tbuckley/cabot-search huggingface dataset:
Identification of an Immunogenic Subset of Metastatic Uveal Melanoma
Authors: Luke D. Rothermel, Arvind C. Sabesan, Daniel J. Stephens, Smita S. Chandran, Biman C. Paria, Abhishek K. Srivastava, Robert Somerville, John R. Wunderlich, Chyi-Chia R. Lee, Liqiang Xi, Trinh H. Pham, Mark Raffeld, Parthav Jailwala, Manjula Kasoji, Udai S. Kammula
Journal: Clinical Cancer Research (2015)

Uveal melanoma is a rare melanoma variant with no effective therapies once metastases develop. Although durable cancer regression can be achieved in metastatic cutaneous melanoma with immunotherapies that augment naturally existing antitumor T-cell responses, the role of these treatments for metastatic uveal melanoma remains unclear. We sought to define the relative immunogenicity of these two melanoma variants and determine whether endogenous antitumor immune responses exist against uveal melanoma.We surgically procured liver metastases from uveal melanoma (n = 16) and cutaneous melanoma (n = 35) patients and compared the attributes of their respective tumor cell populations and their infiltrating T cells (TIL) using clinical radiology, histopathology, immune assays, and whole-exomic sequencing.Despite having common melanocytic lineage, uveal melanoma and cutaneous melanoma metastases differed in their melanin content, tumor differentiation antigen expression, and somatic mutational profile. Immunologic analysis of TIL cultures expanded from these divergent forms of melanoma revealed cutaneous melanoma TIL were predominantly composed of CD8(+) T cells, whereas uveal melanoma TIL were CD4(+) dominant. Reactivity against autologous tumor was significantly greater in cutaneous melanoma TIL compared with uveal melanoma TIL. However, we identified TIL from a subset of uveal melanoma patients which had robust antitumor reactivity comparable in magnitude with cutaneous melanoma TIL. Interestingly, the absence of melanin pigmentation in the parental tumor strongly correlated with the generation of highly reactive uveal melanoma TIL.The discovery of this immunogenic group of uveal melanoma metastases should prompt clinical efforts to determine whether patients who harbor these unique tumors can benefit from immunotherapies that exploit endogenous antitumor T-cell populations. Clin Cancer Res; 22(9); 2237-49. ©2015 AACR.
Are the media losing faith in the NHS
Authors: Alex Vass
Journal: BMJ (2001)

Amid all the debates that have raged over the past couple of decades about how to make the health service more efficient, one thing has always seemed clear: that the NHS is sacred. Even Mrs Thatcher, when her government introduced market forces to the heath service, didn't dare tamper with the idea of an NHS free at the point of use. The NHS has been likened to a theological institution, something that inspires fervent, almost religious belief ( BMJ 1999;319:1588-9): any suggestion that we should deliver health care any other way is likely to be dismissed as heresy.

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Or is it? Have horror stories of arduous trolley waits, filthy wards, staff shortages, and doctors and nurses at breaking point meant that we are now …

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NCCN Guidelines for Survivorship Expanded to Address Two Common Conditions
Authors: Elizabeth Kvale, Susan G. Urba
Journal: Journal of the National Comprehensive Cancer Network (2014)

The NCCN Clinical Practice Guidelines in Oncology for Survivorship include a new section on cancer-associated cognitive impairment and an expanded section on adult cancer pain that more completely addresses chemotherapy-induced peripheral neuropathy. These additions to the guidelines are the result of increasing awareness that long-term cancer survivors struggle with many late effects. Both the assessment and the management of cognitive impairment still lack a strong evidence-based foundation. The management of peripheral neuropathy, including the use of anti-depressants and opioids, often in combination, is backed by data primarily derived from clinical trials performed for various types of peripheral neuropathy.
Abstract P054: Prevalence and Sociodemographic Determinants of Cardiovascular Health in a Sample of Adults From a Developing Country: Results From the Chicamocha Cohort Study
Authors: Víctor M Herrera, Christina M Shay, Yeny Z Castellanos, Juan C Villar
Journal: Circulation (2015)

Background:  The novel AHA9s concept of cardiovascular health (CVH) extends the traditional factor composition by incorporating promotion of primordial prevention into a more comprehensive framework. We aimed to estimate the prevalence of CVH and to identify potential sociodemographic determinants in a sample of adults from Colombia.   Methods:  We conducted a cross-sectional analysis on a subsample of adults, free of transfusion-transmitted infectious and cardiovascular diseases, who attended to a follow-up evaluation of the CHICAMOCHA cohort study. We determined the proportion of participants with ideal healthy behaviors (never/former smoking, ≥150 minutes/week of moderate-vigorous physical activity, and consumption of ≥5 servings of fruits and vegetables per day) and health factors, including body mass index (   Results:  We evaluated 624 participants (mean age = 50.3 years; 64.6% male). Ideal diet was the least prevalent CVH component (0.5%) and ideal smoking status was the most frequent component (90.4%). Prevalence of the number of ideal cardiovascular health components was 2.3%, 48.2%, 46.3%, and 3.2% for 0-1, 2-3, 4-5, and 6-7 items, respectively. Age and educational attainment, but not sex or SES, were associated with higher numbers of CVH components. In a multivariate model including age, sex, and education, older participants were less likely to have a higher number of CVH components and there was evidence of an age-by-education interaction (p=0.018). PRs for a high cardiovascular health score were 0.60 (95%CI: 0.48, 0.75) and 0.40 (95%CI: 0.29, 0.55) in participants with low educational attainment aged 45-55 and ≥55 years old, as compared to participants    Conclusion:  Colombians exhibit fewer components of ideal CVH with increasing age; however, educational attainment seems to attenuate this age-related loss of CVH, an effect that might be explained by higher levels of risk factors awareness and treatment adherence.
Abstract 16719: STIM1 Inhibits GSK3-Beta to Maintain Cardiac Hypertrophy in a Murine Pressure Overload Induced Heart Failure Model
Authors: Ludovic O Bénard, Daniel S Matasic, Jae Gyun Oh, Mathieu Nonnenmacher, Erik Kohlbrenner, Roger J Hajjar, Jean-Sébastien Hulot
Journal: Circulation (2014)

STromal Interaction Molecule 1 (STIM1) is the sensor of endoplasmic reticulum Ca2+ store in non-contractile cells. In cardiac myocytes (CM), we demonstrated that pressure-overload induced hypertrophy led to an increase in STIM1 expression and to the activation of STIM1-induced currents that promote CM hypertrophy.  Our objective was to further investigate the role of STIM1 in the transition to heart failure (HF). We performed Transverse Aortic Constriction surgery (TAC) on control and AAV9.shSTIM1 infected mice to induce cardiac hypertrophy and failure.  In a first approach, STIM1 was silenced before TAC. As compared to TAC-controls, TAC-shSTIM1-treated mice showed a complete prevention of the development of cardiac hypertrophy (IVSd, mm: 1.46±0.07 in control vs. 1.01±0.11 in shSTIM1 mice, p  In a second experiment, STIM1 silencing was performed after TAC at the time when mice had developed compensated hypertrophy. In the 5 weeks following AAV administration, AAV9.shSTIM1-treated mice were unable to maintain the established cardiac hypertrophy, which resulted in a rapid worsening in contractile dysfunction and the development of LV dilation (IVSd, mm: 1.45±0.23 vs. 1.04±0.14 and LVIDd, mm: 3.54±0.54 vs. 4.75±0.38 in control and shSTIM1 mice respectively; p  Western blotting on total hearts and isolated CM from AAV9.shSTIM1-treated mice showed a profound reduction in AKT and GSK3β phosphorylation, thus suggesting GSK3β activation after STIM1 silencing. Concordantly, treatment with a GSK3β pharmacological inhibitor restored the ability of TAC-shSTIM1-treated mice to maintain cardiac hypertrophy and prevent the rapid transition to HF.  In a phospho-proteome profiling in HEK cells, we further observed that activation of STIM1-ORAI complex after thapsigargin-induced Ca2+ store depletion increased phosphorylation of AKT and GSK3β. Treatment of HEK cells with an ORAI inhibitor, blocking STIM1 dependent Ca2+ entry, led to decrease of phosphorylation of AKT and GSK3β.  These data support a model where activation of STIM1 promotes CM growth by repressing the anti-hypertrophic effects of GSK3β through regulation of AKT.
SAR405838: A Novel and Potent Inhibitor of the MDM2:p53 Axis for the Treatment of Dedifferentiated Liposarcoma
Authors: Kate Lynn J. Bill, Jeannine Garnett, Isabelle Meaux, XiaoYen Ma, Chad J. Creighton, Svetlana Bolshakov, Cedric Barriere, Laurent Debussche, Alexander J. Lazar, Bethany C. Prudner, Lucia Casadei, Danielle Braggio, Gonzalo Lopez, Abbie Zewdu, Hemant Bid, Dina Lev, Raphael E. Pollock
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Dedifferentiated liposarcoma (DDLPS) is an aggressive malignancy that can recur locally or disseminate even after multidisciplinary care. Genetically amplified and expressed MDM2, often referred to as a “hallmark” of DDLPS, mostly sustains a wild-type p53 genotype, substantiating the MDM2:p53 axis as a potential therapeutic target for DDLPS. Here, we report on the preclinical effects of SAR405838, a novel and highly selective MDM2 small-molecule inhibitor, in both in vitro and in vivo DDLPS models. Experimental Design: The therapeutic effectiveness of SAR405838 was compared with the known MDM2 antagonists Nutlin-3a and MI-219. The effects of MDM2 inhibition were assessed in both in vitro and in vivo. In vitro and in vivo microarray analyses were performed to assess differentially expressed genes induced by SAR405838, as well as the pathways that these modulated genes enriched. Results: SAR405838 effectively stabilized p53 and activated the p53 pathway, resulting in abrogated cellular proliferation, cell-cycle arrest, and apoptosis. Similar results were observed with Nutlin-3a and MI-219; however, significantly higher concentrations were required. In vitro effectiveness of SAR405838 activity was recapitulated in DDLPS xenograft models where significant decreases in tumorigenicity were observed. Microarray analyses revealed genes enriching the p53 signaling pathway as well as genomic stability and DNA damage following SAR405838 treatment. Conclusions: SAR405838 is currently in early-phase clinical trials for a number of malignancies, including sarcoma, and our in vitro and in vivo results support its use as a potential therapeutic strategy for the treatment of DDLPS.
External validation of the French predictive model to estimate PAH survival: A REVEAL analysis
Authors: Michael McGoon, Raymond Benza, Adaani Frost, David Badesch, C. Gregory Elliott, Olivier Sitbon, Gerald Simonneau, Dave Miller, Erwan Muros Le Rouzic, Marc Humbert
Journal: European Respiratory Journal (2012)

Background: The F rench P ulmonary Hypertension N etwork (FPHN) and R egistry to EV aluate E arly A nd L ong-term Pulmonary Arterial Hypertension (PAH) Disease Management (REVEAL) recently developed models to predict survival in PAH patients (pts).

Aims and Objectives: The FPHN equation was tested in a REVEAL cohort to assess its generalizability in a different PAH population.

Methods: The REVEAL validation cohort had 436 recently diagnosed (<1 year before enrollment), treatment-naive, ≥18-year-old patients (pts) with idiopathic, familial, or anorexigen-induced PAH, divided into subgroups with non-missing (n=292) and missing (n=144) data for all FPHN equation parameters.

Results: The FPHN and REVEAL cohorts had similar characteristics. FPHN follow-up (f/u) was ≥3 years; REVEAL validation cohort and subgroup with non-missing data had a mean f/u from diagnosis of 29.2 and 30.1 months, respectively. FPHN model parameters applied to REVEAL showed a good correlation of estimated hazard ratios between the two studies and robust C index of 0.72 (95% CI, 0.64–0.80). Risk stratification based on the FPHN equation showed good discrimination in REVEAL between high and low-risk pts. Survival in REVEAL correlated with FPHN equation predictions and was slightly better than predicted (Figure).

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Conclusion: The FPHN equation accurately stratified a matched US population according to risk, suggesting its prognostic generalizability in PAH pts.

 [1]: pending:yes
Conserved Curvature of RNA Polymerase I Core Promoter Beyond rRNA Genes: The Case of the Tritryps
Authors: Pablo Smircich, María Ana Duhagon, Beatriz Garat
Journal: Genomics Proteomics & Bioinformatics (2015)

Abstract In trypanosomatids, the RNA polymerase I (RNAPI)-dependent promoters controlling the ribosomal RNA (rRNA) genes have been well identified. Although the RNAPI transcription machinery recognizes the DNA conformation instead of the DNA sequence of promoters, no conformational study has been reported for these promoters. Here we present the in silico analysis of the intrinsic DNA curvature of the rRNA gene core promoters in Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major. We found that, in spite of the absence of sequence conservation, these promoters hold conformational properties similar to other eukaryotic rRNA promoters. Our results also indicated that the intrinsic DNA curvature pattern is conserved within the Leishmania genus and also among strains of T. cruzi and T. brucei. Furthermore, we analyzed the impact of point mutations on the intrinsic curvature and their impact on the promoter activity. Furthermore, we found that the core promoters of protein-coding genes transcribed by RNAPI in T. brucei show the same conserved conformational characteristics. Overall, our results indicate that DNA intrinsic curvature of the rRNA gene core promoters is conserved in these ancient eukaryotes and such conserved curvature might be a requirement of RNAPI machinery for transcription of not only rRNA genes but also protein-coding genes.
The Role of Prostate-specific Antigen Persistence After Radical Prostatectomy for the Prediction of Clinical Progression and Cancer-specific Mortality in Node-positive Prostate Cancer Patients
Authors: Lorenzo Bianchi, Alessandro Nini, Marco Bianchi, Giorgio Gandaglia, Nicola Fossati, Nazareno Suardi, Marco Moschini, Paolo Dell’Oglio, Riccardo Schiavina, Francesco Montorsi, Alberto Briganti
Journal: European Urology (2015)
DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates
Authors: Jieun Shin, Tomoki Maekawa, Toshiharu Abe, Evlambia Hajishengallis, Kavita Hosur, Kalyani Pyaram, Ioannis Mitroulis, Triantafyllos Chavakis, George Hajishengallis
Journal: Science Translational Medicine (2015)

Developmental endothelial locus–1 (DEL-1) is an endogenous homeostatic regulator of osteoclasts that blocks inflammatory bone loss in nonhuman primates.
Extracorporeal Shock Wave Lithotripsy for Urinary Stone Disease: Clinical Experience with the Electromagnetic Lithotriptor ‘Lithostar’
Authors: J. Simon, A. Corbusier, A. Mendes Leal, M. Van Den Bossche, E. Wespes, G. Van Regemorter, C.C. Schulman
Journal: European Urology (1989)
Antidepressant Use During Pregnancy and the Risk of Autism Spectrum Disorder in Children
Authors: Takoua Boukhris, Odile Sheehy, Laurent Mottron, Anick Bérard
Journal: JAMA Pediatrics (2015)

The association between the use of antidepressants during gestation and the risk of autism spectrum disorder (ASD) in children is still controversial. The etiology of ASD remains unclear, although studies have implicated genetic predispositions, environmental risk factors, and maternal depression.To examine the risk of ASD in children associated with antidepressant use during pregnancy according to trimester of exposure and taking into account maternal depression.We conducted a register-based study of an ongoing population-based cohort, the Québec Pregnancy/Children Cohort, which includes data on all pregnancies and children in Québec from January 1, 1998, to December 31, 2009. A total of 145,456 singleton full-term infants born alive and whose mothers were covered by the Régie de l'assurance maladie du Québec drug plan for at least 12 months before and during pregnancy were included. Data analysis was conducted from October 1, 2014, to June 30, 2015.Antidepressant exposure during pregnancy was defined according to trimester and specific antidepressant classes.Children with ASD were defined as those with at least 1 diagnosis of ASD between date of birth and last date of follow-up. Cox proportional hazards regression models were used to estimate crude and adjusted hazard ratios with 95% CIs.During 904,035.50 person-years of follow-up, 1054 children (0.7%) were diagnosed with ASD; boys with ASD outnumbered girls by a ratio of about 4:1. The mean (SD) age of children at the end of follow-up was 6.24 (3.19) years. Adjusting for potential confounders, use of antidepressants during the second and/or third trimester was associated with the risk of ASD (31 exposed infants; adjusted hazard ratio, 1.87; 95% CI, 1.15-3.04). Use of selective serotonin reuptake inhibitors during the second and/or third trimester was significantly associated with an increased risk of ASD (22 exposed infants; adjusted hazard ratio, 2.17; 95% CI, 1.20-3.93). The risk was persistent even after taking into account maternal history of depression (29 exposed infants; adjusted hazard ratio, 1.75; 95% CI, 1.03-2.97).Use of antidepressants, specifically selective serotonin reuptake inhibitors, during the second and/or third trimester increases the risk of ASD in children, even after considering maternal depression. Further research is needed to specifically assess the risk of ASD associated with antidepressant types and dosages during pregnancy.
Preconditioning and limitation of stunning one step closer to the protected protein(s)?
Authors: J Lamers
Journal: Cardiovascular Research (1999)

Brief periods of ischaemia, are known to induce a reversible deficit in myocardial function despite the maintenance of histological and metabolic integrity, a phenomenon initially described by Heyndrickx et al. in 1975, and called stunning several years after [1]. In that first study it was reported that several hours were required for complete recovery of regional contractility following a 5 min occlusion of the left anterior descending coronary artery in conscious dogs and up to 24 h were needed for complete recovery following a 15 min occlusion [1]. Therefore, myocardial stunning is considered to represent reversible injury contrasting the irreversible injury of myocardial infarction. The phenomenon has been described in every species studied so far, does occur in several clinical settings and likely plays an important role in the morbidity of patients with coronary artery disease [2]. Although the principal cause of the reversible contractile dysfunction is not fully understood, there is now consensus that loss of Ca2+ responsiveness of the myofilaments represents a major underlying mechanism as first proposed by Kusuoka et al. in 1987 on basis of experiments with isolated perfused ferret hearts [3]. Initially some studies suggested an additional role of failing sarcoplasmic reticulum Ca2+ pump, but this could not be substantiated [4]. There is evidence that abnormalities in myofilaments also underly stunning induced in clinically relevant large animal models. For instance, it was shown in the in situ porcine model that the potent Ca2+ sensitizer (EMD 60263), without phosphodiesterase inhibitory properties, increased segment length shortening to a greater extent in stunned than in non-stunned myocardium [5]. These findings were consistent with the left-and upward shifts of the p[Ca2+]/Mg2+-ATPase curves induced by Ca2+ sensitizer as observed with isolated myofibrils from stunned pig myocardium … 

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Diagnostic prediction models for suspected pulmonary embolism: systematic review and independent external validation in primary care
Authors: Janneke M T Hendriksen, Geert-Jan Geersing, Wim A M Lucassen, Petra M G Erkens, Henri E J H Stoffers, Henk C P M van Weert, Harry R Büller, Arno W Hoes, Karel G M Moons
Journal: BMJ (2015)

<b>Objective</b> To validate all diagnostic prediction models for ruling out pulmonary embolism that are easily applicable in primary care. <b>Design</b> Systematic review followed by independent external validation study to assess transportability of retrieved models to primary care medicine. <b>Setting</b> 300 general practices in the Netherlands. <b>Participants</b> Individual patient dataset of 598 patients with suspected acute pulmonary embolism in primary care. <b>Main outcome measures</b> Discriminative ability of all models retrieved by systematic literature search, assessed by calculation and comparison of C statistics. After stratification into groups with high and low probability of pulmonary embolism according to pre-specified model cut-offs combined with qualitative D-dimer test, sensitivity, specificity, efficiency (overall proportion of patients with low probability of pulmonary embolism), and failure rate (proportion of pulmonary embolism cases in group of patients with low probability) were calculated for all models. <b>Results</b> Ten published prediction models for the diagnosis of pulmonary embolism were found. Five of these models could be validated in the primary care dataset: the original Wells, modified Wells, simplified Wells, revised Geneva, and simplified revised Geneva models. Discriminative ability was comparable for all models (range of C statistic 0.75-0.80). Sensitivity ranged from 88% (simplified revised Geneva) to 96% (simplified Wells) and specificity from 48% (revised Geneva) to 53% (simplified revised Geneva). Efficiency of all models was between 43% and 48%. Differences were observed between failure rates, especially between the simplified Wells and the simplified revised Geneva models (failure rates 1.2% (95% confidence interval 0.2% to 3.3%) and 3.1% (1.4% to 5.9%), respectively; absolute difference −1.98% (−3.33% to −0.74%)). Irrespective of the diagnostic prediction model used, three patients were incorrectly classified as having low probability of pulmonary embolism; pulmonary embolism was diagnosed only after referral to secondary care. <b>Conclusions</b> Five diagnostic pulmonary embolism prediction models that are easily applicable in primary care were validated in this setting. Whereas efficiency was comparable for all rules, the Wells rules gave the best performance in terms of lower failure rates.
Systemic delivery of messenger RNA for the treatment of pancreatic cancer using polyplex nanomicelles with a cholesterol moiety
Authors: Satoshi Uchida, Hiroaki Kinoh, Takehiko Ishii, Akitsugu Matsui, Theofilus Agrios Tockary, Kaori Machitani Takeda, Hirokuni Uchida, Kensuke Osada, Keiji Itaka, Kazunori Kataoka
Journal: Biomaterials (2015)
The evolution of coordinated vocalizations before language
Authors: Gregory A. Bryant
Journal: Behavioral and Brain Sciences (2014)

Abstract Ackermann et al. briefly point out the potential significance of coordinated vocal behavior in the dual pathway model of acoustic communication. Rhythmically entrained and articulated pre-linguistic vocal activity in early hominins might have set the evolutionary stage for later refinements that manifest in modern humans as language-based conversational turn-taking, joint music-making, and other behaviors associated with prosociality.