tbuckley/cabot-search huggingface dataset:
Association between exercise habits and stroke, heart failure, and mortality in Korean patients with incident atrial fibrillation: A nationwide population-based cohort study
Authors: Hyo-Jeong Ahn, So-Ryoung Lee, Eue-Keun Choi, Kyung-Do Han, Jin-Hyung Jung, Jae-Hyun Lim, Jun-Pil Yun, Soonil Kwon, Seil Oh, Gregory Y. H. Lip
Journal: PLoS Medicine (2021)

There is a paucity of information about cardiovascular outcomes related to exercise habit change after a new diagnosis of atrial fibrillation (AF). We investigated the association between exercise habits after a new AF diagnosis and ischemic stroke, heart failure (HF), and all-cause death. This is a nationwide population-based cohort study using data from the Korea National Health Insurance Service. A retrospective analysis was performed for 66,692 patients with newly diagnosed AF between 2010 and 2016 who underwent 2 serial health examinations within 2 years before and after their AF diagnosis. Individuals were divided into 4 categories according to performance of regular exercise, which was investigated by a self-reported questionnaire in each health examination, before and after their AF diagnosis: persistent non-exercisers (30.5%), new exercisers (17.8%), exercise dropouts (17.4%), and exercise maintainers (34.2%). The primary outcomes were incidence of ischemic stroke, HF, and all-cause death. Differences in baseline characteristics among groups were balanced considering demographics, comorbidities, medications, lifestyle behaviors, and income status. The risks of the outcomes were computed by weighted Cox proportional hazards models with inverse probability of treatment weighting (IPTW) during a mean follow-up of 3.4 ± 2.0 years. The new exerciser and exercise maintainer groups were associated with a lower risk of HF compared to the persistent non-exerciser group: the hazard ratios (HRs) (95% CIs) were 0.95 (0.90-0.99) and 0.92 (0.88-0.96), respectively (p < 0.001). Also, performing exercise any time before or after AF diagnosis was associated with a lower risk of mortality compared to persistent non-exercising: the HR (95% CI) was 0.82 (0.73-0.91) for new exercisers, 0.83 (0.74-0.93) for exercise dropouts, and 0.61 (0.55-0.67) for exercise maintainers (p < 0.001). For ischemic stroke, the estimates of HRs were 10%-14% lower in patients of the exercise groups, yet differences were statistically insignificant (p = 0.057). Energy expenditure of 1,000-1,499 MET-min/wk (regular moderate exercise 170-240 min/wk) was consistently associated with a lower risk of each outcome based on a subgroup analysis of the new exerciser group. Study limitations include recall bias introduced due to the nature of the self-reported questionnaire and restricted external generalizability to other ethnic groups. Initiating or continuing regular exercise after AF diagnosis was associated with lower risks of HF and mortality. The promotion of exercise might reduce the future risk of adverse outcomes in patients with AF.
Comparison of Symptoms and RNA Levels in Children and Adults With SARS-CoV-2 Infection in the Community Setting
Authors: Erin Chung, Eric J. Chow, Naomi C. Wilcox, Roy Burstein, Elisabeth Brandstetter, Peter D. Han, Kairsten Fay, Brian Pfau, Amanda Adler, Kirsten Lacombe, Christina M. Lockwood, Timothy M. Uyeki, Jay Shendure, Jeffrey S. Duchin, Mark J. Rieder, Deborah A. Nickerson, Michael Boeckh, Michael Famulare, James P. Hughes, Lea M. Starita, Trevor Bedford, Janet A. Englund, Helen Y. Chu
Journal: JAMA Pediatrics (2021)

The association between COVID-19 symptoms and SARS-CoV-2 viral levels in children living in the community is not well understood.
HGG-44. REVEALING VULNERABILITIES IN DIPG THROUGH ONC201
Authors: James Stafford, Alqassem Abuarqoub, Tatiana Mcanulty, Richard Possemato, Eyal Amiel, Matija Snuderl
Journal: Neuro-Oncology (2021)

Abstract Emerging evidence from clinical and preclinical studies suggests that the imipridone ONC201 is well tolerated and may have some clinical impact in discrete diffuse intrinsic pontine glioma patients (DIPG). A primary goal of our work is to determine if DIPG are uniquely sensitive to ONC201 and if so, whether ONC201 itself can be used as a tool to illuminate novel vulnerabilities in DIPG. To accomplish this, we are utilizing a combination of patient-derived cell lines as well as mouse xenografts that dovetail with a variety of molecular, epigenetic and metabolomic tools. A central finding from our work is that ONC201 primarily activates the mitochondrial protease, ClpP in DIPG patient-derived cell lines, an effect consistent with recently described ONC201 mechanism of action in other tumors. We further demonstrate that activation of ClpP by ONC201 leads to a host of downstream effects in DIPG model systems including distinctive effects on the metabolome leading to direct alterations in the unique epigenetic signature of DIPG. By directly manipulating these metabolic and epigenetic factors we provide prospective mechanistic insight into how ONC201 as well as ClpP activity impacts DIPG growth and tumorigenicity. These preclinical research findings shed light on potential therapeutic vulnerabilities in DIPG as well as ways that these strategies may be combined to enhance their potential.
EGFR blockade leads to singular oncogene-addiction in ETV6-NTRK3 transformed human epithelial cells and hypersensitization to entrectinib.
Authors: Nagarajan Kannan, Guruprasad Kalthur, Musheer Aalam, Ishaq Viringipurampeer, Chitra Priya Emperumal, Philip A Beer, Anguraj Sadanandam, Joaquin J. Garcia, Jeffrey R. Janus
Journal: Journal of Clinical Oncology (2021)

e18055 Background: Entrectinib, a TRK kinase inhibitor, has been approved for the treatment of tissue agnostic rare tumors positive for TRK fusions. A very low frequency molecular subset of TRK fusion tumors dubbed as secretory carcinoma (SC) are characterized by organ-agnostic epithelial origin, ETV6-NTRK3 (EN) fusion and distinguishable secretory-type tumor cells. These tumors have been frequently miscategorized as acinic cell carcinoma or adenocarcinoma. A previous mouse study identified EGF dependent epithelial progenitors as putative cell-of-origin for SC. Methods: To test the role of EGFR signaling in EN mediated transformation and therapy resistance, we expressed EN, kinase-dead EN-K380M, and drug-resistant EN-G623R in human epithelial MCF10A cells with EGF-dependent primitive function and investigated their ability to grow in the presence and absence of EGF and/or entrectinib. To understand the significance of findings based on our model, we analyzed a total of 22 ‘rare’ patients from Mayo Clinic Tissue Registry and analyzed TCGA PanCan datasets. Results: We report herein that EGF signaling is essential for normal growth but dispensable during EN driven transformation. Our findings suggest that levels equivalent to circulating EGF (0.5-1ng/ml) is sufficient to drive 100% resistance to entrectinib in vitro. Three different strategies to blockade EGF/EGFR axis including depletion of EGF in culture system, genetic depletion of EGFR using shRNA as well as cetuximab antibody-based EGFR neutralization potentiated oncogene-addiction and hypersensitivity to entrectinib in our models. As predicted, models with G623R mutation in EN was refractory to entrectinib under all experimental conditions. Further omics analysis of TCGA PanCan suggested that EN and EGFR mutations are mutually exclusive and entrectinib-resistant G623R mutation were uncommon. Interestingly, nearly all EN tumors from Mayo Clinic Tissue Registry immunostained weakly or strongly for EGFR and showed perfect concordance with pEGFR suggesting pathway activation. Conclusions: Together, these findings raise an important question whether blockade of ‘wildtype’ EGFR signaling could improve medical intervention in SC patients presenting with wildtype EGFR and no drug-resistant mutation in entrectinib, by improving oncogene-addiction and attendant hypersensitization of transformed cells to entrectinib.
The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance
Authors: Guang Yang, Jinhua Wang, Li Tan, Manit Munshi, Xia Liu, Amanda Kofides, Jiaji G. Chen, Nicholas Tsakmaklis, Maria G. Demos, Maria Luisa Guerrera, Lian Xu, Zachary R. Hunter, Jinwei Che, Christopher J. Patterson, Kirsten Meid, Jorge J. Castillo, Nikhil C. Munshi, Kenneth C. Anderson, Michael Cameron, Sara J. Buhrlage, Nathanael S. Gray, Steven P. Treon
Journal: Blood (2021)
High-throughput drug screening models of mature adipose tissues which replicate the physiology of patients’ Body Mass Index (BMI)
Authors: Fiona Louis, Yoshihiro Sowa, Shiro Kitano, Michiya Matsusaki
Journal: Bioactive Materials (2021)

Obesity is a complex and incompletely understood disease, but current drug screening strategies mostly rely on immature in vitro adipose models which cannot recapitulate it properly. To address this issue, we developed a statistically validated high-throughput screening model by seeding human mature adipocytes from patients, encapsulated in physiological collagen microfibers. These drop tissues ensured the maintenance of adipocyte viability and functionality for controlling glucose and fatty acids uptake, as well as glycerol release. As such, patients' BMI and insulin sensitivity displayed a strong inverse correlation: the healthy adipocytes were associated with the highest insulin-induced glucose uptake, while insulin resistance was confirmed in the underweight and severely obese adipocytes. Insulin sensitivity recovery was possible with two type 2 diabetes treatments, rosiglitazone and melatonin. Finally, the addition of blood vasculature to the model seemed to more accurately recapitulate the in vivo physiology, with particular respect to leptin secretion metabolism.
A retrospective study of anlotinib in patients with cervical cancer after chemoradiotherapy.
Authors: Liu Tan, Alan Chu, Yu Yang, Jinjin Yuan, Ge Hou, Rui Song, Cheng Wang, Chenhu Xiao, Ting Chai, Shijia Liu, Pan Zhang, Zongwen Liu
Journal: Journal of Clinical Oncology (2021)

e17509 Background: Anlotinib is a novel small molecule antiangiogenic drug, which can inhibit multiple tyrosine kinase receptor activity. Its antitumor activity has been proved in various cancers, including gynecological tumors. This retrospective study explored the efficacy and safety of anlotinib monotherapy or anlotinib combined chemotherapy in cervical cancer patients who have disease progressed or metastasis after chemoradiotherapy. Methods: 28 patients with cervical cancer admitted to the Second Affiliated Hospital of Zhengzhou University were enrolled. These patients who had received radiotherapy and at least one line chemotherapy had tumor progression or metastasis. 13 patients received anlotinib monotherapy (12mg/d from day 1 to day 14 in a 21-day cycle) and 15 patients received chemotherapy combined with the anlotinib. Treatment was continued until disease progression or death or intolerable adverse events. The primary endpoint was the objective response rate (ORR), and the secondary endpoints were disease control rate (DCR), progression-free survival (PFS) and safety. Results: As of Dec 31 2020, no one was lost follow up. 2 patients were still under treatment, and 26 patients were evaluable. 1 CR, 6 PR, 13 SD, 6 PD, yielding the ORR of 26.92%, and the DCR of 76.92%. The median PFS for receiving anlotinib monotherapy was 4.57 (95% CI, 3.85-5.29) months, and 8.47 (95% CI, 5.09-11.85) months for combination group. The most common adverse events (AEs)were grade 1, including hypertension (46.43%), anemia (42.85%) and fatigue (39.29%). Grade 3 AEs were hypertension(10.71%) and anemia(7.14%). No higher grade AEs occurred. Conclusions: Anlotinib is safe and effective for patients with advanced cervical cancer after chemoradiotherapy, and it is well tolerated.
Veterans on anticancer medications in rural and community environment support (VA CARES) program: A pharmacist-led telemedicine medication management program for veterans receiving oral antineoplastic therapies through the MISSION Act.
Authors: Regan Healy, Deborah Passey, Derek Pinnell, Joshua Qualls, Clayton Hamilton, Zach Burningham, Elizabeth Tilley, Tanya Hood, Brian C Sauer, Ahmad Sami Halwani
Journal: Journal of Clinical Oncology (2021)

1545 Background: Cancer therapies are leveraging oral targeted treatments over traditional cytotoxic chemotherapy (CT) at an increasing rate. Compared to CT, use of oral antineoplastic treatments (OATs) shift some of the burden of medication management onto patients. To address these challenges, several health systems have developed multidisciplinary OAT management teams or ‘clinics’ whereby an Oncology Clinical Pharmacist (OCP) collaborates with oncology teams to ensure optimal use of these agents. Through the VA MISSION Act of 2018, Veterans can be prescribed treatments in the community which are dispensed by VA. These Veterans often live in rural areas and may lack access to comprehensive medication management resources. Methods: The VA CARES Program is a telemedicine medication management ‘clinic’ and care delivery model for patients receiving OATs leveraging custom designed health information technology (HIT) tools to remotely coordinate OAT related care. Veterans are automatically enrolled in the program if they have OATs prescribed by community providers which are to be dispensed by VA. An OCP provides telemedicine medication management services. The OCP performs a screening assessment, ensures appropriate indication and dosing, reviews baseline laboratory results, and performs a thorough drug-drug interaction analysis. The OCP then provides OAT education. Throughout the duration of therapy the OCP ensures necessary therapeutic monitoring, and regularly follows up with the Veterans. Subsequent encounters are to assess knowledge, adherence, toxicities, new drug-drug interactions, and need for OAT refills. The outcome measures for the VA CARES Program include safety (number and type of pharmacist interventions), economic benefits (cost savings or cost avoidance), and patient satisfaction. Results: In the initial 13 months, the VA CARES Program screened N = 78 and enrolled N = 64 (82%) Veterans from three VA medical facilities in VISN-19 from January 2020 to January 2021. The CPS performed n = 342 telemedicine visits and n = 80 interventions leading to improved safety, effectiveness, and/or an economical benefit. The most common interventions included detection and/or prevention of drug-drug interactions (n = 45) and adverse events (n = 18), drug not indicated (n = 13), alternative therapy suggested (n = 7), and limited-quantity dispensed (n = 7). The CPS interventions saved an estimated $210,864 in medication-related costs or avoidance. The Veterans surveyed were highly satisfied with the program services. Conclusions: Telemedicine delivery of oncology medication management by an OCP across systems is feasible, and provides clinical and economic benefits.
Stem cell properties of GT101, a tumor infiltrating lymphocyte (TIL) product with multiple indications.
Authors: Yarong Liu, Deping Zhao, Zixiao Shi, Rong Zhou, Jingwei Sun, Yong Han, Peipei Zhao
Journal: Journal of Clinical Oncology (2021)

e14506 Background: Tumor infiltrating lymphocyte (TIL) is a kind of adoptive T cell therapy that has demonstrated clinical benefits in several types of solid tumors. GT101 is an autologous TIL therapy for the treatment of multiple solid tumors. Previous studies showed that in vitro expansion resulted in over 80% terminally differentiated effector T cells in the final TIL products, which may show good cytotoxicity but weak capability of persistence and proliferation in vivo. Herein we present phenotype and function characterization of our TIL product GT101 with a focus on its stemness attributes. Methods: We have produced more than 30 batches of GT101 TIL samples from 10 different cancer indications and analyzed their proliferation, cytokine production and phenotype at preREP and/or REP stage. Results: GT101 products keep a consistent T cell phenotype and good proliferation capacity, and are capable of secreting large amounts of cytokines after stimulation by anti-CD3/CD28 antibody, reflecting its good functionality. The residues in the final products, such as feeder cells and tumor cells, are below the detection limit. In contrast to equivalent TIL products previously reported across the world, we find that GT101 features a manufacturing process that preserves the stem cell characteristics of T cells. Analysis of all the 30 GT101 TIL samples demonstrates that the average percentage of central memory T cells (Tcm) and naïve T cells is 40-50% and 10-20% respectively in both CD8 + and CD4 + populations at the end of preREP stage. Meanwhile, CD8 + TCF1 + cells are close to 50%, mainly in the form of PD-1 - . In the phase of REP, the stemness of T cell is still well maintained—the average proportion of both Tcm and naïve T cells only decreases by about 5%, and that of CD8 + TCF1 + cells down by about 10%. Conclusions: In general, GT101 demonstrates good stemness with a higher percentage of Tcm and TCF1 + than equivalent products previously reported across the world, suggesting better performance in persistence and proliferation in clinic.
2001年から2016年までの不十分な身体活動における世界的傾向: 1つの100万人の参加者による358人の集団ベース調査のプール分析【JST・京大機械翻訳】
Authors: Guthold Regina, Stevens Gretchen A, Riley Leanne M, Bull Fiona C
Journal: The Lancet Global Health (2018)
Variation in the use of genomic testing in patients with metastatic colorectal cancer.
Authors: Sarah C. Markt, Benjamin Booker, Wyatt Bensken, Fredrick R Schumacher, Johnie Rose, Gregory S. Cooper, Siran M. Koroukian
Journal: Journal of Clinical Oncology (2021)

e15557 Background: Oncology has greatly benefited from the use of clinical genomics to aid diagnostic and treatment decisions. To inform targeted therapy, standard practice dictates molecular testing of metastatic colorectal cancer (mCRC) tumors through genomic testing (GT), including molecular biomarker, single gene, or next-generation sequencing (NGS). While persisting disparities in CRC screening, treatment, and outcomes have been well described, little is known about differences in GT for mCRC. Using all-payer electronic health record-derived de-identified data from a real-world database generated from routine clinical care across the U.S., we identified combinations of demographic and clinical characteristics, rather than individual factors, associated with GT. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. During the study period, the de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). Our study population included 26,524 patients with mCRC during the years 2013-2020. We evaluated documentation of receipt of GT (individual biomarker or NGS) measured within one year of diagnosis of metastatic disease, by demographic (age, sex, and race/ethnicity), payer type, de novo metastatic cancer (vs. progression to metastatic disease), tumor site (colon vs. rectum), Eastern Cooperative Oncology Group (ECOG) performance status, and year of diagnosis. We identified Elixhauser comorbid conditions from ICD codes, and grouped them by count (0-4, 5+). We conducted Classification and Regression Tree (CART) analysis, a machine learning approach to identify combinations of demographic and clinical characteristics associated with receipt of GT. Results: Nearly 83% had documented GT, 90% of whom did so within 6 months of diagnosis. The largest group of patients with GT at 90% consisted of individuals with colon cancer, 64 years of age or younger, 0-4 comorbidities, and an ECOG score of 0 or 1 (n = 2,004). Conversely, the lowest rates of GT ( &lt; 60%) were observed among women 75 years of age or older, despite having 0-4 comorbidities (n = 1,314). In this group of patients, GT was higher among those with ECOG score of 1 than among those with high ECOG scores (66% and 54%, respectively). On the other hand, 71% of patients 75 years of age or older with 5+ comorbidities and high ECOG scores received GT. Conclusions: Considerable variations exist in GT across subgroups of the population. Additional analysis is warranted to characterize young and healthy patients who did not receive GT, and those who did get tested despite their older age and compromised health status. Future analyses will investigate whether documentation of receipt of GT is associated with treatment decisions and outcomes.
Geostatistical analysis, web-based mapping, and environmental determinants of under-5 stunting: evidence from the 2014 Ghana Demographic and Health Survey
Authors: Justice Moses K Aheto, Getachew A Dagne
Journal: The Lancet Planetary Health (2021)

BackgroundStunting rates in children younger than 5 years are among the most important health indicators globally. At the national level, malnutrition accounts for about 40% of under-5 deaths in Ghana. Disease risk mapping provides opportunities for disease surveillance and targeted interventions. We aimed to estimate and map under-5 stunting prevalence in Ghana, with the goal of identifying communities at higher risk where interventions and further research can be targeted.MethodsFor this modelling study, we used data from the 2014 Ghana Demographic and Health Survey. Analyses were done on 2734 children residing in 415 geographical clusters. The outcome variable was the number of stunted children younger than 5 years in each sampled cluster. We employed a Bayesian geostatistical model to investigate both measured and unmeasured spatial risk factors for child stunting, comparing the performance of non-spatial (adjusting for selected covariates without spatial correlation), spatial (including spatial correlation), and null spatial (without the selected covariates) models. We then visualised the stunting prevalence across Ghana by mapping the predicted prevalence and exceedance probabilities to resolutions as refined as 5 km × 5 km.FindingsIn 2014, 535 (19·6%) of 2734 children surveyed in Ghana were stunted. Elevation (log odds mean −0·0017, 95% credible interval −0·0034 to −0·0001), precipitation (0·0403, 0·0192 to 0·0615), and aridity (–3·7013, −6·5478 to −0·8723) were environmental and climatic factors associated with stunting in the non-spatial model, but were not significant in the spatial model. Substantial geographical variations in prevalence of childhood stunting were found. The predicted mean stunting prevalence was 27·7% (SD 3·7%) with predicted prevalence ranging from 4·2% to 45·1% across Ghana. Children residing in parts of the Northern region were at highest risk of stunting, whereas parts of the Greater Accra, Brong-Ahafo, Ashanti, and Eastern regions showed some of the lowest prevalence.InterpretationThere are substantial geographical differences in childhood stunting across Ghana. Our prevalence maps can be used as an effective tool to identify communities that require targeted interventions by programme managers and implementers, as part of an overall strategy to reduce the burden of malnutrition in a country with limited public health resources.FundingNone.