1,710 research outputs found
Validation of the Genetically-Defined DLBCL Subtypes and Generation of a Parsimonious Probabilistic Classifier
No full textDiffuse large B-cell lymphoma (DLBCL) is a clinically and molecularly heterogeneous disease with recognized transcriptional subtypes associated with normal cells of origin, activated B-cell (ABC) and germinal center B-cell (GCB) tumors. Emerging data suggested that additional heterogeneity existed, prompting us to comprehensively characterize genomic signatures of 304 newly diagnosed DLBCLs from patients treated with state-of-the-art therapy. We integrated recurrent mutations, somatic copy number alterations (SCNAs) and structural variants (SVs) and identified 5 genetically distinct DLBCL clusters (C1- C5 DLBCLs; Chapuy, Stewart, Dunford, et al. Nat Med 2018). Specifically, we identified two genetically distinct ABC subtypes, including favorable-risk C1 DLBCLs with features of extrafollicular origin and alterations also seen in transformed marginal zone lymphomas (NOTCH2 and NF-κB pathway member mutations and BCL6 SVs). Unfavorable-risk C5 ABC DLBCLs harbored frequent 18q/BCL2 copy gain and co-occurring CD79B and MYD88L265P mutations. We also identified two genetically distinct GCB subtypes, including unfavorable-risk C3 DLBCLs with frequent BCL2 SVs, mutations in chromatin-modifying enzymes (CREBBP, MLL2, EZH2) and BCR/PI3K signaling pathway members (including inactivating PTEN mutations and copy loss). Favorable-risk C4 GCB DLBCLs had frequent mutations in core and linker histones and signaling intermediates (SGK1, BRAF and STAT3). Additionally, we identified an ABC/GCB-independent subtype, C2 DLBCLs, characterized by frequent bi-allelic TP53 inactivation, 9p21.23/CDKN2A copy loss and associated genomic instability reflected in recurrent SCNAs, increased genome doublings and a distinct outcome following induction therapy. A next step in utilizing the characterized genetic substructure was to confirm it in an independent series and develop a molecular classifier that allows prospective identification of C1-C5 DLBCLs. To this end, we accessed whole exome sequencing, copy number and SV data from a recent cohort of newly diagnosed DLBCLs (39 tumor-normal pairs, 462 tumor-only samples; Schmitz et al. NEJM 2018). All samples were re-analyzed using our mutational and SCNA pipelines and our newly generated tumor-only algorithm (Chapuy, Stewart, Dunford, et al. Nat Med 2018) to avoid batch effects and harmonize the datasets. SVs were used as reported. Purity and ploidy were inferred using ABSOLUTE and samples with missing data or low purity were removed. For the combined cohort (579 samples), we assessed our previously characterized 158 genetic drivers (Chapuy, Stewart, Dunford, et al. Nat Med 2018) and confirmed equal distribution of their marginal frequencies (R=0.88, p=1.5e-51), excluding batch effects. Next, we applied non-negative matrix factorization (NNF) consensus clustering to the combined dataset (158 genetic drivers vs. 579 tumors) and confirmed the C1-C5 DLBCL genetic clusters. Notably, tumors from both series contributed at comparable frequencies to the respective C1-C5 DLBCLs. We also noted an enrichment of the alternative genetic labels from Schmitz et al. in 3 of our C1-C5 DLBCL subtypes (B2N in C1 DLBCLs, p<0.0001; EZB in C3 DLBCLs, p<0.0001; MCD in C5 DLBCLs, p<0.0001). These data confirmed the identity of the C1-C5 DLBCL clusters in an independent cohort. Next, we developed a molecular classifier that prospectively identified C1-C5 DLBCLs using a minimum number of easy-to-measure features. The NMF-defined classes of the combined cohort were used as gold-standard training and validation datasets. We tested different models for classification and selected an artificial neural network approach which provides accurate classification of individual samples and well-calibrated confidence metrics. To minimize potential overtraining, we developed a reduced input feature set of the 22 most discriminating features, constructed confidence metrics for each sample and trained an ensemble of Feed-Forward Neural Networks via 10-fold cross validation. With this approach, our classifier had 84% accuracy for the total set and 94% accuracy for the high-confidence samples (70% of all samples). The newly developed parsimonious classifier will allow prospective identification of the independently confirmed C1-C5 DLBCL subtypes in newly diagnosed patients, a necessity for clinical application. Disclosures Getz: Pharmacyclics: Research Funding; IBM: Research Funding; MuTect, ABSOLTUE, MutSig and POLYSOLVER: Patents & Royalties: MuTect, ABSOLTUE, MutSig and POLYSOLVER. Shipp:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees
High-order chromatin architecture determines the landscape of chromosomal alterations in cancer
Get PDFAuthor Manuscript 2012 June 01.The accumulation of data on structural variation in cancer genomes provides an opportunity to better understand the mechanisms of genomic alterations and the forces of selection that act upon these alterations in cancer. Here we test evidence supporting the influence of two major forces, spatial chromosome structure and purifying (or negative) selection, on the landscape of somatic copy-number alterations (SCNAs) in cancer[superscript 1]. Using a maximum likelihood approach, we compare SCNA maps and three-dimensional genome architecture as determined by genome-wide chromosome conformation capture (HiC) and described by the proposed fractal-globule model[superscript 2, 3]. This analysis suggests that the distribution of chromosomal alterations in cancer is spatially related to three-dimensional genomic architecture and that purifying selection, as well as positive selection, influences SCNAs during somatic evolution of cancer cells.National Institutes of Health (U.S.) (National Cancer Institute (U.S.). Physical Sciences-Oncology Center U54CA143874)National Institutes of Health (U.S.) (U24CA143845)National Institutes of Health (U.S.) (U24CA144025)National Institutes of Health (U.S.) (U24CA143867)National Cancer Institute (U.S.). (The Cancer Genome Atlas Project Investigator
AVICENNA AMONG MEDIEVAL JEWS THE RECEPTION OF AVICENNA'S PHILOSOPHICAL, SCIENTIFIC AND MEDICAL WRITINGS IN JEWISH CULTURES, EAST AND WEST
No full textThe reception of Avicenna by medieval Jewish readers presents an underappreciated enigma. Despite the philosophical and scientific stature of Avicenna, his philosophical writings were relatively little studied in Jewish milieus, be it in Arabic or in Hebrew. In particular, Avicenna's philosophical writings are not among the "Hebraische Ubersetzungen desMittelalters" - only very few of them were translated into Hebrew. As an author associated with a definite corpus of writings, Avicenna hardly existed in Jewish philosophy in Hebrew (contrary to Averroes). Paradoxically, however, some of Avicenna's most distinctive ideas were widely known and embraced by Jewish philosophers. This is the phenomenon that we dub Avicennian knowledge without Avicenna. In contrast with the philosophical treatises, Avicenna's medical writings were widely and intensively studied by Jews, especially in Hebrew, and remained influential until at least the seventeenth century. The present article presents a comprehensive picture of Avicenna's reception within medieval Jewish cultures in both Arabic and Hebrew and tries to explain the Jews' complex attitude to Avicenna.It is a comprehensive historical overview and detailed, with precise reference to all these cases so far examined and the entire bibliography still available, direct and indirect influence exerted by the thought and especially the philosophical and scientific works of Avicenna on Jewish philosophy Judeo-Arabic and Jewish medieval, from 1050 to 1500 or so, in the Mediterranean area
Psychometric properties of the GAD-Q-IV and DERS in older community-dwelling GAD patients and nonanxious controls
No full textRecent research suggests that generalized anxiety disorder (GAD) in late life is common (Flint, 2005) and is associated with severe consequences, such as decreased life satisfaction and increased risk of physical disability (De Beurs et al., 1999). Yet, our understanding of this disorder in late life, including knowledge of efficient assessment tools, lags behind our growing knowledge of GAD in younger adults. The current study investigated the psychometric properties of the Generalized Anxiety Disorder Questionnaire for DSM-IV (GAD-Q-IV; Newman et al., 2002) and the Difficulties in Emotion Regulation Scale (DERS; Gratz & Roemer, 2004) in a community-dwelling, older adult population. Thirty-seven adults diagnosed with GAD and 37 controls (all age 60 or older) completed the GAD-Q-IV, DERS, and other measures of anxiety and depression. Both measures were assessed for internal consistency reliability, construct validity (convergent and discriminant), and test-retest reliability, all of which indicated good psychometric performance. Receiver operating characteristic analyses suggested that the optimal cutoff for diagnosing GAD in this sample was 3.71, with .97 sensitivity and .92 specificity. However, including only those participants diagnosed with GAD in addition to another Axis I disorder (e.g., social phobia, dysthymia, panic disorder with or without agoraphobia; n = 18), revealed a higher optimal cutoff score (4.42; 100% sensitivity and 92% specificity). ROC analyses also revealed an optimal DERS cutoff score of 62.5, which achieved .76 sensitivity and .86 specificity. Findings from the current study support the utility of an emotion regulation deficit model of late-life GAD, and are discussed in relation to age specific characteristics of worry and GAD.M.S.Includes bibliographical referencesby Alison Mary Staple
GAD and Gender Mainstreaming: A Pathway to Sustainable Development?
No full textIn recent years there has been increased attention to the importance of gender in securing long-term development goals. Consensus has now been reached that increasing the social status and economic capacity of women is an effective way of improving outcomes. The subject of this paper is the viability of the ‘Gender and Development’ (GAD) paradigm as a means of establishing socially and politically sustainable gains for women in developing countries. The author examines the GAD paradigm using the case study of ‘Gender Mainstreaming’ in the reconstruction and development of Afghanistan since 2001. Through an analysis of some of the problems encountered so far, the author questions whether such an approach is likely to actually result in long-term, sustainable improvement in that country. Three key issues include: marginalization of ‘Gender Mainstreaming’; lack of state capacity; and failures to fully integrate programs into social and cultural contexts. Though reconstruction efforts have clearly resulted in some improvement, it is argued that it is unclear whether such an approach will lead to long-term progress. Rather, there is strong evidence that GAD can actually contribute to the further politicization of gender and result in a backlash against reforms. Ultimately, the goals that the GAD paradigm attempts to achieve are extremely difficult to translate into effective practice, especially in highly volatile and politicized situations. In conclusion, the author finds that sustainable and transformative change may be elusive if one simply applies new aims to old models of aid provision
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GAD and Gender Mainstreaming: A Pathway to Sustainable Development?
Get PDFIn recent years there has been increased attention to the importance of gender in securing long-term development goals. Consensus has now been reached that increasing the social status and economic capacity of women is an effective way of improving outcomes. The subject of this paper is the viability of the ‘Gender and Development’ (GAD) paradigm as a means of establishing socially and politically sustainable gains for women in developing countries. The author examines the GAD paradigm using the case study of ‘Gender Mainstreaming’ in the reconstruction and development of Afghanistan since 2001. Through an analysis of some of the problems encountered so far, the author questions whether such an approach is likely to actually result in long-term, sustainable improvement in that country. Three key issues include: marginalization of ‘Gender Mainstreaming’; lack of state capacity; and failures to fully integrate programs into social and cultural contexts. Though reconstruction efforts have clearly resulted in some improvement, it is argued that it is unclear whether such an approach will lead to long-term progress. Rather, there is strong evidence that GAD can actually contribute to the further politicization of gender and result in a backlash against reforms. Ultimately, the goals that the GAD paradigm attempts to achieve are extremely difficult to translate into effective practice, especially in highly volatile and politicized situations. In conclusion, the author finds that sustainable and transformative change may be elusive if one simply applies new aims to old models of aid provision
Somatic symptoms of generalized anxiety disorder from the DSM-IV: Associations with pathological worry and depression symptoms in a nonclinical sample
Get PDFThe present study investigates specificity of the six somatic symptoms that are associated with generalized anxiety disorder (GAD), according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders. A nonclinical sample of 183 students provided severity ratings for (a) restlessness, (b) easily fatigued, (c) difficulty concentrating, (d) irritability, (e) muscle tension, and (f) sleep disturbance. In addition, they responded to questionnaires assessing pathological worry and depression symptoms. Partial correlations and multiple regression analyses indicated that only muscle tension showed a unique relation to pathological worry. In contrast, difficulty concentrating was exclusively related to depression symptoms. Present findings corroborate psychophysiological findings that elevated muscle tension is a specific characteristic of pathological worriers. Moreover, they suggest that the problem of unclear boundaries between GAD and major depression may be reduced if future revisions of the somatic symptom list for GAD emphasize muscle tension while de-emphasizing difficulty concentrating
GAD antibody-spectrum disorders: progress in clinical phenotypes, immunopathogenesis and therapeutic interventions
No full textAntibodies against glutamic acid decarboxylase (GAD), originally linked to stiff person syndrome (SPS), now denote the “GAD antibody-spectrum disorders” (GAD-SD) that also include autoimmune epilepsy, limbic encephalitis, cerebellar ataxia and nystagmus with overlapping symptomatology highlighting autoimmune neuronal excitability disorders. The reasons for the clinical heterogeneity among GAD-antibody associated syndromes remain still unsettled, implicating variable susceptibility of GABAergic neurons to anti-GAD or other still unidentified autoantibodies. Although anti-GAD antibody titers do not correlate with clinical severity, very high serum titers, often associated with intrathecal synthesis of anti-GAD-specific IgG, point to in-situ effects of GAD or related autoantibodies within the central nervous system. It remains, however, uncertain what drives these antibodies, why they persist and whether they are disease markers or have pathogenic potential. The review, focused on these concerns, describes the widened clinical manifestations and overlapping features of all GAD-SD; addresses the importance of GAD antibody titers and potential significance of GAD epitopes; summarizes the biologic basis of autoimmune hyperexcitability; highlights the electrophysiological basis of reciprocal inhibition in muscle stiffness; and provides practical guidelines on symptomatic therapies with gamma-aminobutyric acid-enhancing drugs or various immunotherapies. © The Author(s), 2021
GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers
Get PDFWe describe methods with enhanced power and specificity to identify genes targeted by somatic copy-number alterations (SCNAs) that drive cancer growth. By separating SCNA profiles into underlying arm-level and focal alterations, we improve the estimation of background rates for each category. We additionally describe a probabilistic method for defining the boundaries of selected-for SCNA regions with user-defined confidence. Here we detail this revised computational approach, GISTIC2.0, and validate its performance in real and simulated datasets
Super refractory status epilepticus secondary to anti-GAD antibody encephalitis successfully treated with aggressive immunotherapy
Get PDFAntibodies against glutamic acid decarboxylase are reported in association with a number of neurological conditions including limbic encephalitis. We report a case of anti-GAD-antibody associated encephalitis presenting with super-refractory status epilepticus. We describe the clinical course, management, and the outcome. In addition, we review the presentation and outcomes of reported cases of anti-GAD encephalitis. Similar to the reported cases of anti-GAD encephalitis, our case was refractory to treatment with conventional antiseizure medication. Treatment with intravenous immune globulin (IVIG), high dose corticosteroids, and plasmapheresis had partial response, but escalation of treatment to the use of tocilizumab was associated with significant clinical improvement. © 2020 The Author
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