tbuckley/cabot-search huggingface dataset:
Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in <i>RAD51C</i> and <i>RAD51D</i>
Authors: Xin Yang, Honglin Song, Goska Leslie, Christoph Engel, Eric Hahnen, Bernd Auber, Judit Horváth, Karin Kast, Dieter Niederacher, Clare Turnbull, Richard Houlston, Helen Hanson, Chey Loveday, Jill S Dolinsky, Holly LaDuca, Susan J Ramus, Usha Menon, Adam N Rosenthal, Ian Jacobs, Simon A Gayther, Ed Dicks, Heli Nevanlinna, Kristiina Aittomäki, Liisa M Pelttari, Hans Ehrencrona, Åke Borg, Anders Kvist, Barbara Rivera, Thomas V O Hansen, Malene Djursby, Andrew Lee, Joe Dennis, David D Bowtell, Nadia Traficante, Orland Diez, Judith Balmaña, Stephen B Gruber, Georgia Chenevix-Trench, kConFab Investigators, Allan Jensen, Susanne K Kjær, Estrid Høgdall, Laurent Castéra, Judy Garber, Ramunas Janavicius, Ana Osorio, Lisa Golmard, Ana Vega, Fergus J Couch, Mark Robson, Jacek Gronwald, Susan M Domchek, Julie O Culver, Miguel de la Hoya, Douglas F Easton, William D Foulkes, Marc Tischkowitz, Alfons Meindl, Rita K Schmutzler, Paul D P Pharoah, Antonis C Antoniou
Journal: JNCI Journal of the National Cancer Institute (2020)

The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D.
104P Phase II Randomized Study of Pre-Operative Pf-04691502 Plus Letrozole Compared with Letrozole (L) In Patients with Estrogen Receptor-Positive, Her2-Negative Early Breast Cancer (Bc)
Authors: M. Dowsett, M. Koehler, R. Millham, G. Borzillo, R. A'Hern, K. Pierce, J. Barton, C. Giorgetti
Journal: Annals of Oncology (2012)
Association Between Race and Radiographic, Symptomatic, and Clinical Hand Osteoarthritis: A Propensity Score–Matched Study Using Osteoarthritis Initiative Data
Authors: Farhad Pishgar, Robert M. Kwee, Arya Haj‐Mirzaian, Ali Guermazi, Ida K. Haugen, Shadpour Demehri
Journal: Arthritis & Rheumatology (2020)

Objective To determine the associations between Black race and the presence of radiographic, symptomatic, and clinical hand osteoarthritis (OA). Methods Using available hand radiographs from the Osteoarthritis Initiative cohort (total 4,699; n = 849 Black subjects [18.1%], n = 3,850 non‐Black subjects [81.9%]), a propensity score–matching method was used to match Black subjects with non‐Black subjects for known potential risk factors of hand OA (age, sex, body mass index, smoking status, cardiovascular disease, osteoporosis, excessive occupation‐ or recreation‐related hand use, and knee OA). Posteroanterior radiographs of subjects’ dominant hands were reviewed by a musculoskeletal radiologist in a blinded manner. To assess the severity of hand OA, the modified Kellgren/Lawrence (K/L) radiographic OA scoring scale (grades 0–4) was used, and the presence of erosive OA in the hand joints was recorded. Associations between race and the severity of hand OA (measured as the summed modified K/L grade), presence of radiographic hand OA (modified K/L grade ≥2), presence of erosive hand OA, presence of symptomatic hand OA (radiographic OA with hand pain), and presence of clinical hand OA (indicated by clinical findings of Heberden's nodes in the hands) were studied using regression models. In these models, beta coefficients or odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated for the associations between Black race and any of these radiographic and symptomatic hand OA phenotypes. Results Black subjects had less severe hand OA (β = –1.93 [95% CI –2.53, –1.34]), as well as a lower risk of developing radiographic hand OA (OR 0.79 [95% CI 0.66, 0.94]), erosive hand OA (OR 0.23 [95% CI 0.11, 0.47]), symptomatic hand OA (OR 0.63 [95% CI 0.49, 0.82]), and clinical hand OA (OR 0.49 [95% CI 0.41, 0.60]), as compared to non‐Black subjects. Conclusion In contrast to the well‐established association between Black race and knee or hip OA, the findings of this study suggest that the risk of hand OA is lower in Black subjects compared to non‐Black subjects, which is not mediated by known hand OA risk factors. Future studies are warranted to determine the mediating protective factors for hand OA among Black subjects.
Induced Tumor Heterogeneity Reveals Factors Informing Radiation and Immunotherapy Combinations
Authors: Todd A. Aguilera, Eslam A. Elghonaimy, Hussein Shehade, Marjan Rafat, Laura Castellini, Dadi Jiang, Mihalis Kariolis, Albert C. Koong, Quynh-Thu Le, Lesley G. Ellies, Erinn B. Rankin, Edward E. Graves, Amato J. Giaccia
Journal: Clinical Cancer Research (2020)

Abstract Purpose: To investigate how induced tumor heterogeneity influences immune responses to radiotherapy with different proportions of mixed immune-responsive and unresponsive tumor cells in a triple-negative breast cancer model. It is hypothesized that studying the immune environment of mixed tumors and responses to radiotherapy could nominate immune active therapies to enhance immune responses after radiotherapy. Experimental Design: Evaluate efficacy and immune responses generated by radiotherapy in tumors with different proportions of immunologically responsive and unresponsive tumor cells. Then study the cellular responses and transcriptomic differences between the tumors to nominate immunotherapy combinations with radiotherapy and evaluate the combination. Results: The addition of the responsive cells to unresponsive tumors led to a greater than expected therapeutic response to radiotherapy with both innate and adaptive immune components. There was a distinct change in myeloid cells, greater inflammatory macrophage activity, and enhanced antigen presentation with responsive cells after radiotherapy. Because differences in matrix components, cell adhesion biology, and innate immune signaling correlated with myeloid cell response and phenotype, we hypothesized that radiotherapy combined with CD40 agonist antibody would sensitize unresponsive tumors. The combination therapy resulted in improved innate and adaptive immune response. Importantly, CD40 treatment increased tumor response to radiotherapy and protected against metastatic spread in a metastatic model. Conclusions: These data combined with transcriptomics from human patients support radiotherapy and myeloid cell targeting for immunologically cold tumors. The established study model presents opportunities to investigate the complex overlapping biologic mechanisms that limit immunotherapy and to implement radiotherapy with different immunotherapy combinations.
Pharmacokinetics and Pharmacodynamics of Tocilizumab for the Management of Cytokine Release Syndrome (CRS) in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) Treated with CAR T-Cell Therapy, CTL019
Authors: Clarice Lee, Henrique Bittencourt, Susana Rives, Michael W Boyer, Michael A Pulsipher, Michael R Verneris, Gregory Yanik, Birgit Jaitner, Lan Yi, Kathryn Lund, Mimi Leung, Rakesh Awasthi, Patricia A Wood, Shannon L Maude, Stephan A Grupp, Karen Thudium Mueller
Journal: Blood (2017)
Deficiency of Prebiotic Fiber and Insufficient Signaling Through Gut Metabolite-Sensing Receptors Leads to Cardiovascular Disease
Authors: David M. Kaye, Waled A. Shihata, Hamdi A. Jama, Kirill Tsyganov, Mark Ziemann, Helen Kiriazis, Duncan Horlock, Amrita Vijay, Beverly Giam, Antony Vinh, Chad Johnson, April Fiedler, Daniel Donner, Matthew Snelson, Melinda T. Coughlan, Sarah Phillips, Xiao-Jun Du, Assam El-Osta, Grant Drummond, Gavin W. Lambert, Tim D. Spector, Ana M. Valdes, Charles R. Mackay, Francine Z. Marques
Journal: Circulation (2020)

High blood pressure (BP) continues to be a major, poorly controlled but modifiable risk factor for cardiovascular death. Among key Western lifestyle factors, a diet poor in fiber is associated with prevalence of high BP. The impact of lack of prebiotic fiber and the associated mechanisms that lead to higher BP are unknown. Here we show that lack of prebiotic dietary fiber leads to the development of a hypertensinogenic gut microbiota, hypertension and its complications, and demonstrate a role for G-protein coupled-receptors (GPCRs) that sense gut metabolites.One hundred seventy-nine mice including C57BL/6J, gnotobiotic C57BL/6J, and knockout strains for GPR41, GPR43, GPR109A, and GPR43/109A were included. C57BL/6J mice were implanted with minipumps containing saline or a slow-pressor dose of angiotensin II (0.25 mg·kg-1·d-1). Mice were fed diets lacking prebiotic fiber with or without addition of gut metabolites called short-chain fatty acids ([SCFA)] produced during fermentation of prebiotic fiber in the large intestine), or high prebiotic fiber diets. Cardiac histology and function, BP, sodium and potassium excretion, gut microbiome, flow cytometry, catecholamines and methylation-wide changes were determined.Lack of prebiotic fiber predisposed mice to hypertension in the presence of a mild hypertensive stimulus, with resultant pathological cardiac remodeling. Transfer of a hypertensinogenic microbiota to gnotobiotic mice recapitulated the prebiotic-deprived hypertensive phenotype, including cardiac manifestations. Reintroduction of SCFAs to fiber-depleted mice had protective effects on the development of hypertension, cardiac hypertrophy, and fibrosis. The cardioprotective effect of SCFAs were mediated via the cognate SCFA receptors GPR43/GPR109A, and modulated L-3,4-dihydroxyphenylalanine levels and the abundance of T regulatory cells regulated by DNA methylation.The detrimental effects of low fiber Westernized diets may underlie hypertension, through deficient SCFA production and GPR43/109A signaling. Maintaining a healthy, SCFA-producing microbiota is important for cardiovascular health.
The prevalence of cardiovascular disease and its risk factors among prostate cancer patients treated with and without androgen deprivation.
Authors: Jehonathan H. Pinthus, Bobby Shayegan, Laurence Klotz, D. Robert Siemens, Patrick P. Luke, Tamim Niazi, Vincent Fradet, Yves Fradet, Emmanuelle Duceppe, Luke Lavallee, Negareh Mousavi, Robert James Hamilton, Ian Brown, Joseph Chin, Darin Gopaul, Philippe Violette, Margot Davis, Rajibul Mian, Sarah Karampatos, Darryl Leong
Journal: Journal of Clinical Oncology (2020)

364 Background: Cardiovascular disease (CVD) is the second most common cause of death in prostate cancer (PC) patients, yet the prevalence of CVD and its risk factors have been incompletely described in this population. Androgen deprivation therapy (ADT) is a risk factor for CVD. The objective of this study were to describe the CVD characteristics and risk factors in PC patients and the relationship between CVD risk and how ADT is used in real-world practice. Methods: RADICAL-PC (Role of Androgen Deprivation Therapy in CArdiovascular Disease – A Longitudinal Prostate Cancer Study) is an ongoing prospective cohort study. We recruited 2395 consecutive men (mean age 68 years) with newly diagnosed PC or with a plan to prescribe ADT for the first time. Cardiovascular risk was estimated by calculating Framingham risk scores. A Framingham score &gt;17 (corresponding with a predicted 10-year CVD risk of &gt;30%) was considered high-risk. Multivariable logistic regression was performed with ADT use as the outcome variable and CVD risk factors as the exposures of interest. Results: The prevalence of known CVD for the entire cohort was 22% and 35% had a Framingham risk score &gt;17. Most participants (58%) were current or former smokers; 16% had diabetes; 45% had hypertension and 23% had high blood pressure but had not received a diagnosis of hypertension; 31% were obese (BMI ≥30kg/m 2 ); 24% had low levels of physical activity. There was a positive relationship between each major cardiovascular risk factor and the use of ADT. However, after adjustment for age, education, alcohol use, BMI and time from PC diagnosis to eligibility assessment, these associations were significantly attenuated. Participants in whom ADT was planned had higher Framingham risk scores than those not intending to receive ADT. This risk was abolished after adjustment for confounders. Conclusions: One in three men with PC is at high cardiovascular risk. Men receiving ADT are a priori at higher CVD risk than PC patients whose treatment strategy does not include ADT. These differences are explained by confounding factors. Clinical trial information: NCT03127631.
Physiological Traits and Adherence to Obstructive Sleep Apnea Treatment in Patients with Stroke
Authors: Andrey V. Zinchuk, Nancy S. Redeker, Jen-hwa Chu, Jiasheng Liang, Carl Stepnowsky, Cynthia A. Brandt, Dawn M. Bravata, Andrew Wellman, Scott A. Sands, Henry K. Yaggi
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Biomarkers of lung damage with possible predictiveness of ARDS within CS in super high-risk patients with germ cell tumors.
Authors: Katarina Rejlekova, Katarina Kalavska, Peter Celec, Marek Makovnik, Michal Chovanec, Nikola Hapakova, Valentina De Angelis, Jana Obertova, Patrik Palacka, Zuzana Sycova, Jozef Mardiak, Michal Mego
Journal: Journal of Clinical Oncology (2020)

411 Background: Germ cell tumors (GCTs) represent a highly curable disease; however, a small proportion of patients with super-high-risk characteristics (choriocarcinoma, massive lung metastases, choriogonadotropin &gt; 50 000 mIU/ml) can develop choriocarcinoma syndrome (CS) and consecutive acute respiratory distress syndrome (ARDS) shortly after the chemotherapy start with high mortality rate. This study aimed to evaluate biomarkers of lung damage as predictive biomarkers for ARDS development within CS in poor-risk GCTs patients. Methods: This study included 23 poor-risk GCTs treated from November 2000 to May 2018 in National Cancer Institute in Slovakia for whom plasma samples before chemotherapy initiation were available. Plasma levels of lung damage biomarkers (surfactant protein (D-SPD), receptor of advanced glycation end-products (sRAGE), and club cell secretory protein – (CC16)) were evaluated by ELISA assays. Results: Five (22%) of 23 patients developed CS, and all of them died shortly after the chemotherapy start. with median of 7 days (4 - 35 days). Four of them developed ARDS within CS, while one patient died due to massive abdominal hemorrhage. Pre-treatment levels of s-RAGE and SPD but not CC-16 were significantly associated with CS development ( P = 0.03 and P = 0.04). Level of sRAGE and SPD correlated significantly with dyspnea, weight loss, extent of metastatic lung involvement and need of mechanical ventilation after chemotherapy start, as well as with PFS and OS, while CC-16 did not correlate with any of these factors. Conclusions: In this study we identified new predictive biomarkers for CS development in poor-risk GCTs. Abovementioned factors might help to improve the risk stratification of these patients with GCTs as well as discover new treatment approaches preventing ARDS development within CS which may result in enhanced treatment outcome.
<i>ARID1A</i>alterations function as a biomarker for longer progression-free survival after anti-PD-1/PD-L1 immunotherapy
Authors: Ryosuke Okamura, Shumei Kato, Suzanna Lee, Rebecca E Jimenez, Jason K Sicklick, Razelle Kurzrock
Journal: Journal for ImmunoTherapy of Cancer (2020)

Several cancer types harbor alterations in the gene encoding AT-Rich Interactive Domain-containing protein 1A (ARID1A), but there are no approved therapies to address these alterations. Recent studies have shown that
Muscle Complaints or Events in Patients Randomized to Simvastatin or Ezetimibe/Simvastatin
Authors: Michael G. Nanna, Ann Marie Navar, Robert P. Giugliano, Jennifer A. White, Yuliya Lokhnygina, Yale B. Mitchel, Thomas A. Musliner, Christopher P. Cannon, Michael A. Blazing
Journal: Journal of the American College of Cardiology (2020)
Prevalence and landscape of actionable genomic alterations in renal cell carcinoma.
Authors: Kyrollis Attalla, Renzo G. DiNatale, Eduard Reznik, Christopher Fong, Francisco Sanchez-Vega, Andrew W. Silagy, Stanley Weng, Jonathan Coleman, Chung-Han Lee, Maria Isabel Carlo, Paul Russo, Timothy An-thy Chan, Robert J. Motzer, Nikolaus D. Schultz, Martin H Voss, A. Ari Hakimi
Journal: Journal of Clinical Oncology (2020)

616 Background: We report our experience with next-generation sequencing to characterize the prevalence and genomic landscape of actionable genomic alterations in renal cell carcinoma (RCC). Methods: A query of our institutional clinical sequencing database was performed to include tumor samples sequenced across all cancers. Actionable alterations with clinical or biologic evidence supporting an association with response to targeted therapy were stratified by level of evidence using an oncology knowledge database (OncoKB). Results: Data from 35,668 patients was included, and the 15 cancer types with the highest prevalence of actionable alterations were selected for subsequent analysis (28,027 patients). Of these cancers, RCC ranked 13th in prevalence of actionable alterations. Of 708 RCC samples included, 259 (37%) were from metastatic sites. However, of the remaining 449 primary samples, 208 (29%) belonged to patients who had metastatic disease at the time of sequencing. Although 69% of patients with any RCC harbored at least one known oncogenic mutation, only 90/687 (13%) harbored alterations for which compelling clinical data currently exist to justify the use of a standard or an investigational agent (levels of evidence 1 to 3B). This represents an increase from the previously reported prevalence (5% in 2017). The most common histologic subtype, clear cell RCC harbored the vast majority of actionable alterations (52/421; 12%). Regarding the specific genes that harbor these alterations, 31 level 2A alterations were identified, all of which were TSC1/TSC2 mutations; 30 level 2B alterations were identified, of which PIK3CA (22) and BRCA1/BRCA2 (5) mutations were most common; 11 level 3A alterations, all of which were MTOR mutations, and 8 level 3B alterations, of which AKT1 (4) mutation was most common. Conclusions: Although the prevalence of actionable mutations in RCC seems to have doubled in recent years, the role of genetic testing in identifying candidates for targeted therapy in RCC is currently limited relative to other cancer types, emphasizing the need for additional research in this area to further inform targeted therapy decisions.
Tuberculosis in children, adolescents, and women
Authors: Ben J Marais, Farhana Amanullah, Amita Gupta, Mercedes C Becerra, Kathryn Snow, Esther Ngadaya, Mukta Sharma, Anneke C Hesseling, Muhwa Chakaya, Alimuddin Zumla
Journal: The Lancet Respiratory Medicine (2020)
Radium-223 in the treatment of metastatic castrate-resistant prostate cancer: A real-world Irish experience.
Authors: Niamh Peters, John Gaffney, Emma Connolly, Richard Bambury, Derek Gerard Power, Paul J. Kelly, Muhammad faisal Jamaluddin
Journal: Journal of Clinical Oncology (2020)

228 Background: Radium 223 (Ra-223) has been successfully utilised in the trial setting for the treatment of men with metastatic castrate resistant prostate cancer (mCRPC). To date, no real world outcomes from its use in the Irish population have been described. Methods: From September 2016 to March 2019, data from men referred for Ra-223 treatment at our institution was retrospectively collected. We recorded patient characteristics, treatments received and outcomes. Overall Survival (OS) was analysed using the Kaplan-Meier method. Results: 81 men were referred for Ra 223. Complete data was available for 56 men. Median age was 75. 79%(45/56) had over 6 bone metastases and 21%(12/56) had lymph node involvement. The median number of prior systemic treatments for mCRPC was 2. 84%(47/56) of patients were previously treated with Androgen deprivation therapy (ADT); 48%(27/56) Abiraterone, 36%(20/56) Docetaxel, 45%(25/56) Enzalutamide and 9%(5/56) Cabazitaxel. All patients were receiving bone protection agents; 57%(32/56) Zolendronic acid and 43%(24/56) Denosumab. Median ECOG was 1 at the start of treatment and 2 at completion. The median number of treatments received was 4 with 36%(20/56) completing all 6 treatments. The most common toxicity seen was grade1 fatigue occurring in10% (6/56). 17% (10/56) required a blood transfusion during their treatment course. 53%(30/56) required opioid analgesia prior to Ra 223 treatment. 76% of these men (22/30) described improved pain following Rad-223. At a median follow up of 13 months,41%(23/56) were alive. The median OS for the entire group was 7 months. Factors associated with improved OS included ECOG 0-1,fewer than 6 bone metastases, normal alkaline phosphatase level at start of treatment and no prior chemotherapy use. Median OS for those who had not received prior chemotherapy was significantly better than those who had (9 vs 5 months p=0.04). Conclusions: This real world study demonstrates Ra 223 is a well tolerated palliative treatment amongst Irish men with mCRPC. Good performance status, lower alkaline phosphatase, chemotherapy naivety and a low burden of metastatic disease are factors associated with an improved overall survival.
Predicting response to inhaled corticosteroid or long-acting muscarinic antagonist in mild persistent asthma
Authors: Jerry Krishnan, Stephen Lazarus, Kathryn Blake, Ronina Covar, Anne-Marie Dyer, Christine Sorkness, Sally Wenzel, Jason Lang, Njira Lugogo, David Mauger
Journal: Journal of Allergy and Clinical Immunology (2020)