tbuckley/cabot-search huggingface dataset:
Abstract 14311: Gene Guided Antiplatelet Therapy for Acute Coronary Syndrome: An Updated Meta-Analysis
Authors: Senthil S Balasubramanian, APOORVA TANGRI, Arjun Natarajan, Safwan Gaznabi, Arman Qamar
Journal: Circulation (2021)

Introduction: Clopidogrel has been the mainstay oral antiplatelet regimen to treat Acute Coronary syndrome (ACS) post percutaneous coronary intervention (PCI) with stents. However, there is marked inter-individual variability due to genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 in the antiplatelet effects of clopidogrel and a reduced response to this drug may be a risk factor for ischemic complications. There has been varied evidence in gene-guided antiplatelet therapy post PCI. An updated meta-analysis was conducted to study the effect of gene-guided antiplatelet therapy in ACS. Methods: A systematic literature review was performed in Embase, PubMed and SCOPUS for all the related articles until May 2021 yielding 180 publications. Nine studies fulfilled inclusion criteria including 8 randomized clinical trials and 1 observational study. The Mantel- Haenszel random-effects model was used to calculate odds ratio (OR) and 95% confidence intervals (CI). Outcomes analyzed were the composite major adverse cardiovascular events (MACE), stent thrombosis, myocardial infarction (MI), bleeding and cardiovascular (CV) death. Results: Gene guided antiplatelet therapy was performed in 7106 patients and conventional therapy in 3970 patients. The MACE events was significantly lower in gene-guided therapy arm (OR = 0.67, 95% CI [0.51 -0.87], P=0.003) driven by lower stent thrombosis (OR=0.47, 95% CI [0.25 -0.88], P=0.02) and lower MI in the gene guided therapy (OR=0.61, 95% CI [0.41 -0.92], P=0.02). The bleeding rates trended to be lower in the gene guided therapy as well (OR = 0.75, 95% CI [0.54-1.02], P=0.07). There is no significance difference in CV death. (OR=0.57, 95% CI [0.21-1.55]) Conclusions: Genotype guided antiplatelet therapy in ACS has lower adverse cardiovascular outcomes driven by lower stent thrombosis and MI with lower bleeding trends as well.
DDRE-46. REDUCED CANCER CELL SENSITIVITY TO TUMOR TREATING FIELDS (TTFields) THROUGH ACTIVATION OF THE PI3K/AKT/mTOR SIGNALING PATHWAY CAN BE MITIGATED USING PI3K INHIBITORS OR PI3K/mTOR DUAL INHIBITORS
Authors: Anat Klein-Goldberg, Tali Voloshin, Efrat Zemer-Tov, Rom Paz, Lilach Koren, Kerem Wainer-Katsir, Alexandra Volodin, Bella Koltun, Boris Brant, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Neuro-Oncology (2021)

Abstract INTRODUCTION Tumor Treating Fields (TTFields) therapy is an approved anti-cancer treatment modality applied non-invasively and loco-regionally to the tumor region. TTFields have been demonstrated to extend life, however, most patients do eventually progress. The current study aimed to identify potential molecular mechanisms involved in reduced cellular sensitivity to TTFields. METHODS Cancer cells that exhibit reduced sensitivity to TTFields were generated by continuous long duration application of TTFields (7 or 13 days, depending on the cell line). Changes in cellular signaling pathways were evaluated in ovarian A2780 and glioblastoma U-87 MG cancer cells exposed to long-term relative to short-term (3 or 7 days, depending on the cell line) treatment with TTFields using Luminex multiplex assay followed by Western blot validation. The relevance of the affected pathways was confirmed through evaluation of the response to long-term application of TTFields in combination with pharmacological pathway inhibitors by measuring cell counts, apoptosis, and clonogenicity. Relevant pathway markers in tumor sections from tumor-bearing rats treated with TTFields were examined using immunohistochemistry. RESULTS Continuous long-term application of TTFields reduced cellular sensitivity to TTFields and was accompanied by increased levels of phosphorylated AKT, mTOR and additional proteins from the PI3K/AKT/mTOR signaling pathway. Increased phosphorylation of AKT was also evident in tumor sections from rats treated with TTFields. Concomitant use of TTFields with PI3K inhibitors or PI3K/mTOR dual inhibitors sensitized A2780 cells to long-term TTFields application. CONCLUSION Our study demonstrates that decreased cancer cell sensitivity to long-term TTFields application is mediated by activation of the PI3K/AKT/mTOR signaling pathway and provides a rationale for further examining the potential benefit of combining TTFields with PI3K or PI3K/mTOR dual inhibitors.
Sudden Cardiac Death, Genes, and Arrhythmogenesis
Authors: Peter M. Spooner, Christine Albert, Emelia J. Benjamin, Robin Boineau, Robert C. Elston, Alfred L. George, Xavier Jouven, Lewis H. Kuller, Jean W. MacCluer, Eduardo Marbán, James E. Muller, Peter J. Schwartz, David S. Siscovick, Russell P. Tracy, Wojciech Zareba, Douglas P. Zipes
Journal: Circulation (2001)

This is Part II of a 2-part article dealing with malignant ventricular arrhythmias, which are the leading mechanism of death in common cardiac diseases. Genetic population studies directed at discovering common proximal sources of inherited molecular risk most directly linked to arrhythmia initiation and propagation would appear to have considerable potential in helping reduce cardiovascular mortality.
Abstract 9199: A Novel Small Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics or Diastolic Function
Authors: Huamei He, Tomas Baka, James Balschi, Alykhan Motani, Khanh K Nguyen, Qingxiang Liu, Rebecca Slater, brooke rock, Chen Wang, Christopher Hale, Georgios Karamanlidis, James J Hartman, Fady I Malik, jeff D reagan, Ivan Luptak
Journal: Circulation (2021)

Background: Current heart failure (HF) therapies improve cardiac energy balance and prolong survival by unloading the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropic medications, also termed calcitropes, stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. Myotropes are a new class of agents that activate the sarcomere directly, independent of cAMP and calcium. We hypothesize that a novel myotrope, troponin activator (TA1), increases contractility without the deleterious myocardial energetic impact of calcitrope dobutamine (DOB). Methods: We determined the pharmacodynamics of TA1 ex vivo and in vivo in anesthetized normal rats. Isolated rat hearts were perfused with incremental concentrations of TA1 or DOB to compare their effect on cardiac contractility and high-energy phosphate concentrations using 31 P NMR spectroscopy. Results: A dose dependent increase in contractility was observed in vivo by echocardiography after acute administration of TA1. In isolated hearts, increasing concentrations of TA1 and DOB similarly increased rate pressure product (RPP), which is a product of developed pressure (DevP) and heart rate (HR). At equivalent doses (DOB 120 nM, TA1 60 nM), TA1 increased DevP more and HR less compared to DOB. DOB decreased phosphocreatine (PCr) to ATP ratio and free energy of ATP hydrolysis (ΔG ~ATP ) and elevated left ventricular end-diastolic pressure (LVEDP). In contrast, the TA1 increased RPP without any effect on HR, LVEDP, PCr/ATP ratio or ΔG ~ATP . Conclusions: Here we describe a novel myotrope, TA1, that increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long term survival, TA1 may represent a superior alternative to traditional inotropes in HF management.
Tumor microenvironment and cellular senescence: Understanding therapeutic resistance and harnessing strategies
Authors: Hanxin Liu, Huifang Zhao, Yu Sun
Journal: Seminars in Cancer Biology (2021)

The tumor microenvironment (TME) is a major contributor to cancer malignancy including development of therapeutic resistance, a process mediated in part through intercellular crosstalk. Besides diverse soluble factors responsible for pro-survival pathway activation, immune evasion and extracellular matrix (ECM) remodeling further promote cancer resistance. Importantly, therapy-induced senescence (TIS) of cells in the TME is frequently observed in anticancer regimens, an off-target effect that can generate profound impacts on disease progression. By conferring the resistance and fueling the repopulation of remaining cancerous cells, TIS is responsible for tumor relapse and distant metastasis in posttreatment stage. This pathological trajectory can be substantially driven by the pro-inflammatory feature of senescent cells, termed as the senescence-associated secretory phenotype (SASP). Targeting strategies to selectively and efficiently remove senescent cells before they exert non-autonomous but largely deleterious effects, are emerging as an effective solution to prevent drug resistance acquired from a treatment-remodeled TME. In this review, we summarize the TME composition and key activities that affect tissue homeostasis and support treatment resistance. Promising opportunities that allow TME-manipulation and senescent cell-targeting (senotherapy) are discussed, with translational pipelines to overcome therapeutic barriers in clinical oncology projected.
Predictive Biomarkers of Response to the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Decitabine in Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)
Authors: Amer M. Zeidan, Maya Ridinger, Peter J.P. Croucher, Errin Samuëlsz, Mark Erlander, Katherine L. Ruffner, Eunice S. Wang
Journal: Blood (2021)
Combination Therapy of FLT3 Tyrosine Kinase Inhibitors and BH3 Mimetics Targeting Antiapoptotic MCL-1 Synergistically Eliminates FLT3-ITD Acute Myeloid Leukemia Cells <i>in Vitro</i> and <i>In Vivo</i>
Authors: Anna Skwarska, Donia M Moujalled, Paul F Panis, Shraddha Patel, Qi Zhang, Shelley Herbrich, Vinitha Kurvilla, Natalia Baran, Giovanna Pomilio, Ensar Halilovic, Prakash Mistry, Vivian Ruvolo, Peter P. Ruvolo, Alix Derréal, Sebastien Banquet, Magdalena Niemira, Adam Kretowski, Naval Daver, Michael Andreeff, Andrew H. Wei, Marina Konopleva
Journal: Blood (2021)
Covid 19: A strong pandemic response relies on good data
Authors: Fiona Godlee
Journal: BMJ (2021)

A strong pandemic response relies on good data Fiona Godlee editor in chiefMany things are needed to get the world through this pandemic: one of them is high uptake of vaccination.For this we need strong public confidence in the vaccines, justified by reliable and transparently accessible trial data.We need clear messaging, good systems of delivery, and globally equitable distribution in line with the true burden of disease.details and the raw data.
Defining Genomic Probability of Progression to Identify Low-Risk Smoldering Multiple Myeloma
Authors: Anil Aktas-Samur, Mariateresa Fulciniti, Sanika Derebail, Raphael Szalat, Giovanni Parmigiani, Jill Corre, Herve Avet-Loiseau, Mehmet K. Samur, Nikhil C. Munshi
Journal: Blood (2021)
Covid-19 caseload in the UK—assessments and mitigations
Authors: Daniel Altmann, Rosemary Boyton
Journal: BMJ (2021)

The variability of mast cell density within and between leprosy skin lesions was examined as a basis for future studies, and whether the number of mast cells in the lesion was determined by local or systemic factors was evaluated. The mast cell density in the granuloma, skin appendages, and intervening dermis was assessed by counting mast cells in glycol methacylate sections stained with Giemsa stain and relating these counts to area measurements obtained by planimetry. In biopsy specimens taken from the edge of established lesions the density of mast cells within the granulomata was considerably higher than that in the intervening dermis and was comparable with that found in the appendages. No major differences in mast cell density were found between unaffected skin and the centre or edge of individual lesions. Mast cell densities in biopsy specimens from the edge of different lesions on the same patient were also similar, suggesting that the mast cell density within the granulomata is independent of the site of the lesion and is determined systemically.
Abstract PO-016: Directed evolution generates novel oncolytic H-1 parvoviruses with improved therapeutic efficacy in virus-resistant pancreatic cancer cells
Authors: Pierre Garcin, Monireh Kazemimanesh, Hubert Lulka, Nelson Dusetti, Guillaume Labrousse, Emilie Benuzzi, Louis Buscail, Pierre Cordelier
Journal: Cancer Research (2021)

Abstract Despite considerable promise and emerging clinical success, several challenges impede the broader implementation of novel immunotherapies such as oncolytic virus(OV)-based gene therapy, including for patients with pancreatic cancer (PDAC). One of such challenge is inter-patient variability that may impact on OV selectivity and killing efficacy for tumor cells. For this study, we selected the rat parvovirus H-1 (H-1PV) that is nonpathogenic in humans and has a natural oncolytic activity in several cancer models. The safety and tolerability of H-1PV was recently demonstrated in early clinical trials for glioma and PDAC. However, we report here that H-1PV infection, oncolytic and pro-apoptotic activity are limited in PDAC cells, including patient-derived primary cells. To address this concern, we applied a directed evolution strategy to generate H-1PV variants with specific activity towards PDAC cells. Following selection using patient primary cells, we managed to isolate clonal, PDAC-adapted H-1PVs that induce PDAC cells lysis as compared to parental H-1PV while infection of normal pancreatic cells remained negligeable. Genome sequencing of the tumor adapted virus reveals mutations in promoting and viral capsid sequences. In vivo, the tumor-adapted H1PV demonstrates greater anti-tumor effect than parental H-1PV, following intravenous administration in an experimental model of orthotopic pancreatic tumors engrafted in immunodeficient mice. To our knowledge, we report here for the first time the production of highly selective and potent OV using directed evolution to override PDAC resistance to virotherapy. While the molecular mechanisms involved are still under investigation, this project is a first step towards precision medicine strategies based on OV. Citation Format: Pierre Garcin, Monireh Kazemimanesh, Hubert Lulka, Nelson Dusetti, Guillaume Labrousse, Emilie Benuzzi, Louis Buscail, Pierre Cordelier. Directed evolution generates novel oncolytic H-1 parvoviruses with improved therapeutic efficacy in virus-resistant pancreatic cancer cells [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-016.
Chromosome 3 and 8q Aberrations in Uveal Melanoma Show Greater Impact on Survival in Patients with Light Iris versus Dark Iris Color
Authors: Annemijn P.A. Wierenga, Niels J. Brouwer, Maria Chiara Gelmi, Robert M. Verdijk, Marc-Henri Stern, Zeynep Bas, Kabir Malkani, Sjoerd G. van Duinen, Arupa Ganguly, Wilma G.M. Kroes, Marina Marinkovic, Gregorius P.M. Luyten, Carol L. Shields, Martine J. Jager
Journal: Ophthalmology (2021)

Individuals with gray, blue, or green eyes have a higher chance of developing uveal melanoma (UM) than those with brown eyes. We wondered whether iris pigmentation might be related not only to predisposition to UM but also to its behavior; therefore, we compared the clinical, histopathologic, and genetic characteristics of UM between eyes with different colors.We determined iris color in a large cohort of patients enucleated for UM. Clinical and histopathologic tumor characteristics, chromosome status, and survival were compared among 3 groups on the basis of iris color.A total of 412 patients with choroidal/ciliary body UM, who had undergone primary enucleation at the Leiden University Medical Center, Leiden, The Netherlands, between 1993 and 2019, were divided into 3 groups based on iris color: gray/blue, green/hazel, and brown. The validation cohort included 934 patients with choroidal/ciliary body UM treated at Wills Eye Hospital (WEH).Comparison of clinical, histopathologic, and genetic characteristics of UM in patients with different iris colors.Melanoma-related survival in UM patients, divided over 3 iris color groups, in relation to the tumor's chromosome 3 and 8q status.Moderate and heavy tumor pigmentations were especially seen in eyes with a brown iris (P < 0.001). Survival did not differ between patients with different iris colors (P = 0.27); however, in patients with a light iris, copy number changes in chromosome 3 and 8q had a greater influence on survival than in patients with a dark iris. Likewise, chromosome 3 and chromosome 8q status affected survival more among patients with lightly pigmented tumors than in patients with heavily pigmented tumors. The WEH cohort similarly showed a greater influence of chromosome aberrations in light-eyed individuals.Although iris color by itself did not relate to UM-related survival, chromosome 3 and 8q aberrations had a larger influence on survival in patients with a light iris than those with a brown iris. This suggests a synergistic effect of iris pigmentation and chromosome status in the regulation of oncogenic behavior of UM. Iris color should be taken into consideration when calculating a patient's risk for developing metastases.
Is cerclage safe and effective in preventing preterm birth in women presenting early in pregnancy with cervical dilatation?
Authors: N Pilarski, V Hodgetts-Morton, R K Morris
Journal: BMJ (2021)

### What you need to know Preterm birth and its complications account for nearly one million neonatal deaths each year globally.1 Women who present with a dilated cervix in the second trimester are at increased risk of pregnancy loss and preterm birth (fig 1). They generally have no or minimal preceding symptoms such as change in discharge or mild abdominal pain and are detected to have a dilated cervix on examination. Cervical dilatation may also be detected in the anomaly scan. Fig 1 Premature cervical dilatation and exposed unruptured fetal membranes International guidelines from the US, UK, and Canada suggest considering emergency cervical cerclage, or rescue cerclage, to prevent preterm birth in women presenting with cervical dilatation and exposed fetal membranes between 16 and 28 weeks of gestation if there are no signs of bleeding, infection, or uterine activity (see box 1).2 Box 1 ### NICE guidelines for management of preterm labour and birth (NG25)2 #### Women with a closed cervixRETURN TO TEXT
Clinical Outcomes in Patients (Pts) with Dose Reduction of Selinexor in Combination with Bortezomib, and Dexamethasone (XVd) in Previously Treated Multiple Myeloma from the Boston Study
Authors: Sundar Jagannath, Thierry Facon, Ashraf Z. Badros, Moshe Levy, Philippe Moreau, Sosana Delimpasi, Maryana Simonova, Ivan Spicka, Iryna Kriachok, Maria Gavriatopoulou, Halyna Pylypenko, Holger W Auner, Xavier Leleu, Vadim Doronin, Ganna Usenko, Roman Hajek, Reuben Benjamin, Tuphan Kanti Dolai, Dinesh Kumar Sinha, Chris P. Venner, Mamta Garg, Mercedes Gironella Mesa, Artur Jurczyszyn, Tadeusz Robak, Monica Galli, Craig Thomas Wallington-Beddoe, Atanas Radinoff, Galina Salogub, Don Stevens, Supratik Basu, Anna Marina Liberati, Hang Quach, Veselina S Goranova Marinova, Jelena Sreten Bila, Eirini Katodritou, Andrew DeCastro, Yi Chai, Dane R. Van Domelen, Moran Mishal, Ohad S. Bentur, Jatin Shah, Sharon Shacham, Michael G. Kauffman, Sebastian Grosicki, Paul G. Richardson
Journal: Blood (2021)
Functional Immune Tolerance Induced By Sequential Hematopoietic Stem Cell-Solid Organ Transplantation
Authors: Alice Bertaina, Giulia Barbarito, Vasavi V. Ramachandran, Karen Kristovich, Elizabeth Amanda Lippner, Sahar Fathallah-Shaykh, Amira Al-Uzri, Ami J Shah, Geraldine Aubert, Priscila Ferreira Slepicka, Linda Oppizzi, Rajni Agarwal, Maria Grazia Roncarolo, Amy Gallo, Waldo Concepcion, Kenneth I. Weinberg, Robertson Parkman, David B Lewis, Paul C Grimm
Journal: Blood (2021)
"Real-Life" Data of the Efficacy and Safety of Belantamab Mafodotin in Relapsed Multiple Myeloma- the Mayo Clinic Experience
Authors: Iuliana Vaxman, Jithma P. Abeykoon, Angela Dispenzieri, Shaji Kumar, Francis K. Buadi, Martha Q. Lacy, David Dingli, Yi Lisa Hwa, Amie Fonder, Miriam A. Hobbs, Craig B. Reeder, Taimur Sher, Suzanne R. Hayman, Taxiarchis Kourelis, Rahma M Warsame, Eli Muchtar, Nelson Leung, Wilson I Gonsalves, Mustaqeem A. Siddiqui, Robert A. Kyle, S. Vincent Rajkumar, Kirsten McCullough, Prashant Kapoor, Morie A. Gertz
Journal: Blood (2021)
Circular RNAs in Myelodysplastic Syndromes and Impact of <i>SF3B1</i> Mutations on Their Expression
Authors: Michaela Dostalova Merkerova, David Kundrat, Zdenek Krejcik, Andrea Hrustincova, Iva Trsova, Katarina Szikszai, Monika Kaisrlikova, Jitka Vesela, Jiri Klema, Jaroslav Cermak, Monika Belickova
Journal: Blood (2021)
Dexamethasone 12 mg versus 6 mg for patients with COVID-19 and severe hypoxaemia: a pre-planned, secondary Bayesian analysis of the COVID STEROID 2 trial
Authors: Anders Granholm, Marie Warrer Munch, Sheila Nainan Myatra, Bharath Kumar Tirupakuzhi Vijayaraghavan, Maria Cronhjort, Rebecka Rubenson Wahlin, Stephan M. Jakob, Luca Cioccari, Maj-Brit Nørregaard Kjær, Gitte Kingo Vesterlund, Tine Sylvest Meyhoff, Marie Helleberg, Morten Hylander Møller, Thomas Benfield, Balasubramanian Venkatesh, Naomi E. Hammond, Sharon Micallef, Abhinav Bassi, Oommen John, Vivekanand Jha, Klaus Tjelle Kristiansen, Charlotte Suppli Ulrik, Vibeke Lind Jørgensen, Margit Smitt, Morten H. Bestle, Anne Sofie Andreasen, Lone Musaeus Poulsen, Bodil Steen Rasmussen, Anne Craveiro Brøchner, Thomas Strøm, Anders Møller, Mohd Saif Khan, Ajay Padmanaban, Jigeeshu Vasishtha Divatia, Sanjith Saseedharan, Kapil Borawake, Farhad Kapadia, Subhal Dixit, Rajesh Chawla, Urvi Shukla, Pravin Amin, Michelle S. Chew, Christian Aage Wamberg, Christian Gluud, Theis Lange, Anders Perner
Journal: Intensive Care Medicine (2021)

We compared dexamethasone 12 versus 6 mg daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia in the international, randomised, blinded COVID STEROID 2 trial. In the primary, conventional analyses, the predefined statistical significance thresholds were not reached. We conducted a pre-planned Bayesian analysis to facilitate probabilistic interpretation. We analysed outcome data within 90 days in the intention-to-treat population (data available in 967 to 982 patients) using Bayesian models with various sensitivity analyses. Results are presented as median posterior probabilities with 95% credible intervals (CrIs) and probabilities of different effect sizes with 12 mg dexamethasone. The adjusted mean difference on days alive without life support at day 28 (primary outcome) was 1.3 days (95% CrI −0.3 to 2.9; 94.2% probability of benefit). Adjusted relative risks and probabilities of benefit on serious adverse reactions was 0.85 (0.63 to 1.16; 84.1%) and on mortality 0.87 (0.73 to 1.03; 94.8%) at day 28 and 0.88 (0.75 to 1.02; 95.1%) at day 90. Probabilities of benefit on days alive without life support and days alive out of hospital at day 90 were 85 and 95.7%, respectively. Results were largely consistent across sensitivity analyses, with relatively low probabilities of clinically important harm with 12 mg on all outcomes in all analyses. We found high probabilities of benefit and low probabilities of clinically important harm with dexamethasone 12 mg versus 6 mg daily in patients with COVID-19 and severe hypoxaemia on all outcomes up to 90 days.
Auto Hematopoietic Stem Cell Transplantation Combined with Another Target Humanized CAR-T Cells for Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma after Failure of Murinized CD19-CAR-T Therapy
Authors: Kai Hu, Fan Yang, Rui Liu, Teng Xu, Peihao Zheng, Shaomei Feng, Yuelu Guo, Hui Shi, Biping Deng, Xiaoyan Ke, Tong Wu
Journal: Blood (2021)