tbuckley/cabot-search huggingface dataset:
Targeting PARP1 in XRCC1-Deficient Sporadic Invasive Breast Cancer or Preinvasive Ductal Carcinoma <i>In Situ</i> Induces Synthetic Lethality and Chemoprevention
Authors: Reem Ali, Abdulbaqi Al-Kawaz, Michael S. Toss, Andrew R. Green, Islam M. Miligy, Katia A. Mesquita, Claire Seedhouse, Sameer Mirza, Vimla Band, Emad A Rakha, Srinivasan Madhusudan
Journal: Cancer Research (2018)

: Targeting PARP1 for synthetic lethality is a new strategy for breast cancers harboring germline mutations in BRCA. However, these mutations are rare, and reactivation of BRCA-mediated pathways may result in eventual resistance to PARP1 inhibitor therapy. Alternative synthetic lethality approaches targeting more common sporadic breast cancers and preinvasive ductal carcinoma in situ (DCIS) are desirable. Here we show that downregulation of XRCC1, which interacts with PARP1 and coordinates base excision repair, is an early event in human breast cancer pathogenesis. XRCC1-deficient DCIS were aggressive and associated with increased risk of local recurrence. Human invasive breast cancers deficient in XRCC1 and expressing high PARP1 levels also manifested aggressive features and poor outcome. The PARP1 inhibitor olaparib was synthetically lethal in XRCC1-deficient DCIS and invasive breast cancer cells. We conclude that targeting PARP1 is an attractive strategy for synthetic lethality and chemoprevention in XRCC1-deficient breast cancers, including preinvasive DCIS. SIGNIFICANCE: These findings show that loss of XRCC1, which is associated with more malignant DCIS, can be exploited by PARP inhibition, suggesting its application as a promising therapeutic and chemoprevention strategy in XRCC1-deficient tumor cells.
Abstract MP007: Higher Plasma Galectin-3 is Associated With Increased Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Oluwaseun E Fashanu, Faye Norby, David Aguilar, Christie Ballantyne, Ron Hoogeveen, Lin Y Chen, Elsayed Z Soliman, Alvaro Alonso, Aaron R Folsom
Journal: Circulation (2017)

Background: Atrial fibrillation (AF) is a common supraventricular tachyarrhythmia associated with increased risk of cardiovascular sequelae, including heart failure (HF), stroke, and premature mortality. Galectin-3, a beta-galactoside binding lectin involved in important regulatory roles in adhesion, inflammation, immunity, and fibrosis, may be relevant to AF etiology. We tested the hypothesis that plasma galectin-3 concentration would be associated positively with the incidence of AF independent of traditional AF risk factors and incident HF and coronary heart disease (CHD) in a large community-based cohort in the US. Methods: Our analysis included 8,777 participants free of AF at visit 4 (1996-98) and with measures of plasma galectin-3 from the biracial Atherosclerosis Risk in Communities (ARIC) study. Incident AF was ascertained through the end of 2013 from study visit ECGs, hospitalizations and death certificates. Multivariable Cox proportional hazards models, adjusted for AF risk factors (Model 1) plus incident HF and CHD (Model 2), were used to estimate hazards ratios for the association between galectin-3 and incident AF. Results: The mean age (SD) of participants was 62.5 (5.6) years; 58.7% were women and 21.5% blacks. During a median follow-up of 15.7 years, 1,233 incident cases of AF were observed. After adjusting for AF risk factors, participants with galectin-3 levels greater than 19.5 ng/ml had a significantly higher risk of incident AF when compared to the referent group (4.4 - 11.9ng/ml), with hazard ratios of 1.44 for the 90 th - 94.9 th percentile, and 1.61 for the 95 th - 100 th percentile (p-trend = 0.0003). The association between galectin-3 concentration and incident AF was attenuated somewhat after accounting for incident CHD and HF as time dependent variables (p-trend=0.03) (Table 1). Conclusion: Elevated plasma galectin-3 is associated independently with increased risk of incident AF.
The Number of Screening Cycles Needed to Reduce Prostate Cancer Mortality in the Finnish Section of the European Randomized Study of Prostate Cancer (ERSPC)
Authors: Tomi Pakarainen, Jaakko Nevalainen, Kirsi Talala, Kimmo Taari, Jani Raitanen, Paula Kujala, Ulf-Håkan Stenman, Teuvo L.J. Tammela, Anssi Auvinen
Journal: Clinical Cancer Research (2018)

Abstract Purpose: The European Randomized Study of Screening for Prostate Cancer (ERSPC) has shown a 21% reduction in prostate cancer mortality by PSA-based screening. The aim of the study is to evaluate screening effect on prostate cancer incidence and mortality in relation to number of screening rounds attended. Experimental Design: The participants in the screening arm of the Finnish trial (31,867 men) were classified according to screening attendance in a time-dependent fashion. Initially, all men in the screening arm were regarded as nonattenders until the first screening attendance, then remained among the once-screened until the second screen and similarly for the possible third round. The control arm was the reference. Follow-up started at randomization and ended at death, emigration, or end of 2013. Prostate cancer incidence and mortality, as well lung cancer and overall mortality were evaluated. Results: Prostate cancer incidence was increased among screened men, but was not directly related to the number of screening rounds. Prostate cancer mortality was decreased in men screened twice or three times, but did not materially differ in those who did not attend the screening, and in men screened once compared with the control arm. The largest mortality reduction was in men screened three times [HR 0.17; 95% confidence interval (CI), 0.09–0.33]. However, a reduction was also seen in lung cancer (HR 0.59; 95% CI, 0.47–0.73) and overall mortality (HR 0.56; 95% CI, 0.52–0.60). Conclusions: Assuming a similar relative reduction being due to selection bias and screening in prostate cancer as other causes of death (40% reduction), approximately half of the observed prostate cancer mortality reduction by repeated screening is likely to be noncausal and a real screening effect may account for up to 40% reduction in men screened three times. Prostate cancer mortality reduction can only be achieved by repeated screening cycles.
Abstract 15421: Anti-Arrhythmic Effects of Heart-Derived Cell Therapy in a Rat Model of Heart Failure With Preserved Ejection Fraction
Authors: Jae Hyung Cho, Peter J Kilfoil, Ryan Solymani, Kristin Luther, Russell G Rogers, Geoffrey de Couto, Rui Zhang, Lizbeth Sanchez, Joshua I Goldhaber, Eduardo Marban, Eugenio Cingolani
Journal: Circulation (2017)

Introduction: Sudden death is the leading mode of exodus in patients suffering from heart failure with preserved ejection fraction (HFpEF). Cardiosphere-derived cells (CDCs) attenuate hemodynamic a...
A phase II study investigating the safety and efficacy of neoadjuvent atezolizumab in muscle invasive bladder cancer (ABACUS)
Authors: D. Castellano, I. Duran, A. Rodríguez-Vida, S.J. Crabb, M.S. van der Heijden, A. Font Pous, G. Gravis, U. Anido Herranz, A. Protheroe, A. Ravaud, D. Maillet, M.J. Mendez-Vidal, C. Suarez, A. Lorch, C.N. Sternberg, M. Linch, S.-J. Sarker, J. Notta, K. Mousa, T.B. Powles
Journal: Annals of Oncology (2018)
The Oncogenic Transcription Factor RUNX1/ETO Corrupts Cell Cycle Regulation to Drive Leukemic Transformation
Authors: Natalia Martinez-Soria, Lynsey McKenzie, Julia Draper, Anetta Ptasinska, Hasan Issa, Sandeep Potluri, Helen J. Blair, Anna Pickin, Asmida Isa, Paulynn Suyin Chin, Ricky Tirtakusuma, Daniel Coleman, Sirintra Nakjang, Salam Assi, Victoria Forster, Mojgan Reza, Ed Law, Philip Berry, Dorothee Mueller, Cameron Osborne, Alex Elder, Simon N. Bomken, Deepali Pal, James M. Allan, Gareth J. Veal, Peter N. Cockerill, Christian Wichmann, Josef Vormoor, Georges Lacaud, Constanze Bonifer, Olaf Heidenreich
Journal: Cancer Cell (2018)

Highlights•An RNAi screen identifies CCND2 as a crucial transcriptional target of RUNX1/ETO•RUNX1/ETO promotes CCND2 expression by binding to an upstream element•CCND2 knockdown inhibits RUNX1/ETO-driven leukemic expansion in vitro and in vivo•RUNX1/ETO-expressing leukemic cells are highly sensitive to a CDK4/6 inhibitorSummaryOncogenic transcription factors such as the leukemic fusion protein RUNX1/ETO, which drives t(8;21) acute myeloid leukemia (AML), constitute cancer-specific but highly challenging therapeutic targets. We used epigenomic profiling data for an RNAi screen to interrogate the transcriptional network maintaining t(8;21) AML. This strategy identified Cyclin D2 (CCND2) as a crucial transmitter of RUNX1/ETO-driven leukemic propagation. RUNX1/ETO cooperates with AP-1 to drive CCND2 expression. Knockdown or pharmacological inhibition of CCND2 by an approved drug significantly impairs leukemic expansion of patient-derived AML cells and engraftment in immunodeficient murine hosts. Our data demonstrate that RUNX1/ETO maintains leukemia by promoting cell cycle progression and identifies G1 CCND-CDK complexes as promising therapeutic targets for treatment of RUNX1/ETO-driven AML.Graphical abstract
P3.11-18 Implementing One Stop Lung Clinic to Improve Diagnostic Timeliness in Lung Cancer Patients in the North of England
Authors: S. Robinson, V. Dudzevicius, R. Sathyamurthy, R. Mustafa, R. Hartley, G. Andrijevskiene, K. Linkin, T. Jasper, J. Hughes, S. Fenwick, H. Sircus, N. Clerk, R. Shears, A. Charles, C. Taylor, K. Dover, A. Wood
Journal: Journal of Thoracic Oncology (2018)
Krystyna Walton: trauma rehabilitation specialist
Authors: Kathy Oxtoby
Journal: BMJ (2018)

Choosing medicineI was 15 when I decided on a career in medicine.My chemistry teacher thought it would be a good choice because I was good at sciences.Until then I hadn't even considered going to university-my parents were refugees from Poland and Belarus, they were working class, not particularly well educated, and could read but couldn't write in English.
Racial and Ethnic Differences in Anthropometric Measures as Risk Factors for Diabetes
Authors: Juhua Luo, Michael Hendryx, Deepika Laddu, Lawrence S. Phillips, Rowan Chlebowski, Erin S. LeBlanc, David B. Allison, Dorothy A. Nelson, Yueyao Li, Milagros C. Rosal, Marcia L. Stefanick, JoAnn E. Manson
Journal: Diabetes Care (2018)

The study objective was to examine the impact of race/ethnicity on associations between anthropometric measures and diabetes risk.A total of 136,112 postmenopausal women aged 50-79 years participating in the Women's Health Initiative without baseline cancer or diabetes were followed for 14.6 years. BMI, waist circumference (WC), and waist-to-hip ratio (WHR) were measured in all participants, and a subset of 9,695 had assessment of whole-body fat mass, whole-body percent fat, trunk fat mass, and leg fat mass by DXA. Incident diabetes was assessed via self-report. Multivariate Cox proportional hazards regression models were used to assess associations between anthropometrics and diabetes incidence.During follow-up, 18,706 cases of incident diabetes were identified. BMI, WC, and WHR were all positively associated with diabetes risk in each racial and ethnic group. WC had the strongest association with risk of diabetes across all racial and ethnic groups. Compared with non-Hispanic whites, associations with WC were weaker in black women (P < 0.0001) and stronger in Asian women (P < 0.0001). Among women with DXA determinations, black women had a weaker association with whole-body fat (P = 0.02) but a stronger association with trunk-to-leg fat ratio (P = 0.03) compared with white women.In postmenopausal women across all racial/ethnic groups, WC was a better predictor of diabetes risk, especially for Asian women. Better anthropometric measures that reflect trunk-to-leg fat ratio may improve diabetes risk assessment for black women.
Reply to Kathryn L. Penney, Massimo Loda, and Meir J. Stampfer's Letter to the Editor re: Melissa Assel, Anders Dahlin, David Ulmert, et al. Association Between Lead Time and Prostate Cancer Grade: Evidence of Grade Progression from Long-term Follow-up of Large Population-based Cohorts Not Subject to Prostate-specific Antigen Screening. Eur Urol 2018;73:961–7
Authors: Andrew J. Vickers, Hans Lilja, Melissa Assel
Journal: European Urology (2018)
Abstract 13849: Enhancing Anti-thrombotic Efficacy but Reducing Hemorrhage: Comparison and Combination Use of a Novel Integrin Outside-in Signaling Inhibitor With Current Anti-platelet Drugs
Authors: Yujie Cui, Aiming Pang, Xiang Shen, Aleksandra Stojanovic, Xiaoping Du
Journal: Circulation (2016)

Introduction and Hypothesis: Current anti-platelets drugs cause excessive bleeding. We have developed a novel anti-platelet drug, M3mP6, which selectively inhibits integrin outside-in signaling but not ligand binding to integrin αIIbβ3. Here we test the hypothesis that M3mP6 may synergistically enhance anti-thrombotic effects of current anti-platelet drugs but reduce risk of hemorrhage. Methods and Results: One time bolus injection of M3mP6 (10 uMol/kg,15 min) has superior anti-thrombotic effect compared to high doses of clopidogrel (4 mg/kg, oral, 2 hours), and very high doses of aspirin (36 mg/kg, i.p., 1 hour), using a FeCl 3 -induced occlusive carotid artery thrombosis model in mice. However, unlike the high doses of clopidogrel and aspirin, M3mP6 did not affect bleeding using a tail bleeding time model. We found that M3mP6 was comparable with the loading doses of ticagrelor (3 mg/kg) and cangrelor (30 μg/kg) in anti-thrombotic efficacy. However, ticagrelor or cangrelor cause dramatically increased hemorrhage, which is in contrast to M3mP6’s lack of bleeding side effect. To mimic hemorrhage during intravascular/surgical procedures, we designed a carotid artery puncture model of surgical hemorrhage. Cangrelor caused dramatically excessive bleeding even treated with a hemostatic pad. In contrast, M3mP6-treated mice are not different from control. Importantly, M3mP6 exerts synergistic anti-thrombotic effects when used together with current anti-platelets drugs, without further increases in bleeding. Furthermore, when M3mP6 was used in combination with a reduced dose of cangrelor, the anti-thrombotic effect was significantly more potent than high dose cangrelor, but hemorrhage was greatly reduced. Conclusions: M3mP6 is potentially a superior new anti-platelet drug, ideal for patients with bleeding risk, and also for greatly enhancing anti-thrombotic effects of current anti-platelet drugs while reducing hemorrhage.
Abstract 17967: Systemic Hypertension in Children After Superior Cavo-pulmonary Shunt is Associated With Cerebrovascular Dysautoregulation
Authors: Antonio G Cabrera, Ronald B Easley, Rachel Dugan, Michelle Goldsworthy, Katherine K Kibler, Emmett D McKenzie, Charles D Fraser, Jeffrey S Heinle, Dean B Andropoulos, Lara S Shekerdemian, Daniel J Penny, Kenneth M Brady
Journal: Circulation (2015)

Introduction: Hypertension is frequently seen after superior cavo-pulmonary shunt. It is unknown if hypertension is necessary to maintain cerebral blood flow due to increased cerebral venous pressure. We sought to determine the range of arterial blood pressures (ABP) associated with intact and impaired autoregulation after superior cavo-pulmonary shunt. Hypothesis: Hypertension (mean ABP&gt;60 mmHg) is associated with cerebrovascular dysautoregulation after superior cavo-pulmonary shunt. Methods: All patients &lt; 12 months undergoing superior cavo-pulmonary shunt from 10/2014 were eligible. Subjects underwent continuous 100 Hz monitoring of ABP, pulmonary arterial pressure (PAP), and near-infrared spectroscopy measurements of cerebral oximetry (rSO 2 ) and cerebral blood volume (CBV). Cerebrovascular autoregulation was measured by the hemoglobin volume index (HVx). ABP and CBV were low-pass filtered as 10 sec average values. Pearson’s correlation coefficient was performed over 300 sec windows. The associations between HVx changes relative to ABP and PAP were tested using linear regression with generalized estimation of equations. Optimal ABP and PAP defined by lowest HVx was determined using a curve-fit algorithm. The relationship between PAP and ABP was tested by piecewise regression. Results: Ten patients were enrolled. Median age and weight were 6.5 months and 6.2 kg. Optimal ABP and PAP were obtained in 7/10. HVx became impaired with increased ABP (top panel) and increased PAP (middle panel), indicating worse cerebrovascular dysautoregulation. PAP increased with increasing ABP (r = 0.55, p&lt;0.0001) with an intercept of 72 mmHg above which ΔPAP/ΔABP doubled from 0.23 [0.22- 0.24] to 0.46 [0.43 - 0.49] (bottom panel). Elevations of ABP above optimal for HVx did not improve rSO2 (p&gt;0.05). Conclusion: Hypertension after superior cavo-pulmonary shunt is associated with elevated PAP, no improvement in rSO 2 , and cerebrovascular dysautoregulation.
Ethical Considerations for Unblinding a Participant’s Assignment to Interpret a Resolved Adverse Event
Authors: Benjamin S. Wilfond, Christian Morales, Liza-Marie Johnson, Holly A. Taylor
Journal: The American Journal of Bioethics (2018)

"Ethical Considerations for Unblinding a Participant’s Assignment to Interpret a Resolved Adverse Event." The American Journal of Bioethics, 18(10), pp. 66–67
Previous immunotherapy treatments may improve tumor responses with subsequent chemotherapy regimens
Authors: I. Baraibar Argota, P. Martin-Romano, M.F. Sanmamed, M. Rodriguez-Ruiz, J.L. Pérez-Gracia, I. Gil-Bazo, I. Melero, L. Resano, A. Chopitea Ortega, J. Rodriguez, J.M. Aramendia, I. Gardeazabal, L. Ceniceros, P. Sala Elarre, M. Ponz-Sarvisé, E. Castanon Alvarez
Journal: Annals of Oncology (2018)
Abstract 18412: Coronary Lesion Severity and the Predictive Value of Serum 1,5-anhydro-d-glucitol Level for Major Adverse Cardiac and Cerebrovascular Events
Authors: Nobutaka Ikeda, Raisuke Iijima, Hidehiko Hara, Yukio Hiroi, Masato Nakamura
Journal: Circulation (2017)

Introduction: Glucose fluctuation is one of important risk factors of cardiovascular events. The serum 1,5-anhydro-d-glucitol (1,5-AG) rapidly decreases concomitantly with urinary glucose excretion...
Risk Factors for Transformation to Higher-Grade Lymphoma and Its Impact on Survival in a Large Cohort of Patients With Marginal Zone Lymphoma From a Single Institution
Authors: Juan Pablo Alderuccio, Wei Zhao, Amrita Desai, Nicolas Gallastegui, Jeremy Ramdial, Erik Kimble, Macarena I. de la Fuente, Joseph D. Rosenblatt, Jennifer R. Chapman, Francisco Vega, Isildinha M. Reis, Izidore S. Lossos
Journal: Journal of Clinical Oncology (2018)

Given the paucity of data on higher-grade transformation (HGT) to aggressive lymphoma in patients with marginal zone lymphoma (MZL), we report on a large cohort of patients, identify risk factors, and determine HGT impact on overall survival (OS).
Abstract 10570: ABSORB Cohort A Trial: Five Year Clinical and MSCT Results of the ABSORB Bioresorbable Everolimus Eluting Vascular Scaffold
Authors: Koen Nieman, Dariusz Dudek, John Ormiston, Leif Thuesen, Patrick W Serruys
Journal: Circulation (2011)

Background: The ABSORB Cohort A trial results demonstrated the safety of the ABSORB bioresorbable vascular scaffold in 30 patients with single de novo native coronary artery lesions, with a low long-term MACE rate at 4 years of 3.4% and no scaffold thrombosis. Methods: The ABSORB Clinical Investigation enrolled 30 patients (Cohort A) in clinical sites in the European and Asia Pacific regions. The purpose of the ABSORB Clinical Investigation is to assess the safety and performance of the ABSORB Everolimus Eluting Vascular Scaffold (Abbott Vascular, Santa Clara, CA, USA) in the treatment of patients with a single de novo native coronary artery lesion. Key endpoints include ischemia driven major adverse cardiac events (ID-MACE) and its components out to 5 years with angiographic and IVUS endpoints at 6 months and 2 years and Multi-slice Spiral Computed Tomography (MSCT) imaging at 18 months. The ABSORB protocol was amended in the 4 sites who enrolled patients in Cohort A to add an optional additional MSCT im...
Everolimus as first-line or after cytokine therapy in patients with metastatic recurrent and/or unresectable renal cell carcinoma (RCC) (EVERMORE)
Authors: A.M. Abdel Hakim, Y. Nouira, R. Taran, D. Amokrane, M. Ghosn, B. Larbaoui, C. Pripatnanont, K. Slimane, V. Pilipovic, H. Boussen
Journal: Annals of Oncology (2018)
Moving toward Tuberculosis Elimination. Critical Issues for Research in Diagnostics and Therapeutics for Tuberculosis Infection
Authors: Salmaan Keshavjee, Farhana Amanullah, Adithya Cattamanchi, Richard Chaisson, Karen M. Dobos, Gregory J. Fox, Howard E. Gendelman, Richard Gordon, Anneke Hesseling, Hoi Le Van, Beate Kampmann, Bavesh Kana, Gopal Khuller, David M. Lewinsohn, Deborah A. Lewinsohn, Philiana Ling Lin, Lenette Lin Lu, Gary Maartens, Andrew Owen, Marina Protopopova, Jyothi Rengarajan, Eric Rubin, Padmini Salgame, Erwin Schurr, James A. Seddon, Susan Swindells, David M. Tobin, Zarir Udwadia, Gerhard Walzl, Sudha Srinivasan, Roxana Rustomjee, Payam Nahid
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

Tuberculosis (TB) has surpassed HIV to become the leading infectious killer of adults globally, causing almost 2 million deaths annually. 1Although this airborne disease has been treatable since 1948, global rates of TB have dropped less than two percent per year; an estimated 10 million incident cases continue to occur annually, including one million in children. 1,2While transmission of active disease is an important driver of the epidemic, the seedbed that feeds the epidemic is the more than two billion people estimated to have TB infection, five to ten percent of whom will progress to active disease during their lifetime. 3While any successful strategy aimed at TB elimination needs to address this reservoir of TB infection worldwide, much remains to be understood about host and pathogen factors that can be used to identify increased risk for progression to disease, and intervened upon to prevent progression from occurring.
Phase III trial of lurbinectedin versus PLD or topotecan in platinum-resistant ovarian cancer patients: Results of CORAIL trial
Authors: S. Gaillard, A. Oaknin, I.L. Ray-Coquard, I.B. Vergote, G. Scambia, N. Colombo, S.A. Ghamande, A. Soto-Matos, C.M. Fernandez, C. Kahatt, J. Gomez, A. Nieto, N. Torres, B. Pardo-Burdalo, Z. Papai, R.S. Kristeleit, D.M. O’Malley, I. Benjamin, P. Pautier, D. Lorusso
Journal: Annals of Oncology (2018)