tbuckley/cabot-search huggingface dataset:
Efficacy and safety of sunitinib malate (SU11248) in bevacizumab-refractory metastatic renal cell carcinoma (mRCC)
Authors: B. I. Rini, D. J. George, M. D. Michaelson, J. E. Rosenberg, R. M. Bukowski, J. A. Sosman, W. M. Stadler, K. Margolin, T. E. Hutson, C. M. Baum
Journal: Journal of Clinical Oncology (2006)

4522 Background: Sunitinib malate (SU11248) is an oral, multitargeted tyrosine kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR) family, platelet-derived growth factor receptor (PDGFR) and other related receptors. It has demonstrated anti-tumor activity in cytokine-refractory mRCC patients (pts). The activity of sunitinib in pts refractory to VEGF binding agents such as bevacizumab, however, has not been evaluated. It was hypothesized that tumor resistance to bevacizumab may be driven, in part, through pathways sensitive to inhibition by sunitinib. A phase II study evaluating the activity of sunitinib in bevacizumab-refractory mRCC was thus conducted. Methods: Pts with mRCC who demonstrated RECIST-defined disease progression within 3 months after bevacizumab-based therapy were treated with sunitinib (50 mg daily, 4 weeks of a 6-week cycle). Additional eligibility included measurable disease, clear cell histology, ≤ 2 prior systemic regimens, prior nephrectomy, performance status 0 or 1 and adequate organ function. The primary endpoint was objective response by RECIST criteria. A single-stage design was employed to test the null hypothesis that the true response rate is ≤ 5% versus the alternative hypothesis that the true response rate is ≥ 15%. Results: Accrual of 60 patients has been completed. Baseline characteristics include a median age of 59 years; 92% of pts had ≥ 2 metastatic sites and 23% had prior radiotherapy. Thirty-two of 60 pts enrolled are evaluable for response; 28 pts are too early for assessment. Twenty-six pts (81%) demonstrated some degree of tumor shrinkage, including, 4 pts (13%; 95% CI 4%, 29%) demonstrating an objective partial response. The most common treatment-related adverse events (AEs) included fatigue, diarrhea, dysgeusia, and nausea. Serious treatment-related AEs included fatigue, diarrhea, nausea and one fatal cerebral hemorrhage; 3 pts withdrew due to an AE. Conclusions: Sunitinib has substantial antitumor activity in bevacizumab-refractory mRCC pts, suggesting that sunitinib may inhibit signaling pathways involved in bevacizumab resistance. The precise mechanisms of response to sunitinib in bevacizumab-refractory tumors will require additional studies. [Table: see text]
Abstract P398: Uric Acid And Prehypertension: Salt Intake in Addition to Insulin Resistance are not Mediators.
Authors: Paulo A Lotufo, Itamar S Santos, Isabela M Bensenor
Journal: Circulation (2014)

Introduction: The association "uric acid and high blood pressure" is still matter of debate. Therefore, to distinguish serum uric acid as an independent factor for high blood pressure can start new trials to prevent hypertension. A paleoantropological rationale for this association was a knockout of uricase occurred during the Miocene among hominids that induced high levels of uric acid. As consequence, during food shortage times, high uric acid had an evolutionary benefit increasing salt-sensitivity for keep blood pressure and rising insulin resistance that maintaining high blood glucose levels provided fuel for the brain. Nowadays, the average levels of uric acid are substantially higher compared to chimpanzees, a uricase-deficient primate, and among remote populations as the yanomamo. Hypothesis: we assessed the hypothesis that the link between uric acid and blood pressure in individuals without hypertension is independent of sex, age, race, salt and alcohol intakes, glucose homeostasis, body-mass index and renal function. Methods: from the 15105 participants of the Brazilian Longitudinal Study for Adult Health (ELSA-Brasil) aged 35-74 years, we selected 7954 individuals (median age = 48 years-old; women =58.1; White = 56.6%) without hypertension, diabetes, previous cardiovascular diseases. The presence or not of prehypertension (7th JNC criteria) was the dependent variable and quartiles (Q) of serum uric acid, the independent variable. We applied an unconditional logistic regression adjusted for age and sex. After this, according to our hypothesis, we added the following variables: (1) 24-hour urinary sodium; (2) log Homeostasis Model Assessment (fasting blood glucose (mg/dL) х fasting insulin (mg/dL)/450), and (3) a full model, adding race, body-mass index, alcohol intake, and glomerular filtration rate by CKD-epi). Results: the uric acid quartiles ranges (md/dL) were Q1 ≤ 4.1; Q2:4.2-5.0; Q3:5.1-6.0; Q4: ≥ 6.1 and the number of participants were Q1= 1909; Q2=2029; Q3=2000; Q4= 2016. Considering Q1 as reference, the age-sex adjusted odds ratios (95% Confidence Interval) through the quartiles were: Q2= 1.22 (1.05-1.41); Q3= 1.40 (1.20-1.63); Q4= 2.03 (1.71-2.39) [P for trend &lt;0.001]. Adding 24 hour urinary sodium, the ORs (95% CI) were: Q2= 1.19 (1.01-1.40); Q3= 1.37 (1.16-1.62); and 1.94 (1.61-2.33) [P for trend &lt;0.001]. Adding HOMA-IR, the ORs (95% CI) were: Q2= 1.14 (0.97-1.34); Q3= 1.25(1.05-1.48); and Q4=1.62(1.34-1.96) [P for trend &lt;0.001]. Finally, for the full model the ORs were Q2= 1.04 (0.88-1.23); Q3= 1.05 (0.88-1.26) and Q4= 1.32(1.08-1.62) [P for trend &lt;0. 01]. Conclusion: Uric acid levels were correlated to prehypertension among a middle-aged urban population. It occurred independently of other variables classically associated to high blood pressure or the origin of higher uric acid in hominids.
Risk assessment in cancer patients with fever and neutropenia: a prospective, two-center validation of a prediction rule.
Authors: J A Talcott, R D Siegel, R Finberg, L Goldman
Journal: Journal of Clinical Oncology (1992)

The study was undertaken to validate a clinical model for predicting the medical risk of cancer patients with fever and neutropenia.A consecutive sample of 444 cancer patients with fever and neutropenia (granulocyte count less than 500/microL) at two hospitals, a specialized cancer referral center and a university-affiliated general medical hospital, was studied to identify clinical characteristics in the first 24 hours that predict subsequent serious medical complications during the hospital stay. To control for bias, major risk factors and complications were subject to blinded review.Serious medical complications occurred in 34% of patients with risk factors identified in a prior study, including prior inpatient status (group I), outpatients with a serious independent comorbidity (group II), or uncontrolled cancer (group III), compared with 5% of the remaining patients (group IV) (P less than .000001). Two of the complications in group IV patients were transient asymptomatic hypotension, and the remaining three complications occurred after at least 1 week of progressive medical deterioration. These risk groups were independently significant in stepwise logistic regression analysis. Multiple complications (17%) and death (10%) were common among patients in groups I through III but did not occur in group IV patients.This risk assessment model accurately stratified the medical risk of these patients using only clinical information available on the first day of their course. Low-risk patients are an appropriate population in which to study less intensive treatment strategies.
Intratumoral IL-15 potentiates radiation-induced anti-tumor immunity
Authors: Karsten Pilones, Joseph Aryankalayil, Silvia Formenti, Sandra Demaria
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Radiotherapy (RT) can induce T cell-mediated anti-tumor immune responses by multiple mechanisms but is often unable to overcome immunosuppression in the tumor microenvironment. The common gamma-chain cytokines interleukin (IL)-2 and IL-15 promote the proliferation of activated T
Lifetime Risk of Pulmonary Hypertension for All Patients After Shunt Closure
Authors: Annelieke C.M.J. van Riel, Ilja M. Blok, Aeilko H. Zwinderman, Elly M.C.J. Wajon, Arthur S.J.M. Sadee, Mirjam Bakker-de Boo, Arie P.J. van Dijk, Elke S. Hoendermis, Robert K. Riezebos, Barbara J.M. Mulder, Berto J. Bouma
Journal: Journal of the American College of Cardiology (2015)
Genetic variants associated with drugs-induced immediate hypersensitivity reactions: a PRISMA-compliant systematic review
Authors: A. Oussalah, C. Mayorga, M. Blanca, A. Barbaud, A. Nakonechna, J. Cernadas, M. Gotua, K. Brockow, J.-C. Caubet, A. Bircher, M. Atanaskovic, P. Demoly, L. K. Tanno, I. Terreehorst, J. J. Laguna, A. Romano, J.-L. Guéant
Journal: Allergy (2015)

Drug hypersensitivity includes allergic (AR) and nonallergic reactions (NARs) influenced by genetic predisposition. We performed a systematic review of genetic predictors of IgE-mediated AR and NAR with MEDLINE and PubMed search engine between January 1966 and December 2014. Among 3110 citations, the search selected 53 studies, 42 of which remained eligible. These eligible studies have evaluated genetic determinants of immediate reactions (IR) to beta-lactams (n = 19), NAR against aspirin (n = 12) and other nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 8), and IR to biologics (n = 3). We reported two genomewide association studies and four case-control studies on candidate genes validated by replication. Genes involved in IR to beta-lactams belonged to HLA type 2 antigen processing, IgE production, atopy, and inflammation, including 4 genes validated by replications, HLA-DRA, ILR4, NOD2, and LGALS3. Genes involved in NAR to aspirin belonged to arachidonic acid pathway, membrane-spanning 4A gene family, histamine production pathway, and pro-inflammatory cytokines, while those involved in NAR to all NSAIDs belonged to arachidonic acid pathway and HLA antigen processing pathway. ALOX5 was a common predictor of studies on NAR to both aspirin and NSAIDs. Although these first conclusions could be drawn, this review highlights also the lack of reliable data and the need for replicating studies in contrasted populations, taking into account worldwide allele frequencies, gene-gene interactions, and contrasted situations of environmental exposure.
Abstract 16396: Phosphodiesterase-5 Expression and Activity is Increased in Children With Single Ventricle Heart Failure
Authors: Shelley D Miyamoto, Penny Nelson, Rebecca Sobus, Karin Nunley, Valencia Peterson, Brian L Stauffer, Carmen C Sucharov
Journal: Circulation (2014)

Introduction: Single ventricle congenital heart disease (SV) is the leading cause of cardiovascular death and indication for heart transplantation in infancy. There are no proven therapies for SV heart failure (HF). Human and animal models of HF demonstrate that myocardial phosphodiesterase-5 (PDE5) is increased with cardiac stress and treatment with a PDE5 inhibitor (PDE5i) results in enhanced cardiac function and prevents remodeling. Sildenafil, a PDE5i, is increasingly utilized for the treatment of patients suffering from failing SV. The objective of this study was to determine myocardial PDE5 expression and activity in children transplanted for failing SV. Methods: At the time of cardiac transplantation, explanted pediatric hearts were immediately cooled in ice cold oxygenated Tyrodes in the operating room. The tissue is rapidly dissected, flash frozen and stored at -80 0 C until further use. RNA, protein and cytosolic fractions were isolated from explanted right ventricle (RV) tissue from SV and non-failing (NF) donors. RTqPCR for PDE5, Western blot (normalized to calnexin loading control) for PDE5 and PDE5 activity assays were performed. For PDE 5 activity, cGMP hydrolysis was measured using [ 3 H]cGMP as the substrate. Sildenafil was added to measure PDE5 specific activity, and activity was calculated using nonlinear regression. Results: All patients used in the SV analysis had a failing morphologic RV and were selected from a cohort of 17 SV (median age 0.5, range 0.05-10 yrs) and 8 NF controls (median age 7, range 1.3-13 yrs). PDE5 gene expression was higher in SV myocardium compared to NF (1.9±0.7, n=17 SV vs 1.1±0.5 ct fold change, n=8 NF, p=0.02). There was a trend towards higher PDE5 protein expression in SV myocardium compared to NF (1.5±0.7, n=4 SV vs 1.0±0.4 protein expression normalized to NF, n=3 NF; p=ns). There was increased PDE5 activity in SV compared to NF (22.3±1.2, n=3 SV vs 11.9±4.2 pmol/mg/min, n=2 NF; p=0.02). Conclusions: There is increasing evidence that PDE5i has beneficial direct myocardial effects. There is increased PDE5 gene expression and activity in failing SV myocardium compared to NF control suggesting that PDE5 may represent a promising therapeutic target in this challenging population.
Online “living will” tool is launched to help ensure that people’s care wishes are respected
Authors: Clare Dyer
Journal: BMJ (2015)

A campaign has been launched to help people ensure that their wishes about treatment and care are respected, even when they lose the ability to take decisions for themselves.

A non-profit online tool, mylivingwill.org.uk, sets out the law on “living wills” and outlines the steps for creating advance decisions and advance statements that can be downloaded, signed, and given to doctors and patients’ family members.

The website has …
Abstract 18728: Discovery Lipidomic and Metabolomic Profiling Predicts Longitudinal Changes in Metabolic Risk Factors
Authors: Christine M Willinger, Xiaoyan Yin, Peter Juhasz, Paul Courchesne, Pieter Muntendam, Neal Gordon, Aram Adourian, Martin G Larson, Daniel Levy
Journal: Circulation (2014)

BACKGROUND: Metabolic syndrome is associated with increased risk for cardiovascular disease and type 2 diabetes, but the molecular mechanisms underpinning its constituent risk factors are unclear. We sought to identify predictive markers of metabolic risk by testing for associations of lipids and metabolites with longitudinal changes in metabolic traits. METHODS: Discovery liquid chromatography-tandem mass spectrometry profiling of 154 lipids and gas chromatography-mass spectrometry profiling of 119 metabolites was conducted on plasma samples from 554 Framingham Heart Study participants with baseline and follow-up clinic examinations (5-7 years later) at which body mass index (BMI), triglycerides (TG), HDL cholesterol (HDL-C), and glucose were measured. Analytes were tested for association with longitudinal changes (Δ) in metabolic traits using general linear models, and multimarker panels were selected using forward selection. RESULTS: Our single marker analyses revealed distinct signatures of longitudinal changes in metabolic risk factors. Markers associated with ΔBMI were 1-palmitoyl lysophosphatidic acid (LPA 16:0; p=2.8x10 -4 ), its precursor lysophosphatidylcholine (LPC 16:0; p=6.7x10 -5 ), and four other LPC species. Subclasses of sphingomyelins (SMs) were associated with changes in TG, HDL-C, and glucose. Sphingadiene (d18:2) variants were associated with ΔHDL-C [SM(d18:2/24:1), p=2.8x10 -6 ; SM (d18:2/20:0), p=1.2x10 -4 ]. Canonical SMs were associated with ΔTG [SM (d18:1/16:0), p=1.8x10 -5 ; SM (d18:1/17:0), p=2.1x10 -5 ]. Two dihydrosphingosine (d18:0) variants were associated with Δglucose [SM 36:0, p=5.0x10 -5 ; SM (d18:0/24:0), p=3.2x10 -4 ]. Metabolite markers for ΔTG included quinic acid (p=9.1x10 -5 ) and sitosterol (p=1.0x10 -4 ). Top markers were selected in multimarker panels that explained a significant proportion of longitudinal change in each metabolic trait (2.5-15.3%) beyond baseline covariates. CONCLUSIONS: Using lipidomic and metabolomic profiling in parallel, we identified lipid-centric signatures of longitudinal changes in metabolic traits and demonstrated their predictive power. Our results suggest that specific derangements in lipid metabolic pathways may underlie metabolic risk.
Psychological Distress, Interpersonal Closeness and Discrimination following the &lt;b&gt;&lt;i&gt;Charlie Hebdo&lt;/i&gt;&lt;/b&gt; Attacks
Authors: Robin Goodwin, Elazar Leshem, Menachem Ben-Ezra
Journal: Psychotherapy and Psychosomatics (2016)

Terrorist attacks in January 2015 in Paris on the satirical magazine Charlie Hebdo, and related incidents on subsequent days, left 17 dead and 22 injured. Reported as ‘the French 9/11’ these were portrayed by some as leading to national trauma across the country (1).  Widespread indirect exposure via media coverage can amplify psychological distress and promote emotional responses well away from the ‘bulls-eye’ of any event, with media exposure following terrorist attacks more strongly associated with PTSD than direct exposure (2). Switching between multiple media outlets may be particularly taxing (3), as individuals are exposed to both traditional media and graphic content through social media. Shared social stresses may subsequently impact on personal relationships with close others, as well as members of potential out-groups. Terror management theories (4) suggest we seek intimacy and support from others to cope with personal threats. This then reduces existential distress by validating self-esteem and personal beliefs. In contrast, mortality threats can lead to the rejection of others who threaten or undermine our world views, leading to scapegoating and stigmatisation (5). We report data from a national survey exploring the association between media use, psychological distress, relational intimacy, and willingness to interact with Muslims four weeks after the attacks.
Cathepsin S Cleavage of Protease-Activated Receptor-2 on Endothelial Cells Promotes Microvascular Diabetes Complications
Authors: Santhosh Kumar VR, Murthy N. Darisipudi, Stefanie Steiger, Satish Kumar Devarapu, Maia Tato, Onkar P. Kukarni, Shrikant R. Mulay, Dana Thomasova, Bastian Popper, Jana Demleitner, Gabriele Zuchtriegel, Christoph Reichel, Clemens D. Cohen, Maja T. Lindenmeyer, Helen Liapis, Solange Moll, Emma Reid, Alan W. Stitt, Brigitte Schott, Sabine Gruner, Wolfgang Haap, Martin Ebeling, Guido Hartmann, Hans-Joachim Anders
Journal: Journal of the American Society of Nephrology (2015)

Endothelial dysfunction is a central pathomechanism in diabetes-associated complications. We hypothesized a pathogenic role in this dysfunction of cathepsin S (Cat-S), a cysteine protease that degrades elastic fibers and activates the protease-activated receptor-2 (PAR2) on endothelial cells. We found that injection of mice with recombinant Cat-S induced albuminuria and glomerular endothelial cell injury in a PAR2-dependent manner. In vivo microscopy confirmed a role for intrinsic Cat-S/PAR2 in ischemia-induced microvascular permeability. In vitro transcriptome analysis and experiments using siRNA or specific Cat-S and PAR2 antagonists revealed that Cat-S specifically impaired the integrity and barrier function of glomerular endothelial cells selectively through PAR2. In human and mouse type 2 diabetic nephropathy, only CD68(+) intrarenal monocytes expressed Cat-S mRNA, whereas Cat-S protein was present along endothelial cells and inside proximal tubular epithelial cells also. In contrast, the cysteine protease inhibitor cystatin C was expressed only in tubules. Delayed treatment of type 2 diabetic db/db mice with Cat-S or PAR2 inhibitors attenuated albuminuria and glomerulosclerosis (indicators of diabetic nephropathy) and attenuated albumin leakage into the retina and other structural markers of diabetic retinopathy. These data identify Cat-S as a monocyte/macrophage-derived circulating PAR2 agonist and mediator of endothelial dysfunction-related microvascular diabetes complications. Thus, Cat-S or PAR2 inhibition might be a novel strategy to prevent microvascular disease in diabetes and other diseases.
Complete, understandable information is essential
Authors: A. M C Webb, N. S Khan, A. Butler
Journal: BMJ (1996)

EDITOR,—We share David R Bromham's concern that users lose out when misleading information about contraception limits choice.1 Between September 1993 and the end of June 1995, levonorgestrel implant capsules were inserted on 184 occasions in the community family planning clinics in Manchester. All were inserted by doctors during or after completion of the training programme organised by the manufacturers.

We carried out an audit of all the women who had had implants inserted. Our outcome measures were continuation rates and levels of satisfaction among …
Abstract 11065: Paradoxical Impact of Overweightness on Mortality in Lung Transplantation
Authors: Kongkiat Chaikriangkrai, Hye Yeon Jhun, Soma Jyothula
Journal: Circulation (2014)

Background: Prognostic value of body mass index (BMI) and cardiorespiratory fitness (CRF) has been described extensively in various populations. The objective of this study was to examine impact of BMI and CRF on all-cause mortality in isolated lung transplant recipients. Methods: Consecutive isolated lung transplant recipients from 2008 to 2013 were identified. Pre-transplant cardio-metabolic risk factors were collected. The cohort was categorized using BMI into normal (BMI 18.5-24.9 kg/m 2 ), underweight (BMI &lt; 18.5 kg/m 2 ), overweight (BMI 25.0-29.9 kg/m 2 ) and obese (BMI ≥ 30 kg/m 2 ). Fit patient was defined as those who had pre-transplant six-minute-walk distance &gt; 300 m. Results: The study comprised of 324 patients with mean age of 57 ± 13 years. Fifty eight percent were male. Primary lung pathologies were 26.9% obstructive, 2.5% vascular, 6.5% cystic fibrosis and 64.2% restrictive lung diseases. Pertinent cardio-metabolic risk factors included 36.7% normal weight, 9.9% underweight, 33.6% overweight, 19.8% obese, 21.9% unfit, 13.9% coronary artery disease, 55.6% hypertension, 29.6% diabetes mellitus, 42.3% hyperlipidemia, 42.9% smoking history. Annualized mortality rate stratified by BMI exhibited J-shaped distribution with lowest mortality in overweight group (p 0.005). Kaplan Meier analysis correspondingly showed highest survival in overweight strata (p 0.006). In subgroup analysis by CRF, paradoxical impact of overweightness on mortality was diminished in fit patients (p&gt;0.05) but not in those who were unfit (p&lt;0.05) as shown in figure 1. Conclusion: In our lung transplant cohort, BMI and mortality had J-shaped relationship with highest survival in overweight group. This paradoxical impact was diminished in patients who were fit. Our findings extend the paradigm of obesity paradox into lung transplantation arena.