tbuckley/cabot-search huggingface dataset:
FDA Approval Summary: Selpercatinib for the Treatment of Lung and Thyroid Cancers with<i>RET</i>Gene Mutations or Fusions
Authors: Diana Bradford, Erin Larkins, Sirisha L. Mushti, Lisa Rodriguez, Amy M. Skinner, Whitney S. Helms, Lauren S.L. Price, Jeanne Fourie Zirkelbach, Yangbing Li, Jiang Liu, Rosane Charlab, Francisca Reyes Turcu, Dun Liang, Soma Ghosh, Donna Roscoe, Reena Philip, Autumn Zack-Taylor, Shenghui Tang, Paul G. Kluetz, Julia A. Beaver, Richard Pazdur, Marc R. Theoret, Harpreet Singh
Journal: Clinical Cancer Research (2020)

On May 8, 2020, the FDA granted accelerated approval to selpercatinib for (i) adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC), (ii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer who require systemic therapy, and (iii) adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine refractory (if radioactive iodine is appropriate). Approval was granted on the basis of the clinically important effects on the overall response rate (ORR) with prolonged duration of responses observed in a multicenter, open-label, multicohort clinical trial (LIBRETTO-001, NCT03157128) in patients whose tumors had RET alterations. ORRs within the approved patient populations ranged from 64% [95% confidence interval (CI), 54-73] in prior platinum-treated RET fusion-positive NSCLC to 100% (95% CI, 63-100) in systemic therapy-naïve RET fusion-positive thyroid cancer, with the majority of responders across indications demonstrating responses of at least 6 months. The product label includes warnings and precautions for hepatotoxicity, hypertension, QT interval prolongation, hemorrhagic events, hypersensitivity, risk of impaired wound healing, and embryo-fetal toxicity. This is the first approval of a drug specifically for patients with RET alterations globally.
Organoids and Spheroids as Models for Studying Cholestatic Liver Injury and Cholangiocarcinoma
Authors: Keisaku Sato, Wenjun Zhang, Samira Safarikia, Abdulkadir Isidan, Angela M. Chen, Ping Li, Heather Francis, Lindsey Kennedy, Leonardo Baiocchi, Domenico Alvaro, Shannon Glaser, Burcin Ekser, Gianfranco Alpini
Journal: Hepatology (2020)

Cholangiopathies, such as primary sclerosing cholangitis, biliary atresia, and cholangiocarcinoma, have limited experimental models. Not only cholangiocytes but also other hepatic cells including hepatic stellate cells and macrophages are involved in the pathophysiology of cholangiopathies, and these hepatic cells orchestrate the coordinated response against diseased conditions. Classic two-dimensional monolayer cell cultures do not resemble intercellular cell-to-cell interaction and communication; however, three-dimensional cell culture systems, such as organoids and spheroids, can mimic cellular interaction and architecture between hepatic cells. Previous studies have demonstrated the generation of hepatic or biliary organoids/spheroids using various cell sources including pluripotent stem cells, hepatic progenitor cells, primary cells from liver biopsies, and immortalized cell lines. Gene manipulation, such as transfection and transduction can be performed in organoids, and established organoids have functional characteristics which can be suitable for drug screening. This review summarizes current methodologies for organoid/spheroid formation and a potential for three-dimensional hepatic cell cultures as in vitro models of cholangiopathies.
Efficacy and Safety of Third-Generation Full Length Recombinant Human Coagulation Factor VIII in the Standard Prophylactic Treatment of Childhood Patients with Moderate-to-Severe Hemophilia A: A Single Center Experience
Authors: Rong-Fu Zhou, Qian Li, Jian Ouyan, Min Zhou, Bing Chen, Yong Xu, Ping Li
Journal: Blood (2017)
Abstract 13756: Direct Oral Anticoagulants versus Warfarin for Left Ventricular Thrombi: The RED VELVT Study
Authors: Austin A Robinson, Cory R Trankle, Grayson Eubanks, Christopher Schumann, Paul Thomspon, Ryan Wallace, Shouri Gottiparthi, Benjamin Ruth, Christopher M Kramer, Michael Salerno, Kenneth C Bilchick, Cody S Deen, Michael C Kontos, John M Dent
Journal: Circulation (2019)

Introduction: LV thrombi (LVT) arise in the setting of myocardial dysfunction and may lead to ischemic stroke and systemic embolization (SSE). Warfarin has historically been used to reduce the risk...
Comparison of Opioids Prescribed for Patients at Risk for Opioid Misuse Before and After Publication of the Centers for Disease Control and Prevention’s Opioid Prescribing Guidelines
Authors: Jeffrey F. Scherrer, Jane Tucker, Joanne Salas, Zidong Zhang, Richard Grucza
Journal: JAMA Network Open (2020)

<h3>Importance</h3> It is not known whether decreases in Schedule II (high abuse potential) vs Schedule IV (lower abuse potential) opioid prescriptions overall and among high-risk patients followed publication of the Centers for Disease Control and Prevention (CDC) opioid prescribing guideline on March 15, 2016. <h3>Objectives</h3> To compare the odds of new Schedule II opioid (codeine, hydrocodone, oxycodone) prescriptions vs Schedule IV opioid (tramadol) prescriptions in the 18-month periods before and after the CDC guideline release to determine whether new prescriptions for Schedule II opioids decreased relative to new prescriptions for tramadol and to assess whether patients with benzodiazepine prescriptions or those with depression, anxiety, or substance use disorders had a greater decrease in receipt of Schedule II vs Schedule IV opioids. <h3>Design, Setting, and Participants</h3> Cross-sectional study of Optum's deidentified Integrated Claims-Clinical data set for 5 million US adults 18 months before and 18 months after March 15, 2016. Eligible patients were 18 years or older, free of HIV and cancer diagnoses, and had a noncancer painful condition. Patients received new prescriptions for codeine, hydrocodone, oxycodone, or tramadol. Data were analyzed from September 5, 2014, to September 14, 2017. <h3>Exposure</h3> The CDC opioid prescribing guideline published on March 15, 2016. <h3>Main Outcomes and Measures</h3> The odds of prescriptions for each Schedule II opioid vs tramadol after guideline publication. <h3>Results</h3> Data from 279 435 patients were included in the study. The mean (SD) age of patients was 52.9 (16.5) years; 61% were female and 79.4% were White. The prevalence of new prescriptions for each drug before and after guideline publication was as follows: codeine, 7.1% vs 7.0%; hydrocodone, 47.4% vs 45.6%; oxycodone, 22.4% vs 24.0%; and tramadol, 23.0% vs 23.4%. Overall, the odds of being prescribed hydrocodone or oxycodone vs tramadol significantly decreased after guideline publication (odds ratios, 0.95; 95% CI, 0.91-0.98 and 0.86; 95% CI, 0.82-0.90, respectively). Odds of being prescribed a Schedule II opioid vs tramadol after vs before guideline publication were similar in patients with and without benzodiazepine comedication or psychiatric disorders. <h3>Conclusions and Relevance</h3> In the 18 months after compared with the 18 months before publication of the CDC prescribing guideline, a 14% decrease in oxycodone prescriptions was observed relative to tramadol. Little change in prescriptions of other Schedule II opioids was observed. Schedule II opioids continue to be prescribed to high-risk patients 18 months after publication of the CDC guideline.
Do not attempt cardiopulmonary resuscitation: detoxifying the conversation about values and needs
Authors: Sue Hampshire, Zoe Fritz
Journal: BMJ (2020)

Resuscitation Council UK welcomes David Oliver’s article1 about the public conversation around do not attempt cardiopulmonary resuscitation (DNACPR) decisions.

At Resuscitation Council UK, we have been concerned by reports of people being subjected to DNACPR decisions without their consent or with little involvement during the pandemic.

There is limited public understanding that a DNACPR recommendation should not affect …
Abstract 12507: Spatial Gradients in Wall Shear Stress Promote Collective Human Lymphatic Microvascular Endothelial Cell Migration and Alignment Through Sphingosine 1-phosphate Receptor 1
Authors: Vinay N Surya, Eleftheria Michalaki, Eva Y Huang, Gerald G Fuller, Alexander R Dunn
Journal: Circulation (2016)

Introduction: Spatial variations in fluid flow are thought to help trigger the formation of valves within the blood and lymphatic circulatory systems during embryonic development. However, how the physical stimulus drives the collective cell movements and changes in gene expression that underlie valve formation is not known. This knowledge gap is of considerable importance since valve failure within the lymphatic and venous vessels is significant in a wide variety of cardiovascular disease states. Methods: In this study, we developed in vitro fluid flow devices that allow us to replicate key aspects of the fluid flow environment found in the vicinity of developing valves within the lymphatic and venous vasculatures. We developed an impinging flow chamber as a model for vessel bifurcations, applying a spatial gradient in wall shear stress (WSS). We have also developed a device which applies flow through a constriction such as is commonly found at sites of valve initiation. Results: Using these devices, we examined the migration of human lymphatic microvascular ECs (MVECs) subjected to spatial gradients in WSS. We found that lymphatic MVECs subjected to a variety of WSS ranges from 0 to 9, 33, or 72 dynes/cm 2 align and collectively migrate against the flow direction over the course of 20 hours. When subjected to flow through a constriction, lymphatic MVECs turned perpendicular to the flow direction at regions near the site of maximum constriction. We determined that the G-Protein Coupled Receptor, Sphingosine 1-Phosphate Receptor 1 (S1PR1) was required for both lymphatic MVEC alignment and collective migration: a 70% S1PR1 mRNA knockdown relative to scrambled siRNA control was sufficient to prevent the collective migration and perpendicular alignment phenotypes we observed in our in vitro flow devices. In addition, these shear stress gradients resulted in higher nuclear levels of Prospero Homeobox Protein 1, a transcription factor known to be required for valvulogenesis, relative to cells in the absence of flow (Impinging Flow; 9.8 +/- 2.2 fold, Constriction; 5.1 +/- 0.8 fold). Conclusions: Our observations implicate S1PR1 as a key component in both the phenotypic and transcriptional responses of LECs to gradients in WSS, such as those at sites of valve formation.
Rapid single-molecule digital detection of protein biomarkers for continuous monitoring of systemic immune disorders
Authors: Yujing Song, Erin Sandford, Yuzi Tian, Qingtian Yin, Andrew G. Kozminski, Shiuan-Haur Su, Tao Cai, Yuxuan Ye, Meng Ting Chung, Ryan Lindstrom, Annika Goicochea, Jenny Barabas, Mary Olesnavich, Michelle Rozwadowski, Yongqing Li, Hasan B. Alam, Benjamin H. Singer, Monalisa Ghosh, Sung Won Choi, Muneesh Tewari, Katsuo Kurabayashi
Journal: Blood (2020)
Covid-19: UK government asks regulator to assess Oxford vaccine as questions are raised over interim data
Authors: Elisabeth Mahase
Journal: BMJ (2020)

<h3>Background:</h3> Evidence-based clinical guidelines aim to improve the quality of care. In The Netherlands, considerable time and effort have been invested in the development and implementation of evidence-based guidelines since the 1990s. Thus far, no reviews are available on their effectiveness. The primary aim of this article was to assess the evidence for the effectiveness of Dutch evidence-based clinical guidelines in improving the quality of care. <h3>Methods:</h3> A systematic review of studies evaluating the effects of Dutch evidence-based guidelines on both the process and structure of care and patient outcomes was conducted. The electronic databases <i>Medline</i> and <i>Embase (1990–2007)</i> and relevant scientific journals were searched. Studies were only selected if they included a controlled trial, an interrupted time series design or a before and after design. <h3>Results:</h3> A total of 20 studies were included. In 17 of 19 studies that measured the effects on the process or structure of care, significant improvements were reported. Thirteen of these studies reported improvement with respect to some of the recommendations studied. In addition, the size of the observed effects varied largely across the recommendations within guidelines. Six of nine studies that measured patient health outcomes showed significant but small improvements as a result of the use of clinical guidelines. <h3>Conclusions:</h3> This review demonstrates that Dutch evidence-based clinical guidelines can be effective in improving the process and structure of care. The effects of guidelines on patient health outcomes were studied far less and data are less convincing. The high level of variation in effects across recommendations suggests that implementation strategies tailored to individual recommendations within the guideline are needed to establish relevant improvements in healthcare. Moreover, the results highlight the need for well-designed studies focusing on the level of the recommendations to determine which factors influence guideline utilisation and improved patient outcomes.
16003 Orally administered EDP1815, a monoclonal strain of Prevotella histicola, has potent systemic anti-inflammatory effects
Authors: Andrea Itano, Taylor Cormack, Kritika Ramani, Kristie L. Hilliard-Barth, Holly E. Ponichtera, Tanmoy Ganguly, Mark Bodmer
Journal: Journal of the American Academy of Dermatology (2020)
Outcomes of Autologous Stem Cell Transplantation in Very Elderly Patients with Multiple Myeloma
Authors: Phyllis McKiernan, David Siegel, David H. Vesole, Scott D. Rowley, Tracy Andrews, Andrea Ortega, Alan P Skarbnik, Noa Biran, Joshua R Richter, Andrew L. Pecora, Andre Goy, Rima M Panchal, Nino Aleksidze, Michele L. Donato
Journal: Blood (2017)
Water/pH dual responsive in situ calcium supplement collaborates simvastatin for osteoblast promotion mediated osteoporosis therapy via oral medication
Authors: Shan Tao, Fangying Yu, Yanqing Song, Wentao Zhou, Jianghong Lv, Rui Zhao, Cheng Wang, Fuqiang Hu, Hong Yuan
Journal: Journal of Controlled Release (2020)
Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions
Authors: Charles L Bennett, Martin W Schoen, Shamia Hoque, Bartlett J Witherspoon, David M Aboulafia, Catherine S Hwang, Paul Ray, Paul R Yarnold, Brian K Chen, Benjamin Schooley, Matthew A Taylor, Michael D Wyatt, William J Hrushesky, Y Tony Yang
Journal: The Lancet Oncology (2020)
Coca-Cola sought to shift blame for obesity by funding public health conferences, study reports
Authors: Shaun Griffin
Journal: BMJ (2020)

The Coca-Cola Company worked with its sponsored researchers on topics to present at major international public health conferences in order to shift blame for rising obesity and diet related diseases away from its products onto physical activity and individual choice, according to a new report.1

Academics in Australia and the US worked with US Right to Know, which lobbies for transparency in the food industry, to obtain and analyse emails between Coke and public health figures about events run by the International Society for Physical Activity and Health (ISPAH).

They analysed 36 931 pages of documents to identify exchanges referencing Coke’s sponsorship of the International Congresses on Physical Activity and Public Health (ICPAPH) held in Sydney in 2012 and Rio de Janeiro in 2014.

Using a …
Patient‐Specific 3D Bioprinted Models of Developing Human Heart
Authors: Alexander D. Cetnar, Martin L. Tomov, Liqun Ning, Bowen Jing, Andrea S. Theus, Akaash Kumar, Amanda N. Wijntjes, Sai Raviteja Bhamidipati, Katherine Pham Do, Athanasios Mantalaris, John N. Oshinski, Reza Avazmohammadi, Brooks D. Lindsey, Holly D. Bauser‐Heaton, Vahid Serpooshan
Journal: Advanced Healthcare Materials (2020)

Abstract The heart is the first organ to develop in the human embryo through a series of complex chronological processes, many of which critically rely on the interplay between cells and the dynamic microenvironment. Tight spatiotemporal regulation of these interactions is key in heart development and diseases. Due to suboptimal experimental models, however, little is known about the role of microenvironmental cues in the heart development. This study investigates the use of 3D bioprinting and perfusion bioreactor technologies to create bioartificial constructs that can serve as high‐fidelity models of the developing human heart. Bioprinted hydrogel‐based, anatomically accurate models of the human embryonic heart tube (e‐HT, day 22) and fetal left ventricle (f‐LV, week 33) are perfused and analyzed both computationally and experimentally using ultrasound and magnetic resonance imaging. Results demonstrate comparable flow hemodynamic patterns within the 3D space. We demonstrate endothelial cell growth and function within the bioprinted e‐HT and f‐LV constructs, which varied significantly in varying cardiac geometries and flow. This study introduces the first generation of anatomically accurate, 3D functional models of developing human heart. This platform enables precise tuning of microenvironmental factors, such as flow and geometry, thus allowing the study of normal developmental processes and underlying diseases.
Interplay between endoplasmic reticulum stress and non-coding RNAs in cancer
Authors: Tianming Zhao, Juan Du, Hui Zeng
Journal: Journal of Hematology & Oncology (2020)

Abstract To survive, cancer cells are subjected to various internal and external adverse factors, including genetic mutations, hypoxia, nutritional deficiencies, and drug toxicity. All of these factors result in the accumulation of unfolded proteins in the endoplasmic reticulum, which leads to a condition termed endoplasmic reticulum stress (ER stress) and triggers the unfolded protein response (UPR). UPR downstream components strictly control transcription and translation reprogramming to ensure selective gene expression, including that of non-coding RNA (ncRNAs), to adapt to adverse environments. NcRNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play important roles in regulating target gene expression and protein translation, and their aberrant expression is related to tumor development. Dysregulation of ncRNAs is involved in the regulation of various cellular characteristics of cancer cells, including growth, apoptosis, metastasis, angiogenesis, drug sensitivity, and tumor stem cell properties. Notably, ncRNAs and ER stress can regulate each other and collaborate to determine the fate of tumor cells. Therefore, investigating the interaction between ER stress and ncRNAs is crucial for developing effective cancer treatment and prevention strategies. In this review, we summarize the ER stress-triggered UPR signaling pathways involved in carcinogenesis followed by the mutual regulation of ER stress and ncRNAs in cancer, which provide further insights into the understanding of tumorigenesis and therapeutic strategies.
Origins and Long-Term Patterns of Copy-Number Variation in Rhesus Macaques
Authors: Gregg W C Thomas, Richard J Wang, Jelena Nguyen, R Alan Harris, Muthuswamy Raveendran, Jeffrey Rogers, Matthew W Hahn
Journal: Molecular Biology and Evolution (2020)

Mutations play a key role in the development of disease in an individual and the evolution of traits within species. Recent work in humans and other primates has clarified the origins and patterns of single-nucleotide variants, showing that most arise in the father's germline during spermatogenesis. It remains unknown whether larger mutations, such as deletions and duplications of hundreds or thousands of nucleotides, follow similar patterns. Such mutations lead to copy-number variation (CNV) within and between species, and can have profound effects by deleting or duplicating genes. Here, we analyze patterns of CNV mutations in 32 rhesus macaque individuals from 14 parent-offspring trios. We find the rate of CNV mutations per generation is low (less than one per genome) and we observe no correlation between parental age and the number of CNVs that are passed on to offspring. We also examine segregating CNVs within the rhesus macaque sample and compare them to a similar data set from humans, finding that both species have far more segregating deletions than duplications. We contrast this with long-term patterns of gene copy-number evolution between 17 mammals, where the proportion of deletions that become fixed along the macaque lineage is much smaller than the proportion of segregating deletions. These results suggest purifying selection acting on deletions, such that the majority of them are removed from the population over time. Rhesus macaques are an important biomedical model organism, so these results will aid in our understanding of this species and the disease models it supports.
191P First-line liposomal irinotecan + 5 fluorouracil/leucovorin + oxaliplatin in patients with pancreatic ductal adenocarcinoma: Results from a phase I/II study
Authors: A. Dean, T. Bekaii-Saab, P.M. Boland, F. Dayyani, T. Macarulla Mercade, K. Mody, B. Belanger, F. Maxwell, Y. Moore, A. Thiagalingam, T. Wang, B. Zhang, Z.A. Wainberg
Journal: Annals of Oncology (2020)
Genotype–Phenotype Relationship in the Long QT Syndrome: Brimming With Knowledge but Thirsting for a Therapeutic Solution⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Koonlawee Nademanee
Journal: Journal of the American College of Cardiology (2009)
Reply to Vérane Achard, Alan Dal Pra, and Thomas Zilli’s Letter to the Editor re: Carlo A. Bravi, Nicola Fossati, Giorgio Gandaglia, et al. Long-term Outcomes of Salvage Lymph Node Dissection for Nodal Recurrence of Prostate Cancer After Radical Prostatectomy: Not as Good as Previously Thought. Eur Urol 2020;78:661–9
Authors: Carlo A. Bravi, Francesco Montorsi, Alberto Briganti
Journal: European Urology (2020)
1720P How do oncological patients perceive the COVID-19 pandemic? Experience from CHU Liège in Belgium
Authors: C.E. Onesti, H. Schroeder, A. Rorive, B. Sautois, M. Lecocq, M. Goffin, E. Gonne, A. Collinge, L. Nicolaers, O. Wera, A. Catot, C. Loly, A. Paulus, A. Sibille, L.E. Lousberg, F. Troisfontaine, J. Collignon, C. Gennigens, P. Freres, G. Jerusalem
Journal: Annals of Oncology (2020)