tbuckley/cabot-search huggingface dataset:
Abstract 888: Exosomes Derived From Endothelial Progenitor Cells Modulate Flow-Induced Remodeling and Increase Angiogenesis/Arteriogenesis in Mesenteric Arteries of Mice
Authors: Ana Paula V Dantas, Joaquim Bobi, Linda Grimaud, Emilie Vessieres, Daniel Henrion
Journal: Circulation Research (2019)

Exosomes are key regulators of cell-to-cell communication, becoming valuable tool as disease biomarker and in the development of new therapeutic strategies. We aimed to determine the role of endothelial progenitor cell (EPC)-derived exosomes (EXO) in vascular remodeling induced by flow. C57BL/6 mice underwent chronic changes in flow by mesenteric resistance arteries ligation. Arteries were thus submitted to high flow (HF), low flow (LF), or normal flow (NF). The day before surgery mice received I.P. injection with saline or exosomes (3x10 9 particle/kg), following the treatment every 3 days until sacrifice. After 14 days, arteries were studied in vitro in a pressure arteriograph. Increase in diameter and compliance by pressure found in HF arteries were not seen in EXO treated mice (Fig A). Decrease in diameter observed in saline treated LF arteries, was also abolished by EXO treatment. Network analysis of miRNA content in exosomes and arterial mRNA expression revealed an increased expression of components involved in angiogenesis/arteriogenesis (Fig B), which could contribute to flow maintenance in the tissue. Mesenteric arteries submitted to LF, HF and NF were isolated and placed in Matrigel matrix for angiogenesis analysis. We observed that change in flow is a trigger for vasculogenesis, which is enhanced by EXO treatment (Fig C). This study establishes the potential role of EPC-derived exosomes to regulate vascular remodeling during changes in flow. The mechanisms for these effects involve exosome-derived miRNA regulation of a network of mRNAs implicated in collateral angiogenesis/arteriogenesis, which in turn, may contribute to maintenance of tissue homeostasis.
Variants of uncertain significance in BRCA testing: Impact on risk perception, worry, prevention, and counseling.
Authors: Tracy Graham, Andrea Eisen, Sue Richter, Iman Haroun, Ellen Warner
Journal: Journal of Clinical Oncology (2012)

1555 Background: Genetic testing for BRCA1 and BRCA2 is an instrumental tool in clinical decision-making. Variants of uncertain significance (VUS) can occur in up to 25% of individuals and pose clinical challenges. We compared i) result recall ii) risk perception iii) worry and iv) risk modifying behaviours in individuals with VUS, a pathogenic mutation (PM) or an uninformative result (UR). Care provider attitudes to VUS were also studied. Methods: A questionnaire was mailed to women testing positive for a VUS, PM or UR. Items included demographics, time from disclosure, result recall and cancer worry using the validated Trask score. Likelihood of risk modifying behaviours or intensified screening was evaluated by 5 point Likert scale. 9 regional genetic counselors and 11 referring physicians were surveyed on VUS management. Responses were evaluated by chi square and ANOVA. Results: All groups had similar age, marital status and education. Failure to correctly identify a result as uninformative occurred in 32% of VUS; 90% had low economic status. 87% (VUS) and 44% (PMC) had personal history of breast cancer. Perceived risk increased after disclosure in 29% (VUS), 70%(PM) and 10% (UR) (p&lt;0.001). Mean Trask scores were 7.6 (VUS) and 9.8 (PMC) (p=0.006, t-test). In affected patients, mastectomy was 22% (VUS) and 55% (PMC) (p=0.01), oophorectomy 39% (VUS) and 85% (PMCs) (p&lt;0.001) with75% and 95% intensified screening 75% in unaffected VUS and PM (p=0.16). 3% (VUS) and 6% (PMC) agreed with chemoprophylaxis (p=NS). Genetic counselors unanimously reported low comprehension in VUS vs PM. VUS was disclosed only 75% of the time with poor comprehension, perceived anxiety and negative family history as reasons. Referring physicians recommended predictive testing for relatives of VUS carriers (100%). Conclusions: Nearly 1/3 of patients fail to recall their VUS as uninformative. Perceived risk was increased after VUS disclosure but lower than PMC. Worry scores showed impact on daily functioning. Uptake of prophylactic surgery was lower in affected VUS vs PMC carriers with similar rates of intensified screening if unaffected. Patients with low economic status or anxiety are at particular risk of incomplete counseling.
Abstract 102: Molecular, Cellular and Systemic Mechanism of Nonlinear Dynamic Patterns of Ventricular Repolarization and Spontaneous Arrhythmic Sudden Death in Non-ischemic Heart Failure
Authors: Daiana C Vieira, Jeffrey S Crocker, Krina Desai, Neha Reddy Sanagala, Daniel R Wendelken, Kenneth G Parks, Ting Liu, Brian O'Rourke, Swati Dey, Deeptankar DeMazumder
Journal: Circulation Research (2019)

Introduction: Sudden cardiac death (SCD) is the leading cause of death in USA. Heart failure (HF) confers high SCD risk, but most SCD victims do not have HF or well-defined genetic abnormalities. The underlying mechanisms are poorly understood, precluding the design of more effective strategies for risk stratification and therapy. We previously showed that distinct non-linear patterns of cardiac repolarization strongly and independently predict SCD in HF patients [PMID: 27044982]. We also showed in a unique guinea pig HF model that increased levels of mitochondrial reactive oxygen species (mROS) drive spontaneous SCD, even before HF onset [PMID: 29898892]. Herein, we further dissect the underlying mechanisms. Hypothesis: Increased mROS levels in pressure overloaded hearts reduce K+ currents, destabilize the resting membrane potential, increase repolarization lability and cause SCD. Methods: Guinea pigs were randomized to Sham, aortic banding (AC), or AC with daily brief low-dose β-adrenergic stress (ACi) with and without in vivo mROS scavenger MitoTEMPO (ACi+MT). We performed time series analyses on recordings of: (1) 24-hour ECG QT interval in freely ambulating animals before sacrifice at 4 weeks; (2) pressure-volume and electrophysiology (EP) in excised perfused hearts; and (3) duration of action potential (APd), calcium transient (CaTd) and sarcomere shortening (SSd) in isolated LV myocytes. Results: About 50% of ACi animals had SCD by 4 weeks. Increased QT entropy in ACi (at 1 week) predicted SCD over followup, similar to HF patients. Compared to Sham and ACi+MT, LV myocytes isolated from AC and ACi had reduced inward (IK1) and delayed slow (IKs) and rapid (IKr) rectifier currents; and increased beat-to-beat lability in APd, CaTd and SSd. The late Na and L-type Ca currents were similar between models. Acute exposure to isoproterenol (Iso) and carbachol (CCh) increased lability in LV myocytes compared to Iso or CCh alone. Conclusions: High mROS levels reduce repolarization reserve in LV myocytes and contribute, at least in part, to the non-linear dynamics of ventricular repolarization (reflected by high QT entropy), leading to spontaneous arrhythmic SCD. These findings provide important new mechanistic insight with direct clinical implications.
Abstract 617: <i>In vivo</i> Titin Oxidation as a Modulator of Sarcomeric Contractibility
Authors: Ines Martinez-martin, Elías Herrero-Galán, Natalia Vicente, Cristina Sánchez-González, Diana Velázquez-Carreras, Elena Bonzón-Kulichenko, Enrique Calvo, Jesús Vázquez, Jorge Alegre-Cebollada
Journal: Circulation Research (2019)

Titin is the sarcomeric protein responsible for the passive elasticity of muscle. Its function is based on the unfolding and refolding of the immunoglobulin-like (Ig) domains located in the I-band, thus described as the mechanically active region of the protein. Previous in vitro studies have shown that oxidation of cysteines located in these domains modulates the mechanical properties of the protein. However, the extent of these redox modifications and the identity of the modified residues in vivo remains unexplored. Here we show for the first time that titin is oxidized in vivo and that oxidative modifications target conserved cysteines of the mechanically active Ig domains. We have set up a biochemical method for in-gel determination of oxidized thiols by which we found that titin is remarkably oxidized when compared to myosin, which is not a target of cysteine redox modifications. By mass spectrometry, we also detected that the conserved cysteines previously described as mechanically relevant are in fact oxidized. We propose that characterizing the oxidation of titin Ig domains will lead to a better understanding of the regulation of muscle elasticity, and could explain the pathological effects of an imbalanced redox status, such as during myocardial infarction or ischemia.
Towards Improved Models of NPM-ALK Induced T-Cell Lymphoma
Authors: Sophia Ehrenfeld, Khalid Shoumariyeh, Teresa Poggio, Robin Khan, Desiree Melanie Redhaber, Stefanie Kreutmair, Cathrin Klingeberg, Anna Lena Illert, Justus Duyster, Cornelius Miething
Journal: Blood (2018)
Recovery of Specific Subsets of Natural Killer and T Cells Highly Associated with Graft-Versus-Host Disease after Haploidentical Stem Cell Transplantation in Acute Leukemia
Authors: Jieun Jang, Haerim Chung, Yu Ri Kim, Hoi-kyung Jeung, Ju-In Eom, So-Young Seol, Soo-Jeong Kim, Jin Seok Kim, June-Won Cheong, Yoo Hong Min
Journal: Blood (2018)
Elevated FANCA Expression Marks a Worse Prognosis in Chronic Lymphocytic Leukemia. Evidence of a New Role of FANCA in the Stability of p53 By a Neddylation-Related Mechanism
Authors: Carlos Pipaon, Sara Bravo Navas, Iñigo Romon, Eulogio Conde, Lucrecia Yanez San Segundo
Journal: Blood (2018)
Sports and exercise medicine education in the USA: call to action
Authors: Irfan M Asif, Jonathan A Drezner
Journal: British Journal of Sports Medicine (2019)

US healthcare has been ranked as both the costliest and the poorest quality1 among high-income countries. Our traditional fee-for-service model clearly incentivises treatment of sickness and disease ahead of disease prevention. One of us (IA) works in Alabama, a prime example of a US state with poor health outcomes. Alabama is ranked 48th out of 50 states for overall health, 45th in the proportion of people who meet physical activity guidelines, 49th in cardiovascular health and 44th in mental health, and is among the five worst states for obesity and in the top three for increasing prevalence of diabetes.2

To address the challenge of poor health outcomes, the US healthcare system has begun moving towards a value-based reimbursement system with the passage of the Affordable Care Act, which aims to lower costs and improve quality. Since 80% of diseases (eg, hypertension, heart disease, type 2 diabetes, obesity, multiple cancers and osteoporosis) in the USA are related to poor lifestyles,3 the promotion of physical activity and healthy eating are low-cost measures that could significantly impact quality outcomes. Given …
Management of toxicity to isoform α-specific PI3K inhibitors
Authors: S.E. Nunnery, I.A. Mayer
Journal: Annals of Oncology (2019)

Alterations in the phosphoinositide 3-kinase (PI3K)/AKT pathway are frequently found in cancer and are especially common in breast cancer, where it is estimated that 70% of tumors have some type of genetic alteration that could lead to pathway hyperactivation. A variety of PI3K pathway inhibitors have been developed in an attempt to target this pathway and improve cancer control. One of the challenges in treating patients with PI3K/AKT pathway inhibitors is the associated toxicity from on-target and off-target effects. Such side-effects are common, but reversible, and include hyperglycemia, rash, stomatitis, diarrhea, nausea, and fatigue. As a result, dose reductions, treatment delays, and treatment discontinuation are frequently reported. This impairs not only patients' quality of life but also treatment efficacy. Most side-effects are reversible with drug interruption, since these drugs typically have a short half-life and are manageable with early intervention. An interdisciplinary approach with proactive management of patients receiving PI3K pathway inhibitors should include comprehensive education of patients about the range of toxicities, frequent monitoring, early toxicity recognition, active intervention, as well as prophylactic strategies.
An Analysis of Real Life Data Obtained from 30 Years Follow-up of Primary Myelodysplastic Syndromes (MDS) Patients Confirms a Leading Role of Stem Cell Transplantation (SCT) for Achievement of Prolonged Survival
Authors: Jaroslav Cermak, Antonin Vitek, Dana Mikulenkova, Jacqueline Soukupova, Jana Brezinova, Marketa Stastna, Veronika Valkova, Monika Belickova, Kyra Michalova, Petr Cetkovsky
Journal: Blood (2018)
Response to: ‘Circulating regulatory T cells were absolutelydecreased in dermatomyositis/polymyositispatients and restored by low-dose IL-2’ by Zhang<i>et al</i>
Authors: David Klatzmann
Journal: Annals of the Rheumatic Diseases (2019)

In this issue, Zhang et al report that a short course of low-dose IL-2 improved patients with polymyositis or dermatomyositis. This adds to the list of diseases for which efficacy of low-dose IL-2 has been reported.1 This is in line with the main activity of low-dose IL-2, the stimulation and expansion of regulatory T cells (Tregs).1 Tregs are key to maintaining immune homeostasis. They control inflammation and the activation of effector T cells with autoimmune potential.2 Their depletion immediately unleashes major activation of effector T cells leading to fatal inflammation and the attack of otherwise healthy tissues, leading to multiorgan autoimmunity.3 This observation indicates that, at homeostasis, there is a balance between Tregs and effector T cells that prevents severe inflammation and autoimmunity. This, in turn, teaches us that any chronic breach of this homeostasis, that is, an autoimmune condition, inherently signals Treg insufficiency.1 Such Treg insufficiency does not imply a Treg deficiency, but reflects …
Publisher Correction: Innate-like functions of natural killer T cell subsets result from highly divergent gene programs
Authors: Isaac Engel, Grégory Seumois, Lukas Chavez, Daniela Samaniego-Castruita, Brandie White, Ashu Chawla, Dennis Mock, Pandurangan Vijayanand, Mitchell Kronenberg
Journal: Nature Immunology (2019)
“I had already made up my mind.” The impact of prior experience and health care perceptions on decision making in women with early-stage breast cancer.
Authors: Rebecca England, Valerie Lawhon, Audrey S. Wallace, Stacey A. Ingram, Courtney Williams, Gabrielle Betty Rocque
Journal: Journal of Clinical Oncology (2019)

228 Background: Shared decision-making (SDM) occurs when informed patients partner with their oncologists to incorporate personal preferences into treatment. Even before engaging with an oncologist about treatment options, patients may have personal experiences or knowledge of other’s experiences with breast cancer that frame their decision-making. This study sought to understand how prior experiences and knowledge drive preferences in early stage breast cancer treatment approaches. Methods: This qualitative study included early stage breast cancer (BC) patients at an academic medical center in the Deep South. Women age ≥18 with an AJCC stage I-III BC diagnosis were invited to complete semi-structured interviews with a trained interviewer. Interviews were audio-recorded, transcribed, and analyzed by two independent coders utilizing a constant comparative method from an a priori conceptual model based on the Ottawa Framework. Major themes and exemplary quotes related to decision-making preferences were extracted. Results: Women (n = 33) interviewed were an average age of 74 (4.2 SD), and 19% of participants were African American. Many women were given the option to omit treatments, such as chemotherapy or radiation therapy, based on hormone receptor status and axillary node involvement. Major themes related to a desire for more treatment were past experiences with family members having cancer or an impression that additional treatment would be more effective. For women that opted out of treatments, prior knowledge of potential physical side effects from friends, family, and other cancer survivors were cited as a major deterrent. Perceptions of low recurrence risk also influenced desire to forgo treatments. Conclusions: Women presenting with early stage BC had varied healthcare experiences, which resulted in preconceived ideas about receiving breast cancer treatments. Consideration of these themes may aid physicians’ ability to address individual concerns to further personalize patient care, thus enhancing the patient-physician partnership. These findings will ultimately assist in improving patient engagement in SDM.
Abstract 715: A Metabolic Mechanism for Cardiomyocyte Cell Cycle Arrest
Authors: Richard J Mills
Journal: Circulation Research (2019)

The mammalian heart undergoes maturation during postnatal life to meet the increased functional requirements of the adult. However, the key drivers of this process remain poorly defined. We are currently unable to recapitulate postnatal maturation in human pluripotent stem cell-derived cardiomyocytes (hPSC-CM), limiting their potential as a model system to discover regenerative therapeutics. Here, we provide a summary of our studies where we developed a 96-well device for functional screening in human pluripotent stem cell-derived cardiac organoids (hCOs). Through interrogation of &gt;10,000 organoids, we systematically optimize parameters, including extracellular matrix, metabolic substrate and growth factor conditions that enhance cardiac tissue viability, function and maturation. Under optimized maturation conditions, functional and molecular characterization revealed that a switch to fatty acid metabolism was a central driver of cardiac maturation. Under these conditions hPSC-CMs were refractory to mitogenic stimuli and we found key proliferation pathways including β-catenin and YAP1 were repressed. This proliferative barrier imposed by fatty acid metabolism in hCOs could be rescued by simultaneous activation of both β-catenin and YAP1 using genetic approaches or a small molecule activating both pathways. These studies highlight that human organoids coupled with higher throughput screening platforms have the potential to rapidly expand our knowledge of human biology and potentially unlock novel therapeutic strategies.
Ticagrelor or Prasugrel in Acute Coronary Syndromes — The Winner Takes It All?
Authors: Hani Jneid
Journal: New England Journal of Medicine (2019)

Orville Wright said, “If we all worked on the assumption that what is accepted as true is really true, there would be little hope of advance.” Approximately one person in the United States has a myocardial infarction every 40 seconds, and more than 1 million coronary events occur each year, of which one third are recurrent events.1 Antiplatelet medications and strategies to lower levels of low-density lipoprotein are cornerstone therapies to reduce recurrent atherothrombotic events after an acute coronary syndrome. Since the advent of dual oral antiplatelet therapy for acute coronary syndromes (with clopidogrel having an incremental benefit over aspirin . . .
Financial conflicts of interest among the National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline (CPG) Panelists in 2019.
Authors: Aakash Desai, Madhuri Chengappa, Ronald S. Go, Thejaswi Poonacha
Journal: Journal of Clinical Oncology (2019)

15 Background: CPG are evidence-based guidelines, which serve as a standard of care in practice, quality improvement, and reimbursement. The extent of financial conflicts of Interest (FCOI) in NCCN guidelines has not been recently evaluated. Our study evaluated the extent of FCOI in the NCCN CPG among the 10 most common malignancies in the US. Methods: We examined the latest 2019 version of the NCCN CPG for the 10 most common cancers by incidence in the US. Using disclosure lists, we catalogued the FCOIs for the panelists under various categories outlined in the CPG. We also tabulated the companies/institutions involved in each disclosure. An “episode” describes 1 instance of participation of a panelist in 1 company in 1 category of each guideline. “Affiliation” describes a commercial, industry, or institute affiliation reported by a panelist in each episode. Results: Of the 491 panelists on the CPG, 483 (98.3%) completed FCOI disclosures. 224 (46.38%) reported at least 1 FCOI. A total of 1,103 episodes were disclosed with an average of 4.9 episodes per panelist with FCOI. Being a part of scientific advisory boards, consultant, or expert witness was the most common FCOI category (19.9%). A total of 191 companies were associated with 1,103 episodes of FCOI. The top companies were Bristol Myers Squibb, Merck, Genentech and AstraZeneca. Among the top 10 cancers, the prevalence of FCOI were lung (56%), bladder (52%), pancreatic (52%), non-Hodgkin lymphoma (50%), kidney (49%), colorectal (43%), breast (42%), melanoma (40%), prostate (38%), and uterine (32%). Among the panelists with FCOI, 26%, 17%, and 57% reported 1, 2, and &gt; 3 episodes, respectively. There were 127 episodes among the CPG chairs/vice chairs who reported FCOI (mean 6.4). The chairs/vice chairs of uterine, pancreatic, melanoma, and prostate cancer CPG did not have any FCOI. Conclusions: FCOI are very prevalent among the top 10 NCCN CPG panelists. In almost half of the CPG, the majority of the panelists had at least 1 FCOI. Over half of the CPG chairs/vice chairs reported multiple FCOI. Further studies are necessary to determine the impact of these FCOI.