tbuckley/cabot-search huggingface dataset:
Performance of anti-CD19 chimeric antigen receptor T cells in genetically defined classes of chronic lymphocytic leukemia
Authors: Veronika Mancikova, Helena Peschelova, Veronika Kozlova, Aneta Ledererova, Adriana Ladungova, Jan Verner, Tomas Loja, Frantisek Folber, Jiri Mayer, Sarka Pospisilova, Michal Smida
Journal: Journal for ImmunoTherapy of Cancer (2020)

While achieving prolonged remissions in other B cell-derived malignancies, chimeric antigen receptor (CAR) T cells still underperform when injected into patients with chronic lymphocytic leukemia (CLL). We studied the influence of genetics on CLL response to anti-CD19 CAR T-cell therapy. First, we studied 32 primary CLL samples composed of 26 immunoglobulin heavy-chain gene variable (IGHV)-unmutated (9 ATM-mutated, 8 TP53-mutated, and 9 without mutations in ATM, TP53, NOTCH1 or SF3B1) and 6 IGHV-mutated samples without mutations in the above-mentioned genes. Then, we mimicked the leukemic microenvironment in the primary cells by '2S stimulation' through interleukin-2 and nuclear factor kappa B. Finally, CRISPR/Cas9-generated ATM -knockout and TP53-knockout clones (four and seven, respectively) from CLL-derived cell lines MEC1 and HG3 were used. All these samples were exposed to CAR T cells. In vivo survival study in NSG mice using HG3 wild-type (WT), ATM -knockout or TP53-knockout cells was also performed. Primary unstimulated CLL cells were specifically eliminated after >24 hours of coculture with CAR T cells. '2S' stimulated cells showed increased survival when exposed to CAR T cells compared with unstimulated ones, confirming the positive effect of this stimulation on CLL cells' in vitro fitness. After 96 hours of coculture, there was no difference in survival among the genetic classes. Finally, CAR T cells were specifically activated in vitro in the presence of target knockout cell lines as shown by the production of interferon-γ when compared with control (CTRL) T cells (p=0.0020), but there was no difference in knockout cells' survival. In vivo, CAR T cells prolonged the survival of mice injected with WT, TP53-knockout and ATM-knockout HG3 tumor cells as compared with CTRL T cells (p=0.0485, 0.0204 and <0.0001, respectively). When compared with ATM-knockout, TP53-knockout disease was associated with an earlier time of onset (p<0.0001), higher tumor burden (p=0.0002) and inefficient T-cell engraftment (p=0.0012). While in vitro no differences in survival of CLL cells of various genetic backgrounds were observed, CAR T cells showed a different effectiveness at eradicating tumor cells in vivo depending on the driver mutation. Early disease onset, high-tumor burden and inefficient T-cell engraftment, associated with TP53-knockout tumors in our experimental setting, ultimately led to inferior performance of CAR T cells.
Abstract P4-01-02: Circulating tumor cells detected after neoadjuvant therapy for inflammatory breast cancer are associated with early relapse despite pCR
Authors: Carolyn Hall, Salyna Meas, Boomadevi Narendran, Vanessa Sarli, Joshua Upshaw, Naoto Ueno, Bora Lim, Vicente Valero, Anthony Lucci
Journal: Cancer Research (2020)

Abstract Background: IBC is a rare and aggressive subtype of breast cancer. A significant number of IBC patients who achieve pathologic complete response (no residual tumor in breast and axillary nodes, pCR), still relapse after neoadjuvant chemotherapy (NAC). We hypothesized that circulating tumor cells (CTCs) identified in blood after NAC would add additional relapse risk information beyond just PCR alone. Methods: Blood was assessed for CTCs after NAC in 128 stage III IBC patients as part of an IRB approved study, (LAB04-0698) using the Cell Search® System (Menarini Silicon Biosystems). The presence of ≥ 1 CTC meeting morphological criteria for malignancy was considered a positive result. Fisher exact test was used to evaluate associations between CTC detection and clinicopathologic characteristics, and log-rank test was used to analyze associations between CTC detection after NAC, pCR, and relapse free survival. Results: Median follow-up was 2.4 years and mean patient age was 53 years. One or more CTC was identified after NAC in 36/128 (28%) of patients. Thirty-six patients (28%) had pCR following NAC. CTC detection was not associated with body mass index, estrogen, progesterone, or human epithelial growth factor receptor-2 (HER2) status, or Ki-67 staining (P= NS). Participants were grouped according to their post NAC CTC and pCR statuses as follows: CTC- and pCR (n = 28), CTC- and no pCR (n = 48), ≥1 CTC and pCR (n = 5) and ≥1 CTC and no pCR (n =18). Difference in recurrence free survival were identified in these groups, with worse relapse-free survival at 2 years identified in those with ≥1 CTCs and no pCR (log-rank p-value = &amp;lt;0.0001). Conclusions: CTC detection after NAC identified non-metastatic IBC patients who achieved pCR, but remained at risk for relapse. This study warrants larger studies combining both PCR and CTC information in IBC patients to improve risk stratification and to identify patients who could derive benefit from additional adjuvant therapies to reduce their risk for relapse. Citation Format: Carolyn Hall, Salyna Meas, Boomadevi Narendran, Vanessa Sarli, Joshua Upshaw, Naoto Ueno, Bora Lim, Vicente Valero, Anthony Lucci. Circulating tumor cells detected after neoadjuvant therapy for inflammatory breast cancer are associated with early relapse despite pCR [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-01-02.
Helen Salisbury: Coronavirus diaries
Authors: Helen Salisbury
Journal: BMJ (2020)

I am writing in the lull before the storm, which will have surely arrived by the time you read this. We have been getting to grips with a new version of general practice this week, doing nearly all our work remotely. We are on the phone constantly, some doctors are using video, and one of my partners is self-isolating with a feverish family but doing telephone triage from home. We are seeing very few patients face to face, to protect both them and us. Our waiting room looks like the late stages of an abandoned game of musical chairs—only a few seats left, widely spaced and unoccupied.

Demand for some healthcare …
Augmenting Computerized Cognitive Training With Vortioxetine for Age-Related Cognitive Decline: A Randomized Controlled Trial
Authors: Eric J. Lenze, Angela Stevens, Jill D. Waring, Vy T. Pham, Rita Haddad, Josh Shimony, J. Philip Miller, Christopher R. Bowie
Journal: American Journal of Psychiatry (2020)

Age-related cognitive decline, the deterioration in functions such as memory and executive function, is faced by most older adults and affects function and quality of life. No approved treatments exist for age-related cognitive decline. Computerized cognitive training has been shown to provide consistent albeit modest improvements in cognitive function as measured by neuropsychological testing. Vortioxetine, an antidepressant medication, has putative procognitive and proneuroplastic properties and therefore may be able to augment cognitive training. In this placebo-controlled study, the authors tested the cognitive benefits of vortioxetine added to cognitive training for adults age 65 or older with age-related cognitive decline.After a 2-week lead-in period of cognitive training, 100 participants were randomly assigned to receive either vortioxetine or placebo in addition to cognitive training for 26 weeks. The primary outcome measure was global cognitive performance, assessed by the NIH Toolbox Cognition Battery Fluid Cognition Composite. The secondary outcome measure was functional cognition, assessed by the UCSD Performance-Based Skills Assessment. All participants received motivational messaging and support from study staff to maximize adherence to the training.Participants who received vortioxetine with cognitive training showed a greater increase in global cognitive performance compared with those who received placebo with cognitive training. This separation was significant at week 12 but not at other assessment time points. Both groups showed improvement in the secondary outcome measure of functional cognition, with no significant difference between groups.Vortioxetine may be beneficial for age-related cognitive decline when combined with cognitive training. These findings provide new treatment directions for combating cognitive decline in older adults.
Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial
Authors: Kelly E Dooley, Radojkam Savic, Akshay Gupte, Mark A Marzinke, Nan Zhang, Vinodh A Edward, Lisa Wolf, Modulakgotla Sebe, Morongwe Likoti, Mark J Fyvie, Innocent Shibambo, Trevor Beattie, Richard E Chaisson, Gavin J Churchyard
Journal: The Lancet HIV (2020)
In Situ Expansion, Differentiation, and Electromechanical Coupling of Human Cardiac Muscle in a 3D Bioprinted, Chambered Organoid
Authors: Molly E. Kupfer, Wei-Han Lin, Vasanth Ravikumar, Kaiyan Qiu, Lu Wang, Ling Gao, Didarul B. Bhuiyan, Megan Lenz, Jeffrey Ai, Ryan R. Mahutga, DeWayne Townsend, Jianyi Zhang, Michael C. McAlpine, Elena G. Tolkacheva, Brenda M. Ogle
Journal: Circulation Research (2020)

Rationale: One goal of cardiac tissue engineering is the generation of a living, human pump in vitro that could replace animal models and eventually serve as an in vivo therapeutic. Models that replicate the geometrically complex structure of the heart, harboring chambers and large vessels with soft biomaterials, can be achieved using 3-dimensional bioprinting. Yet, inclusion of contiguous, living muscle to support pump function has not been achieved. This is largely due to the challenge of attaining high densities of cardiomyocytes—a notoriously nonproliferative cell type. An alternative strategy is to print with human induced pluripotent stem cells, which can proliferate to high densities and fill tissue spaces, and subsequently differentiate them into cardiomyocytes in situ. Objective: To develop a bioink capable of promoting human induced pluripotent stem cell proliferation and cardiomyocyte differentiation to 3-dimensionally print electromechanically functional, chambered organoids composed of contiguous cardiac muscle. Methods and Results: We optimized a photo-crosslinkable formulation of native ECM (extracellular matrix) proteins and used this bioink to 3-dimensionally print human induced pluripotent stem cell–laden structures with 2 chambers and a vessel inlet and outlet. After human induced pluripotent stem cells proliferated to a sufficient density, we differentiated the cells within the structure and demonstrated function of the resultant human chambered muscle pump. Human chambered muscle pumps demonstrated macroscale beating and continuous action potential propagation with responsiveness to drugs and pacing. The connected chambers allowed for perfusion and enabled replication of pressure/volume relationships fundamental to the study of heart function and remodeling with health and disease. Conclusions: This advance represents a critical step toward generating macroscale tissues, akin to aggregate-based organoids, but with the critical advantage of harboring geometric structures essential to the pump function of cardiac muscle. Looking forward, human chambered organoids of this type might also serve as a test bed for cardiac medical devices and eventually lead to therapeutic tissue grafting.
Abstract 12131: Comparison of Ultrasonic Cardiac Output Monitor (USCOM) With Other Methods for Cardiac Output Monitoring in Various Clinical Settings and Clinical Outcomes and Costs: A Systematic Review and Meta-Analysis
Authors: Muhammed K Elfaituri, Nguyen Lam Vuong, Soon Khai Low, Mariam El-Sayed, Midhat L Lakhani, Sedralmontaha Istanbuly, Akash Sharma, Samar Muhammad, Tran Thanh Tuan, Vincent Hou, Samar Tarek Farahat, Ahmed Eladely, Nguyen Tien Huy, Muhammad Salman Faisal
Journal: Circulation (2018)

Introduction: Cardiac output (CO) measurement and monitoring is crucial for the guidance of diagnostic and therapeutic decisions clinically, especially in cardiology, critically ill and surgical pa...
Sustainability of and Adherence to Preschool Health Promotion Among Children 9 to 13 Years Old
Authors: Rodrigo Fernández-Jiménez, German Briceño, Jaime Céspedes, Sarha Vargas, Jennifer Guijarro, Jorge Baxter, Marilyn Hunn, Gloria Santos-Beneit, Carla Rodríguez, Maria Paula Céspedes, Emilia Bagiella, Zorayda Moreno, Isabel Carvajal, Valentin Fuster
Journal: Journal of the American College of Cardiology (2020)

Long-term evaluations of child health promotion programs are required to assess their sustainability and the need for reintervention. This study sought to explore the long-term impact of a preschool health promotion intervention delivered in an urban low-income area of Colombia (phase 1) and to assess the effect of a new community-based intervention (phase 2). In phase 1, a cross-sectional analysis of knowledge, attitudes, and habits (KAH) toward a healthy lifestyle and ideal cardiovascular health (ICH) scores of 1,216 children 9 to 13 years old was performed. Of the total, 596 had previously received a preschool health promotion intervention at 3 to 5 years old, whereas the remaining 620 were not previously intervened (intervention-naive group). In phase 2, all children were cluster randomized 1:1 to receive either a 4-month educational intervention (the SI! Program) to instill healthy behaviors in community centers (24 clusters, 616 children) or to control (24 clusters, 600 children). Previously intervened and intervention-naive children were not mixed in the same cluster. The primary outcomes were the change from baseline in KAH and ICH scores. Intervention effects were tested for with linear mixed-effects models. In phase 1, ∼85% of children had nonideal cardiovascular health, and those who previously received a preschool intervention showed a negligible residual effect compared with intervention-naive children. In phase 2, the between-group (control vs. intervention) differences in the change of the overall KAH and ICH scores were 0.92 points (95% confidence interval [CI]: −0.28 to 2.13; p = 0.133) and −0.20 points (95% CI: −0.43 to 0.03; p = 0.089), respectively. No booster effect was detected. However, a dose-response effect was observed, with maximal benefit in children attending >75% of the scheduled intervention; the difference in the change of KAH between the high- and low-adherence groups was 3.72 points (95% CI: 1.71 to 5.73; p < 0.001). Although overall significant differences between the intervention and control groups were not observed, high adherence rates to health promotion interventions may improve effectiveness and outcomes in children. Reintervention strategies may be required at multiple stages to induce sustained health promotion effects (Salud Integral Colombia [SI! Colombia II]; NCT03119792)
Initial Invasive or Conservative Strategy for Stable Coronary Disease
Authors: David J. Maron, Judith S. Hochman, Harmony R. Reynolds, Sripal Bangalore, Sean M. O’Brien, William E. Boden, Bernard R. Chaitman, Roxy Senior, Jose López-Sendón, Karen P. Alexander, Renato D. Lopes, Leslee J. Shaw, Jeffrey S. Berger, Jonathan D. Newman, Mandeep S. Sidhu, Shaun G. Goodman, Witold Ruzyllo, Gilbert Gosselin, Aldo P. Maggioni, Harvey D. White, Balram Bhargava, James K. Min, G.B. John Mancini, Daniel S. Berman, Michael H. Picard, Raymond Y. Kwong, Ziad A. Ali, Daniel B. Mark, John A. Spertus, Mangalath N. Krishnan, Ahmed Elghamaz, Nagaraja Moorthy, Whady A. Hueb, Marcin Demkow, Kreton Mavromatis, Olga Bockeria, Jesus Peteiro, Todd D. Miller, Hanna Szwed, Rolf Doerr, Matyas Keltai, Joseph B. Selvanayagam, P. Gabriel Steg, Claes Held, Shun Kohsaka, Stavroula Mavromichalis, Ruth Kirby, Neal O. Jeffries, Frank E. Harrell, Frank W. Rockhold, Samuel Broderick, T. Bruce Ferguson, David O. Williams, Robert A. Harrington, Gregg W. Stone, Yves Rosenberg
Journal: New England Journal of Medicine (2020)

Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.
The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2
Authors: Liang Chen, Xiangjie Li, Mingquan Chen, Yi Feng, Chenglong Xiong
Journal: Cardiovascular Research (2020)

Abstract A new type of pneumonia caused by a novel coronavirus SARS-CoV-2 outbreaks recently in China and spreads into many other countries. This disease, named as COVID-19, is similar to patients infected by SARS-CoV and MERS-CoV, and nearly 20% of patients developed severe condition. Cardiac injury is a prevalent complication of severe patients, exacerbating the disease severity in coronavirus disease 2019 (COVID-19) patients. Angiotensin-converting enzyme 2 (ACE2), the key host cellular receptor of SARS-CoV-2, has been identified in multiple organs, but its cellular distribution in human heart is not illuminated clearly. This study performed the first state-of-art single cell atlas of adult human heart, and revealed that pericytes with high expression of ACE2 might act as the target cardiac cell of SARS-CoV-2. The pericytes injury due to virus infection may result in capillary endothelial cells dysfunction, inducing microvascular dysfunction. And patients with basic heart failure disease showed increased ACE2 expression at both mRNA and protein levels, meaning that if infected by the virus these patients may have higher risk of heart attack and critically ill condition. The finding of this study explains the high rate of severe cases among COVID-19 patients with basic cardiovascular disease; and these results also perhaps provide important reference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2.
Abstract OT3-14-01: GERA: A health economic trial to analyze the impact of ehealth in breast cancer care
Authors: Tanja Eggersmann, Christoph Riese, Claudia Wenzel, Timo Schinkoethe, Tom Degenhardt, Rachel Wuerstlein, Nadia Harbeck, Manfred Welslau
Journal: Cancer Research (2020)

Abstract Background: In breast oncology, the increasing number of oral drug therapies pose great challenges for patient management. Numerous studies demonstrate that well-informed patients develop higher confidence in their treatment and a greater sense of disease control, resulting in increased adherence and persistence as well as potentially better outcome. Patients need knowledge, skills and confidence to actively participate in their own care. Moreover, such skills also contribute to reduction of planned and unplanned visits and of accompanying a time expenditure of the practice staff, thus lowering the costs of the whole treatment. Enhanced quality of life also affects financial resources by reducing sick leaves at work. The electronic Patient Reported Outcome (ePRO) tool CANKADO is designed to help oncologists to bridge the gap between good, personalized care and a time and resource-saving treatment for cancer patients. CANKADO helps patients and their physicians regarding therapy management by a standardized documentation procedure and, if needed, direct feedback to patients by the integrated Pro-React system. Methods: Aim of GERA is to assess the economic impact of an ePRO tool in breast cancer care. It is a prospective, single arm, non-interventional trial, based on questionnaires that answered by patients via the CANKADO Patient App. All patients undergoing systemic therapy for breast cancer with access to CANKADO will be included in the evaluation. This study will take place in 10 German centers and 337 patients will be included in the study. The enrollment phase of patients will last 6 months, while the individual patient observation and accompaniment phase through CANKADO will continue for 3 months. Primary objective is to gain knowledge on the health economic impact of CANKADO resource utilization in breast cancer care including the evaluation of physicians’ time and patient experience. As secondary objectives, exploratory analysis of all collected information is planned. This includes the socio-demographic patient information, clinical characteristics, quality-of life and patient documentation behavior. Results: The GERA trial is ongoing. Results will be presented at the conference. Conflict of interest: None declared Citation Format: Tanja Eggersmann, Christoph Riese, Claudia Wenzel, Timo Schinkoethe, Tom Degenhardt, Rachel Wuerstlein, Nadia Harbeck, Manfred Welslau. GERA: A health economic trial to analyze the impact of ehealth in breast cancer care [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT3-14-01.
Decreasing antibiotic use, the gut microbiota, and asthma incidence in children: evidence from population-based and prospective cohort studies
Authors: David M Patrick, Hind Sbihi, Darlene L Y Dai, Abdullah Al Mamun, Drona Rasali, Caren Rose, Fawziah Marra, Rozlyn C T Boutin, Charisse Petersen, Leah T Stiemsma, Geoffrey L Winsor, Fiona S L Brinkman, Anita L Kozyrskyj, Meghan B Azad, Allan B Becker, Piush J Mandhane, Theo J Moraes, Malcolm R Sears, Padmaja Subbarao, B Brett Finlay, Stuart E Turvey
Journal: The Lancet Respiratory Medicine (2020)
Development and validation of risk prediction platform for pancreatic fistula after pancreatoduodenectomy using artificial intelligence
Authors: In Woong Han, Kyeongwon Cho, Youngju Ryu, Myung Jin Chung, Sang Hyun Shin, Jin Seok Heo, Dong Wook Choi, Baek Hwan Cho
Journal: International Journal of Surgery (2020)
Interpreting test results: don’t blame the tools
Authors: Santhanam Sundar
Journal: BMJ (2020)

McCormack and Holmes discuss the imprecision of medical measurements and suggest a method for estimating variation in test results.1 Byron’s paraphrased proverb, “Good workmen never quarrel with their tools,” aptly summarises the art of interpreting test results.2

If there were a perfect laboratory test for a given condition, patients could cut …
Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation
Authors: Zeda Zhang, Chuanli Zhou, Xiaoling Li, Spencer D. Barnes, Su Deng, Elizabeth Hoover, Chi-Chao Chen, Young Sun Lee, Yanxiao Zhang, Choushi Wang, Lauren A. Metang, Chao Wu, Carla Rodriguez Tirado, Nickolas A. Johnson, John Wongvipat, Kristina Navrazhina, Zhen Cao, Danielle Choi, Chun-Hao Huang, Eliot Linton, Xiaoping Chen, Yupu Liang, Christopher E. Mason, Elisa de Stanchina, Wassim Abida, Amaia Lujambio, Sheng Li, Scott W. Lowe, Joshua T. Mendell, Venkat S. Malladi, Charles L. Sawyers, Ping Mu
Journal: Cancer Cell (2020)

Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.
Abstract 10626: Right Atrial Pressures Compared to Left Ventricular Pressures as Predictors of Ventricular Fibrillation in Commotio Cordis
Authors: Michael P Gannon, Mark S Link
Journal: Circulation (2018)

Introduction: Commotio cordis is sudden cardiac death described in young athletes suffering blunt impact. Swine models have elucidated ventricular fibrillation (VF) from increased left ventricular ...