tbuckley/cabot-search huggingface dataset:
Patient and caregiver benefit-risk preferences for non-metastatic castration-resistant prostate cancer treatment (nmCRPC).
Authors: Sandy Srinivas, Ateesha F. Mohamed, Sreevalsa Appukkuttan, Marc Botteman, Xinyi Ng, Namita Joshi, Jui-Hua Tsai, Jarjieh Fang, Adrian Reg Waldeck, Stacey J. Simmons
Journal: Journal of Clinical Oncology (2019)

196 Background: Second-generation androgen receptor inhibitors (SGARIs) have been recently approved for the management of nmCRPC based on documented improvements in metastasis-free survival. We used a discrete choice experiment (DCE) to examine how nmCRPC patients (pts) and caregivers perceive the benefits versus risks of SGARIs. Methods: nmCRPC pts and caregivers were invited to complete an online DCE survey of 14 treatment choice questions, each comparing 2 hypothetical medication profiles varying in terms of 5 safety attributes (frequency or severity of adverse events [AEs]: fatigue, skin rash, cognitive problems, serious falls, and serious fractures) and 2 efficacy attributes (duration of overall survival [OS] and time to pain progression). These attributes were selected based on in-depth qualitative interviews with pts, caregivers, and physicians. We used random parameters logit models to estimate preference weights and relative importance scores for each attribute. Results: 143 nmCRPC pts and 149 caregivers were included in the analysis. Both pts and caregivers viewed safety attributes in the following decreasing order of importance: fractures, falls, cognitive problems, fatigue, and rash. Compared to a reduction in rash severity from moderate to none, a similar reduction in cognitive problems severity was considered nearly as important by patients but twice as important by caregivers. On average, pts were willing to trade 5.8 and 4.0 months of OS to reduce the risks of serious fractures and falls, respectively, from 3% to 0%; the corresponding figures caregivers were willing to trade were 6.6 and 5.4 months of OS. Of note, 8.4% of pts and 14.8% of caregivers consistently chose the treatment profile with the lowest fall or fracture risk, regardless of the other attributes' values. Conclusions: nmCRPC pts and caregivers preferred treatments with lower AE burdens and were willing to trade substantial amounts of OS to avoid AEs. They viewed the reduction of fractures, falls, and cognitive problems as most important. In this relatively asymptomatic population, carefully balancing risks and benefits when selecting SGARI treatments is important to optimizing quality of survival.
Abstract 877: Thioredoxin-1 Maintains Cardiac Function and Metabolic Gene Expression via mTOR Signaling
Authors: Shinichi Oka, Wataru Mizushima, Chun-yang Huan, Junichi Sadoshima
Journal: Circulation Research (2019)

Thioredoxin-1 (Trx1) is a 12 kDa oxidoreductase that reduces proteins with disulfide bonds through thiol disulfide exchange reactions. Several lines of evidence show that Trx1 protects cardiomyocytes against stress, such as ischemia and pressure overload. However, due to the embryonic lethality of systemic Trx1 knockout mice, the role of endogenous Trx1 in cardiac function has not been tested with loss-of-function mice. In this study, we generated cardiac-specific Trx1 knockout (Trx1cKO) mice, using Trx1floxflox and αMHC-Cre transgenic mice, to elucidate the physiological role of Trx1 in the postnatal heart. The Trx1cKO mice were viable but started dying at 13 days of age. The median survival age was 27 days. Echocardiographic analyses indicated cardiac dysfunction in Trx1cKO mice, evidenced by reduced ejection fraction (WT: 0.78; Trx1cKO: 0.50*; p&lt;0.05 vs. WT). RNA-sequencing and pathway analyses revealed that metabolic genes involved in energy production were most prominently downregulated in Trx1cKO mice. Mitochondrial morphological abnormality and increased oxidative stress were evident in Trx1cKO mice. Among Trx1 substrates possibly involved in metabolic gene expression, mechanistic target of rapamycin (mTOR) was oxidized and inhibited in Trx1cKO mice. In cultured cardiomyocytes, Trx1 knockdown inhibited mTOR signaling, as evidenced by reduced phosphorylation of mTOR substrates, such as S6K and 4EBP1. Trx1 knockdown in cardiomyocytes inhibited mitochondrial protein expression, respiration and ATP production (relative ATP production in isolated mitochondria; control: 1; Trx1 knockdown: 0.69*; p&lt;0.05 vs. control), suggesting that Trx1 maintains mitochondrial function in a cell autonomous manner. Importantly, mTOR-C1483F mutant is resistant against oxidation and inactivation induced by downregulation of Trx1. Trx1 knockdown suppressed reporter gene activity driven by the promoter sequences of endogenous metabolic genes, such as Ndufa1 and Ndufs1, which was rescued by mTOR-C1483F. These results suggest that Trx1 is essential for cardiac function and metabolism, possibly through reduction of mTOR at Cys1483.
Hypertension in adults: summary of updated NICE guidance
Authors: Rebecca J Boffa, Margaret Constanti, Christopher N Floyd, Anthony S Wierzbicki
Journal: BMJ (2019)

### What you need to know

Hypertension is a leading global cause of morbidity and mortality. More than 25% of the adult UK population has hypertension, and in about 30% blood pressure remains uncontrolled.1 In August, the National Institute for Health and Care Excellence (NICE) published its updated guideline on the diagnosis and management of hypertension. The guideline reviews further evidence that has emerged since it was last updated in 2011 from randomised trials investigating the initiation, monitoring, and choice of antihypertensive treatment. The scope of the updated guideline has increased to also include people with type 2 diabetes, but does not make recommendations for people with chronic kidney disease, established cardiovascular disease, or hypertension in pregnancy.

This article summarises the most recent recommendations from NICE and includes information considered to be most relevant to primary care clinicians. Key changes to current practice include offering drug treatment to people at a lower threshold for 10 year risk of cardiovascular disease, emphasis on maintaining blood pressure below target, and clarifying criteria for same day specialist review in people with accelerated hypertension.

NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of …
Differences in lung function between children with sickle cell anaemia from West Africa and Europe
Authors: Michele Arigliani, Luigi Castriotta, Ramatu Zubair, Livingstone Gayus Dogara, Chiara Zuiani, Emma Raywood, Katy Vecchiato, Enrico Petoello, Ashel Dache Sunday, Sharon Ndoro, Mario Canciano Canciani, Atul Gupta, Paola Cogo, Baba Inusa
Journal: Thorax (2019)

Introduction Lung function abnormalities are common in sickle cell anaemia (SCA) but data from sub-Saharan Africa are limited. We hypothesised that children with SCA from West Africa had worse lung function than their counterparts from Europe. Methods This prospective cross-sectional study evaluated spirometry and anthropometry in black African individuals with SCA (haemoglobin phenotype SS) aged 6–18 years from Nigeria and the UK, when clinically stable. Age-matched controls were also included in Nigeria to validate the Global Lung Initiative spirometry reference values. Results Nigerian SCA patients (n=154) had significant reductions in both FEV 1 and FVC of ~1 z-score compared with local controls (n=364) and ~0.5 z-scores compared with the UK patients (n=101). Wasting (body mass index z-score&lt;−2) had a prevalence of 27% in Nigerian patients and 7% in the UK ones (p&lt;0.001). Among children with SCA, being resident in Nigeria (OR 2.4, 95% CI 1.1 to 4.9), wasting (OR 2.3, 95% CI 1.1 to 5.0) and each additional year of age (OR 1.2, 95% CI 1.1 to 1.4) were independently associated with increased risk of restrictive spirometry (FVC z-score&lt;−1.64+FEV 1 /FVC≥−1.64). Conclusions This study showed that chronic respiratory impairment is more severe in children with SCA from West Africa than Europe. Our findings suggest the utility of implementing respiratory assessment in African children with SCA to early identify those with chronic lung injury, eligible for closer follow-up and more aggressive therapies.
Emergency department surge and overcrowding: An interdisciplinary solution for an institutional issue.
Authors: Susan Gaeta, Toni Edwards, Sorayah Bourenane, Carmen E. Gonzalez, Karen McFarland, Danielle Milling
Journal: Journal of Clinical Oncology (2019)

242 Background: Emergency Department (ED) surges at MD Anderson Cancer Center (MDACC) lead to overcrowding, safety risks, privacy concerns, staff burnout, and adverse events associated with delays in care, including death. In 2015, the ED Interdisciplinary Quality &amp; Safety Committee (EDIQSC) at MDACC was developed to review and address safety events. We report on the preliminary results of a quality improvement project with a long-term goal of developing a systematic solution of proactively responding to ED surge and overcrowding (EDSO). Methods: First, EDIQSC reviewed the current literature regarding EDSO. Subsequently an ED Surge and ED Overcrowding Committee (EDSOC) was established to identify solutions to address patient safety risks and improve patient experience in the ED. Results: Literature review showed that NEDOCS (Weiss, SJ et al) was the best scoring tool to calculate ED Overcrowding levels. EDSOC’s weekly meetings facilitated by the Office of Performance Improvement (OPI) explored factors related to EDSO via FMEA a quality improvement tool that proactively evaluate process associated risks. In addition, the following immediate solutions were implemented in the ED: daily status reporting by ED to institutional leaders, a “fast-track” care area implementation, senior executive rounding during ED Surge, electronic medical record (EMR) configuration for high census accommodation, continuous ED Nursing Leadership unit needs assessment, and prioritization of needs based on hospital throughput. Additional interventions in current development include a real-time EMR dashboard accurately reflecting ED capacity, and a NEDOCS guided interdisciplinary operational action plan. Conclusions: ED Surge &amp; Overcrowding is a complex issue with various external and internal contributing factors that cannot be solved with one approach. It is a dynamic, interdisciplinary system that requires vigilant planning, assessment of downstream change effects, stakeholder agility and continuous risk anticipation. EDSOC continues these efforts in an attempt to develop and implement a comprehensive, interdisciplinary tool to direct institutional operations during times of ED Surge &amp; Overcrowding.
Long-noncoding RNAs (lncRNAs) in drug metabolism and disposition, implications in cancer chemo-resistance
Authors: Yue Wang, Zihui Fang, Mei Hong, Da Yang, Wen Xie
Journal: Acta Pharmaceutica Sinica B (2019)

Drug metabolism is an orchestrated process in which drugs are metabolized and disposed through a series of specialized enzymes and transporters. Alterations in the expression and/or activity of these enzymes and transporters can affect the bioavailability (pharmacokinetics, or PK) and therapeutic efficacy (pharmacodynamics, or PD) of drugs. Recent studies have suggested that the long non-coding RNAs (lncRNAs) are highly relevant to drug metabolism and drug resistance, including chemo-resistance in cancers, through the regulation of drug metabolism and disposition related genes. This review summarizes the regulation of enzymes, transporters, or regulatory proteins involved in drug metabolism by lncRNAs, with a particular emphasis on drug metabolism and chemo-resistance in cancer patients. The perspective strategies to integrate multi-dimensional pharmacogenomics data for future in-depth analysis of drug metabolism related lncRNAs are also proposed. Understanding the role of lncRNAs in drug metabolism will not only facilitate the identification of novel regulatory mechanisms, but also enable the discovery of lncRNA-based biomarkers and drug targets to personalize and improve the therapeutic outcome of patients, including cancer patients.
Abstract 855: Crif1 Haploinsufficiency in Heart Impairs Mitochondrial Oxidative Capacity and Leads to Aggravated Cardiac Dysfunction in Ioproterenol Infusion Model
Authors: Seon-Ah Jin, Hee Jung Seo, Jin-Ok Jeong
Journal: Circulation Research (2019)

Heart requires high energy metabolism to maintain contractile activity and pump sufficient blood flow to body. The optimal supply of energy from the mitochondria is very important for maintaining normal cardiac function. Crif1 is a critical protein for the synthesis and insertion of the OxPhos complex in mitochondria. Recent studies reported that conditional knockout of Crif1 in specific tissues is associated with mitochondrial dysfunction. To investigate the role of Crif1 and mitochondrial dysfunction in heart, we generated cardiac-specific, Crif1 haploinsufficient mice. Haploinsufficient Crif1 in heart resulted in abnormal structure of mitochondria and decreased maximal values of oxygen consumption rates in cardiomyocytes. Although cardiac specific, haploinsufficient Crif1 results in mitochondrial dysfunction, cardiac phenotype was still normal. However, their cardiac function was aggravated by stress condition, showing more decreased EF and FS after 4 weeks isoproterenol infusion. Cardiac hypertrophy, which is considered as normal compensatory mechanism, was not occurred during isoproterenol infusion. These indicate that Crif1 plays a critical role in the maintenance of mitochondrial structure and function of cardiomyocyte. Also, mitochondrial abnormalities in heart inhibit the compensatory mechanisms for stress and aggravate cardiac function.
Calcium Mobilization in Unfavorable-Prognosis Chronic Lymphocytic Leukemia Patients Mediates Focal Adhesion Kinase (FAK) Cleavage, Thereby Its Activation
Authors: Federica Frezzato, Veronica Martini, Filippo Severin, Flavia Raggi, Marco Piccoli, Andrea Visentin, Edoardo Scomazzon, Stefano Pravato, Silvia Imbergamo, Francesco Piazza, Monica Facco, Gianpietro Semenzato, Livio Trentin
Journal: Blood (2018)
Abstract 402: Adiponectin Receptor 3 is Associated With Endothelial Nitric Oxide Synthase Dysfunction and Predicts Insulin Resistance in South Asians
Authors: Mark Chandy, Nazish Sayed, Edward Lau, Chun Liu, Tzu-Tang Wei, Ian Y Chen, Dilip Thomas, June Rhee, Brad Oh, Lejla Pepic, Mansoor Husain, Thomas Quertermous, Shriram Nallamshetty, Joseph Wu
Journal: Circulation Research (2019)

Type 2 diabetes (T2DM) is a global epidemic affecting over 400 million people and causes significant morbidity and mortality. T2DM has a strong association with cardiovascular disease (CVD), the number one cause of death globally with 17.5 million deaths per year. A precursor of T2DM, insulin resistance is central to the development of T2DM and is a risk factor for CVD. Insulin resistance is difficult to diagnose and individuals are often untreated prior to the onset of T2DM or CVD. South Asians are more likely to have insulin resistance, diabetes and cardiovascular disease when compared to age matched European cohorts. The molecular mechanisms of why South Asians are predisposed to insulin resistance and consequently cardiovascular disease were investigated using induced pluripotent stem cells (iPSCs) derived endothelial cells (iPSC-EC). Endothelial cells line blood vessels of the cardiovascular system. Unlike previous models, iPSC-EC are unique because they contain the individual's genetic information and the environmental influences retained in epigenetic marks are removed via reprogramming and differentiation. iPSC-ECs from insulin resistant South Asians show evidence of impaired insulin signaling as evidenced by decreased Akt phosphorylation, and paradoxically overexpression of eNOS and adiponectin receptor 3. In the cellular milieu of prediabetes, insulin resistance iPSC-ECs show impaired tubule formation and nitric oxide release. When adiponectin receptor 3 expression is suppressed using siRNA, eNOS expression decreases and expression of components of the insulin signaling cascade are improved to levels observed in control iPSC-ECs. Multiple linear regression modeling of clinical characteristics and gene and cellular phenotype was used to develop a scoring system that predicts a patient’s risk of developing insulin resistance and hence subsequently diabetes and cardiovascular complications. To our knowledge, this is the first iPSC-derived endothelial cell risk calculator with the potential to identify South Asian patients at risk for developing insulin resistance and cardiovascular disease before disease onset, which would allow for the early implementation of interventions that prevent morbidity and mortality.
The Transition from Childhood to Adulthood in Chronic Immune Thrombocytopenia Patients: Clinical Management and the Role of Splenectomy and Thrombopoietin Receptor Agonists in a Single Center Experience
Authors: Monica Carpenedo, Marco Spinelli, Sara Pezzatti, Momcilo Jancovic, Rossella Renso, Andrea Biondi, Carlo Gambacorti-Passerini
Journal: Blood (2018)
Potential impact of clinical trial (CT) participation on survival of patients with metastatic non-small cell lung cancer (NSCLC).
Authors: Cristina Merkhofer, Keith D. Eaton, Renato G. Martins, Scott David Ramsey, Bernardo H. L. Goulart
Journal: Journal of Clinical Oncology (2019)

137 Background: Evidence is conflicting as to whether enrollment in therapeutic drug trials confers a survival benefit for NSCLC patients. We assessed the effect of CT participation on overall survival in a cohort of metastatic NSCLC patients treated at a single large academic center. Methods: We retrospectively revised medical records of patients with metastatic NSCLC diagnosed between 1/1/2007 and 12/31/2015 that received treatment at the Seattle Cancer Care Alliance. Eligibility criteria included receipt of ≥ 1 anti-cancer drug within 180 days of M1 diagnosis, no active second malignancy, and 60 day minimum survival. We abstracted patient sociodemographic characteristics, smoking history, ECOG score, tumor histology, EGFR and ALK status, presence of brain metastases, systemic treatment history up to 5 lines, drug trial enrollment, and trial characteristics. We obtained death dates from the Washington State cancer registry complemented by medical records, censoring patients that were alive at end of follow-up (3/7/2019). We used multivariate Cox regression to test whether enrollment in ≥ 1 CT was associated with overall survival. Results: Of 371 eligible patients (median age 63.9 years, 47% male, 94% non-squamous histology, 30% never-smokers, 58% ECOG 0-1, 20% EGFR positive and 8% ALK positive, and 27% brain metastases), 118 (32%) enrolled in ≥ 1 CT. Of CT enrollees: 19% enrolled in &gt; 1 CT, 89% in phase I/II trials, 15% in phase III trials, 26% in randomized trials, and 51% in trials of drugs later approved by the FDA. Median survival in CT enrollees was 838 days (95% CI 688, 1,021), as compared to 454 days in non-enrollees (95% CI 378, 511). After adjusting for sex, ECOG score, smoking, histology, EGFR and ALK status, and presence of brain metastases, CT enrollees had a 47% lower risk of death relative to non-enrollees (HR 0.53; 95% CI 0.13, 0.92; P = 0.002). Conclusions: Participation in therapeutic drug trials is associated with longer overall survival in advanced NSCLC. Besides supporting drug development, CT participation may directly benefit NSCLC patients by providing access to promising agents and/or enhanced supportive care.
Prognostic Assessment of the PET-CT Role in Primary Patients with Hodgkin Lymphoma: Do We Still Need More Data?
Authors: Olga Novosad, Tetiana Skrypets, Ian Pastushenko, Oleksandr Gorbach, Andrij Ashykhmin, Yaroslav Kmetyuk, Olga Karpova, Larisa Mykhalska, Olga Kindrakevych, Viktor Kozlov, Mykola Novikov, Viktoriia Kosinova, Olena Oliinichenko, Nina Kostiukova, Oksana Tkachenko, Oksana Karnabeda, Viktoriya Stratienko, Iryna Kriachok
Journal: Blood (2018)
SLN124, a Galnac-siRNA Conjugate Targeting TMPRSS6, for the Treatment of Iron Overload and Ineffective Erythropoiesis Such As in Beta-Thalassemia
Authors: Sandro Altamura, Sandro Altamura, Martina U. Muckenthaler, Sibylle Dames, Christian Frauendorf, Steffen Schubert, Manuela Aleku, Jim Vadolas, George Grigoriadis, Ulrich Zügel
Journal: Blood (2018)
Abstract 420: S-nitrosylation Promotes Cell Cycle, Cell Viability and Proliferation by Activating the Snail/Slug Pathway in miPSC-derived CM
Authors: Alessandro Salerno, Amarylis Wanschel, Konstantinos Hatzistergos, Raul Dulce, Wayne Balkan, Joshua Hare
Journal: Circulation Research (2019)

Introduction: Epithelial-to-mesenchymal transition (EMT), is a crucial step in cardiac differentiation. Snail and Slug are increased and E-cadherin is decreased during EMT. Expression of Snail and Slug is reduced by GSK3β, a key regulator of the Wnt/β-catenin signaling pathway. S-nitrosylation (S-NO) of GSK3β inhibits its activity. Objective: We hypothesized that in the absence of S-nitrosoglutathione reductase (GSNOR), the Snail/Slug pathway is activated in miPSC-derived cardiomyocytes. Methods: We compared the initial growth and differentiation of iPSCs derived from GSNOR –/– (iPSC GSNOR-/- ) and wild type (WT [control], iPSC WT ) mice on days (D) 0-6 in cell culture. Cell morphology was assessed and MTT, BrdU and transwell invasion assays performed to determine cell proliferation, invasion and migration. EMT-related transcription factors and members of the GSK3β pathway were measured at D0-D6. Results: During early differentiation, iPSC GSNOR-/- cells exhibited accelerated loss of pluripotency markers and, from D4, greater proliferation/differentiation, and apparent EMT compared to iPSC WT . MTT, BrdU and migration assays demonstrated that loss of GSNOR stimulated cell proliferation and migration. Slug and Snail were upregulated and E-Cadherin was downregulated in iPSC GSNOR-/- suggesting that increased NO levels reduced GSK3β activity in iPSC GSNOR-/- . Conclusions: Our results suggest that the deletion of GSNOR affects early CM differentiation and promote EMT. These findings have important implications for regenerative medicine and provide new targets for iPSC-based therapy.