tbuckley/cabot-search huggingface dataset:
Abstract PO-077: Use of aromatase inhibitors and risk of cardiovascular disease: A population-based study
Authors: Lauren McVicker, Christopher Cardwell, Úna McMenamin
Journal: Clinical Cancer Research (2020)

Abstract Background: Adjuvant endocrine therapy, including aromatase inhibitors (AI) or tamoxifen, is recommended for women diagnosed with estrogen receptor- and/or progesterone receptor-positive breast cancer as it significantly reduces the risk of recurrence and breast cancer-specific mortality. AIs are the preferred treatment for postmenopausal women; however, concerns have been raised with respect to their cardiovascular safety. Some meta-analyses of randomized controlled trials report an increase in cardiovascular disease (CVD) risk with use of AIs compared to tamoxifen; however, “real-world” observational studies have yielded inconsistent findings. Objectives: We aimed to conduct a population-based study in Scotland to investigate whether breast cancer patients treated with AIs are at an increased risk of cardiovascular disease compared to patients treated with tamoxifen. Methods: Women newly diagnosed with breast cancer, from 2009 to 2017, were identified from the Scottish Cancer Registry. AI and tamoxifen use were identified from the nationwide Scottish Prescribing Information System. The primary outcome was CVD, based on incidence or death from CVD obtained from hospital admission and death records, respectively. Cox regression models calculated hazard ratios (HRs) and 95% intervals (CIs) comparing AI use to tamoxifen use and risk of CVD, using an as treated exposure definition. Analyses were adjusted for a range of potential confounders and subgroup analysis investigated risk by CVD subtypes including myocardial infarction, heart failure, ischemic stroke, venous thromboembolism, and angina. Results: The cohort contained 28,712 breast cancer patients, followed for 110,999 person years, during which there were 776 cardiovascular events. Compared to tamoxifen use, AI use was associated with an increased risk of any CVD event (adjusted HR 1.14, 95% CI: 1.02, 1.27), which was particularly marked for ischemic stroke (adjusted HR 1.27, 95% CI: 0.99, 1.63). There were no clear associations for other CVD subtypes. Conclusions: Our preliminary results suggest an increased risk of CVD, and specifically ischemic stroke, in AI users compared to tamoxifen. Additional analyses will be conducted to further investigate these associations, including dose-response. Citation Format: Lauren McVicker, Christopher Cardwell, Úna McMenamin. Use of aromatase inhibitors and risk of cardiovascular disease: A population-based study [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-077.
15730 A randomized, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of CBP-201 administered to healthy adult subjects
Authors: Mike A. Royal, Jeffery White, Ben Snyder, Zheng Wei, Wubin Pan, Junying Wang, Kenneth J. Sansone, Xin Yang
Journal: Journal of the American Academy of Dermatology (2020)
Linear and Nonlinear Mendelian Randomization Analyses of the Association Between Diastolic Blood Pressure and Cardiovascular Events
Authors: Marios Arvanitis, Guanghao Qi, Deepak L. Bhatt, Wendy S. Post, Nilanjan Chatterjee, Alexis Battle, John W. McEvoy
Journal: Circulation (2020)

Background: Recent clinical guidelines support intensive blood pressure treatment targets. However, observational data suggest that excessive diastolic blood pressure (DBP) lowering might increase the risk of myocardial infarction (MI), reflecting a J- or U-shaped relationship. Methods: We analyzed 47 407 participants from 5 cohorts (median age, 60 years). First, to corroborate previous observational analyses, we used traditional statistical methods to test the shape of association between DBP and cardiovascular disease (CVD). Second, we created polygenic risk scores of DBP and systolic blood pressure and generated linear Mendelian randomization (MR) estimates for the effect of DBP on CVD. Third, using novel nonlinear MR approaches, we evaluated for nonlinearity in the genetic relationship between DBP and CVD events. Comprehensive MR interrogation of DBP required us to also model systolic blood pressure, given that the 2 are strongly correlated. Results: Traditional observational analysis of our cohorts suggested a J-shaped association between DBP and MI. By contrast, linear MR analyses demonstrated an adverse effect of increasing DBP increments on CVD outcomes, including MI (MI hazard ratio, 1.07 per unit mm Hg increase in DBP; P &lt;0.001). Furthermore, nonlinear MR analyses found no evidence for a J-shaped relationship; instead confirming that MI risk decreases consistently per unit decrease in DBP, even among individuals with low values of baseline DBP. Conclusions: In this analysis of the genetic effect of DBP, we found no evidence for a nonlinear J- or U-shaped relationship between DBP and adverse CVD outcomes; including MI.
Increased anticoagulation reduces proximal deep vein thrombosis in mechanically ventilated COVID-19 patients
Authors: Sebastian Voicu, Benjamin G. Chousterman, Philippe Bonnin, Nicolas Deye, Isabelle Malissin, Arthur Le Gall, Romain Barthélémy, Laetitia Sutterlin, Giulia Naim, Aymen Mrad, Adrien Pepin-Lehalleur, Matthieu Le Dorze, Charles de Roquetaillade, Jean-Michel Ekhérian, Etienne Gayat, Georgios Sidéris, Alexandre Mebazaa, Bruno Mégarbane
Journal: Journal of Infection (2020)
Abstract S02-02: Covid-19 treatment candidate hydroxychloroquine impairs tumor response to anti-PD1
Authors: Simon Wabitsch, Jack C McVey, Chi Ma, Benjamin Ruf, Laurence Diggs, Bernd Heinrich, Tim F Greten
Journal: Clinical Cancer Research (2020)

Abstract Background and Aims: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a worldwide health crisis. As of now, only one treatment has been established for the coronavirus infection disease 2019 (Covid-19), which has disproportionally affected patients with comorbidities such as cancer. Hydroxychloroquine (HCQ) has been studied as a potential treatment for Covid-19. Here we studied whether HCQ treatment could influence the effect of immunotherapy against colorectal and liver cancer. Methods: In vitro studies were conducted to assess the effect of HCQ on lymphocyte activation and proliferation as well as cell growth and antigen presentation. Mouse cell lines used included MC38, CT26, RIL-175, SB1, and LD1 while human tumor cell lines used were TFK-1 and EGI-1. Mice bearing subcutaneous MC38, CT26, and RIL-175 tumors were treated with HCQ, anti-PD1, or both. Tumor volume was measured over 19 days. Systemic and tumor-infiltrating immune cells were analyzed by flow cytometry. Results: HCQ treatment impairs T-cell production of TNF-α and IFNγ in vitro and in vivo. Whereas cell growth was decreased in all tumor cell lines, in vitro treatment of tumor cells with HCQ revealed an upregulation of MHC-1 in CT26, SB1, LD1, TFK-1, and EGI-1 but not in MC38 and RIL-175. HCQ treatment impaired response to anti-PD1 treatment in all subcutaneous models. Compared to control, HCQ treatment led to increased tumor growth in MC38 tumors. Flow cytometry analysis revealed an impaired activation of CD4+ T cells as well as tumor-infiltrating cytotoxic antigen-specific CD8+ T cells. Conclusion: This study shows that HCQ treatment can result in immunotherapy failure due to a systematic immunosuppressive effect that overcomes the increased MHC expression on tumor cells. Citation Format: Simon Wabitsch, Jack C McVey, Chi Ma, Benjamin Ruf, Laurence Diggs, Bernd Heinrich, Tim F Greten. Covid-19 treatment candidate hydroxychloroquine impairs tumor response to anti-PD1 [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S02-02.
AB1235 SALIVARY LEVEL OF CALPROTECTIN (MRP 8/14) AS A BIOMARKER FOR SJÖGREN SYNDROME – A PROSPECTIVE OBSERVATIONAL STUDY
Authors: P. Chebbi, J. Kabeer, P. Sandhya, M. Gowri, D. Danda
Journal: Annals of the Rheumatic Diseases (2020)

Background: Objectives: Calprotectin (MRP 8/14) is secreted by neutrophils and monocytes in an inflammatory milieu(1). Increased levels of calprotectin in blood and faeces has been previously shown in patients with primary Sjogren’s syndrome(pSS)(2). We hypothesised Calprotectin in saliva may therefore potentially reflect inflammation in salivary glands. In the present study, we aimed to assess the utility of salivary calprotectin as a biomarker in pSS and to evaluate the potential association of calprotectin with clinical features, laboratory markers and disease activity indexes in pSS. Methods: Consecutive patients attending rheumatology clinic between September 2016 and July 2017 of age more than 18 years fulfilling either American European Consensus Group (AECG) 2002 or 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjogren’s Syndrome, constituted the case group. Patients with sicca non-pSS and rheumatoid arthritis patients satisfying ACR/EULAR criteria 2010 were recruited as disease controls. Age and sex-matched healthy subjects were recruited as a controls. Patient history, signs and symptoms, laboratory investigations, ESSDAI and ESSPRI scoring were noted for cases and disease controls. Unstimulated saliva was collected by the spitting method. Salivary calprotectin levels were quantified by commercially available ELISA kit(R&amp;D Systems, MN, USA). Results: A total of 42 pSS cases (41.59 11.21 years, 40 women), 40 disease controls (47.62 9.81 years, 39 women) and 30 healthy controls (36 10.65 years, 29 women) were recruited. In pSS and disease controls, the median levels of salivary calprotectin [38.5(81) and 52(69.5 ng/ml)] were significantly higher compared to healthy controls [26.5(29) {p=0.001}]. Salivary calprotectin levels in pSS was positively associated with oral symptoms and negatively associated with immunosuppression of 1 year and more(P=0.04 and 0.03 respectively),but not ESSDAI,ESSPRI scores or lab parameters. Conclusion: Salivary calprotectin was elevated in pSS compared to healthy subjects and was found to be positively associated with oral symptoms and with immunosuppressive treatment. References: [ 1]Stroncek DF, Shankar RA, Skubitz KM. The subcellular distribution of myeloid-related protein 8 (MRP8) and MRP14 in human neutrophils. J Transl Med. 2005 Sep 28;3:36. [2]Fagerhol MK, Larsen A, Brun JG, Hammer HB, Angel K, Kvien TK, et al. Large molecular size EDTA-resistant complexes containing S100A12, ERAC, in serum during inflammatory conditions. Scand J Clin Lab Invest. 2012 Apr;72(2):129–36. Disclosure of Interests: None declared
Probability of Success and Timelines for the Development of Vaccines for Emerging and Reemerged Viral Infectious Diseases
Authors: Amanda MacPherson, Nora Hutchinson, Oliver Schneider, Elisabeth Oliviero, Emma Feldhake, Charlotte Ouimet, Jacky Sheng, Fareed Awan, Catherine Wang, Jesse Papenburg, Nicole E. Basta, Jonathan Kimmelman
Journal: Annals of Internal Medicine (2020)

Anticipated success rates and timelines for COVID-19 vaccine development vary. Recent experience with developing and testing viral vaccine candidates can inform expectations regarding the development of safe and effective vaccines.To estimate timelines and probabilities of success for recent vaccine candidates.ClinicalTrials.gov was searched to identify trials testing viral vaccines that had not advanced to phase 2 before 2005, and the progress of each vaccine from phase 1 through to U.S. Food and Drug Administration (FDA) licensure was tracked. Trial characteristics were double-coded. (Registration: Open Science Framework [https://osf.io/dmuzx/]).Trials launched between January 2005 and March 2020.Preventive viral vaccine candidates for 23 emerging or reemerged viral infectious diseases.The primary end point was the probability of vaccines advancing from launch of phase 2 to FDA licensure within 10 years.In total, 606 clinical trials forming 220 distinct development trajectories (267 343 enrolled participants) were identified. The probability of vaccines progressing from phase 2 to licensure within 10 years was 10.0% (95% CI, 2.6% to 16.9%), with most approvals representing H1N1 or H5N1 vaccines. The average timeline from phase 2 to approval was 4.4 years (range, 6.4 weeks to 13.9 years). The probabilities of advancing from phase 1 to 2, phase 2 to 3, and phase 3 to licensure within the total available follow-up time were 38.2% (CI, 30.7% to 45.0%), 38.3% (CI, 23.1% to 50.5%), and 61.1% (CI, 3.7% to 84.3%), respectively.The study did not account for preclinical development and relied primarily on ClinicalTrials.gov and FDA resources. Success probabilities do not capture the varied reasons why vaccines fail to advance to regulatory approval.Success probabilities and timelines varied widely across different vaccine types and diseases. If a SARS-CoV-2 vaccine is licensed within 18 months of the start of the pandemic, it will mark an unprecedented achievement for noninfluenza viral vaccine development.McGill Interdisciplinary Initiative in Infection and Immunity (MI4) Emergency COVID-19 Research Funding program.
Racial/Ethnic Disparities in All-Cause Mortality among Patients Diagnosed with Triple-Negative Breast Cancer
Authors: Fei Wang, Wei Zheng, Christina E. Bailey, Ingrid A. Mayer, Jennifer A. Pietenpol, Xiao-Ou Shu
Journal: Cancer Research (2020)

It is unclear whether racial/ethnic disparities in triple-negative breast cancer (TNBC) mortality remain after accounting for clinical characteristics, treatment, and access-to-care-related factors. In this study, women with a primary diagnosis of TNBC during 2010-2014 were identified from the National Cancer Database. Hazard ratios (HR) and 95% confidence intervals (CI) for 3- and 5-year all-cause mortality associated with race/ethnicity were estimated using Cox proportional hazards models with stepwise adjustments for age, clinical characteristics, treatment, and access-to-care-related factors. Of 78,708 patients, non-Hispanic (NH) black women had the lowest 3-year overall survival rates (79.4%), followed by NH-whites (83.1%), Hispanics (86.0%), and Asians (87.1%). After adjustment for clinical characteristics, NH-blacks had a 12% higher risk of dying 3 years post-diagnosis (HR, 1.12; 95% CI, 1.07-1.17), whereas Hispanics and Asians had a 24% (HR, 0.76; 95% CI, 0.70-0.83) and 17% (HR, 0.83; 95% CI, 0.73-0.94) lower risk than their NH-white counterparts. The black-white disparity became non-significant after combined adjustment for treatment and access-to-care-related factors (HR, 1.04; 95% CI, 0.99-1.09), whereas the white-Hispanic and white-Asian differences remained. Stratified analyses revealed that among women aged less than or equal to 50 with stage III cancer, the elevated risk among NH-blacks persisted (HR, 1.20; 95% CI, 1.04-1.39) after full adjustments. Similar results were seen for 5-year mortality. Overall, clinical characteristics, treatment, and access-to-care-related factors accounted for most of the white-black differences in all-cause mortality of TNBC but explained little about Hispanic- and Asian-white differences. SIGNIFICANCE: These findings highlight the need for equal healthcare to mitigate the black-white disparity and for investigations of contributors beyond healthcare for lower mortality among Asians and Hispanics.
Targeting the myeloid checkpoint receptor SIRPα potentiates innate and adaptive immune responses to promote anti-tumor activity
Authors: Tracy C. Kuo, Amy Chen, Ons Harrabi, Jonathan T. Sockolosky, Anli Zhang, Emma Sangalang, Laura V. Doyle, Steven E. Kauder, Danielle Fontaine, Sangeetha Bollini, Bora Han, Yang-Xin Fu, Janet Sim, Jaume Pons, Hong I. Wan
Journal: Journal of Hematology & Oncology (2020)

Abstract Background Signal regulatory protein α (SIRPα) is a myeloid-lineage inhibitory receptor that restricts innate immunity through engagement of its cell surface ligand CD47. Blockade of the CD47–SIRPα interaction synergizes with tumor-specific antibodies and T-cell checkpoint inhibitors by promoting myeloid-mediated antitumor functions leading to the induction of adaptive immunity. Inhibition of the CD47–SIRPα interaction has focused predominantly on targeting CD47, which is expressed ubiquitously and contributes to the accelerated blood clearance of anti-CD47 therapeutics. Targeting SIRPα, which is myeloid-restricted, may provide a differential pharmacokinetic, safety, and efficacy profile; however, SIRPα polymorphisms and lack of pan-allelic and species cross-reactive agents have limited the clinical translation of antibodies against SIRPα. Here, we report the development of humanized AB21 (hAB21), a pan-allelic anti-SIRPα antibody that binds human, cynomolgus monkey, and mouse SIRPα alleles with high affinity and blocks the interaction with CD47. Methods Human macrophages derived from donors with various SIRPα v1 and v2 allelic status were used to assess the ability of hAB21 to enhance phagocytosis. HAB21_IgG subclasses were evaluated for targeted depletion of peripheral blood mononuclear cells, phagocytosis and in vivo efficacy in xenograft models. Combination therapy with anti-PD1/anti-PD-L1 in several syngeneic models was performed. Immunophenotyping of tissues from MC38 tumor-bearing mice treated with AB21 and anti-PD-1 was evaluated. PK, PD and tolerability of hAB21 were evaluated in cynomolgus monkeys. Results SIRPα blockade with hAB21 promoted macrophage-mediated antibody-dependent phagocytosis of tumor cells in vitro and improved responses to rituximab in the Raji human tumor xenograft mouse model. Combined with PD-1/PD-L1 blockade, AB21 improved response rates by facilitating monocyte activation, dendritic cell activation, and T cell effector functions resulting in long term, durable antitumor immunity. In cynomolgus monkeys, hAB21 has a half-life of 5.3 days at 10 mg/kg and complete target occupancy with no hematological toxicity or adverse findings at doses up to 30 mg/kg. Conclusions The in vitro and in vivo antitumor activity of hAB21 broadly recapitulates that of CD47 targeted therapies despite differences in ligand expression, binding partners, and function, validating the CD47–SIRPα axis as a fundamental myeloid checkpoint pathway and its blockade as promising therapeutic intervention for treatment of human malignancies.
Opportunities and Challenges in Drug Development for Pediatric Cancers
Authors: Theodore W. Laetsch, Steven G. DuBois, Julia Glade Bender, Margaret E. Macy, Lucas Moreno
Journal: Cancer Discovery (2020)

Abstract The use of targeted small-molecule therapeutics and immunotherapeutics has been limited to date in pediatric oncology. Recently, the number of pediatric approvals has risen, and regulatory initiatives in the United States and Europe have aimed to increase the study of novel anticancer therapies in children. Challenges of drug development in children include the rarity of individual cancer diagnoses and the high prevalence of difficult-to-drug targets, including transcription factors and epigenetic regulators. Ongoing pediatric adaptation of biomarker-driven trial designs and further exploration of agents targeting non-kinase drivers constitute high-priority objectives for future pediatric oncology drug development. Significance: Increasing attention to drug development for children with cancer by regulators and pharmaceutical companies holds the promise of accelerating the availability of new therapies for children with cancer, potentially improving survival and decreasing the acute and chronic toxicities of therapy. However, unique approaches are necessary to study novel therapies in children that take into account low patient numbers, the pediatric cancer genomic landscape and tumor microenvironment, and the need for pediatric formulations. It is also critical to evaluate the potential for unique toxicities in growing hosts without affecting the pace of discovery for children with these life-threatening diseases.
Abstract 11769: Plasma Levels of Melatonin in Dilated and Hypertrophic Cardiomyopathies
Authors: Tomofumi Misaka, Akiomi Yoshihisa, Yasuhiro Ichijyo, Takatoyo Kiko, Yusuke Kimishima, Yu Sato, Yuki Kanno, Mai Takiguchi, Tetsuro Yokokawa, Satoshi Abe, Takamasa Sato, Masayoshi Oikawa, Atsushi Kobayashi, Takayoshi Yamaki, Hiroyuki Kunii, Kazuhiko Nakazato, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2018)

Backgrounds: Melatonin represents an important chronobiological regulatory molecule which is released from the pineal gland. Melatonin has an important role in a variety of cardiovascular process v...
256O Associations of OX40 and tumour microenvironment with outcomes in diffuse large B-cell lymphoma
Authors: X-H. Wang, Y. Li, Y. Hong, X. Liu, L. Li, L. Qiu, Z. Qian, S. Zhou, L. Jiao, Q. Zhai, B. Meng, K. Fu, H. Zhang
Journal: Annals of Oncology (2020)
Predicting Periprocedural Myocardial Infarction: Target-Lesion Plaque Characterization With Coronary Computed Tomography Angiography⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Jennifer Malpeso, Matthew J. Budoff
Journal: Journal of the American College of Cardiology (2012)