tbuckley/cabot-search huggingface dataset:
Histone Deacetylase 3 Regulates Smooth Muscle Differentiation in Neural Crest Cells and Development of the Cardiac Outflow Tract
Authors: Nikhil Singh, Chinmay M. Trivedi, MinMin Lu, Shannon E. Mullican, Mitchell A. Lazar, Jonathan A. Epstein
Journal: Circulation Research (2011)

Rationale: The development of the cardiac outflow tract (OFT) and great vessels is a complex process that involves coordinated regulation of multiple progenitor cell populations. Among these populations, neural crest cells make important contributions to OFT formation and aortic arch remodeling. Although numerous signaling pathways, including Notch, have been implicated in this process, the role of epigenetics in OFT development remains largely unexplored. Objective: Because histone deacetylases (Hdacs) play important roles in the epigenetic regulation of mammalian development, we have investigated the function of Hdac3, a class I Hdac, during cardiac neural crest development in mouse. Methods and Results: Using 2 neural crest drivers, Wnt1-Cre and Pax3 Cre , we show that loss of Hdac3 in neural crest results in perinatal lethality and cardiovascular abnormalities, including interrupted aortic arch type B, aortic arch hypoplasia, double-outlet right ventricle, and ventricular septal defect. Affected embryos are deficient in aortic arch artery smooth muscle during midgestation, despite intact neural crest cell migration and preserved development of other cardiac and truncal neural crest derivatives. The Hdac3-dependent block in smooth muscle differentiation is cell autonomous and is associated with downregulation of the Notch ligand Jagged1, a key driver of smooth muscle differentiation in the aortic arch arteries. Conclusions: These results indicate that Hdac3 plays a critical and specific regulatory role in the neural crest-derived smooth muscle lineage and in formation of the OFT.
PTTG1 expression is associated with hyperproliferative disease and poor prognosis in multiple myeloma
Authors: Jacqueline E. Noll, Kate Vandyke, Duncan R. Hewett, Krzysztof M. Mrozik, Rachel J. Bala, Sharon A. Williams, Chung H. Kok, Andrew CW Zannettino
Journal: Journal of Hematology & Oncology (2015)

Multiple myeloma (MM) is an incurable haematological malignancy characterised by the clonal proliferation of malignant plasma cells within the bone marrow. We have previously identified pituitary tumour transforming gene 1 (Pttg1) as a gene that is significantly upregulated in the haematopoietic compartment of the myeloma-susceptible C57BL/KaLwRij mouse strain, when compared with the myeloma-resistant C57BL/6 mouse. Over-expression of PTTG1 has previously been associated with malignant progression and an enhanced proliferative capacity in solid tumours. In this study, we investigated PTTG1 gene and protein expression in MM plasma cells from newly diagnosed MM patients. Gene expression profiling was used to identify gene signatures associated with high PTTG1 expression in MM patients. Additionally, we investigated the effect of short hairpin ribonucleic acid (shRNA)-mediated PTTG1 knockdown on the proliferation of the murine myeloma plasma cell line 5TGM1 in vitro and in vivo. PTTG1 was found to be over-expressed in 36–70 % of MM patients, relative to normal controls, with high PTTG1 expression being associated with poor patient outcomes (hazard ratio 2.49; 95 % CI 1.28 to 4.86; p = 0.0075; log-rank test). In addition, patients with high PTTG1 expression exhibited increased expression of cell proliferation-associated genes including CCNB1, CCNB2, CDK1, AURKA, BIRC5 and DEPDC1. Knockdown of Pttg1 in 5TGM1 cells decreased cellular proliferation, without affecting cell cycle distribution or viability, and decreased expression of Ccnb1, Birc5 and Depdc1 in vitro. Notably, Pttg1 knockdown significantly reduced MM tumour development in vivo, with an 83.2 % reduction in tumour burden at 4 weeks (p < 0.0001, two-way ANOVA). This study supports a role for increased PTTG1 expression in augmenting tumour development in a subset of MM patients.
Diabetes-Related Autoantibodies and Gestational Diabetes
Authors: Alberto de Leiva, Dídac Mauricio, Rosa Corcoy
Journal: Diabetes Care (2007)

Gestational diabetes mellitus (GDM) has long been recognized as a heterogeneous disorder (1,2), with autoimmunity against the β-cell contributing in a small subset of patients (3).

Autoimmune diabetes is caused by the destruction of β-cells of pancreatic islets by an immune-mediated process, promoted by the interaction of genetic and environmental factors (4). Autoantibodies (AAs) against pancreatic β-cell antigens precede the clinical onset of type 1 diabetes (4). Circulating islet cell antibodies, originally described by indirect immunofluorescence in 1974 (5), have been demonstrated in the great majority of individuals with type 1 diabetes, both at the preclinical state and at the onset of clinically overt diabetes, and they persist in the circulation for a long time. Islet cell AAs include autoantibodies to islet cell cytoplasm (islet cell autoantibodies [ICAs]), to native insulin (insulin autoantibodies [IAAs]), to GAD (GADA) (6–8), and to tyrosine phosphatases (insulinoma-associated antigens IA-2A and IA-2β) (9,10).

Age not only modifies the risk of autoimmune diabetes, but also the presence of AAs, the intensity of β-cell destruction, the rate of progression to overt diabetes, and the degree of residual insulin secretion. Approximately 30% of subjects with classic autoimmune diabetes (type 1A diabetes) present after age 35 years (11). Childhood autoimmune diabetes is associated with an increased prevalence of alleles DR3, DQB1*0201 and DR4, and DQB1*0302, with the proportion of heterozygotes declining with age at diagnosis (12). Children with the allele HLA DR2, DQB1*0602, almost never develop diabetes, whereas this allele confers a much lower protection for adult-onset autoimmune diabetes (13).

Since the discovery of AAs against islet cell antigens, it has been recognized that a fraction of adults considered to have type 2 diabetes probably have autoimmune diabetes and that the presence of GADAs indicates a strong possibility of requiring …
A phase II randomized study evaluating the addition of iniparib to gemcitabine plus cisplatin as first-line therapy for metastatic non-small-cell lung cancer
Authors: S. Novello, B. Besse, E. Felip, F. Barlesi, J. Mazieres, G. Zalcman, J. von Pawel, M. Reck, F. Cappuzzo, D. Ferry, E. Carcereny, A. Santoro, I. Garcia-Ribas, G. Scagliotti, J.-C. Soria
Journal: Annals of Oncology (2014)
Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration
Authors: Benoit Favier, Antoine Alam, Pauline Barron, Jacques Bonnin, Patricia Laboudie, Pierre Fons, Marie Mandron, Jean-Pascal Herault, Gera Neufeld, Pierre Savi, Jean-Marc Herbert, Françoise Bono
Journal: Blood (2006)
Impact of Body Mass Index on Survival After Colorectal Cancer Diagnosis: The Cancer Prevention Study-II Nutrition Cohort
Authors: Peter T. Campbell, Christina C. Newton, Ahmed N. Dehal, Eric J. Jacobs, Alpa V. Patel, Susan M. Gapstur
Journal: Journal of Clinical Oncology (2011)

Purpose The impact of body mass index (BMI) on survival after colorectal cancer diagnosis is poorly understood. This study assessed the association of pre- and postdiagnosis BMI with all-cause and cause-specific survival among men and women diagnosed with colorectal cancer in a prospective cohort. Patients and Methods Participants in the Cancer Prevention Study-II Nutrition Cohort reported weight and other risk factor information via a self-administered questionnaire at baseline in 1992 to 1993. Updated information on current weight and incident cancer was reported via periodic follow-up questionnaires. This analysis includes 2,303 cohort participants who were diagnosed with nonmetastatic colorectal cancer between baseline and mid 2007 and were observed for mortality from diagnosis through December 2008. Results A total of 851 participants with colorectal cancer died during the 16-year follow-up period, including 380 as a result of colorectal cancer and 153 as a result of cardiovascular disease (CVD). In analyses of prediagnosis BMI (weight reported at baseline in 1992 to 1993; mean, 7 years before colorectal cancer diagnosis), obese BMI (≥ 30 kg/m 2 ) relative to normal BMI (18.5 to 24.9 kg/m 2 ) was associated with higher risk of mortality resulting from all causes (relative risk [RR], 1.30; 95% CI, 1.06 to 1.58), colorectal cancer (RR, 1.35; 95% CI, 1.01 to 1.80), and CVD (RR, 1.68; 95% CI, 1.07 to 2.65). Postdiagnosis BMI (based on weight reported; mean, 1.5 years after diagnosis) was not associated with all-cause or cause-specific mortality. Conclusion This study suggests that prediagnosis BMI, but not postdiagnosis BMI, is an important predictor of survival among patients with nonmetastatic colorectal cancer.
MEMORY AND ELECTROCONVULSIVE THERAPY
Authors: EMIL N. ZAMORA, RUDOLF KAELBLING
Journal: American Journal of Psychiatry (1965)

Unilateral electrode placement over the dominant hemisphere has recently been shown to avoid memory disturbance after ECT while retaining therapeutic efficacy(4, 9, 10). However, the only controls used were patients on bilateral ECT and, therefore, these studies did not conclusively show the role played by dominance. Furthermore, dominance was not established by detailed testing in any of the previous papers. The present experiment answers these questions by using as controls, patients who received unilateral ECT on their dominant hemisphere, and by the use of a special test battery to establish the preferred laterality for hand, leg and eye. Twenty-eight patients were randomly assigned to receive ECT either over the dominant or over the minor hemisphere. Electrodes were placed as described by Lancaster; otherwise standard, modified ECT was employed. Memory was tested with the Wechsler Memory Scale before the first ECT and after the fifth treatment. Drug intake was restricted during the study. Patients were chosen for ECT by their regular physician, but included in the study only if they had not received ECT within the last year, and if they had no evidence of neurological brain damage. The mean scores and standard deviations for each group of 14 patients were calculated. There was no significant difference in scores before ECT, but the second test showed a decrease of 8.1 percent in the group receiving ECT on the dominant side, while the patients with electrode placement over the nondominant hemisphere had an increase in their score of 10.6 percent. Analysis of variance for repeated measures was applied. The interaction effect of shock treatment and the dominance factor was significant beyond the .001 level. The effects of shock treatment and the dominance factor when considered individually were not significant. Thus the results conclusively show that only electrode placement over the dominant hemisphere is associated with memory loss, and that memory disturbance cannot be avoided simply by unilateral electrode placement regardless of dominance. ECT need no longer be accompanied by memory disturbance. More detailed testing for dominance, such as the battery employed in this study, can guide the psychiatrist in preventing this disturbing side effect. With the substantiation of other appropriate tests the design of this study can serve to elucidate asymmetrical localization of mental functions other than verbal memory, as well as to delineate variations to be expected in ambidextrous and left-handed patients.
Intravenous immunoglobulin promotes apoptosis of mature human B lymphocytes by using CD22 to modulate their antigen B cell receptor
Authors: S. Hillion, J.-F. Seite, J.-O. Pers, P. Youinou
Journal: Annals of the Rheumatic Diseases (2010)

Although widely used to treat inflammatory diseases, the mechanism by which intravenous immunoglobulin (IVIg) modulates immune function is not fully understood.

B cells from the blood of healthy volunteers and tonsils …
Human TLRs and IL-1Rs in Host Defense: Natural Insights from Evolutionary, Epidemiological, and Clinical Genetics
Authors: Jean-Laurent Casanova, Laurent Abel, Lluis Quintana-Murci
Journal: Annual Review of Immunology (2011)

Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) have TIR intracellular domains that engage two main signaling pathways, via the TIR-containing adaptors MyD88 (which is not used by TLR3) and TRIF (which is used only by TLR3 and TLR4). Extensive studies in inbred mice in various experimental settings have attributed key roles in immunity to TLR- and IL-1R-mediated responses, but what contribution do human TLRs and IL-1Rs actually make to host defense in the natural setting? Evolutionary genetic studies have shown that human intracellular TLRs have evolved under stronger purifying selection than surface-expressed TLRs, for which the frequency of missense and nonsense alleles is high in the general population. Epidemiological genetic studies have yet to provide convincing evidence of a major contribution of common variants of human TLRs, IL-1Rs, or their adaptors to host defense. Clinical genetic studies have revealed that rare mutations affecting the TLR3-TRIF pathway underlie herpes simplex virus encephalitis, whereas mutations in the TIR-MyD88 pathway underlie pyogenic bacterial diseases in childhood. A careful reconsideration of the contributions of TLRs and IL-1Rs to host defense in natura is required.
Diagnostic strategy for the assessment of rheumatoid vasculitis
Authors: A E Voskuyl
Journal: Annals of the Rheumatic Diseases (2003)

To determine the clinical features associated with histologically proven rheumatoid vasculitis (HRV) and the additional diagnostic value of serological markers in an inception cohort of 81 patients with rheumatoid arthritis (RA) suspected of RV.The presence and number of recently developed extra-articular manifestations (EAMs) and a weighted EAM score, as well as the levels of serological markers, were compared between 31 patients with RA with histologically proven vasculitis and 50 patients with RA in whom vasculitis could not be documented histologically. The following markers were evaluated: circulating immune complexes, complement components C3 and C4, class-specific rheumatoid factors (IgM RF, IgG RF, IgA RF), antineutrophil cytoplasmic antibodies, antinuclear antibodies, antiendothelial antibodies, circulating intercellular adhesion molecule-1 and -3, circulating vascular cell adhesion molecule and E-selectin, cellular fibronectin, von Willebrand factor antigen, and C reactive protein. The diagnostic value of these markers, in addition to the clinical features, was evaluated with logistic regression analysis.Peripheral neuropathy or purpura/petechiae, or both, were the most important clinical features to discriminate patients with RA with and without histologically proven RV. The presence of a high number of EAMs and a higher weighted EAM score in patients with RA suspected of vasculitis were also associated with an increased probability of histologically proven RV. After adjustment for EAMs, only the combination of an increased serum IgA RF level and a decreased serum C3 level appeared to make an additional contribution to the diagnosis histologically proven RV. Evidence of systemic vasculitis was found in a muscle biopsy of the rectus femoris in 9/14 (64%) patients with vasculitis with neuropathy and in 3/11 (27%) patients with purpura/petechiae and vasculitis of the skin.In the diagnostic process of RV the presence of peripheral neuropathy and/or purpura/petechiae or a high weighted EAM score will increase the probability of histologically proven RV. Of the circulating factors previously suggested to be markers for RV only IgA RF and C3 further increase the probability of histologically proven RV and may be useful to guide diagnostic decisions.
Some 'brain' in the heart: a novel microdomain with neuronal Na channels responsible for arrhythmias?
Authors: L. S. Maier
Journal: Cardiovascular Research (2015)

This editorial refers to ‘Neuronal Na+ channel blockade suppresses arrhythmogenic diastolic Ca2+ release’ by P.B. Radwanski et al ., doi:10.1093/cvr/cvu262. 

Arrhythmias are a well-accepted cause for morbidity and mortality. This is true both for atrial as well as ventricular arrhythmias. In general, atrial fibrillation can lead to the progression of cardiac diseases such as heart failure whereas ventricular arrhythmias can lead to sudden cardiac death.

Although several antiarrhythmic drugs are currently available and invasive ablation therapies have been established throughout the recent years both for atrial as well as ventricular arrhythmias, the prognosis has not been improved except for ICD therapy.

One reason for this caveat may be that the basic mechanisms for arrhythmias are still poorly understood. Moreover, some of the novel mechanisms for arrhythmias have not been translated into clinical routine yet.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare congenital arrhythmogenic disease leading to sudden cardiac death without structural heart disease. Several mutations were described including the RyR2 gene1 encoding the cardiac isoform of the sarcoplasmic reticulum (SR) Ca-release channel (ryanodine receptor) as well as the SR Ca-binding protein calsequestrin (CASQ2).2,3

Radwanski et al. 4 describe a new proarrhythmogenic mechanism in the well-known CASQ2 (R33Q) CPVT mouse model3 that seems clinically …
Evolutionary Dynamics of Rhodopsin Type 2 Opsins in Vertebrates
Authors: Shozo Yokoyama, Takashi Tada
Journal: Molecular Biology and Evolution (2009)

Among the five groups of visual pigments in vertebrates, the rhodopsin type 2 (RH2) group shows the largest number of gene duplication events. We have isolated three intact and one nonfunctional RH2 opsin genes each from Northern lampfish (Stenobrachius leucopsarus) and scabbardfish (Lepidopus fitchi). Using the deduced amino acid sequences of these and other representative RH2 opsin genes in vertebrates, we have estimated the divergence times and evolutionary rates of amino acid substitution at various stages of RH2 opsin evolution. The results show that the duplications of the lampfish and scabbardfish RH2 opsins have occurred ∼60 and ∼30 million years ago (Ma), respectively. The evolutionary rates of RH2 opsins in the early vertebrate ancestors were ∼0.25 × 10−9/site/year, which increased to ∼1 × 10−9 to 3 × 10−9/site/year in euteleost lineages and to ∼0.3 × 10−9 to 0.5 × 10−9/site/year in coelacanth and tetrapods.
Pre-operative liver biopsy in cirrhotic patients with early hepatocellular carcinoma represents a safe and accurate diagnostic tool for tumour grading assessment
Authors: Antonio Colecchia, Eleonora Scaioli, Lucia Montrone, Amanda Vestito, Anna Rita Di Biase, Martina Pieri, Antonia D’Errico-Grigioni, Maria Letizia Bacchi-Reggiani, Matteo Ravaioli, Gian Luca Grazi, Davide Festi
Journal: Journal of Hepatology (2010)
Validity of Controlled Clinical Trials of Psychotherapy: Findings From the NIMH Treatment of Depression Collaborative Research Program
Authors: J Stuart Ablon, Enrico E Jones
Journal: American Journal of Psychiatry (2002)

OBJECTIVE: This research extends a series of studies that have examined the process of psychotherapy. The authors hypothesized that manualized regimens of psychotherapy compared in a controlled clinical trial would overlap considerably in process and technique and that intervention strategies common to both treatments would be responsible for promoting patient change. METHOD: Expert therapists developed prototypes of the ideal regimens of brief interpersonal psychotherapy and cognitive behavior therapy using the Psychotherapy Process Q-Set, an instrument designed to provide a standard language for describing treatment processes. A separate set of clinical judges then used the Psychotherapy Process Q-Set to score the actual transcripts of interpersonal psychotherapy and cognitive behavior therapy sessions conducted as part of the NIMH Treatment of Depression Collaborative Research Program. The expert prototypes were then compared with actual therapy administered in order to determine the extent to which each form of therapy conformed to its ideal prototype. RESULTS: Both the interpersonal psychotherapy and cognitive behavior therapy sessions adhered most strongly to the ideal prototype of cognitive behavior therapy. In addition, adherence to the cognitive behavior therapy prototype yielded more positive correlations with outcome measures across both types of treatment. CONCLUSIONS: Relying on brand names of therapy can be misleading. These findings suggest that the basic premise of controlled clinical trials (i.e., that the compared interventions represent separate and distinct treatments) may not have been met in the NIMH Treatment of Depression Collaborative Research Program. The implications of these findings for using controlled clinical trials to study psychotherapy are discussed.
Anti-interferon gamma treatment blocks the ability of glutaraldehyde-polymerized allergens to inhibit specific IgE responses.
Authors: K T HayGlass, B P Stefura
Journal: The Journal of Experimental Medicine (1991)

The lymphokines interleukin 4 and interferon gamma (IFN-gamma) have been shown to play an important role in regulation of polyclonal immunoglobulin E (IgE) and IgG2a responses in vitro and in vivo. We demonstrate here that treatment with chemically modified ovalbumin (OA) results in long-lived, 97-99% inhibition of allergen-specific murine IgE responses and 10(3)-10(4)-fold increases in anti-OA IgG2a. Responses to unrelated antigens are not affected. Treatment with unmodified OA under the same conditions fails to inhibit primary or secondary IgE responses or to increase IgG2a but does lead to pronounced increases in OA-specific IgG1 production. Glutaraldehyde-polymerized ovalbumin (OA-POL)-induced changes in IgE and IgG2a responses are abrogated by in vivo treatment with purified monoclonal anti-IFN-gamma antibody (XMG 1.2), a finding indicative of preferential IFN-gamma production upon exposure to chemically modified, but not native, allergen. The results suggest the possibility that the pattern of cytokine synthesis elicited after exposure to protein antigens, and the resulting immune response, may be dependent upon the form of antigen to which the individual is exposed and consequently may be subject to manipulation.