tbuckley/cabot-search huggingface dataset:
A Fully Magnetically Levitated Left Ventricular Assist Device — Final Report
Authors: Mandeep R. Mehra, Nir Uriel, Yoshifumi Naka, Joseph C. Cleveland, Melana Yuzefpolskaya, Christopher T. Salerno, Mary N. Walsh, Carmelo A. Milano, Chetan B. Patel, Steven W. Hutchins, John Ransom, Gregory A. Ewald, Akinobu Itoh, Nirav Y. Raval, Scott C. Silvestry, Rebecca Cogswell, Ranjit John, Arvind Bhimaraj, Brian A. Bruckner, Brian D. Lowes, John Y. Um, Valluvan Jeevanandam, Gabriel Sayer, Abeel A. Mangi, Ezequiel J. Molina, Farooq Sheikh, Keith Aaronson, Francis D. Pagani, William G. Cotts, Antone J. Tatooles, Ashok Babu, Don Chomsky, Jason N. Katz, Paul B. Tessmann, David Dean, Arun Krishnamoorthy, Joyce Chuang, Ia Topuria, Poornima Sood, Daniel J. Goldstein
Journal: New England Journal of Medicine (2019)

In two interim analyses of this trial, patients with advanced heart failure who were treated with a fully magnetically levitated centrifugal-flow left ventricular assist device were less likely to have pump thrombosis or nondisabling stroke than were patients treated with a mechanical-bearing axial-flow left ventricular assist device.We randomly assigned patients with advanced heart failure to receive either the centrifugal-flow pump or the axial-flow pump irrespective of the intended goal of use (bridge to transplantation or destination therapy). The composite primary end point was survival at 2 years free of disabling stroke or reoperation to replace or remove a malfunctioning device. The principal secondary end point was pump replacement at 2 years.This final analysis included 1028 enrolled patients: 516 in the centrifugal-flow pump group and 512 in the axial-flow pump group. In the analysis of the primary end point, 397 patients (76.9%) in the centrifugal-flow pump group, as compared with 332 (64.8%) in the axial-flow pump group, remained alive and free of disabling stroke or reoperation to replace or remove a malfunctioning device at 2 years (relative risk, 0.84; 95% confidence interval [CI], 0.78 to 0.91; P<0.001 for superiority). Pump replacement was less common in the centrifugal-flow pump group than in the axial-flow pump group (12 patients [2.3%] vs. 57 patients [11.3%]; relative risk, 0.21; 95% CI, 0.11 to 0.38; P<0.001). The numbers of events per patient-year for stroke of any severity, major bleeding, and gastrointestinal hemorrhage were lower in the centrifugal-flow pump group than in the axial-flow pump group.Among patients with advanced heart failure, a fully magnetically levitated centrifugal-flow left ventricular assist device was associated with less frequent need for pump replacement than an axial-flow device and was superior with respect to survival free of disabling stroke or reoperation to replace or remove a malfunctioning device. (Funded by Abbott; MOMENTUM 3 ClinicalTrials.gov number, NCT02224755.).
Trypsin-like proteinases, kinin system and inhibitors in blood plasma of patients with stomach cancer or splenic lymphoma.
Authors: Andrey A. Maslov, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Larisa Kozlova, Sergey A. Malinin
Journal: Journal of Clinical Oncology (2015)

e15102 Background: In oncological diseases of hollow and parenchymatous organs their functions are impaired as a result of ischemia, edema, and pain syndrome development; activation of trypsin-like proteinases (TLP) and kallikrein-kinin system (KKS) may play an important role. Methods: TLP, kallikrein (K), carboxypeptidase N (CPN), prekallikrein (PK) content were measured in blood plasma of 26 stomach cancer (SC) patients (T2N0M0) and 22 splenic lymphoma (SL) patients (T2N0M0) by spectrophotometric methods. The results were compared with the indices in blood plasma of 32 practically healthy donors. Results: TLP exceeded the norm by 1,6 and 2 times in SC and SL, but the indices were higher by 27,8% in SL in comparison with SC (р < 0,01). K activities in SC and SL were equal (2,7 times higher than the norm), PK content in SC and SL was 2 times lower than the norm. CPN activity in SC and SL was 2,6 and 2,3 times lower than the norm respectively. PK/K ratio was lower than the norm: by 4,9 times in SC and 5,7 times in SL, but it was by 15,4% (р = 0,05) higher in SC than in SL which means steady downward tendency in SL in comparison with SC. PK content was close to depletion in both diseases, though to a greater extent in SL. Difference was observed in TLP level that was higher in SL with a high degree of reliability. TLP/K ratio was1,8 times lower than the norm in SC and by 1,2 times in SL, while the indices exceeded the norm, which proves TLP domination in SL development. In neoplasm development, trypsin-like enzymes loosen the intercellular matrix, facilitating migration processes, some of them have mitogenic activity and enter the blood if the activation is excessive; the fact was recorded during the study. Conclusions: Comparison of KKS changes in blood plasma in SC and SL with the indices in healthy donors showed their obvious similarity, hence the type of KKS reaction is analogous in development of hollow and parenchymatous organs. Trypsin-like proteinases such as trypsin, plasmin, plasminogen activators, elastase, collagenase are supposed to be prior in SL progression during that stage of SC and SL (T2).
Mutational Landscape and Temporal Evolution during Treatment of Relapsed Acute Lymphoblastic Leukemia
Authors: Benshang Li, Yongjin Li, Shuhong Shen, Yingchi Zhang, Samuel Brady, Xiaotu Ma, Yu Liu, Ningling Wang, Diane Flasch, Matthew Myers, Heather Mulder, Yanling Liu, Liqing Tian, Kohei Hagiwara, Hui Zhang, Ying Shao, Hongye Sun, Lele Sun, Ting-Nien Lin, Lijuan Du, Fan Yang, Michael Rusch, Michael Edmonson, John Easton, Xiaofan Zhu, Jingliao Zhang, Cheng Cheng, Benjamin Raphael, Jing-Yan Tang, James R. Downing, Bin-Bing Zhou, Ching-Hon Pui, Jun J. Yang, Jinghui Zhang
Journal: Blood (2018)
Abstract P391: Association of Peripheral Artery Disease With the Use of Smokeless Tobacco, Cigars, or Pipes in the Atherosclerosis Risk in Communities Study
Authors: Jeremy R Van’t Hof, Wendy Wang, Kunihiro Matsushita, Rachel Widome, Aaron R Folsom, Pamela L Lutsey
Journal: Circulation (2019)

Background: Cigarette smoking is one of the strongest modifiable risk factors for peripheral artery disease (PAD), a disease which affects over 200 million people worldwide. Though cigarette use has decreased across time, use of cigars, pipes and smokeless tobacco remains unchanged or slightly increased. The association of PAD and non-cigarette tobacco use is not well described. Thus, we tested the hypothesis that the use of cigars, pipes or smokeless tobacco is associated with incident PAD even after adjustment for cigarette use. Methods: A total of 14,395 Atherosclerosis Risk in Communities (ARIC) Study participants with no history of prevalent PAD were followed from 1987 to 2015 for PAD events (hospitalizations with PAD diagnosis or leg revascularization). Baseline pipe, cigar smoking and smokeless tobacco use was self-reported. Multivariable-adjusted Cox proportional hazards regression was used. Results: At enrollment the 14,395 participants included in the study were on average (SD) 54 (6) years old, 55% female and 27% African American; 489 (3.4%) were current users of smokeless tobacco and 481 (3.3%) current users of cigars or pipes. A total of 1,289 incident PAD events occurred during a median of 25.9 years of follow-up. After adjustment for demographics and cigarette smoking status, risk of incident PAD was higher among current (versus never) users of smokeless tobacco [HR (95% CI): 1.66 (1.29-2.12)], though this association was attenuated with adjustment for CVD risk factors (Table). Cigar and pipe use were not associated with PAD incidence, regardless of degree of adjustment (Table). Conclusion: Active use of smokeless tobacco was associated with increased risk for incident PAD compared to non-use, independent of cigarette smoking, although this relationship was not statistically significant after adjustment for cardiovascular risk factors. No association was observed with use of pipes or cigars. Use of smokeless tobacco may increase PAD risk and could be a potential target for intervention.
Effect of the Serious Illness Care Program in Outpatient Oncology
Authors: Rachelle Bernacki, Joanna Paladino, Bridget A. Neville, Mathilde Hutchings, Jane Kavanagh, Olaf P. Geerse, Joshua Lakin, Justin J. Sanders, Kate Miller, Stuart Lipsitz, Atul A. Gawande, Susan D. Block
Journal: JAMA Internal Medicine (2019)

High-quality conversations between clinicians and seriously ill patients about values and goals are associated with improved outcomes but occur infrequently.To examine feasibility, acceptability, and effect of a communication quality-improvement intervention (Serious Illness Care Program) on patient outcomes.A cluster randomized clinical trial of the Serious Illness Care Program in an outpatient oncology setting was conducted. Patients with advanced cancer (n = 278) and oncology clinicians (n = 91) participated between September 1, 2012, and June 30, 2016. Data analysis was performed from September 1, 2016, to December 27, 2018. All analyses were conducted based on intention to treat.Tools, training, and system changes.The coprimary outcomes included goal-concordant care (Life Priorities) and peacefulness (Peace, Equanimity, and Acceptance in the Cancer Experience questionnaire) at the end of life. Secondary outcomes included therapeutic alliance (Human Connection Scale), anxiety (Generalized Anxiety Disorder 7 scale), depression (Patient Health Questionnaire 9), and survival. Uptake and effectiveness of clinician training, clinician use of the conversation tool, and conversation duration were evaluated.Data from 91 clinicians in 41 clusters (72.9% participation; intervention, n = 48; control, n = 43; 52 [57.1%] women) and 278 patients (45.8% participation; intervention, n = 134; control, n = 144; 148 [53.2%] women) were analyzed. Forty-seven clinicians (97.9%) rated the training as effective (mean [SD] score, 4.3 [0.7] of 5.0 possible); of 39 who received a reminder, 34 (87.2%) completed at least 1 conversation (median duration, 19 minutes; range, 5-70). Peacefulness, therapeutic alliance, anxiety, and depression did not differ at baseline. The coprimary outcomes were evaluated in 64 patients; no significant differences were found between the intervention and control groups. However, the trial demonstrated significant reductions in the proportion of patients with moderate to severe anxiety (10.2% vs 5.0%; P = .05) and depression symptoms (20.8% vs 10.6%; P = .04) in the intervention group at 14 weeks after baseline. Anxiety reduction was sustained at 24 weeks (10.4% vs 4.2%; P = .02), but depression reduction was not sustained (17.8% vs 12.5%; P = .31). Survival and therapeutic alliance did not differ between groups.The results of this cluster randomized clinical trial were null with respect to the coprimary outcomes of goal-concordant care and peacefulness at the end of life. Methodologic challenges for the primary outcomes, including measure selection and sample size, limit the conclusions that can be drawn from the study. However, the significant reductions in anxiety and depression in the intervention group are clinically meaningful and require further study.ClinicalTrials.gov identifier: NCT01786811.
Finding the needle in the haystack: BMP9 and 10 emerge from the genome in pulmonary arterial hypertension
Authors: Nicholas W. Morrell
Journal: European Respiratory Journal (2019)

<b>Two new studies confirm the role of <i>BMP9</i> mutations as a cause of heritable PAH and provide the first evidence that mutations in <i>BMP10</i> might also be causal; these results have relevance for the development of new treatments for PAH</b>http://ow.ly/UHmG30nCl3x
Twenty-Year Trends in Outcomes for Older Adults With Acute Myocardial Infarction in the United States
Authors: Harlan M. Krumholz, Sharon-Lise T. Normand, Yun Wang
Journal: JAMA Network Open (2019)

Medicare and other organizations have focused on improving quality of care for patients with acute myocardial infarction (AMI) over the last 2 decades. However, there is no comprehensive perspective on the evolution of outcomes for AMI during that period, and it is unknown whether temporal changes varied by patient subgroup, hospital, or county.To provide a comprehensive evaluation of national trends in inpatient outcomes and costs of AMI during this period.This cohort study included analysis of data from a sample of 4 367 485 Medicare fee-for-service beneficiaries aged 65 years or older from January 1, 1995, through December 31, 2014, across 5680 hospitals in the United States. Analyses were conducted from January 15 to June 5, 2018.Thirty-day all-cause mortality at the patient, hospital, and county levels. Additional outcomes included 30-day all-cause readmissions; 1-year recurrent AMI; in-hospital mortality; length of hospital stay; 2014 Consumer Price Index-adjusted median Medicare inpatient payment per AMI discharge; and rates of catheterization, percutaneous coronary intervention, and coronary artery bypass graft surgery.The cohort included 4 367 485 Medicare fee-for-service patients aged 65 years or older hospitalized for AMI during the study period. Between 1995 and 2014, the mean (SD) age of patients increased from 76.9 (7.2) to 78.2 (8.7) years, the percentage of female patients declined from 49.5% to 46.1%, the percentage of white patients declined from 91.0% to 86.2%, and the percentage of black patients increased from 5.9% to 8.0%. There were declines in AMI hospitalizations (914 to 566 per 100 000 beneficiary-years); 30-day mortality (20.0% to 12.4%; difference, 7.6 percentage points; 95% CI, 7.3-7.8 percentage points); 30-day all-cause readmissions (21.0% to 15.3%; difference, 5.7 percentage points; 95% CI, 5.4-6.0 percentage points); and 1-year recurrent AMI (7.1% to 5.1%; difference, 2.0 percentage points; 95% CI, 1.8-2.2 percentage points). There were increases in the 2014 Consumer Price Index-adjusted median (interquartile range) Medicare inpatient payment per AMI discharge ($9282 [$6969-$12 173] to $11 031 [$8099-$16 861]); 30-day inpatient catheterization (44.2% to 59.9%; difference, 15.7 percentage points; 95% CI, 15.4-16.0 percentage points); and inpatient percutaneous coronary intervention (18.8% to 43.3%; difference, 24.5 percentage points; 95% CI, 24.2-24.7 percentage points). Coronary artery bypass graft surgery rates decreased from 14.4% to 10.2% (difference, 4.2 percentage points; 95% CI, 3.9-4.3 percentage points). There was heterogeneity by hospital and county in the mortality changes over time.This study shows marked improvements in short-term mortality and readmissions, with an increase in in-hospital procedures and payments, for the increasingly smaller number of Medicare beneficiaries with AMI.
Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy
Authors: Changlong Liu, Carolyn E. Banister, Phillip J. Buckhaults
Journal: Cancer Research (2019)

Abstract TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDA-approved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified 27 cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null hESC in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively resensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the resensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Moreover, we confirmed that targeting ZNF207/BuGZ sensitizes p53-null hESC to cisplatin. These data indicate that targeted inhibition of spindle assembly checkpoints (SAC) and chromosomal organizing centers may provide a way to treat p53-deficient cancer cells with standard chemotherapy drugs. Development of small-molecule inhibitors of SAC proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53-mutant cancers. Significance: These findings show that inhibition of spindle assembly checkpoints and chromosomal organizing centers may provide a new way to treat p53-deficient cancer cells with standard chemotherapy drugs.
Randomly Distributed K14+ Breast Tumor Cells Polarize to the Leading Edge and Guide Collective Migration in Response to Chemical and Mechanical Environmental Cues
Authors: Priscilla Y. Hwang, Audrey Brenot, Ashley C. King, Gregory D. Longmore, Steven C. George
Journal: Cancer Research (2019)

Abstract Collective cell migration is an adaptive, coordinated interactive process involving cell–cell and cell–extracellular matrix (ECM) microenvironmental interactions. A critical aspect of collective migration is the sensing and establishment of directional movement. It has been proposed that a subgroup of cells known as leader cells localize at the front edge of a collectively migrating cluster and are responsible for directing migration. However, it is unknown how and when leader cells arrive at the front edge and what environmental cues dictate leader cell development and behavior. Here, we addressed these questions by combining a microfluidic device design that mimics multiple tumor microenvironmental cues concurrently with biologically relevant primary, heterogeneous tumor cell organoids. Prior to migration, breast tumor leader cells (K14+) were present throughout a tumor organoid and migrated (polarized) to the leading edge in response to biochemical and biomechanical cues. Impairment of either CXCR4 (biochemical responsive) or the collagen receptor DDR2 (biomechanical responsive) abrogated polarization of leader cells and directed collective migration. This work demonstrates that K14+ leader cells utilize both chemical and mechanical cues from the microenvironment to polarize to the leading edge of collectively migrating tumors. Significance: These findings demonstrate that pre-existing, randomly distributed leader cells within primary tumor organoids use CXCR4 and DDR2 to polarize to the leading edge and direct migration.
Keynote-676: Phase 3 study of bacillus calmette-guerin (BCG) with or without pembrolizumab (pembro) for high-risk (HR) non–muscle invasive bladder cancer (NMIBC) that is persistent or recurrent following BCG induction.
Authors: Ashish M. Kamat, Neal D. Shore, Noah M. Hahn, Shaheen Alanee, Hiroyuki Nishiyama, Shahrokh Shariat, Kijoeng Nam, Ekta Kapadia, Tara L. Frenkl, Gary D. Steinberg
Journal: Journal of Clinical Oncology (2019)

TPS502 Background: Intravesical instillation of BCG is the standard of care for patients with HR NMIBC. However, many patients have persistent/recurrent HR NMIBC after BCG induction and are at a particularly increased risk for progression, representing a significant unmet need. Programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment may attenuate responses to BCG. KEYNOTE-676 is a randomized, comparator-controlled, phase 3 trial to evaluate the efficacy and safety of the PD-1 inhibitor pembro plus BCG in patients with persistent/recurrent HR NMIBC after BCG therapy. Methods: Adult (≥18 years) patients with histologically confirmed persistent/recurrent HR NMIBC of the bladder after adequate BCG induction therapy are eligible. Patients are required to have undergone cystoscopy/transurethral resection of bladder tumor within 12 weeks prior to randomization, to have no concurrent extravesical disease, and to have ECOG performance status score 0-2, adequate organ function, and tissue for biomarker analysis. Patients will be randomly assigned 1:1 to continue on BCG therapy alone or receive BCG plus pembro 200 mg every 3 weeks. Treatment will be stratified by carcinoma in situ (CIS) histology (presence/absence), PD-L1 combined positive score (≥10/˂10), and timing of NMIBC persistence/recurrence (0 to ≤6, ˃6 to ≤12, or ˃12 to ≤24 mo). Primary end point is complete response rate in participants with CIS. Secondary end points will include event-free survival, patient-reported outcomes, and safety. Responses will be assessed by cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1-2 and every 24 weeks for years 3-5 and by computed tomography urography every 18 months through year 5. Treatment will continue with pembro for up to 2 years and BCG for 3 years or until pathology-confirmed HR NMIBC persistence, recurrence, or disease progression, unacceptable toxicity, or patient/physician decision to withdraw. Recruitment will begin November 2018 and will continue until ~550 patients are enrolled. (NCT03711032). Clinical trial information: NCT03711032.
Abstract P237: Relation of Egg Intake to Blood Pressure: The International Study on Macro/Micronutrients and Blood Pressure (INTERMAP)
Authors: Thanh-Huyen T Vu, Linda Van Horn, Queenie Chan, Martha L Daviglus, Jeremiah Stamler
Journal: Circulation (2019)

Background: Data regarding associations of egg intake, a major source of dietary cholesterol, with blood pressure (BP) are limited, especially from large, diverse population samples, and findings have been inconsistent. Methods: Associations between egg intake and BP were examined using data on 4680 men and women, aged 40-59 years, between 1996 and 1999, from the INTERMAP study that included 17 population samples in the United States (US), United Kingdom (UK), China and Japan. Data were collected from four 24-hour dietary recalls, 2 timed 24-hour urine collections and 8 BP measurements. Egg intake was calculated as amount consumed per day using the Nutrient Data Software for Research (University of Minnesota, USA). Multivariable linear regression models were used to estimate differences in BP per 2-SD of egg intake (50.71g/day). Country-specific regression coefficients were pooled, weighted by inverse of their variance to estimate overall association. Results: Of 4680 participants, 50% were women. Daily egg intake was highest among individuals from Japan (mean 37.74, SD 24.3g/day). With adjustment for age, sex, population sample, and average dietary energy intake/day, egg intake was significantly associated with SBP in both the pooled sample and the US sample. With each 2-SD higher egg intake, US mean SBP was significantly higher by 2mmHg (Model 1-Table). The associations remained significant with further adjustment for education level, family history of hypertension, smoking status, and use of dietary supplement (Model 2-Table). With further adjustment for urinary sodium and urinary potassium or BMI, the associations were no longer significant. No association was found for other countries, and for DBP. Conclusion: An adverse association between egg intake and SBP was observed in the US but not in other countries. Notably, this association was strongly attenuated by urinary sodium, urinary potassium and BMI. Further research is needed to better understand the relation of egg intake and BP.