tbuckley/cabot-search huggingface dataset:
KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition
Authors: Sandra Misale, Jackson P. Fatherree, Eliane Cortez, Chendi Li, Samantha Bilton, Daria Timonina, David T. Myers, Dana Lee, Maria Gomez-Caraballo, Max Greenberg, Varuna Nangia, Patricia Greninger, Regina K. Egan, Joseph McClanaghan, Giovanna T. Stein, Ellen Murchie, Patrick P. Zarrinkar, Matthew R. Janes, Lian-Sheng Li, Yi Liu, Aaron N. Hata, Cyril H. Benes
Journal: Clinical Cancer Research (2018)

Abstract Purpose: KRAS-mutant lung cancers have been recalcitrant to treatments including those targeting the MAPK pathway. Covalent inhibitors of KRAS p.G12C allele allow for direct and specific inhibition of mutant KRAS in cancer cells. However, as for other targeted therapies, the therapeutic potential of these inhibitors can be impaired by intrinsic resistance mechanisms. Therefore, combination strategies are likely needed to improve efficacy. Experimental Design: To identify strategies to maximally leverage direct KRAS inhibition we defined the response of a panel of NSCLC models bearing the KRAS G12C–activating mutation in vitro and in vivo. We used a second-generation KRAS G12C inhibitor, ARS1620 with improved bioavailability over the first generation. We analyzed KRAS downstream effectors signaling to identify mechanisms underlying differential response. To identify candidate combination strategies, we performed a high-throughput drug screening across 112 drugs in combination with ARS1620. We validated the top hits in vitro and in vivo including patient-derived xenograft models. Results: Response to direct KRAS G12C inhibition was heterogeneous across models. Adaptive resistance mechanisms involving reactivation of MAPK pathway and failure to induce PI3K–AKT pathway inactivation were identified as likely resistance events. We identified several model-specific effective combinations as well as a broad-sensitizing effect of PI3K-AKT–mTOR pathway inhibitors. The G12Ci+PI3Ki combination was effective in vitro and in vivo on models resistant to single-agent ARS1620 including patient-derived xenografts models. Conclusions: Our findings suggest that signaling adaptation can in some instances limit the efficacy of ARS1620 but combination with PI3K inhibitors can overcome this resistance.
Cannabis: Canada sees queues and shortages as it legalises recreational use
Authors: Owen Dyer
Journal: BMJ (2018)

Thank you for your interest in spreading the word about The BMJ.NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address. Username * Your Email * Send To * You are going to email the following Cannabis: Canada sees queues and shortages as it legalises recreational use Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Abstract 13823: Impact of Dynamic Mitral Regurgitation on Functional Capacity in Heart Failure Patients
Authors: Francesco Bandera, Greta Generati, Marta Pellegrino, Valentina Labate, Eleonora Alfonzetti, Marco Guazzi
Journal: Circulation (2014)

Introduction: In heart failure reduced ejection fraction (HFrEF) patients the severity of mitral regurgitation (MR) at rest has a well-established prognostic value. MR increase during exercise further adds to an increased risk. MR plays a central role in determining pulmonary flow overload and pulmonary hypertension (PH), which is associated with poor prognosis. Hypothesis: Our aim was to define the relationship between dynamic MR, echocardiographic phenotypes and functional capacity in a cohort of HFrEF patients. Methods: 102 HFrEF patients (age 65±11; male 71%; ischemic etiology 60%; EF 33±9%; NYHA class I, II, III and IV 21, 34, 36, 9%) underwent cardiopulmonary exercise test (CPET) on tiltable cycle-ergometer (standard incremental ramp protocol) combined with exercise-echocardiography. The population was studied according to the degree of functional MR and data were analyzed looking at CPET- and echo-derived phenotypes. Results: Study population was divided into three groups according to the degree of...
Therapeutic advances in anaplastic thyroid cancer: a current perspective
Authors: Shikha Saini, Kiara Tulla, Ajay V. Maker, Kenneth D. Burman, Bellur S. Prabhakar
Journal: Molecular Cancer (2018)

Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, about 2–3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success.
Letter by Donzelli et al Regarding Article, “Benefit of Adding Ezetimibe to Statin Therapy on Cardiovascular Outcomes and Safety in Patients With Versus Without Diabetes Mellitus: Results From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial)”
Authors: Alberto Donzelli, Alessandro Schivalocchi, Giulia Giudicatti
Journal: Circulation (2018)
Exercise for the prevention and treatment of low back, pelvic girdle and lumbopelvic pain during pregnancy: a systematic review and meta-analysis
Authors: Margie H Davenport, Andree-Anne Marchand, Michelle F Mottola, Veronica J Poitras, Casey E Gray, Alejandra Jaramillo Garcia, Nick Barrowman, Frances Sobierajski, Marina James, Victoria L Meah, Rachel J Skow, Laurel Riske, Megan Nuspl, Taniya S Nagpal, Anne Courbalay, Linda G Slater, Kristi B Adamo, Gregory A Davies, Ruben Barakat, Stephanie-May Ruchat
Journal: British Journal of Sports Medicine (2018)

Objective The purpose of this review was to investigate the relationship between prenatal exercise, and low back (LBP), pelvic girdle (PGP) and lumbopelvic (LBPP) pain. Design Systematic review with random effects meta-analysis and meta-regression. Data sources Online databases were searched up to 6 January 2017. Study eligibility criteria Studies of all designs were eligible (except case studies and reviews) if they were published in English, Spanish or French, and contained information on the population (pregnant women without contraindication to exercise), intervention (subjective or objective measures of frequency, intensity, duration, volume or type of exercise, alone [“exercise-only”] or in combination with other intervention components [eg, dietary; “exercise + co-intervention”]), comparator (no exercise or different frequency, intensity, duration, volume and type of exercise) and outcome (prevalence and symptom severity of LBP, PGP and LBPP). Results The analyses included data from 32 studies (n=52 297 pregnant women). ‘Very low’ to ‘moderate’ quality evidence from 13 randomised controlled trials (RCTs) showed prenatal exercise did not reduce the odds of suffering from LBP, PGP and LBPP either in pregnancy or the postpartum period. However, ‘very low’ to ‘moderate’ quality evidence from 15 RCTs identified lower pain severity during pregnancy and the early postpartum period in women who exercised during pregnancy (standardised mean difference −1.03, 95% CI −1.58, –0.48) compared with those who did not exercise. These findings were supported by ‘very low’ quality evidence from other study designs. Conclusion Compared with not exercising, prenatal exercise decreased the severity of LBP, PGP or LBPP during and following pregnancy but did not decrease the odds of any of these conditions at any time point.
A composite disease activity index for early drug development in ulcerative colitis: development and validation of the UC-100 score
Authors: Vipul Jairath, Jenny Jeyarajah, Guangyong Zou, Claire E Parker, Allan Olson, Reena Khanna, Geert R D'Haens, William J Sandborn, Brian G Feagan
Journal: The Lancet. Gastroenterology & hepatology (2018)
Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection
Authors: Tatiana N. Pashirova, Anissa Braïki, Irina V. Zueva, Konstantin A. Petrov, Vasily M. Babaev, Evgenia A. Burilova, Darya A. Samarkina, Ildar Kh. Rizvanov, Eliana B. Souto, Ludovic Jean, Pierre-Yves Renard, Patrick Masson, Lucia Ya. Zakharova, Oleg G. Sinyashin
Journal: Journal of Controlled Release (2018)
Quantification of HBV core antibodies may help revisit infectious occult hepatitis B virus
Authors: Hung-Chih Yang, Jia-Horng Kao
Journal: Gut (2018)

We read with great interest the paper by Candotti et al and the commentary by Locarnini and Raimondo.1 2 Occult hepatitis B virus (HBV) infection (OBI) poses a potential risk of viral reactivation and transmission in several aspects of clinical practices.3–7 Candotti et al confirmed the HBV transfusion transmission from OBI patients who had undetectable HBV DNA measured by the very sensitive nucleic acid testing (NAT). The infectious HBV produced from the intrahepatic persistent and replication-competent covalently closed circular (ccc) DNA is probably beyond the detection limit (3.4 IU/mL) of current NAT. The authors estimated the HBV infectious dose by transfusion could be as low as 3 IU of HBV DNA. They, thus, suggested that the development of ultrasensitive NAT (detection limit of 0.15 IU/mL) and …
GW29-e1787 Echocardiographic parameters to predict ischemic stroke in nonvalvular atrial fibrillation patients with coronary stenting
Authors: Li Zhao, Ge Wang, Boyang Zhang, Nannan Wang, Pengfei Liu, Feng Wang, Haihong Tang, Can Hua, Haifeng Yuan, Xiufeng Xie, Jianyong Zheng, Yubin Wang, Tianchang Li
Journal: Journal of the American College of Cardiology (2018)
Abstract 19851: A Novel Inotropic Class With Unique Mechanism of Action Identified by a Phenotypic Screen
Authors: Jonathan E Hempel, Charles H Williams, Tromondae K Feaster, Adrian G Cadar, Hyun S Hwang, Joseph M Metzger, Bjorn K Knollmann, Charles C Hong
Journal: Circulation (2016)

Introduction: Heart failure (HF) is a leading cause of disability and mortality in US, and there is tremendous unmet need for therapies targeting advanced systolic HF (SHF) or HF with preserve ejec...
Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice
Authors: Bin Gu, Kelly E. Carstens, Matthew C. Judson, Katherine A. Dalton, Marie Rougié, Ellen P. Clark, Serena M. Dudek, Benjamin D. Philpot
Journal: Journal of Clinical Investigation (2018)

Angelman syndrome (AS) is a neurodevelopmental disorder in which epilepsy is common (~90%) and often refractory to antiepileptics. AS is caused by mutation of the maternal allele encoding the ubiquitin protein ligase E3A (UBE3A), but it is unclear how this genetic insult confers vulnerability to seizure development and progression (i.e., epileptogenesis). Here, we implemented the flurothyl kindling and retest paradigm in AS model mice to assess epileptogenesis and to gain mechanistic insights owed to loss of maternal Ube3a. AS model mice kindled similarly to wild-type mice, but they displayed a markedly increased sensitivity to flurothyl-, kainic acid-, and hyperthermia-induced seizures measured a month later during retest. Pathological characterization revealed enhanced deposition of perineuronal nets in the dentate gyrus of the hippocampus of AS mice in the absence of overt neuronal loss or mossy fiber sprouting. This pro-epileptogenic phenotype resulted from Ube3a deletion in GABAergic but not glutamatergic neurons, and it was rescued by pancellular reinstatement of Ube3a at postnatal day 21 (P21), but not during adulthood. Our results suggest that epileptogenic susceptibility in AS patients is a consequence of the dysfunctional development of GABAergic circuits, which may be amenable to therapies leveraging juvenile reinstatement of UBE3A.
Abstract 16496: Relationship Between Sleep Duration and Ideal Cardiovascular Health in a Large Employee Population: The Baptist Health South Florida Employee Study
Authors: Ehimen Aneni, Adnan Younus, Emeka Osondu, Maribeth Rouseff, Sankalp Das, Henry Guzman, Thinh H Tran, Wasim Maziak, Rameez Ahmad, Muhammad A Latif, Rehan Malik, Oluseye Ogunmoroti, Theodore Feldman, Arthur S Agatston, Emir Veledar, Khurram Nasir
Journal: Circulation (2015)

Introduction: There has been increased focus on the relationship between sleep duration and cardiovascular disease, however, there is limited understanding of the association of sleep duration with cardiovascular health (CVH). In this study we examine the relationship between sleep duration and the American Heart Association’s ideal CVH in a large employee population. Methods: Data for this study was collected from participants at the 2014 health risk assessment in which they reported their average hours of sleep, their dietary patterns. In person, participants were weighed and their heights were measured. They also had blood pressure, blood glucose, total cholesterol measurements as well as breath carbon monoxide tests for smoking. The ideal for each CVH metric was estimated for each of the 7 metrics. Sleep duration was grouped into less than 6 hours, 6 to 7.9 hours and 8 or more hours. Ideal CVH was classified as presence of 6-7 ideal metrics. Results: A total of 9700 participants (mean age 43yrs, 74% female) completed the 2014 health risk assessment and had complete data on the variables of interest. Overall, more females and persons without college degrees slept for less than 6 hours. Compared to those with less than 6 hours of sleep, those with 8 or more hours of sleep had 1.6 times the odds of ideal diet (95% CI: 1.1-2.6), 1.7 times the odds of having ideal BMI (95% CI: 1.4-2.1), 1.3 times the odds of having ideal BP (95% CI: 1.1-1.5) and 2.4 times the odds of achieving ideal physical activity (95% CI: 2.4 - 2.9) after controlling for age, sex and educational levels. Comparing to those with less than 6 hours of sleep and with a reference of 0-2 ideal metrics, participants with 8 or more hours of sleep were 2.7 times as likely to have ideal CVH (see figure). Conclusions: Our study findings underscore the importance of promoting sleep health for optimizing ideal CVH. Further studies are needed to determine generalizability of our results.
Why did IL-23p19 inhibition fail in AS: a tale of tissues, trials or translation?
Authors: Stefan Siebert, Neal L Millar, Iain B McInnes
Journal: Annals of the Rheumatic Diseases (2018)

Figure 1 Proposed notional emerging tissue cytokine hierarchy based on current clinical trial data.There is now increasing evidence suggesting that different cytokines may enjoy distinct hierarchical roles in tissues across the spondyloarthritis spectrum.This figure highlights those pathways with demonstrable effects in each discrete tissues against those in which clinical responses were not observed.In the absence of formal head-to-head studies, these comparators should be taken as potential rather than proven.Future analyses are now required to ascribe formal within-tissue hierarchies.
Risk Factors for the Presence and Progression of Cardiovascular Autonomic Neuropathy in Type 2 Diabetes: ADDITION-Denmark
Authors: Signe T. Andersen, Daniel R. Witte, Jesper Fleischer, Henning Andersen, Torsten Lauritzen, Marit E. Jørgensen, Troels S. Jensen, Rodica Pop-Busui, Morten Charles
Journal: Diabetes Care (2018)

OBJECTIVE To examine the course of cardiovascular autonomic neuropathy (CAN) and related cardiometabolic risk factors in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS CAN and cardiometabolic risk factors were assessed in the Danish arm of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Denmark) at 6-year (n = 777) and 13-year (n = 443) follow-up examinations. Cardiovascular autonomic reflex tests (CARTs)—that is, lying to standing, deep breathing, and the Valsalva maneuver—and 2-min resting heart rate variability (HRV) indices were obtained as the main measures of CAN. Risk factors related to CAN status, as determined by CARTs, were studied by using multivariate logistic regressions. The effects of risk factors on continuous CARTs and HRV indices, and their changes over time, were estimated in linear mixed models. RESULTS A progressive yet heterogeneous course of CAN occurred between the 6- and 13-year follow-ups. Higher HbA1c, weight, BMI, and triglycerides were associated with prevalent CAN. No significant effect of risk factors on CARTs was found when they were analyzed as continuous variables. CART indices decreased over time, and a trend of decreasing HRV indices was seen. Higher HbA1c and BMI were associated with lower HRV index values, but these differences diminished over time. CONCLUSIONS These data confirm that hyperglycemia, obesity, and hypertriglyceridemia are negatively related to indices of CAN, although these effects diminish over time. The observed heterogeneous course of CAN may challenge the present clinical approach of categorically classifying CARTs to diagnose CAN and the notion of CAN being irreversible.
Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis
Authors: Won Ho Yang, Douglas M. Heithoff, Peter V. Aziz, Benjamin Haslund-Gourley, Julia S. Westman, Sonoko Narisawa, Anthony B. Pinkerton, José Luis Millán, Victor Nizet, Michael J. Mahan, Jamey D. Marth
Journal: Cell Host & Microbe (2018)
Ischemia Techniques in Nephron-sparing Surgery: A Systematic Review and Meta-Analysis of Surgical, Oncological, and Functional Outcomes
Authors: Francesco Greco, Riccardo Autorino, Vincenzo Altieri, Steven Campbell, Vincenzo Ficarra, Inderbir Gill, Alexander Kutikov, Alex Mottrie, Vincenzo Mirone, Hendrik van Poppel
Journal: European Urology (2018)
Abstract 14968: Drug-Eluting Stent for Lower Extremity Peripheral Artery Disease; is It Better Than Percutaneous Angioplasty or Bare-Metal Stent? A Meta-Analysis of Randomized Controlled Trials
Authors: Alejandro Lemor, Shawn Lee, Abel Casso Dominguez, Carlos A Gongora, Farid Gholitabar, Supreeti Behuria, Ramesh M Gowda
Journal: Circulation (2016)

Introduction: Current guidelines recommend percutaneous angioplasty as the treatment of choice for lower extremity peripheral artery disease (PAD); stent placement is recommended as a possible alternative. Recent advances in endovascular treatment have made drug-eluting stent (DES) placement a novel option for treatment of PAD with good clinical outcomes. A meta-analysis was performed with the purpose of evaluating the impact of DES in the management of PAD on the effect on clinical outcomes. Methods: We searched PubMed, Scopus and ClinicalTrials.gov databases until June 2016 for RCTs that compared DES to percutaneous transluminal angioplasty (PTA) or bare-metal stents (BMS) placement for the treatment of lower extremity PAD with a minimal follow up of 6 months. We evaluated the following clinical endpoints: Binary stenosis (>50% stenosis), revascularization (composite of total lesion revascularization and total vessel revascularization), amputations (major and minor) and all-cause mortality. Risk ratios ...
Pain Susceptibility Phenotypes in Those Free of Knee Pain With or at Risk of Knee Osteoarthritis: The Multicenter Osteoarthritis Study
Authors: Lisa C. Carlesso, Neil A. Segal, Laura Frey‐Law, Yuqing Zhang, Lu Na, Michael Nevitt, Core E. Lewis, Tuhina Neogi
Journal: Arthritis & Rheumatology (2018)

It is not clear why some individuals develop pain with knee osteoarthritis (OA). We undertook this study to identify pain susceptibility phenotypes (PSPs) and their relationship to incident persistent knee pain (PKP) 2 years later.We identified individuals free of PKP from the Multicenter Osteoarthritis Study, a longitudinal cohort of older adults with or at risk of knee OA. Latent class analysis was used to determine PSPs that may contribute to development of PKP apart from structural pathology. These included widespread pain, poor sleep, and psychological factors as well as pressure pain threshold and temporal summation (TS) as determined by quantitative sensory testing (QST). We used logistic regression to evaluate the association of sociodemographic factors with PSPs and the relationship of PSPs to the development of PKP over 2 years.A total of 852 participants were included (mean age 67 years, body mass index 29.5 kg/m2 , 55% women). Four PSPs were identified, primarily characterized by varying proportions (low/absent, moderate, or high) of the presence of pressure pain sensitivity and of facilitated TS, reflecting different measures of sensitization. Subjects in the PSP with a high proportion of pressure pain sensitivity and a moderate proportion of facilitated TS were twice as likely to develop incident PKP over 2 years (odds ratio 1.98 [95% confidence interval 1.07-3.68]) compared with subjects in the PSP having a low proportion of sensitization by both measures.Four PSPs were identified, 3 of which were predominated by QST evidence of sensitization and 1 of which was associated with developing PKP 2 years later. Prevention or amelioration of sensitization may be a novel approach to preventing onset of PKP in OA.
Early Pulmonary Vascular Disease in Preterm Infants Is Associated with Late Respiratory Outcomes in Childhood
Authors: Peter M. Mourani, Erica W. Mandell, Maxene Meier, Adel Younoszai, John T. Brinton, Brandie D. Wagner, Sanne Arjaans, Brenda B. Poindexter, Steven H. Abman
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Rationale: Early pulmonary vascular disease (PVD) after preterm birth is associated with a high risk for developing bronchopulmonary dysplasia (BPD), but its relationship with late respiratory outcomes during early childhood remains uncertain.Objectives: To determine whether PVD at 7 days after preterm birth is associated with late respiratory disease (LRD) during early childhood.Methods: This was a prospective study of preterm infants born before 34 weeks postmenstrual age (PMA). Echocardiograms were performed at 7 days and 36 weeks PMA. Prenatal and early postnatal factors and postdischarge follow-up survey data obtained at 6, 12, 18, and 24 months of age were analyzed in logistic regression models to identify early risk factors for LRD, defined as a physician diagnosis of asthma, reactive airways disease, BPD exacerbation, bronchiolitis, or pneumonia, or a respiratory-related hospitalization during follow-up.Measurements and Main Results: Of the 221 subjects (median, 27 wk PMA; interquartile range, 25–28 and 920 g; interquartile range, 770–1090 g) completing follow-up, 61% met LRD criteria. Gestational diabetes and both mechanical ventilator support and PVD at 7 days were associated with LRD. The combination of PVD and mechanical ventilator support at 7 days was among the strongest prognosticators of LRD (odds ratio, 8.1; confidence interval, 3.1–21.9; P < 0.001). Modeled prenatal and early postnatal factors accurately informed LRD (area under the curve, 0.764). Adding BPD status at 36 weeks PMA to the model did not change the accuracy (area under the curve, 0.771).Conclusions: Early echocardiographic evidence of PVD after preterm birth in combination with other perinatal factors is a strong risk factor for LRD, suggesting that early PVD may contribute to the pathobiology of BPD.