-I gene, and the majority of these cells were identified as macrophages. Solitary follicular dendritic cells exhibited IGF-I. A few T lymphocytes, and no B lymphocytes, contained IGF-I immunoreactive material. Furthermore, IGF-I immunoreactive cells outside the follicles that did not react with CD3, CD20, S100 or podoplanin markers were identified as high-endothelial venule (HEV) cells. From this we conclude that the main task of IGF-I in human non-tumoral lymph node may be autocrine and paracrine regulation of the differentiation, stimulation and survival of lymphocytes, antigen-presenting cells and macrophages and the differentiation and maintenance of HEV cells.

  1. Recombination events and variability among full-length genomes of co-circulating molluscum contagiosum virus subtypes 1 and 2.

    PubMed

    López-Bueno, Alberto; Parras-Moltó, Marcos; López-Barrantes, Olivia; Belda, Sylvia; Alejo, Alí

    2017-05-01

    Molluscum contagiosum virus (MCV) is the sole member of the Molluscipoxvirus genus and causes a highly prevalent human disease of the skin characterized by the formation of a variable number of lesions that can persist for prolonged periods of time. Two major genotypes, subtype 1 and subtype 2, are recognized, although currently only a single complete genomic sequence corresponding to MCV subtype 1 is available. Using next-generation sequencing techniques, we report the complete genomic sequence of four new MCV isolates, including the first one derived from a subtype 2. Comparisons suggest a relatively distant evolutionary split between both MCV subtypes. Further, our data illustrate concurrent circulation of distinct viruses within a population and reveal the existence of recombination events among them. These results help identify a set of MCV genes with potentially relevant roles in molluscum contagiosum epidemiology and pathogenesis.

  2. DNA methylation signature (SAM40) identifies subgroups of the Luminal A breast cancer samples with distinct survival

    PubMed Central

    Aure, Miriam Ragle; Louhimo, Riku; Pladsen, Arne V.; Ottestad, Lars; Touleimat, Nizar; Laakso, Marko; Halvorsen, Ann Rita; Alnæs, Grethe I. Grenaker; Riis, Margit L.H.; Helland, Åslaug; Hautaniemi, Sampsa; Lønning, Per Eystein; Naume, Bjørn; Børresen-Dale, Anne-Lise; Tost, Jörg; Kristensen, Vessela N.

    2017-01-01

    Breast cancer patients with Luminal A disease generally have a good prognosis, but among this patient group are patients with good prognosis that are currently overtreated with adjuvant chemotherapy, and also patients that have a bad prognosis and should be given more aggressive treatment. There is no available method for subclassification of this patient group. Here we present a DNA methylation signature (SAM40) that segregates Luminal A patients based on prognosis, and identify one good prognosis group and one bad prognosis group. The prognostic impact of SAM40 was validated in four independent patient cohorts. Being able to subdivide the Luminal A patients may give the two-sided benefit of identifying one subgroup that may benefit from a more aggressive treatment than what is given today, and importantly, identifying a subgroup that may benefit from less treatment. PMID:27911866

  3. A Novel Approach to Identify Two Distinct Receptor Binding Surfaces of Insulin-like Growth Factor II*S⃞

    PubMed Central

    Alvino, Clair L.; McNeil, Kerrie A.; Ong, Shee Chee; Delaine, Carlie; Booker, Grant W.; Wallace, John C.; Whittaker, Jonathan; Forbes, Briony E.

    2009-01-01

    Very little is known about the residues important for the interaction of insulin-like growth factor II (IGF-II) with the type 1 IGF receptor (IGF-1R) and the insulin receptor (IR). Insulin, to which IGF-II is homologous, is proposed to cross-link opposite halves of the IR dimer through two receptor binding surfaces, site 1 and site 2. In the present study we have analyzed the contribution of IGF-II residues equivalent to insulin's two binding surfaces toward the interaction of IGF-II with the IGF-1R and IR. Four “site 1” and six “site 2” analogues were produced and analyzed in terms of IGF-1R and IR binding and activation. The results show that Val43, Phe28, and Val14 (equivalent to site 1) are critical to IGF-1R and IR binding, whereas mutation to alanine of Gln18 affects only IGF-1R and not IR binding. Alanine substitutions at Glu12, Asp15, Phe19, Leu53, and Glu57 analogues resulted in significant (>2-fold) decreases in affinity for both the IGF-1R and IR. Furthermore, taking a novel approach using a monomeric, single-chain minimized IGF-1R we have defined a distinct second binding surface formed by Glu12, Phe19, Leu53, and Glu57 that potentially engages the IGF-1R at one or more of the FnIII domains. PMID:19139090

  4. Thermally identified subgroups of marginal zone neurons project to distinct regions of the ventral posterior lateral nucleus in rats.

    PubMed

    Zhang, Xijing; Davidson, Steve; Giesler, Glenn J

    2006-05-10

    Spinal marginal zone (MZ) neurons play a crucial role in the transmission of nociceptive and thermoreceptive information to the brain. The precise areas to which physiologically characterized MZ neurons project in the ventral posterior lateral (VPL) nucleus of the thalamus have not been clearly established. Here, we examine this projection in rats using the method of antidromic activation to map the axon terminals of neurons recorded from the MZ. Thirty-three neurons were antidromically activated using pulses of < or =30 microA in the contralateral VPL. In every case, the most rostral point from which the MZ neuron could be antidromically activated was surrounded by stimulating tracks in which large-amplitude current pulses failed to activate the examined neuron, indicating the termination of the spinothalamic tract (STT) axon. Each of 30 examined neurons responded to noxious but not innocuous mechanical stimuli applied to their cutaneous receptive fields, which ranged in size from two digits to the entire limb. Of 17 thermally tested neurons, 16 responded to innocuous or noxious thermal stimuli. Among STT neurons that responded to thermal stimuli, 50% responded to innocuous cooling as well as noxious heat and cold, 31% responded to noxious heat and cold, and 19% responded only to noxious heat. Axons from cells responsive to innocuous cooling terminated in the core region of VPL, significantly dorsal and medial relative to other thermally responsive subgroups. In rats, thermally responsive subgroups of MZ neurons project directly to distinct regions of VPL.

  5. Resolution of Novel Pancreatic Ductal Adenocarcinoma Subtypes by Global Phosphotyrosine Profiling*

    PubMed Central

    Humphrey, Emily S.; Su, Shih-Ping; Nagrial, Adnan M.; Hochgräfe, Falko; Pajic, Marina; Lehrbach, Gillian M.; Parton, Robert G.; Yap, Alpha S.; Horvath, Lisa G.; Chang, David K.; Biankin, Andrew V.; Wu, Jianmin; Daly, Roger J.

    2016-01-01

    Comprehensive characterization of signaling in pancreatic ductal adenocarcinoma (PDAC) promises to enhance our understanding of the molecular aberrations driving this devastating disease, and may identify novel therapeutic targets as well as biomarkers that enable stratification of patients for optimal therapy. Here, we use immunoaffinity-coupled high-resolution mass spectrometry to characterize global tyrosine phosphorylation patterns across two large panels of human PDAC cell lines: the ATCC series (19 cell lines) and TKCC series (17 cell lines). This resulted in the identification and quantification of over 1800 class 1 tyrosine phosphorylation sites and the consistent segregation of both PDAC cell line series into three subtypes with distinct tyrosine phosphorylation profiles. Subtype-selective signaling networks were characterized by identification of subtype-enriched phosphosites together with pathway and network analyses. This revealed that the three subtypes characteristic of the ATCC series were associated with perturbations in signaling networks associated with cell-cell adhesion and epithelial-mesenchyme transition, mRNA metabolism, and receptor tyrosine kinase (RTK) signaling, respectively. Specifically, the third subtype exhibited enhanced tyrosine phosphorylation of multiple RTKs including the EGFR, ERBB3 and MET. Interestingly, a similar RTK-enriched subtype was identified in the TKCC series, and 'classifier' sites for each series identified using Random Forest models were able to predict the subtypes of the alternate series with high accuracy, highlighting the conservation of the three subtypes across the two series. Finally, RTK-enriched cell lines from both series exhibited enhanced sensitivity to the small molecule EGFR inhibitor erlotinib, indicating that their phosphosignature may provide a predictive biomarker for response to this targeted therapy. These studies highlight how resolution of subtype-selective signaling networks can provide a

  6. Porcine Skin-Derived Progenitor (SKP) Spheres and Neurospheres: Distinct “Stemness” Identified by Microarray Analysis

    PubMed Central

    Zhao, Ming-Tao; Whitworth, Kristin M.; Lin, Hui; Zhang, Xia; Isom, S. Clay; Dobbs, Kyle B.; Bauer, Bethany; Zhang, Yong

    2010-01-01

    Abstract Skin-derived progenitors (SKP) are neural crest derived and can generate neural and mesodermal progeny in vitro, corresponding to the multipotency of neural crest stem cells. Likewise, neural stem/progenitor cells (displaying as neurospheres) have the capacity of self-renewing, and can produce most phenotypes in the nervous system. Both form spheres when cultured with epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Although the “stemness” of neural stem/progenitor cells has been extensively investigated, the molecular comparison of SKP spheres and neurospheres has not been elucidated. Here, SKP spheres and neurospheres from the same individual porcine fetuses were isolated with the same culture medium, and the multipotency was tested by in vitro differentiation assays. Microarray analysis was used to illustrate the “stemness” of SKP spheres and neurospheres. The upregulated genes that were in common in the SKP spheres and neurospheres are involved in ribosome, tight junction, gap junction, cell communication, calcium signaling, ErbB signaling, JAK–STAT signaling, MAPK signaling, etc. The differentially expressed genes between SKP spheres and neurospheres are mainly involved in ECM–receptor interaction and the transforming growth factor-beta (TGF-β) signaling pathway. Finally, treatment with leukemia inhibitory factor (LIF) or MEK inhibitor results in a distinctive impact on the “stemness” and differentiation genes of SKP spheres and neurospheres. Thus, the cell-intrinsic genetic program may contribute to the innate “stemness” of SKP spheres and neurospheres in a similar local microenvironment. PMID:20694160

  7. In vivo electrophysiological recordings in amygdala subnuclei reveal selective and distinct responses to a behaviorally identified predator odor.

    PubMed

    Govic, Antonina; Paolini, Antonio G

    2015-03-01

    Chemosensory cues signaling predators reliably stimulate innate defensive responses in rodents. Despite the well-documented role of the amygdala in predator odor-induced fear, evidence for the relative contribution of the specific nuclei that comprise this structurally heterogeneous structure is conflicting. In an effort to clarify this we examined neural activity, via electrophysiological recordings, in amygdala subnuclei to controlled and repeated presentations of a predator odor: cat urine. Defensive behaviors, characterized by avoidance, decreased exploration, and increased risk assessment, were observed in adult male hooded Wistar rats (n = 11) exposed to a cloth impregnated with cat urine. Electrophysiological recordings of the amygdala (777 multiunit clusters) were subsequently obtained in freely breathing anesthetized rats exposed to cat urine, distilled water, and eugenol via an air-dilution olfactometer. Recorded units selectively responded to cat urine, and frequencies of responses were distributed differently across amygdala nuclei; medial amygdala (MeA) demonstrated the greatest frequency of responses to cat urine (51.7%), followed by the basolateral and basomedial nuclei (18.8%) and finally the central amygdala (3.0%). Temporally, information transduction occurred primarily from the cortical amygdala and MeA (ventral divisions) to other amygdala nuclei. Interestingly, MeA subnuclei exhibited distinct firing patterns to predator urine, potentially revealing aspects of the underlying neurocircuitry of predator odor processing and defensiveness. These findings highlight the critical involvement of the MeA in processing olfactory cues signaling predator threat and converge with previous studies to indicate that amygdala regulation of predator odor-induced fear is restricted to a particular set of subnuclei that primarily include the MeA, particularly the ventral divisions. Copyright © 2015 the American Physiological Society.

  8. Molecular Diagnostic and Prognostic Subtyping of Gliomas in Tunisian Population.

    PubMed

    Trabelsi, Saoussen; Chabchoub, Imen; Ksira, Iadh; Karmeni, Nadhir; Mama, Nadia; Kanoun, Samia; Burford, Anna; Jury, Alexa; Mackay, Alan; Popov, Sergey; Bouaouina, Noureddine; Ben Ahmed, Slim; Mokni, Moncef; Tlili, Kalthoum; Krifa, Hedi; Yacoubi, Mohamed Tahar; Jones, Chris; Saad, Ali; H'mida Ben Brahim, Dorra

    2017-05-01

    It has become increasingly evident that morphologically similar gliomas may have distinct clinical phenotypes arising from diverse genetic signatures. To date, glial tumours from the Tunisian population have not been investigated. To address this, we correlated the clinico-pathology with molecular data of 110 gliomas by a combination of HM450K array, MLPA and TMA-IHC. PTEN loss and EGFR amplification were distributed in different glioma histological groups. However, 1p19q co-deletion and KIAA1549:BRAF fusion were, respectively, restricted to Oligodendroglioma and Pilocytic Astrocytoma. CDKN2A loss and EGFR overexpression were more common within high-grade gliomas. Furthermore, survival statistical correlations led us to identify Glioblastoma (GB) prognosis subtypes. In fact, significant lower overall survival (OS) was detected within GB that overexpressed EGFR and Cox2. In addition, IDH1R132H mutation seemed to provide a markedly survival advantage. Interestingly, the association of IDHR132H mutation and EGFR normal status, as well as the association of differentiation markers, defined GB subtypes with good prognosis. By contrast, poor survival GB subtypes were defined by the combination of PTEN loss with PDGFRa expression and/or EGFR amplification. Additionally, GB presenting p53-negative staining associated with CDKN2A loss or p21 positivity represented a subtype with short survival. Thus, distinct molecular subtypes with individualised prognosis were identified. Interestingly, we found a unique histone mutation in a poor survival young adult GB case. This tumour exceptionally associated the H3F3A G34R mutation and MYCN amplification as well as 1p36 loss and 10q loss. Furthermore, by exhibiting a remarkable methylation profile, it emphasised the oncogenic power of G34R mutation connecting gliomagenesis and chromatin regulation.

  9. Two distinct extracellular RNA signatures released by a single cell type identified by microarray and next-generation sequencing

    PubMed Central

    Lässer, Cecilia; Shelke, Ganesh Vilas; Yeri, Ashish; Kim, Dae-Kyum; Crescitelli, Rossella; Raimondo, Stefania; Sjöstrand, Margareta; Gho, Yong Song; Van Keuren Jensen, Kendall; Lötvall, Jan

    2017-01-01

    ABSTRACT Cells secrete extracellular RNA (exRNA) to their surrounding environment and exRNA has been found in many body fluids such as blood, breast milk and cerebrospinal fluid. However, there are conflicting results regarding the nature of exRNA. Here, we have separated 2 distinct exRNA profiles released by mast cells, here termed high-density (HD) and low-density (LD) exRNA. The exRNA in both fractions was characterized by microarray and next-generation sequencing. Both exRNA fractions contained mRNA and miRNA, and the mRNAs in the LD exRNA correlated closely with the cellular mRNA, whereas the HD mRNA did not. Furthermore, the HD exRNA was enriched in lincRNA, antisense RNA, vault RNA, snoRNA, and snRNA with little or no evidence of full-length 18S and 28S rRNA. The LD exRNA was enriched in mitochondrial rRNA, mitochondrial tRNA, tRNA, piRNA, Y RNA, and full-length 18S and 28S rRNA. The proteomes of the HD and LD exRNA-containing fractions were determined with LC-MS/MS and analyzed with Gene Ontology term finder, which showed that both proteomes were associated with the term extracellular vesicles and electron microscopy suggests that at least a part of the exRNA is associated with exosome-like extracellular vesicles. Additionally, the proteins in the HD fractions tended to be associated with the nucleus and ribosomes, whereas the LD fraction proteome tended to be associated with the mitochondrion. We show that the 2 exRNA signatures released by a single cell type can be separated by floatation on a density gradient. These results show that cells can release multiple types of exRNA with substantial differences in RNA species content. This is important for any future studies determining the nature and function of exRNA released from different cells under different conditions. PMID:27791479

  10. Distinct deregulation of the hypoxia inducible factor by PHD2 mutants identified in germline DNA of patients with polycythemia

    PubMed Central

    Ladroue, Charline; Hoogewijs, David; Gad, Sophie; Carcenac, Romain; Storti, Federica; Barrois, Michel; Gimenez-Roqueplo, Anne-Paule; Leporrier, Michel; Casadevall, Nicole; Hermine, Olivier; Kiladjian, Jean-Jacques; Baruchel, André; Fakhoury, Fadi; Bressac-de Paillerets, Brigitte; Feunteun, Jean; Mazure, Nathalie; Pouysségur, Jacques; Wenger, Roland H.; Richard, Stéphane; Gardie, Betty

    2012-01-01

    Background Congenital secondary erythrocytoses are due to deregulation of hypoxia inducible factor resulting in overproduction of erythropoietin. The most common germline mutation identified in the hypoxia signaling pathway is the Arginine 200-Tryptophan mutant of the von Hippel-Lindau tumor suppressor gene, resulting in Chuvash polycythemia. This mutant displays a weak deficiency in hypoxia inducible factor α regulation and does not promote tumorigenesis. Other von Hippel-Lindau mutants with more deleterious effects are responsible for von Hippel-Lindau disease, which is characterized by the development of multiple tumors. Recently, a few mutations in gene for the prolyl hydroxylase domain 2 protein (PHD2) have been reported in cases of congenital erythrocytosis not associated with tumor formation with the exception of one patient with a recurrent extra-adrenal paraganglioma. Design and Methods Five PHD2 variants, four of which were novel, were identified in patients with erythrocytosis. These PHD2 variants were functionally analyzed and compared with the PHD2 mutant previously identified in a patient with polycythemia and paraganglioma. The capacity of PHD2 to regulate the activity, stability and hydroxylation of hypoxia inducible factor α was assessed using hypoxia-inducible reporter gene, one-hybrid and in vitro hydroxylation assays, respectively. Results This functional comparative study showed that two categories of PHD2 mutants could be distinguished: one category with a weak deficiency in hypoxia inducible factor α regulation and a second one with a deleterious effect; the mutant implicated in tumor occurrence belongs to the second category. Conclusions As observed with germline von Hippel-Lindau mutations, there are functional differences between the PHD2 mutants with regards to hypoxia inducible factor regulation. PHD2 mutation carriers do, therefore, need careful medical follow-up, since some mutations must be considered as potential candidates for

  11. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology.

  12. HIV-1 LTR subtype and perinatal transmission.

    PubMed

    Blackard, J T; Renjifo, B; Fawzi, W; Hertzmark, E; Msamanga, G; Mwakagile, D; Hunter, D; Spiegelman, D; Sharghi, N; Kagoma, C; Essex, M

    2001-09-01

    Multiple subtypes of HIV-1 have been identified; however, there is little data on the relative transmissibility of viruses belonging to different subtypes. A matched case-control study addressed whether viruses with different long terminal repeat (LTR) subtypes were transmitted equally from mother to infant. The LTR subtype was determined for 45 matched cases and controls who participated in a clinical trial in Tanzania. HIV-1 subtypes A, C, and D and intersubtype recombinant sequences were identified. Exact matched logistic regression analysis showed that viruses containing subtype A or intersubtype recombinant LTRs were 3.2 and 4.8 times more likely to be transmitted from mother to infant than viruses with subtype D LTRs. Viruses containing subtype C LTRs were 6.1 times more likely to be transmitted than those with subtype D LTRs. These differences in transmission were independent of maternal CD4 at enrollment. Thus, it appears that HIV-1 subtype may be associated with differing rates of perinatal transmission in Tanzania. Copyright 2001 Academic Press.

  13. Validity of DSM-IV attention–deficit/hyperactivity disorder symptom dimensions and subtypes

    PubMed Central

    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

  14. Validity of DSM-IV attention deficit/hyperactivity disorder symptom dimensions and subtypes.

    PubMed

    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

    2012-11-01

    Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for attention deficit/hyperactivity disorder (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 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, we conclude 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

  15. Exome Sequencing of Cell-Free DNA from Metastatic Cancer Patients Identifies Clinically Actionable Mutations Distinct from Primary Disease

    PubMed Central

    Butler, Timothy M.; Johnson-Camacho, Katherine; Peto, Myron; Wang, Nicholas J.; Macey, Tara A.; Korkola, James E.; Koppie, Theresa M.; Corless, Christopher L.; Gray, Joe W.; Spellman, Paul T.

    2015-01-01

    The identification of the molecular drivers of cancer by sequencing is the backbone of precision medicine and the basis of personalized therapy; however, biopsies of primary tumors provide only a snapshot of the evolution of the disease and may miss potential therapeutic targets, especially in the metastatic setting. A liquid biopsy, in the form of cell-free DNA (cfDNA) sequencing, has the potential to capture the inter- and intra-tumoral heterogeneity present in metastatic disease, and, through serial blood draws, track the evolution of the tumor genome. In order to determine the clinical utility of cfDNA sequencing we performed whole-exome sequencing on cfDNA and tumor DNA from two patients with metastatic disease; only minor modifications to our sequencing and analysis pipelines were required for sequencing and mutation calling of cfDNA. The first patient had metastatic sarcoma and 47 of 48 mutations present in the primary tumor were also found in the cell-free DNA. The second patient had metastatic breast cancer and sequencing identified an ESR1 mutation in the cfDNA and metastatic site, but not in the primary tumor. This likely explains tumor progression on Anastrozole. Significant heterogeneity between the primary and metastatic tumors, with cfDNA reflecting the metastases, suggested separation from the primary lesion early in tumor evolution. This is best illustrated by an activating PIK3CA mutation (H1047R) which was clonal in the primary tumor, but completely absent from either the metastasis or cfDNA. Here we show that cfDNA sequencing supplies clinically actionable information with minimal risks compared to metastatic biopsies. This study demonstrates the utility of whole-exome sequencing of cell-free DNA from patients with metastatic disease. cfDNA sequencing identified an ESR1 mutation, potentially explaining a patient’s resistance to aromatase inhibition, and gave insight into how metastatic lesions differ from the primary tumor. PMID:26317216

  16. Iterative Focused Screening with Biological Fingerprints Identifies Selective Asc-1 Inhibitors Distinct from Traditional High Throughput Screening.

    PubMed

    Kutchukian, Peter S; Warren, Lee; Magliaro, Brian C; Amoss, Adam; Cassaday, Jason A; O'Donnell, Gregory; Squadroni, Brian; Zuck, Paul; Pascarella, Danette; Culberson, J Chris; Cooke, Andrew J; Hurzy, Danielle; Schlegel, Kelly-Ann Sondra; Thomson, Fiona; Johnson, Eric N; Uebele, Victor N; Hermes, Jeffrey D; Parmentier-Batteur, Sophie; Finley, Michael

    2017-02-17

    N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer's disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine-serine-cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs. To identify novel Asc-1 inhibitors, two different screening approaches were performed with whole-cell amino acid uptake in heterologous cells stably expressing human Asc-1: (1) a high-throughput screen (HTS) of 3 M compounds measuring (35)S l-cysteine uptake into cells attached to scintillation proximity assay beads in a 1536 well format and (2) an iterative focused screen (IFS) of a 45 000 compound diversity set using a (3)H d-serine uptake assay with a liquid scintillation plate reader in a 384 well format. Critically important for both screening approaches was the implementation of counter screens to remove nonspecific inhibitors of radioactive amino acid uptake. Furthermore, a 15 000 compound expansion step incorporating both on- and off-target data into chemical and biological fingerprint-based models for selection of additional hits enabled the identification of novel Asc-1-selective chemical matter from the IFS that was not identified in the full-collection HTS.

  17. TRAF3/CYLD mutations identify a distinct subset of human papillomavirus‐associated head and neck squamous cell carcinoma

    PubMed Central

    Hajek, Michael; Sewell, Andrew; Kaech, Susan; Burtness, Barbara

    2017-01-01

    BACKGROUND The incidence of human papillomavirus (HPV)‐associated (HPV‐positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise. Newly diagnosed HPV‐positive HNSCCs in the United States currently outnumber any other HPV‐associated cancers, including cervical cancer. Despite introduction of the HPV vaccine, the epidemic of HPV‐positive HNSCC is expected to continue for approximately 60 years. Compared with patients who have tobacco‐associated HNSCC, those who have HPV‐positive HNSCC have better overall survival and response to treatment. Current treatment, including chemotherapy and radiation therapy, is associated with lifelong morbidity, and there are limited treatments and no curative options for patients who develop recurrent metastatic disease. Therapeutic de‐escalation (decreased radiation dose) is being tested through clinical trials; however, those studies select patients based solely on tumor and patient smoking characteristics. Mechanisms of HPV‐driven carcinogenesis in HNSCC are not well understood, which limits new therapeutic strategies and hinders the appropriate selection of patients for de‐escalation therapy. METHODS The authors analyzed HNSCC data from The Cancer Genome Atlas to identify molecular characteristics that correlate with outcomes and integration status of the HPV genome. RESULTS The current investigations identified a subset of HPV‐positive HNSCCs with mutations in the genes TRAF3 (tumor necrosis factor receptor‐associated factor 3) and CYLD (cylindromatosis lysine 63 deubiquitinase). Defects in TRAF3 and CYLD correlated with the activation of transcriptional factor nuclear factor κB, episomal HPV status of tumors, and improved patient survival. CONCLUSIONS Defects in TRAF3/CYLD were accompanied with the activation of nuclear factor κB signaling and maintenance of episomal HPV in tumors, suggesting that these mutations may

  18. An EST-based analysis identifies new genes and reveals distinctive gene expression features of Coffea arabica and Coffea canephora.

    PubMed

    Mondego, Jorge Mc; Vidal, Ramon O; Carazzolle, Marcelo F; Tokuda, Eric K; Parizzi, Lucas P; Costa, Gustavo Gl; Pereira, Luiz Fp; Andrade, Alan C; Colombo, Carlos A; Vieira, Luiz Ge; Pereira, Gonçalo Ag

    2011-02-08

    Coffee is one of the world's most important crops; it is consumed worldwide and plays a significant role in the economy of producing countries. Coffea arabica and C. canephora are responsible for 70 and 30% of commercial production, respectively. C. arabica is an allotetraploid from a recent hybridization of the diploid species, C. canephora and C. eugenioides. C. arabica has lower genetic diversity and results in a higher quality beverage than C. canephora. Research initiatives have been launched to produce genomic and transcriptomic data about Coffea spp. as a strategy to improve breeding efficiency. Assembling the expressed sequence tags (ESTs) of C. arabica and C. canephora produced by the Brazilian Coffee Genome Project and the Nestlé-Cornell Consortium revealed 32,007 clusters of C. arabica and 16,665 clusters of C. canephora. We detected different GC3 profiles between these species that are related to their genome structure and mating system. BLAST analysis revealed similarities between coffee and grape (Vitis vinifera) genes. Using KA/KS analysis, we identified coffee genes under purifying and positive selection. Protein domain and gene ontology analyses suggested differences between Coffea spp. data, mainly in relation to complex sugar synthases and nucleotide binding proteins. OrthoMCL was used to identify specific and prevalent coffee protein families when compared to five other plant species. Among the interesting families annotated are new cystatins, glycine-rich proteins and RALF-like peptides. Hierarchical clustering was used to independently group C. arabica and C. canephora expression clusters according to expression data extracted from EST libraries, resulting in the identification of differentially expressed genes. Based on these results, we emphasize gene annotation and discuss plant defenses, abiotic stress and cup quality-related functional categories. We present the first comprehensive genome-wide transcript profile study of C. arabica and C

  19. An EST-based analysis identifies new genes and reveals distinctive gene expression features of Coffea arabica and Coffea canephora

    PubMed Central

    2011-01-01

    Background Coffee is one of the world's most important crops; it is consumed worldwide and plays a significant role in the economy of producing countries. Coffea arabica and C. canephora are responsible for 70 and 30% of commercial production, respectively. C. arabica is an allotetraploid from a recent hybridization of the diploid species, C. canephora and C. eugenioides. C. arabica has lower genetic diversity and results in a higher quality beverage than C. canephora. Research initiatives have been launched to produce genomic and transcriptomic data about Coffea spp. as a strategy to improve breeding efficiency. Results Assembling the expressed sequence tags (ESTs) of C. arabica and C. canephora produced by the Brazilian Coffee Genome Project and the Nestlé-Cornell Consortium revealed 32,007 clusters of C. arabica and 16,665 clusters of C. canephora. We detected different GC3 profiles between these species that are related to their genome structure and mating system. BLAST analysis revealed similarities between coffee and grape (Vitis vinifera) genes. Using KA/KS analysis, we identified coffee genes under purifying and positive selection. Protein domain and gene ontology analyses suggested differences between Coffea spp. data, mainly in relation to complex sugar synthases and nucleotide binding proteins. OrthoMCL was used to identify specific and prevalent coffee protein families when compared to five other plant species. Among the interesting families annotated are new cystatins, glycine-rich proteins and RALF-like peptides. Hierarchical clustering was used to independently group C. arabica and C. canephora expression clusters according to expression data extracted from EST libraries, resulting in the identification of differentially expressed genes. Based on these results, we emphasize gene annotation and discuss plant defenses, abiotic stress and cup quality-related functional categories. Conclusion We present the first comprehensive genome-wide transcript

  20. TRAF3/CYLD mutations identify a distinct subset of human papillomavirus-associated head and neck squamous cell carcinoma.

    PubMed

    Hajek, Michael; Sewell, Andrew; Kaech, Susan; Burtness, Barbara; Yarbrough, Wendell G; Issaeva, Natalia

    2017-05-15

    The incidence of human papillomavirus (HPV)-associated (HPV-positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise. Newly diagnosed HPV-positive HNSCCs in the United States currently outnumber any other HPV-associated cancers, including cervical cancer. Despite introduction of the HPV vaccine, the epidemic of HPV-positive HNSCC is expected to continue for approximately 60 years. Compared with patients who have tobacco-associated HNSCC, those who have HPV-positive HNSCC have better overall survival and response to treatment. Current treatment, including chemotherapy and radiation therapy, is associated with lifelong morbidity, and there are limited treatments and no curative options for patients who develop recurrent metastatic disease. Therapeutic de-escalation (decreased radiation dose) is being tested through clinical trials; however, those studies select patients based solely on tumor and patient smoking characteristics. Mechanisms of HPV-driven carcinogenesis in HNSCC are not well understood, which limits new therapeutic strategies and hinders the appropriate selection of patients for de-escalation therapy. The authors analyzed HNSCC data from The Cancer Genome Atlas to identify molecular characteristics that correlate with outcomes and integration status of the HPV genome. The current investigations identified a subset of HPV-positive HNSCCs with mutations in the genes TRAF3 (tumor necrosis factor receptor-associated factor 3) and CYLD (cylindromatosis lysine 63 deubiquitinase). Defects in TRAF3 and CYLD correlated with the activation of transcriptional factor nuclear factor κB, episomal HPV status of tumors, and improved patient survival. Defects in TRAF3/CYLD were accompanied with the activation of nuclear factor κB signaling and maintenance of episomal HPV in tumors, suggesting that these mutations may support an alternative mechanism of HPV tumorigenesis in head and

  1. A global proteomic study identifies distinct pathological features of IgG4-related and primary sclerosing cholangitis.

    PubMed

    Zen, Yoh; Britton, David; Mitra, Vikram; Pike, Ian; Heaton, Nigel; Quaglia, Alberto

    2016-05-01

    This combined proteomic and histopathological study was aimed to compare tissue characteristics of immunoglobulin (Ig)G4-related sclerosing cholangitis (ISC) and primary sclerosing cholangitis (PSC) in a global, non-biased manner. Tissue proteomes and phosphorylomes of frozen large bile duct samples were analysed by a conventional liquid chromatography-tandem mass spectrometry (LC-MS/MS) protocol and additional phosphopeptide enrichment methods. The proteomic examination identified 23 373 peptides and 4870 proteins, including 4801 phosphopeptides and 1121 phosphoproteins. The expression profiles of phosphopeptides discriminated ISC from PSC more clearly than those of non-phosphopeptides. In the pathway analysis, ISC was found to have 11 more activated signal cascades, including three immunological pathways, all B cell- or immunoglobulin-related. On immunostaining, two immunological markers (FYN-binding protein and allograft inflammatory factor-1) up-regulated in ISC were expressed mainly in M2 macrophages, consistent with increased phagocytotic activity induced by the immunoglobulin (Ig)G-Fcγ receptor interaction. In contrast, PSC had two more activated signal pathways related to extracellular matrix (ECM) remodelling. Filamin-A involved in ECM remodelling was expressed aberrantly in injured bile ducts and associated cholangiocarcinomas in PSC, suggesting its possible roles in periductal fibrosis and carcinogenesis in PSC. This study suggested crucial roles of B cells and macrophages in ISC, and more dynamic ECM remodelling in PSC. © 2015 John Wiley & Sons Ltd.

  2. Phenologically distinct phytoplankton regions on the Faroe Shelf - identified by satellite data, in-situ observations and model

    NASA Astrophysics Data System (ADS)

    Eliasen, Sólvá Káradóttir; Hátún, Hjálmar; Larsen, Karin Margretha H.; Hansen, Bogi; Rasmussen, Till Andreas S.

    2017-05-01

    Marked inter-annual fluctuations in the primary production on the Faroe shelf propagate to higher trophic levels and influence commercial fish stocks. This has previously been demonstrated based on weekly chlorophyll samples from a coastal station, dating back to 1997. However, the spatial extent, for which the coastal samples are representative, has not been well defined, and potential bio-geographical segregations of the shelf have not been considered. By integrating 18 years of chlorophyll satellite data, supplemented by in-situ, model, and meteorological reanalysis data, we identify three regions with unique characteristics with regards to surface chlorophyll and vertical structure - the Central Shelf, the Outer Shelf and the Eastern Banks. The observed difference in timing of the spring bloom in these regions helps explain different spawning patterns of important fish stocks, and the spatial division of the Faroe Shelf should be considered when studying biology and hydrography in these waters. A positive correlation between annual means on the outer Faroe Shelf and parts of the outer northwest Scottish Shelf indicates similarities between these neighbouring regions. We suggest that this similarity arises from the commonality in nutrient composition of the water masses shared by these neighbouring regions.

  3. Epidemiology of constipation (EPOC) study in the United States: relation of clinical subtypes to sociodemographic features.

    PubMed

    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

    Constipation is a common heterogeneous condition, possibly encompassing different clinical subtypes. Little is known about the comparative epidemiology of constipation subtypes. This study was conducted to estimate the prevalence of constipation subtypes and determine whether subtypes differ by sociodemographic factors. Between June and September 1997, a telephone interview was conducted with individuals about their bowel habits in the preceding 3 months. Survey data on 15 constipation-related symptoms were used to identify individuals who met prespecified symptom criteria for the following mutually exclusive subgroups: functional constipation, irritable bowel syndrome (IBS), outlet obstruction or delay (outlet), both IBS and outlet (IBS-outlet), and frequent laxative users (i.e., at least every other day). A total of 10,018 eligible individuals in the United States 18 yr of age or older completed the interview. Test-retest reliability of reporting symptoms was assessed in a separate national survey. The Spearman's correlation coefficient for reporting symptoms ranged from 0.54 to 0.83; all but three symptoms had correlations above 0.68. The overall prevalence of constipation was 14.7%. By subtype, prevalence was 4.6% for functional, 2.1% for IBS, 4.6% for outlet, and 3.4% for IBS-outlet. An additional 1.8% of respondents reported laxative use at least every other day. Outlet was the most common subtype among women, whereas functional constipation was the most common subtype among men. The gender ratio varied by subtype, with elevated ratios for outlet (F/M = 1.65) and IBS-outlet (F/M = 2.27) subtypes. The age pattern differed among each of the four subtypes. Prevalence of functional subtype decreased with increasing age. In contrast, outlet subtype did not seem to vary by age, and IBS (both men and women) and IBS-outlet (women only) subtypes increased to age 35 yr and declined thereafter. Prevalence of functional constipation increased with increasing education

  4. Comparative Gene Expression Analyses Identify Luminal and Basal Subtypes of Canine Invasive Urothelial Carcinoma That Mimic Patterns in Human Invasive Bladder Cancer.

    PubMed

    Dhawan, Deepika; Paoloni, Melissa; Shukradas, Shweta; Choudhury, Dipanwita Roy; Craig, Bruce A; Ramos-Vara, José A; Hahn, Noah; Bonney, Patty L; Khanna, Chand; Knapp, Deborah W

    2015-01-01

    More than 160,000 people are expected to die from invasive urothelial carcinoma (iUC) this year worldwide. Research in relevant animal models is essential to improving iUC management. Naturally-occurring canine iUC closely resembles human iUC in histopathology, metastatic behavior, and treatment response, and could provide a relevant model for human iUC. The molecular characterization of canine iUC, however, has been limited. Work was conducted to compare gene expression array results between tissue samples from iUC and normal bladder in dogs, with comparison to similar expression array data from human iUC and normal bladder in the literature. Considerable similarities between enrichment patterns of genes in canine and human iUC were observed. These included patterns mirroring basal and luminal subtypes initially observed in human breast cancer and more recently noted in human iUC. Canine iUC samples also exhibited enrichment for genes involved in P53 pathways, as has been reported in human iUC. This is particularly relevant as drugs targeting these genes/pathways in other cancers could be repurposed to treat iUC, with dogs providing a model to optimize therapy. As part of the validation of the results and proof of principal for evaluating individualized targeted therapy, the overexpression of EGFR in canine bladder iUC was confirmed. The similarities in gene expression patterns between dogs and humans add considerably to the value of naturally-occurring canine iUC as a relevant and much needed animal model for human iUC. Furthermore, the finding of expression patterns that cross different pathologically-defined cancers could allow studies of dogs with iUC to help optimize cancer management across multiple cancer types. The work is also expected to lead to a better understanding of the biological importance of the gene expression patterns, and the potential application of the cross-species comparisons approach to other cancer types as well.

  5. Quantitative morphometry of electrophysiologically identified CA3b interneurons reveals robust local geometry and distinct cell classes.

    PubMed

    Ascoli, Giorgio A; Brown, Kerry M; Calixto, Eduardo; Card, J Patrick; Galván, E J; Perez-Rosello, T; Barrionuevo, Germán

    2009-08-20

    The morphological and electrophysiological diversity of inhibitory cells in hippocampal area CA3 may underlie specific computational roles and is not yet fully elucidated. In particular, interneurons with somata in strata radiatum (R) and lacunosum-moleculare (L-M) receive converging stimulation from the dentate gyrus and entorhinal cortex as well as within CA3. Although these cells express different forms of synaptic plasticity, their axonal trees and connectivity are still largely unknown. We investigated the branching and spatial patterns, plus the membrane and synaptic properties, of rat CA3b R and L-M interneurons digitally reconstructed after intracellular labeling. We found considerable variability within but no difference between the two layers, and no correlation between morphological and biophysical properties. Nevertheless, two cell types were identified based on the number of dendritic bifurcations, with significantly different anatomical and electrophysiological features. Axons generally branched an order of magnitude more than dendrites. However, interneurons on both sides of the R/L-M boundary revealed surprisingly modular axodendritic arborizations with consistently uniform local branch geometry. Both axons and dendrites followed a lamellar organization, and axons displayed a spatial preference toward the fissure. Moreover, only a small fraction of the axonal arbor extended to the outer portion of the invaded volume, and tended to return toward the proximal region. In contrast, dendritic trees demonstrated more limited but isotropic volume occupancy. These results suggest a role of predominantly local feedforward and lateral inhibitory control for both R and L-M interneurons. Such a role may be essential to balance the extensive recurrent excitation of area CA3 underlying hippocampal autoassociative memory function.

  6. Identifying distinct phytoplankton regions based on ocean colour data supplemented by in-situ and model data

    NASA Astrophysics Data System (ADS)

    Eliasen, Solva; Hátún, Hjálmar; Margretha Larsen, Karin; Hansen, Bogi

    2016-04-01

    The Faroe Shelf hosts a rich and diverse marine ecosystem, which sustains a large portion of the economy of the Islands. The primary production, even though often referred to as being important to the higher trophic levels, is still not thoroughly understood. A high resolution chlorophyll time series from coastal station S, dating back to 1997, has given valuable information about the phytoplankton concentrations on the central shelf, and interannual fluctuations (with a factor of 4-5) in this time series have been linked to several other biological indicators. However, with regards to phytoplankton and primary production farther off-shore, only CTD fluorescence observations from research cruises are available and a thorough analysis of these temporally and spatially scattered data is difficult to conduct and yet to be done. Thus, the spatial extent of the region, for which the station S phytoplankton concentrations are representative, is not well defined. In this study we compare satellite ocean colour data from 1998-2015 with in-situ data from station S and identify the region which station S represents. Moreover, we use the ocean colour data to identity biogeographical regions in which phytoplankton is uniquely and coherently varying and compare these with the breeding and feeding grounds of commercially important fish stocks. The surface chlorophyll pattern does not necessarily represent the primary production in the water column. We therefore supplement the results with hydrographic observations and model simulations and from these extract information about the total carbon production in the various regions. The ocean colour data are consistent with the in-situ observations and the results from combining these with the other data types have enhanced our understanding of timing and strength of the phytoplankton spring bloom farther off-shore and contribute to the understanding of the shelf ecosystem in general.

  7. Oppositional defiant disorder dimensions and subtypes among detained male adolescent offenders.

    PubMed

    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

  8. Differential expression of vesicular glutamate transporters 1 and 2 may identify distinct modes of glutamatergic transmission in the macaque visual system.

    PubMed

    Balaram, Pooja; Hackett, Troy A; Kaas, Jon H

    2013-05-01

    Glutamate is the primary neurotransmitter utilized by the mammalian visual system for excitatory neurotransmission. The sequestration of glutamate into synaptic vesicles, and the subsequent transport of filled vesicles to the presynaptic terminal membrane, is regulated by a family of proteins known as vesicular glutamate transporters (VGLUTs). Two VGLUT proteins, VGLUT1 and VGLUT2, characterize distinct sets of glutamatergic projections between visual structures in rodents and prosimian primates, yet little is known about their distributions in the visual system of anthropoid primates. We have examined the mRNA and protein expression patterns of VGLUT1 and VGLUT2 in the visual system of macaque monkeys, an Old World anthropoid primate, in order to determine their relative distributions in the superior colliculus, lateral geniculate nucleus, pulvinar complex, V1 and V2. Distinct expression patterns for both VGLUT1 and VGLUT2 identified architectonic boundaries in all structures, as well as anatomical subdivisions of the superior colliculus, pulvinar complex, and V1. These results suggest that VGLUT1 and VGLUT2 clearly identify regions of glutamatergic input in visual structures, and may identify common architectonic features of visual areas and nuclei across the primate radiation. Additionally, we find that VGLUT1 and VGLUT2 characterize distinct subsets of glutamatergic projections in the macaque visual system; VGLUT2 predominates in driving or feedforward projections from lower order to higher order visual structures while VGLUT1 predominates in modulatory or feedback projections from higher order to lower order visual structures. The distribution of these two proteins suggests that VGLUT1 and VGLUT2 may identify class 1 and class 2 type glutamatergic projections within the primate visual system (Sherman and Guillery, 2006).

  9. Identification of nine novel loci associated with white blood cell subtypes in a Japanese population.

    PubMed

    Okada, Yukinori; Hirota, Tomomitsu; Kamatani, Yoichiro; Takahashi, Atsushi; Ohmiya, Hiroko; Kumasaka, Natsuhiko; Higasa, Koichiro; Yamaguchi-Kabata, Yumi; Hosono, Naoya; Nalls, Michael A; Chen, Ming Huei; van Rooij, Frank J A; Smith, Albert V; Tanaka, Toshiko; Couper, David J; Zakai, Neil A; Ferrucci, Luigi; Longo, Dan L; Hernandez, Dena G; Witteman, Jacqueline C M; Harris, Tamara B; O'Donnell, Christopher J; Ganesh, Santhi K; Matsuda, Koichi; Tsunoda, Tatsuhiko; Tanaka, Toshihiro; Kubo, Michiaki; Nakamura, Yusuke; Tamari, Mayumi; Yamamoto, Kazuhiko; Kamatani, Naoyuki

    2011-06-01

    White 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 study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10(-8), of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits.

  10. Discovery and validation of breast cancer subtypes

    PubMed Central

    Kapp, Amy V; Jeffrey, Stefanie S; Langerød, Anita; Børresen-Dale, Anne-Lise; Han, Wonshik; Noh, Dong-Young; Bukholm, Ida RK; Nicolau, Monica; Brown, Patrick O; Tibshirani, Robert

    2006-01-01

    Background Previous studies demonstrated breast cancer tumor tissue samples could be classified into different subtypes based upon DNA microarray profiles. The most recent study presented evidence for the existence of five different subtypes: normal breast-like, basal, luminal A, luminal B, and ERBB2+. Results Based upon the analysis of 599 microarrays (five separate cDNA microarray datasets) using a novel approach, we present evidence in support of the most consistently identifiable subtypes of breast cancer tumor tissue microarrays being: ESR1+/ERBB2-, ESR1-/ERBB2-, and ERBB2+ (collectively called the ESR1/ERBB2 subtypes). We validate all three subtypes statistically and show the subtype to which a sample belongs is a significant predictor of overall survival and distant-metastasis free probability. Conclusion As a consequence of the statistical validation procedure we have a set of centroids which can be applied to any microarray (indexed by UniGene Cluster ID) to classify it to one of the ESR1/ERBB2 subtypes. Moreover, the method used to define the ESR1/ERBB2 subtypes is not specific to the disease. The method can be used to identify subtypes in any disease for which there are at least two independent microarray datasets of disease samples. PMID:16965636

  11. Cognitive subtypes of mathematics learning difficulties in primary education.

    PubMed

    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.

  12. Targeting the subtypes of breast cancer: rethinking investigational drugs.

    PubMed

    Curigliano, Giuseppe; Locatelli, Marzia; Fumagalli, Luca; Brollo, Janaina; Munzone, Elisabetta; Nolé, Franco; Criscitiello, Carmen; Goldhirsch, Aron

    2012-02-01

    The choice of adjuvant treatments for women with breast cancer is based on several features that take into account the heterogeneity of the disease. Questions raised during the decision process include the following: i) What leads to the use of endocrine therapy? ii) What leads to the use of anti-HER2 therapy? iii) What justifies the use of chemotherapy? Choices of adjuvant treatment are based on parameters defined by molecular characterization of breast cancer subtypes or by approximations to this classification using traditional clinical-pathological features. Clinicians should consider cases within the various distinct subpopulation in order to properly select the most 'personalized' adjuvant therapeutic approach. Sensitivity to chemotherapy and/or targeted agents in subtypes of breast cancers are predictable based on gene pathway alterations and associated gene products. This review covers several clinical data on several investigational agents for early-stage breast cancer molecular subtypes. We selected from literature data prospective Phase I, II and III clinical trials of chemotherapy (weekly or daily schedules), including indicators of activity and toxicity and data on survival/mortality. The future of many investigational therapeutics in breast cancer is linked to our ability to identify the most druggable target in each subtype.

  13. Sequence Analysis of 96 Genomic Regions Identifies Distinct Evolutionary Lineages within CC156, the Largest Streptococcus pneumoniae Clonal Complex in the MLST Database

    PubMed Central

    Moschioni, Monica; Lo Sapio, Morena; Crisafulli, Giovanni; Torricelli, Giulia; Guidotti, Silvia; Muzzi, Alessandro; Barocchi, Michèle A.; Donati, Claudio

    2013-01-01

    Multi-Locus Sequence Typing (MLST) of Streptococcus pneumoniae is based on the sequence of seven housekeeping gene fragments. The analysis of MLST allelic profiles by eBURST allows the grouping of genetically related strains into Clonal Complexes (CCs) including those genotypes with a common descent from a predicted ancestor. However, the increasing use of MLST to characterize S. pneumoniae strains has led to the identification of a large number of new Sequence Types (STs) causing the merger of formerly distinct lineages into larger CCs. An example of this is the CC156, displaying a high level of complexity and including strains with allelic profiles differing in all seven of the MLST loci, capsular type and the presence of the Pilus Islet-1 (PI-1). Detailed analysis of the CC156 indicates that the identification of new STs, such as ST4945, induced the merging of formerly distinct clonal complexes. In order to discriminate the strain diversity within CC156, a recently developed typing schema, 96-MLST, was used to analyse 66 strains representative of 41 different STs. Analysis of allelic profiles by hierarchical clustering and a minimum spanning tree identified ten genetically distinct evolutionary lineages. Similar results were obtained by phylogenetic analysis on the concatenated sequences with different methods. The identified lineages are homogenous in capsular type and PI-1 presence. ST4945 strains were unequivocally assigned to one of the lineages. In conclusion, the identification of new STs through an exhaustive analysis of pneumococcal strains from various laboratories has highlighted that potentially unrelated subgroups can be grouped into a single CC by eBURST. The analysis of additional loci, such as those included in the 96-MLST schema, will be necessary to accurately discriminate the clonal evolution of the pneumococcal population. PMID:23593373

  14. Clinical implications of the intrinsic molecular subtypes of breast cancer.

    PubMed

    Prat, Aleix; Pineda, Estela; Adamo, Barbara; Galván, Patricia; Fernández, Aranzazu; Gaba, Lydia; Díez, Marc; Viladot, Margarita; Arance, Ana; Muñoz, Montserrat

    2015-11-01

    Gene-expression profiling has had a considerable impact on our understanding of breast cancer biology. During the last 15 years, 5 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched, Basal-like and Claudin-low) have been identified and intensively studied. In this review, we will focus on the current and future clinical implications of the intrinsic molecular subtypes beyond the current pathological-based classification endorsed by the 2013 St. Gallen Consensus Recommendations. Within hormone receptor-positive and HER2-negative early breast cancer, the Luminal A and B subtypes predict 10-year outcome regardless of systemic treatment administered as well as residual risk of distant recurrence after 5 years of endocrine therapy. Within clinically HER2-positive disease, the 4 main intrinsic subtypes can be identified and dominate the biological and clinical phenotype. From a clinical perspective, patients with HER2+/HER2-enriched disease seem to benefit the most from neoadjuvant trastuzumab, or dual HER2 blockade with trastuzumab/lapatinib, in combination with chemotherapy, and patients with HER2+/Luminal A disease seem to have a relative better outcome compared to the other subtypes. Finally, within triple-negative breast cancer (TNBC), the Basal-like disease predominates (70-80%) and, from a biological perspective, should be considered a cancer-type by itself. Importantly, the distinction between Basal-like versus non-Basal-like within TNBC might predict survival following (neo)adjvuvant multi-agent chemotherapy, bevacizumab benefit in the neoadjuvant setting (CALGB40603), and docetaxel vs. carboplatin benefit in first-line metastatic disease (TNT study). Overall, this data suggests that intrinsic molecular profiling provides clinically relevant information beyond current pathology-based classifications.

  15. (S)-lacosamide inhibition of CRMP2 phosphorylation reduces postoperative and neuropathic pain behaviors through distinct classes of sensory neurons identified by constellation pharmacology.

    PubMed

    Moutal, Aubin; Chew, Lindsey A; Yang, Xiaofang; Wang, Yue; Yeon, Seul Ki; Telemi, Edwin; Meroueh, Seeneen; Park, Ki Duk; Shrinivasan, Raghuraman; Gilbraith, Kerry B; Qu, Chaoling; Xie, Jennifer Y; Patwardhan, Amol; Vanderah, Todd W; Khanna, May; Porreca, Frank; Khanna, Rajesh

    2016-07-01

    Chronic pain affects the life of millions of people. Current treatments have deleterious side effects. We have advanced a strategy for targeting protein interactions which regulate the N-type voltage-gated calcium (CaV2.2) channel as an alternative to direct channel block. Peptides uncoupling CaV2.2 interactions with the axonal collapsin response mediator protein 2 (CRMP2) were antinociceptive without effects on memory, depression, and reward/addiction. A search for small molecules that could recapitulate uncoupling of the CaV2.2-CRMP2 interaction identified (S)-lacosamide [(S)-LCM], the inactive enantiomer of the Food and Drug Administration-approved antiepileptic drug (R)-lacosamide [(R)-LCM, Vimpat]. We show that (S)-LCM, but not (R)-LCM, inhibits CRMP2 phosphorylation by cyclin dependent kinase 5, a step necessary for driving CaV2.2 activity, in sensory neurons. (S)-lacosamide inhibited depolarization-induced Ca influx with a low micromolar IC50. Voltage-clamp electrophysiology experiments demonstrated a commensurate reduction in Ca currents in sensory neurons after an acute application of (S)-LCM. Using constellation pharmacology, a recently described high content phenotypic screening platform for functional fingerprinting of neurons that uses subtype-selective pharmacological agents to elucidate cell-specific combinations (constellations) of key signaling proteins that define specific cell types, we investigated if (S)-LCM preferentially acts on certain types of neurons. (S)-lacosamide decreased the dorsal root ganglion neurons responding to mustard oil, and increased the number of cells responding to menthol. Finally, (S)-LCM reversed thermal hypersensitivity and mechanical allodynia in a model of postoperative pain, and 2 models of neuropathic pain. Thus, using (S)-LCM to inhibit CRMP2 phosphorylation is a novel and efficient strategy to treat pain, which works by targeting specific sensory neuron populations.

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

    PubMed

    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

  17. Isolation of rat genomic clones encoding subtypes of the alpha 2-adrenergic receptor. Identification of a unique receptor subtype.

    PubMed

    Lanier, S M; Downing, S; Duzic, E; Homcy, C J

    1991-06-05

    alpha 2-Adrenergic receptors (alpha 2-AR) exist as subtypes that are expressed in a tissue-specific manner and differ in 1) their ligand recognition properties, 2) their extent of receptor protein glycosylation, and possible 3) their mechanism of signal transduction. Genomic or cDNA clones encoding three receptor subtypes have been characterized; however, both functional and radioligand binding studies in rodents suggest the existence of a fourth receptor subtype. To isolate the rat genes encoding receptor subtypes we screened a rat genomic library with an oligonucleotide probe encompassing the third membrane span of the human C-4 alpha 2-AR. Two intronless rat genes were isolated that encode distinct receptor subtypes (RG10, RG20). RG10 and RG20 encode proteins of 458 and 450 amino acids, respectively, that are 56% homologous and possess the structural features expected of this class of membrane-bound receptors. RG10 identifies a mRNA species of approximately 2500 nucleotides that is found primarily in brain, whereas RG20 identifies a larger mRNA species (approximately 4000 nucleotides) that is found in several tissues including brain, kidney, and salivary gland. RG10 is 88% homologous to the human C-4 alpha 2-AR and exhibits similar binding properties ( [3H]rauwolscine KD = 0.7 +/- 0.3 nM) as determined following transient expression of the receptor in COS-1 cells. RG20 exhibits ligand binding properties distinct from the three receptor subtypes identified by molecular cloning. Saturation binding studies indicate an affinity constant of 15 +/- 1.2 nM for the alpha 2-AR antagonist [3H]rauwolscine, a value 6-20 times higher than that observed for the three cloned receptor subtypes. In competition binding studies the potency order of competing ligands for RG20 is phentolamine greater than idazoxan greater than yohimbine greater than rauwolscine greater than prazosin. Of the three previously cloned alpha 2-AR, RG20 is most closely related to the human C-10 alpha 2-AR

  18. Genetic and Functional Diversity of Human Immunodeficiency Virus Type 1 Subtype B Nef Primary Isolates

    PubMed Central

    Foster, John L.; Molina, Rene P.; Luo, Tianci; Arora, Vivek K.; Huang, Yaoxing; Ho, David D.; Garcia, J. Victor

    2001-01-01

    We have characterized the functional integrity of seven primary Nef isolates: five from a long-term nonprogressing human immunodeficiency virus (HIV)-infected individual and one each from two patients with AIDS. One of the seven Nefs was defective for CD4 downregulation, two others were defective for PAK-2 activation, and one Nef was defective for PAK-2 activation and major histocompatibility complex (MHC) class I downregulation. Five of the Nefs were tested and found to be functional for the enhancement of virus particle infectivity. The structural basis for each of the functional defects has been analyzed by constructing a consensus nef, followed by mutational analysis of the variant amino acid residues. Mutations A29V and F193I were deleterious to CD4 downregulation and PAK-2 activation, respectively, while S189R rendered Nef defective for both MHC class I downregulation and PAK-2 activation. A search of the literature identified HIVs from five patients with Nefs predominantly mutated at F193 and from one patient with Nefs predominantly mutated at A29. A29 is highly conserved in all HIV subtypes except for subtype E. F193 is conserved in subtype B (and possibly in the closely related subtype D), but none of the other HIV group M subtypes. Our results suggest that functional distinctions may exist between HIV subtypes. PMID:11160665

  19. The caM kinase, Pnck, is spatially and temporally regulated during murine mammary gland development and may identify an epithelial cell subtype involved in breast cancer.

    PubMed

    Gardner, H P; Ha, S I; Reynolds, C; Chodosh, L A

    2000-10-01

    While screening for protein kinases expressed in the murine mammary gland, we identified previously a Ca2+/calmodulin-dependent kinase, Pnck, that is most closely related to CaMKI. In this report, we show that Pnck is temporally regulated during murine mammary development with highest levels of expression observed late in pregnancy, concomitant with the decreased cellular proliferation and terminal differentiation of the mammary epithelium. Consistent with this finding, Pnck is up-regulated in confluent mammary epithelial cells and is down-regulated as serum-starved cells are stimulated to reenter the cell cycle. In the mammary gland, Pnck is expressed in an epithelial-specific and markedly heterogeneous manner, suggesting that the expression of this kinase may be restricted to a particular mammary epithelial cell type. Potentially related to its heterogeneous in vivo expression pattern, Pnck expression is oncogene-associated in murine epithelial cell lines derived from mammary tumors arising in different transgenic mouse models of breast cancer; cell lines derived from mammary tumors initiated by c-myc or int-2/Fgf3 express Pnck, whereas cell lines initiated by neu or H-ras do not. In an analogous manner, expression of the human homologue of Pnck is restricted to a subset of human breast cancer cell lines. Moreover, PNCK was found to be highly overexpressed in a subset of human primary human breast cancers compared with benign mammary tissue. Together, our data suggest that Pnck may play a role in mammary development, and that expression of this kinase may be restricted to a mammary epithelial cell type that is transformed in a subset of human breast cancers.

  20. Degraded mitochondrial DNA is a newly identified subtype of the damage associated molecular pattern (DAMP) family and possible trigger of neurodegeneration.

    PubMed

    Mathew, Alex; Lindsley, Tara A; Sheridan, Anna; Bhoiwala, Devang L; Hushmendy, Shazaan F; Yager, Eric J; Ruggiero, Elizabeth A; Crawford, Dana R

    2012-01-01

    We previously showed a preferential degradation and down-regulation of mitochondrial DNA and RNA in hamster fibroblasts in response to hydrogen peroxide. Subsequent studies by others demonstrated that mitochondrial DNA can stimulate immune cells as a DAMP (damage associated molecular patterns) family member. However, the actual physical structure of this mitochondrial DNA DAMP and its importance in non-immune cell types are poorly understood. Here we report that transfected oxidant-initiated degraded mitochondrial polynucleotides, which we term "DeMPs", strongly induce the proinflammatory cytokines interleukin 6, monocyte chemotactic protein-1, and tumor necrosis factor α in mouse primary astrocytes. Additionally, proinflammatory IL1β was induced, implicating DeMPs in inflammasome activation. Furthermore, human cerebrospinal fluid (CSF) and plasma were found to contain detectable DeMP signal. Finally, significant degradation of mitochondrial DNA was observed in response to either a bolus or steady state hydrogen peroxide. Combined, these studies demonstrate, all for the first time, that a pathophysiologically relevant form of mitochondrial DNA (degraded) can elicit a proinflammatory cytokine induction; that a brain cell type (astrocytes) elicits a proinflammatory cytokine induction in response to these DeMPs; that this induction includes the inflammasome; that astrocytes are capable of inflammasome activation by DeMPs; that DeMPs are detectable in CSF and plasma; and that hydrogen peroxide can stimulate an early stage cellular degradation of mitochondrial DNA. These results provide new insights and are supportive of our hypothesis that DeMPs are a newly identified trigger of neurodegenerative diseases such as Alzheimer's disease, which are known to be associated with early stage inflammation and oxidation.

  1. Distinct parasite populations infect individuals identified through passive and active case detection in a region of declining malaria transmission in southern Zambia.

    PubMed

    Searle, Kelly M; Katowa, Ben; Kobayashi, Tamaki; Siame, Mwiche N S; Mharakurwa, Sungano; Carpi, Giovanna; Norris, Douglas E; Stevenson, Jennifer C; Thuma, Philip E; Moss, William J

    2017-04-19

    Substantial reductions in the burden of malaria have been documented in parts of sub-Saharan Africa, with elimination strategies and goals being formulated in some regions. Within this context, understanding the epidemiology of low-level malaria transmission is crucial to achieving and sustaining elimination. A 24 single-nucleotide-polymorphism Plasmodium falciparum molecular barcode was used to characterize parasite populations from infected individuals identified through passive and active case detection in an area approaching malaria elimination in southern Zambia. The study was conducted in the catchment area of Macha Hospital in Choma District, Southern Province, Zambia, where the parasite prevalence declined over the past decade, from 9.2% in 2008 to less than 1% in 2013. Parasite haplotypes from actively detected, P. falciparum-infected participants enrolled in a serial cross-sectional, community-based cohort study from 2008 to 2013 and from passively detected, P. falciparum-infected individuals enrolled at five rural health centres from 2012 to 2015 were compared. Changes in P. falciparum genetic relatedness, diversity and complexity were analysed as malaria transmission declined. Actively detected cases identified in the community were most commonly rapid diagnostic test negative, asymptomatic and had submicroscopic parasitaemia. Phylogenetic reconstruction using concatenated 24 SNP barcode revealed a separation of parasite haplotypes from passively and actively detected infections, consistent with two genetically distinct parasite populations. For passively detected infections identified at health centres, the proportion of detectable polyclonal infections was consistently low in all seasons, in contrast with actively detected infections in which the proportion of polyclonal infections was high. The mean genetic divergence for passively detected infections was 34.5% for the 2012-2013 transmission season, 37.8% for the 2013-2014 season, and 30.8% for the

  2. Genetic overlap between diagnostic subtypes of ischemic stroke

    PubMed Central

    Holliday, Elizabeth G; Traylor, Matthew; Malik, Rainer; Bevan, Steve; Falcone, Guido; Hopewell, Jemma C; Cheng, Yu-Ching; Cotlarciuc, Ioana; Bis, Joshua C; Boerwinkle, Eric; Boncoraglio, Giorgio B; Clarke, Robert; Cole, John W; Fornage, Myriam; Furie, Karen L; Ikram, M Arfan; Jannes, Jim; Kittner, Steven J; Lincz, Lisa F; Maguire, Jane M; Meschia, James F; Mosley, Thomas H; Nalls, Mike A; Oldmeadow, Christopher; Parati, Eugenio A; Psaty, Bruce M; Rothwell, Peter M; Seshadri, Sudha; Scott, Rodney J; Sharma, Pankaj; Sudlow, Cathie; Wiggins, Kerri L; Worrall, Bradford B; Rosand, Jonathan; Mitchell, Braxton D; Dichgans, Martin; Markus, Hugh S; Levi, Christopher; Attia, John; Wray, Naomi R

    2015-01-01

    Background and Purpose Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for shared genetic etiology among the three major subtypes: large artery atherosclerosis (LAA), cardioembolism (CE) and small vessel disease (SVD), to inform potential cross-subtype analyses. Methods Analyses used genome-wide summary data for 12,389 ischemic stroke cases (including 2,167 LAA, 2,405 CE and 1,854 SVD) and 62,004 controls from the Metastroke consortium. For 4,561 cases and 7,094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models (LMM) and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4,021 cases, 51,976 controls) was performed to identify shared risk alleles. Results High genetic correlation was identified between LAA and SVD using LMM (rg=0.96, SE=0.47, P=9×10−4) and profile scores (rg=0.72; 95% CI: 0.52 – 0.93). Between LAA and CE, and SVD and CE, correlation was moderate using LMM but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10−7) for SNPs near the opioid receptor μ1 (OPRM1) gene. Conclusions Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes. PMID:25613305

  3. Genetic overlap between diagnostic subtypes of ischemic stroke.

    PubMed

    Holliday, Elizabeth G; Traylor, Matthew; Malik, Rainer; Bevan, Steve; Falcone, Guido; Hopewell, Jemma C; Cheng, Yu-Ching; Cotlarciuc, Ioana; Bis, Joshua C; Boerwinkle, Eric; Boncoraglio, Giorgio B; Clarke, Robert; Cole, John W; Fornage, Myriam; Furie, Karen L; Ikram, M Arfan; Jannes, Jim; Kittner, Steven J; Lincz, Lisa F; Maguire, Jane M; Meschia, James F; Mosley, Thomas H; Nalls, Mike A; Oldmeadow, Christopher; Parati, Eugenio A; Psaty, Bruce M; Rothwell, Peter M; Seshadri, Sudha; Scott, Rodney J; Sharma, Pankaj; Sudlow, Cathie; Wiggins, Kerri L; Worrall, Bradford B; Rosand, Jonathan; Mitchell, Braxton D; Dichgans, Martin; Markus, Hugh S; Levi, Christopher; Attia, John; Wray, Naomi R

    2015-03-01

    Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses. Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles. High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene. Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes. © 2015 American Heart Association, Inc.

  4. High-resolution functional MRI identified distinct global intrinsic functional networks of nociceptive posterior insula and S2 regions in squirrel monkey brain.

    PubMed

    Wu, Ruiqi; Wang, Feng; Yang, Pai-Feng; Chen, Li Min

    2017-07-15

    Numerous functional imaging and electrophysiological studies in humans and animals indicate that the two contiguous areas of secondary somatosensory cortex (S2) and posterior insula (pIns) are core regions in nociceptive processing and pain perception. In this study, we tested the hypothesis that the S2-pIns connection serves as a hub for connecting distinct sensory and affective nociceptive processing networks in the squirrel monkey brain. At 9.4T, we first mapped the brain regions that respond to nociceptive heat stimuli with high-resolution fMRI, and then used seed-based resting-state fMRI (rsfMRI) analysis to delineate and refine the global intrinsic functional connectivity circuits of the proximal S2 and pIns regions. In each subject, nociceptive (47.5°C) heat-evoked fMRI activations were detected in many brain regions, including primary somatosensory (S1), S2, pIns, area 7b, anterior cingulate cortex (ACC), primary motor cortex, prefrontal cortex, supplementary motor area, thalamus, and caudate. Using the heat-evoked fMRI activation foci in S2 and pIns as the seeds, voxel-wise whole-brain resting-state functional connectivity (rsFC) analysis revealed strong functional connections between contralateral S2 and pIns, as well as their corresponding regions in the ipsilateral hemisphere. Spatial similarity and overlap analysis identified each region as part of two distinct intrinsic functional networks with 7% overlap: sensory S2-S1-area 7b and affective pIns-ACC-PCC networks. Moreover, a high degree of overlap was observed between the combined rsFC maps of nociceptive S2 and pIns regions and the nociceptive heat-evoked activation map. In summary, our study provides evidence for the existence of two distinct intrinsic functional networks for S2 and pIns nociceptive regions, and these two networks are joined via the S2-pIns connection. Brain regions that are involved in processing nociceptive inputs are also highly interconnected at rest. The presence of robust

  5. A de novo interstitial deletion of 8p11.2 including ANK1 identified in a patient with spherocytosis, psychomotor developmental delay, and distinctive facial features.

    PubMed

    Miya, Kazushi; Shimojima, Keiko; Sugawara, Midori; Shimada, Shino; Tsuri, Hiroyuki; Harai-Tanaka, Tomomi; Nakaoka, Sachiko; Kanegane, Hirokazu; Miyawaki, Toshio; Yamamoto, Toshiyuki

    2012-09-10

    The contiguous gene syndrome involving 8p11.2 is recognized as a combined phenotype of both Kallmann syndrome and hereditary spherocytosis, because the genes responsible for these 2 clinical entities, the fibroblast growth factor receptor 1 (FGFR1) and ankyrin 1 (ANK1) genes, respectively, are located in this region within a distance of 3.2Mb. We identified a 3.7Mb deletion of 8p11.2 in a 19-month-old female patient with hereditary spherocytosis. The identified deletion included ANK1, but not FGFR1, which is consistent with the absence of any phenotype or laboratory findings of Kallmann syndrome. Compared with the previous studies, the deletion identified in this study was located on the proximal end of 8p, indicating a pure interstitial deletion of 8p11.21. This patient exhibited mild developmental delay and distinctive facial findings in addition to hereditary spherocytosis. Thus, some of the genes included in the deleted region would be related to these symptoms.

  6. Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease.

    PubMed

    Kono, Michihiro; Sugiura, Kazumitsu; Suganuma, Mutsumi; Hayashi, Masahiro; Takama, Hiromichi; Suzuki, Tamio; Matsunaga, Kayoko; Tomita, Yasushi; Akiyama, Masashi

    2013-09-01

    Reticulate acropigmentation of Kitamura (RAK) is a rare genetic disorder of cutaneous pigmentation with an autosomal dominant pattern of inheritance and a high penetration rate. The characteristic skin lesions are reticulate, slightly depressed pigmented macules mainly affecting the dorsa of the hands and feet, which first appear before puberty and subsequently expand to the proximal limb and the trunk. To identify mutations that cause RAK, we performed exome sequencing of four family members in a pedigree with RAK. Fifty-three SNV/Indels were considered as candidate mutations after some condition narrowing. We confirmed the mutation status in each candidate gene of four other members in the same pedigree to find the gene that matched the mutation status and phenotype of each member. A mutation in ADAM10 encoding a zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), was identified in the RAK family. ADAM10 is known to be involved in the ectodomain shedding of various substrates in the skin. Sanger sequencing of four additional unrelated RAK patients revealed four additional ADAM10 mutations. We identified a total of three truncating mutations, a splice site mutation and a missense mutation in ADAM10. We searched for mutations in the KRT5 gene, a causative gene for the similar pigmentation disorder Dowling-Degos disease (DDD), in all the patients and found no KRT5 mutation. These results reveal that mutations in ADAM10 are a cause of RAK and that RAK is an independent clinical entity distinct from DDD.

  7. Identification of M(1) muscarinic receptor subtype in rat stomach using a tissue segment binding method, and the effects of immobilization stress on the muscarinic receptors.

    PubMed

    Anisuzzaman, Abu Syed Md; Morishima, Shigeru; Suzuki, Fumiko; Tanaka, Takashi; Muramatsu, Ikunobu

    2008-12-03

    Distinct muscarinic acetylcholine receptor subtypes widely distribute in stomach tissues and are involved in many physiological functions. Although mRNA of M(1) subtype was found in gastric mucosa, the M(1) subtype has not been detected by conventional membrane binding assays. In the present study, muscarinic receptor subtypes in the rat stomach were reevaluated by using the tissue segment binding technique recently developed to recognize the inherent/native profiles of receptors without receptor environment perturbation. [(3)H]-N-methylscopolamine (NMS) bound to muscarinic receptors in the intact segments of rat gastric mucosa and muscle layers. The muscarinic receptors in the mucosal segments were composed of M(1), M(2) and M(3) subtypes, among which the M(1) subtype selectively showed high affinity for pirenzepine. However, in the membrane preparations, binding sites with high affinity for pirenzepine could not be detected. In the muscle layer, M(2) and M(3) subtypes, but not M(1), were identified in tissue segment and conventional membrane binding assays. Western blotting analysis recognized the M(1) subtype in the membrane preparations of mucosal but not muscle layers. Chronic immobilization stress increased the M(3) subtype in mucosal and muscle layers and decreased the M(2) subtype in the muscle layer, whereas M(1) and M(2) subtypes in mucosal layer did not change after the stress. The current study shows that M(1) subtype occurs as a pirenzepine-high affinity entity in intact segments of rat gastric mucosa, but that it loses the affinity for pirenzepine upon homogenization. Careful identification of native in vivo muscarinic receptors may further elucidate their functions in stomach.

  8. Comparative analysis of Edwardsiella isolates from fish in the eastern United States identifies two distinct genetic taxa amongst organisms phenotypically classified as E. tarda

    USGS Publications Warehouse

    Griffin, Matt J.; Quiniou, Sylvie M.; Cody, Theresa; Tabuchi, Maki; Ware, Cynthia; Cipriano, Rocco C.; Mauel, Michael J.; Soto, Esteban

    2013-01-01

    Edwardsiella tarda, a Gram-negative member of the family Enterobacteriaceae, has been implicated in significant losses in aquaculture facilities worldwide. Here, we assessed the intra-specific variability of E. tarda isolates from 4 different fish species in the eastern United States. Repetitive sequence mediated PCR (rep-PCR) using 4 different primer sets (ERIC I & II, ERIC II, BOX, and GTG5) and multi-locus sequence analysis of 16S SSU rDNA, groEl, gyrA, gyrB, pho, pgi, pgm, and rpoA gene fragments identified two distinct genotypes of E. tarda (DNA group I; DNA group II). Isolates that fell into DNA group II demonstrated more similarity to E. ictaluri than DNA group I, which contained the reference E. tarda strain (ATCC #15947). Conventional PCR analysis using published E. tarda-specific primer sets yielded variable results, with several primer sets producing no observable amplification of target DNA from some isolates. Fluorometric determination of G + C content demonstrated 56.4% G + C content for DNA group I, 60.2% for DNA group II, and 58.4% for E. ictaluri. Surprisingly, these isolates were indistinguishable using conventional biochemical techniques, with all isolates demonstrating phenotypic characteristics consistent with E. tarda. Analysis using two commercial test kits identified multiple phenotypes, although no single metabolic characteristic could reliably discriminate between genetic groups. Additionally, anti-microbial susceptibility and fatty acid profiles did not demonstrate remarkable differences between groups. The significant genetic variation (<90% similarity at gyrA, gyrB, pho, phi and pgm; <40% similarity by rep-PCR) between these groups suggests organisms from DNA group II may represent an unrecognized, genetically distinct taxa of Edwardsiella that is phenotypically indistinguishable from E. tarda.

  9. 1 + 1 = 3: Development and validation of a SNP-based algorithm to identify genetic contributions from three distinct inbred mouse strains.

    PubMed