tbuckley/cabot-search huggingface dataset:
Early 3+3 Trial Dose-Escalation Phase I Clinical Trial Design and Suitability for Immune Checkpoint Inhibitors
Authors: Osama E. Rahma, Joshua E. Reuss, Anita Giobbie-Hurder, Ghazaleh Shoja E Razavi, Osama Abu-Shawer, Pooja Mehra, Seema Gupta, Richard Simon, Samir N. Khleif
Journal: Clinical Cancer Research (2020)

Despite the expansion of immune checkpoint inhibitor (ICI) indications, the relationship between ICI dose and toxicity or response is not well established. To understand this correlation, we performed a meta-analysis of ICI trials that used dose escalation.We searched PubMed and abstracts presented at (inter)national meetings for trials using FDA-approved ICIs. The reported rates of grade 3-5 adverse events (G3-5 AE), immune-related adverse events (irAE), and response were correlated with doses within each ICI using marginal exact generalized linear models.A total of 74 trials (7,469 patients) published between January 2010 and January 2017 were included. For ipilimumab, the incidence of G3-5 AEs was 34% with a significant 27% reduced risk in lower doses (P = 0.002). However, no relationship was observed between dose and irAEs or response. For nivolumab, the incidence of G3-5 AEs was 20.1% which was lower in non-small cell lung cancer (NSCLC) compared with renal cell carcinoma (RCC) or melanoma (P ≤ 0.05) with no dose-toxicity relationship. In melanoma and NSCLC, a dose-response association was observed, which was not observed in RCC. For pembrolizumab, the incidence of G3-5 AEs was 13.3%, which was lower in melanoma compared with NSCLC (P = 0.03) with no dose-toxicity relationship. In melanoma, lower dose levels correlated with decreased odds of response (P = 0.01), a relationship that was not observed in NSCLC.Our analysis shows a lack of consistent dose-toxicity or dose-response correlation with ICIs. Therefore, dose escalation is not an appropriate design to conduct ICI studies. Here we present an innovative trial design for immune-modulating agents.
Effect of Athena SWAN funding incentives on women’s research leadership
Authors: Pavel V Ovseiko, Mark Taylor, Ruth E Gilligan, Jacqueline Birks, Leena Elhussein, Mike Rogers, Sonja Tesanovic, Jazmin Hernandez, Glenn Wells, Trisha Greenhalgh, Alastair M Buchan
Journal: BMJ (2020)

Analysis shows that funding incentives can work and more funders should trial them, say Pavel V Ovseiko and colleagues "Is it difficult being a woman scientist?" the biochemist Dorothy Crowfoot Hodgkin was asked at high table dinner in an Oxford college by the man sitting next to her. "Not since I won the Nobel Prize," she replied.1 In 1964, the British press had reacted to her award with the headlines: "Oxford housewife wins Nobel" and "British woman wins Nobel Prize—£18 750 prize to mother of three."2 While such overtly sexist treatment of female scientists by the media is now rare, progress towards gender equality in universities has been astonishingly slow. A UK parliamentary inquiry into women in scientific careers found that with only 17% of professors in science, technology, engineering, and mathematics (STEM) in 2011-12 women were still under-represented at senior levels across all STEM disciplines.3 Concerned with the sustainability of increasing the scientific workforce, the inquiry concluded that efforts to inspire more women into science were wasted if they were subsequently disadvantaged compared with men and recommended that universities should do more to support and retain women in scientific careers.3 To accelerate women's advancement and leadership, the UK's National Institute for Health Research (NIHR) introduced an innovative policy intervention in 2011 linking its research funding to the implementation by universities of gender equality action plans through the Athena SWAN (Scientific Women's Academic Network) charter (box 1). We examine the effect of this policy on women's research leadership in NIHR funded research and theorise how such incentives may work. Box 1 ### Athena SWAN charter The Athena SWAN charter provides a peer review framework for developing action plans and gaining recognition for the advancement of gender equality in higher education and research. The charter was established in 2005 under the ownership of the … RETURN TO TEXT
TCT CONNECT-379 Adverse Outcomes in High Bleeding Risk Patients Undergoing Percutaneous Coronary Intervention for Stable Coronary Artery Disease
Authors: Johny Nicolas, Davide Cao, Bimmer Claessen, Mauro Chiarito, Samantha Sartori, Hanbo Qiu, Anastasios Roumeliotis, Matteo Nardin, Frans Beerkens, Ridhima Goel, Zhongjie Zhang, Rishi Chandiramani, Zaha Waseem, Roja Thapi, Joseph Sweeny, Annapoorna Kini, Samin Sharma, George Dangas, Roxana Mehran
Journal: Journal of the American College of Cardiology (2020)
TCT CONNECT-248 Optimal Duration of Dual Antiplatelet Therapy After Percutaneous Coronary Intervention in Patients With Acute Coronary Syndrome: Insights From a Network Meta-Analysis of Randomized Trials
Authors: Toshiki Kuno, Hiroki Ueyama, Hisato Takagi, John Fox, Sripal Bangalore
Journal: Journal of the American College of Cardiology (2020)
Therapeutic potential of polypeptide-based conjugates: Rational design and analytical tools that can boost clinical translation
Authors: Tetiana Melnyk, Snežana Đorđević, Inmaculada Conejos-Sánchez, María J. Vicent
Journal: Advanced Drug Delivery Reviews (2020)

The clinical success of polypeptides as polymeric drugs, covered by the umbrella term "polymer therapeutics," combined with related scientific and technological breakthroughs, explain their exponential growth in the development of polypeptide-drug conjugates as therapeutic agents. A deeper understanding of the biology at relevant pathological sites and the critical biological barriers faced, combined with advances regarding controlled polymerization techniques, material bioresponsiveness, analytical methods, and scale up-manufacture processes, have fostered the development of these nature-mimicking entities. Now, engineered polypeptides have the potential to combat current challenges in the advanced drug delivery field. In this review, we will discuss examples of polypeptide-drug conjugates as single or combination therapies in both preclinical and clinical studies as therapeutics and molecular imaging tools. Importantly, we will critically discuss relevant examples to highlight those parameters relevant to their rational design, such as linking chemistry, the analytical strategies employed, and their physicochemical and biological characterization, that will foster their rapid clinical translation.
TCT CONNECT-28 Left Ventricular End-Diastolic Pressure in Acute Myocardial Infarction, Association With Infarct Pathology, Left Ventricular Function, and Health Outcomes
Authors: Peter McCartney, Annette Maznyczka, Margaret McEntegart, Hany Eteiba, John Greenwood, Douglas Muir, Saqib Chowdhary, Anthony Gershlick, Clare Appleby, James Cotton, Andrew Wragg, Nick Curzen, Keith Oldroyd, Mitchell Lindsay, Paul Rocchiccioli, Aadil Shaukat, Richard Good, Stuart Watkins, Keith Robertson, Christopher John Malkin, Damien Collison, Lynsey Gillespie, Lynn Martin, Tom Ford, Mark Petrie, Robin Weir, Aengus Murphy, Colin Petrie, Kirsty Wetherall, Peter Macfarlane, Alex McConnachie, Colin Berry
Journal: Journal of the American College of Cardiology (2020)
The Clinical Kinase Index: A Method to Prioritize Understudied Kinases as Drug Targets for the Treatment of Cancer
Authors: Derek Essegian, Rimpi Khurana, Vasileios Stathias, Stephan C. Schürer
Journal: Cell Reports Medicine (2020)

The approval of the first kinase inhibitor, Gleevec, ushered in a paradigm shift for oncological treatment-the use of genomic data for targeted, efficacious therapies. Since then, over 48 additional small-molecule kinase inhibitors have been approved, solidifying the case for kinases as a highly druggable and attractive target class. Despite the role deregulated kinase activity plays in cancer, only 8% of the kinome has been effectively "drugged." Moreover, 24% of the 634 human kinases are understudied. We have developed a comprehensive scoring system that utilizes differential gene expression, pathological parameters, overall survival, and mutational hotspot analysis to rank and prioritize clinically relevant kinases across 17 solid tumor cancers from The Cancer Genome Atlas. We have developed the clinical kinase index (CKI) app (http://cki.ccs.miami.edu) to facilitate interactive analysis of all kinases in each cancer. Collectively, we report that understudied kinases have potential clinical value as biomarkers or drug targets that warrant further study.
PET Imaging as a Tool for Assessing COVID-19 Brain Changes
Authors: Igor C. Fontana, Salvatore Bongarzone, Antony Gee, Diogo O. Souza, Eduardo R. Zimmer
Journal: Trends in Neurosciences (2020)

A substantial fraction of coronavirus disease 2019 (COVID-19) patients experience neurological manifestations. Nevertheless, brain changes caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain largely unknown. Here, we provide a brief overview of positron emission tomography (PET) applications that could advance current understanding of CNS pathophysiological alterations associated with SARS-CoV-2 infection.
TCT CONNECT-261 Direct Stenting Outcomes in the OPTIMIZE IDE Trial: Exploring a Direct Stenting Indication for the Slender IDS and Direct RX Sirolimus-Eluting Stents
Authors: Ronald Caputo, Robert Feldman, A.J.J. IJsselmuiden, Giovanni Amoroso, Samer Somi, S. Chiu Wong, John Lasala, Pieter Stella, Sunil Rao, Dean Kereiakes
Journal: Journal of the American College of Cardiology (2020)
Can the Elections End the Health Reform Stalemate?
Authors: Jonathan Oberlander, Phillip M. Singer, David K. Jones
Journal: New England Journal of Medicine (2020)

Interview with Dr. Jonathan Oberlander on health reform and the 2020 elections. (10:25)Download The political and economic instability wrought by Covid-19, frustrations with the Affordable Care Act's limitations, and a polarized environment in which parties are willing to legislate without bipartisan support mean that major health policy change is possible.
De novo cutaneous connective tissue disease temporally associated with immune checkpoint inhibitor therapy: A retrospective analysis
Authors: Ai-Tram N. Bui, Sean Singer, Jesse Hirner, Amy C. Cunningham-Bussel, Cecilia Larocca, Joseph F. Merola, Christine G. Lian, Nicole R. LeBoeuf
Journal: Journal of the American Academy of Dermatology (2020)
Concurrent use of bedaquiline and delamanid for the treatment of fluoroquinolone-resistant multidrug-resistant tuberculosis: a nationwide cohort study in South Korea
Authors: Yong-Soo Kwon, Doosoo Jeon, Hyungseok Kang, Jae-Joon Yim, Tae Sun Shim
Journal: European Respiratory Journal (2020)

Multidrug-resistant tuberculosis (MDR-TB), a major global health concern, requires long-term treatment with multiple drugs, which can cause many side-effects [1]. Therefore, an effective regimen with a minimum number of drugs is essential to control this disease. Bedaquiline (Bdq) and delamanid (Dlm) are new drugs that exhibit good efficacy and safety for MDR-TB treatment [1]. However, adding only one of the new drugs to a regimen may be insufficient to cure this disease when the infecting strain has a high level of drug resistance, such as fluoroquinolone-resistant MDR-TB or extensively drug-resistant TB (XDR-TB) [1–3]. Therefore, the concurrent use of Bdq and Dlm can effectively strengthen the treatment regimen if the best practices in "off-label" use are followed [4–10]. This study analysed the efficacy and safety of concurrent use of Bdq and Dlm in patients with MDR-TB and XDR-TB treated under a programmatic condition. Concurrent use of bedaquiline and delamanid is safe and effective for the treatment of high-level resistant tuberculosis <https://bit.ly/2T0ckC8>
TCT CONNECT-463 Computed Tomography Angiography-Fluoroscopy Fusion Imaging for the Guidance of Cerebral Embolic Protection Deployment During Transcatheter Aortic Valve Replacement
Authors: Denny Wang, Craig Basman, Luigi Pirelli, Hazim El-Haddad, Efstathia Mihelis, Priti Mehla, Nirav C. Patel, Jacob Scheinerman, Chad Kliger
Journal: Journal of the American College of Cardiology (2020)
TCT CONNECT-204 Volumetric Quantification of Absolute Coronary Flow to Assess Flow Reserve
Authors: Elena Izaga-Torralba, Alejandro Gutierrez-Barrios, Fernando Rivero, Livia L. Gheorghe, Josep Gomez Lara, Etel Silva, Dolores Cañadas, Ricardo De Zayas Rueda, Rafael Vázquez-García, German Calle Perez, Fernando Alfonso
Journal: Journal of the American College of Cardiology (2020)
Age and sex differences for malignant melanoma in the pediatric population—childhood versus adolescence: analysis of current nationwide data from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program
Authors: Ryan C. Kelm, Yasmeen Ali, Kelsey Orrell, Stephanie M. Rangel, Lacey Kruse, Annette M. Wagner, Pedram Gerami, Dennis P. West, Beatrice Nardone
Journal: Journal of the American Academy of Dermatology (2020)
Abstract 16587: Proinflammatory Monocytes and Fibrotic Alveolar Macrophages Are Associated With Progression of Pulmonary Arterial Hypertension in a Primate Model of Human Immunodeficiency Virus Infection
Authors: Finja Schweitzer, Rebecca Tarantelli, Marc Simon, Whitney Rabacal, Emily Rayens, Karen Norris
Journal: Circulation (2017)

Introduction: HIV-infected are at risk of co-morbidities associated with chronic inflammation and advanced age, e.g. cardiovascular disease, chronic obstructive pulmonary disease and PAH. PAH is ch...
Atrial nitroso-redox balance and refractoriness following on-pump cardiac surgery: a randomized trial of atorvastatin
Authors: Raja Jayaram, Michael Jones, Svetlana Reilly, Mark J Crabtree, Nikhil Pal, Nicola Goodfellow, Keshav Nahar, Jillian Simon, Ricardo Carnicer, Ravi DeSilva, Chandana Ratnatunga, Mario Petrou, Rana Sayeed, Andrea Roalfe, Keith M Channon, Yaver Bashir, Timothy Betts, Michael Hill, Barbara Casadei
Journal: Cardiovascular Research (2020)

Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial.
TCT CONNECT-279 Transradial PCI Outcomes in the OPTIMIZE IDE Trial: Exploring a Transradial PCI Indication for the Slender IDS and DIRECT RX Sirolimus-Eluting Coronary Stents
Authors: Sunil Rao, A.J.J. IJsselmuiden, Floris Kauer, Giovanni Amoroso, James Zidar, Pim Tonino, Ronald Caputo, Steven Yakubov, Shigeru Saito, Dean Kereiakes
Journal: Journal of the American College of Cardiology (2020)
How current assay approval policies are leading to unintended imprecision medicine
Authors: Roberto Salgado, Andrew M Bellizzi, David Rimm, John M S Bartlett, Torsten Nielsen, Moch Holger, Anne-Vibeke Laenkholm, Cecily Quinn, Gábor Cserni, Isabela W Cunha, Isabel Alvarado-Cabrero, Ian Cree
Journal: The Lancet Oncology (2020)
Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer’s and Parkinson’s diseases
Authors: M. Ryan Corces, Anna Shcherbina, Soumya Kundu, Michael J. Gloudemans, Laure Frésard, Jeffrey M. Granja, Bryan H. Louie, Tiffany Eulalio, Shadi Shams, S. Tansu Bagdatli, Maxwell R. Mumbach, Boxiang Liu, Kathleen S. Montine, William J. Greenleaf, Anshul Kundaje, Stephen B. Montgomery, Howard Y. Chang, Thomas J. Montine
Journal: Nature Genetics (2020)
BRD4 (Bromodomain-Containing Protein 4) Interacts with GATA4 (GATA Binding Protein 4) to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes
Authors: Arun Padmanabhan, Michael Alexanian, Ricardo Linares-Saldana, Bárbara González-Terán, Gaia Andreoletti, Yu Huang, Andrew J. Connolly, Wonho Kim, Austin Hsu, Qiming Duan, Sarah A.B. Winchester, Franco Felix, Juan A. Perez-Bermejo, Qiaohong Wang, Li Li, Parisha P. Shah, Saptarsi M. Haldar, Rajan Jain, Deepak Srivastava
Journal: Circulation (2020)

Background: Gene regulatory networks control tissue homeostasis and disease progression in a cell type–specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown. Methods: We combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis. Results: Here, we show that cardiomyocyte-specific deletion of Brd4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators Ppargc1a, Ppargc1b , and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity. Conclusions: These results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.
TCT CONNECT-74 Comparison of Survival Between Patients With Degenerated Bioprostheses and Aortic Stenosis Who Underwent Transcatheter Aortic Valve Replacement
Authors: Erika Muñoz-Garcia, Manuel Muñoz Garcia, Antonio J. Muñoz-Garcia, Juan H. Alonso Briales, Jose Maria Hernandez
Journal: Journal of the American College of Cardiology (2020)
Abstract 10668: Measurement of Extracellular Volume Fraction by Cardiac Magnetic Resonance Imaging Detects Diffuse Myocardial Fibrosis in Systemic Sclerosis
Authors: Alejandro Aquino, Maria M Izquierdo Gomez, Sanjiv J Shah, Monique Hinchcliff, John Varga, Sofia Podlusky, Brandon Benefield, Maria L Carr, Aya Kino, James C Carr, Edwin Wu, Daniel C Lee
Journal: Circulation (2011)

Introduction: Primary cardiac involvement is common in systemic sclerosis (SSc) and responsible for 25% of deaths. Myocardial extravascular extracellular volume fraction (Ve), derived from cardiac ...
SAT0160 The effect of calcitonin on pain and quality of life in postmenopausal osteoporotic women
Authors: D Ofluoglu, G Akyuz, O Kayhan, O Umay
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Back pain is the most frequent symptom in osteoporosis. <h3>Objectives</h3> The aim of this study was to investigate the effect of calcitonin on plasma beta-endorphin levels, pain and quality of life in postmenopausal women with osteoporosis. <h3>Methods</h3> In our study, 100 IU salmon calcitonin with subcutaneous or placebo injection was given for 2 weeks and was continued with same dose of nasal spray or placebo for 3 months to postmenopausal women who had severe back pain due to osteoporosis. All patients took 1000 mg elementary Calcium per day. We investigated the effectiveness of calcitonin on plasma beta-endorphin levels, pain, and quality of life. There were thirty patients with a mean age of 58.17+5.36 years in the treatment group and twenty-six patients with a mean age of 58.77+5.15 years in the placebo group. Baseline plasma beta-endorphin levels were measured and repeated after two weeks and 3 months. Patients? pain was evaluated by visual analogue scale (VAS), and the modified face scale (MFS); and the quality of life was also assessed by Beck Depression Index (BDI) and Nottingham Health Profile (NHP) at the end of the second week and the third month. <h3>Results</h3> We found that the measurements of the plasma beta-endorphin level of the treatment group were significantly higher than those of the placebo group both at the end of the second week and the third month (p &lt; 0.001). Visual analogue scale, MFS, BDI and NHP scores were improved at the end of the second week in both groups (p &lt; 0.05). However, the improvement of these scores decreased in three months in the placebo group. They did not change in the placebo group at the end of the 3rd month statistically (p &gt; 0.05). <h3>Conclusion</h3> As a result, we suggest that calcitonin is a very strong analgesic agent via increasing the plasma beta-endorphin levels in postmenopausal osteoporosis and improves their physical activities and the quality of life due to decreasing back pain. <h3>References</h3> Cantarelli FB, Szejnfeld VL, Oliveira LM, <i>et al</i>. Quality of life in patients with osteoporosis fractures: cultural adaptation, reliability and validity of the osteoporosis assessment questionnaire. Clin Exp Rheumatol. 1999;17(5):547–51 Civitelli R. Calcitonin. In: Marcus R, Feldman D, Kelsey J, eds. <i>Osteoporosis</i>. Sandiego/CA: Academic Press, 1996: 1235–58 Lyrýtýs GP, Ioannidis GV, Karachalios T, <i>et al</i>. Pain relief from nasal salmon calcitonin in osteoporotic vertebral crush fractures. A double blind, placebo-controlled clinical study. Acta Orthop Scand. 1997;68(Suppl 275):112–14
AB0153 Gout in yuzhno-sakhalinsk residents
Authors: LM Lazareva, S Erdesz
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Prevalence of gout in the population of Russian cities 20 years ago according to the data of multicentral study was 0.02–0.06%. Since that time there were no studies on epidemiology of this disease. <h3>Objectives</h3> To assess the prevalence and clinical manifestations of gout among Sakhalin population (residents of Yuzhno-Sakhalin city). <h3>Methods</h3> Clinical manifestations in 120 gout pts (M:F = 117:3) examined in Municipal Diagnostical Centre of the city of Yuzhno-Sakhalinsk from 1990 to 1999 were studied. Population of the city includes 7% of Koreans and the rest are Slavs. <h3>Results</h3> In the result of analysis it was found that gout prevalence among Korean population (300 per 100000 of population) was 6.3 times higher than among Slavs (47 per 100000). In Korean population the disease was found only in males and in Slavs the relation M:F = 26:1. Among Slavs the median period of gout attack was 7–10 days per year whereas in Koreans 3–5 days by 4–5 times a year. Tofies in Koreans were found in 2% of cases, and in the rest – in 17%. Family aggregation of the disease was noticed in 25% of Korean pts and 7% in pts of other ethnicity. <h3>Conclusion</h3> In similar environmental circumstances the prevalence and clinical manifestations of gout are closely related to nationality, that is the certain genotype.
Intracellular Phosphate and ATP Depletion Measured by Magnetic Resonance Spectroscopy in Patients Receiving Maintenance Hemodialysis
Authors: Guillaume Chazot, Sandrine Lemoine, Gabriel Kocevar, Emilie Kalbacher, Dominique Sappey-Marinier, Olivier Rouvière, Laurent Juillard
Journal: Journal of the American Society of Nephrology (2020)

The precise origin of phosphate that is removed during hemodialysis remains unclear; only a minority comes from the extracellular space. One possibility is that the remaining phosphate originates from the intracellular compartment, but there have been no available data from direct assessment of intracellular phosphate in patients undergoing hemodialysis.