tbuckley/cabot-search huggingface dataset:
The Influence of Polyploidy on the Evolution of Yeast Grown in a Sub-Optimal Carbon Source
Authors: Amber L. Scott, Phillip A. Richmond, Robin D. Dowell, Anna M. Selmecki
Journal: Molecular Biology and Evolution (2017)

Polyploidization events have occurred during the evolution of many fungi, plant, and animal species and are thought to contribute to speciation and tumorigenesis, however little is known about how ploidy level contributes to adaptation at the molecular level. Here we integrate whole genome sequencing, RNA expression analysis, and relative fitness of ∼100 evolved clones at three ploidy levels. Independent haploid, diploid, and tetraploid populations were grown in a low carbon environment for 250 generations. We demonstrate that the key adaptive mutation in the evolved clones is predicted by a gene expression signature of just five genes. All of the adaptive mutations identified encompass a narrow set of genes, however the tetraploid clones gain a broader spectrum of adaptive mutations than haploid or diploid clones. While many of the adaptive mutations occur in genes that encode proteins with known roles in glucose sensing and transport, we discover mutations in genes with no canonical role in carbon utilization (IPT1 and MOT3), as well as identify novel dominant mutations in glucose signal transducers thought to only accumulate recessive mutations in carbon limited environments (MTH1 and RGT1). We conclude that polyploid cells explore more genotypic and phenotypic space than lower ploidy cells. Our study provides strong evidence for the beneficial role of polyploidization events that occur during the evolution of many species and during tumorigenesis.
Phase Ib trial of atezolizumab in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer (mTNBC).
Authors: Sylvia Adams, Jennifer Robinson Diamond, Erika Paige Hamilton, Paula Raffin Pohlmann, Sara M. Tolaney, Luciana Molinero, Xian He, Daniel Waterkamp, Roel Peter Funke, John D. Powderly
Journal: Journal of Clinical Oncology (2016)

1009 Background: Atezolizumab (atezo; MPDL3280A) is a humanized MAb that inhibits binding of PD-L1 to PD-1 and B7.1, thus restoring tumor-specific T-cell immunity. Atezo has single-agent activity in mTNBC. Combining atezo with chemotherapy is hypothesized to enhance tumor-specific T-cell immunity by exposing the immune system to high levels of tumor antigens and modulating T-cell and NK cell functions. This arm of a Phase Ib study evaluated atezo + nab-paclitaxel (pac) in patients (pts) with mTNBC treated with ≤ 3 prior lines of therapy. Methods: Primary endpoints were safety and tolerability; secondary endpoints included clinical activity. Pts received atezo 800 mg q2w (d1,15) and nab-pac 125 mg/m2 q1w (d1,8,15) q3 of 4 wks. After nab-pac discontinuation, maintenance atezo was allowed until loss of clinical benefit. ORR was assessed by RECIST v1.1. PD-L1 staining on tumor cells and tumor-infiltrating immune cells was scored using the SP142 IHC assay. Results: 32 pts were safety evaluable (median follow-up 5.21 mo [range 0.6-12.6]). All pts were female, with a median age of 56 y (range 32-84); 81% were ECOG PS 1, and 87% had prior taxanes. The most common treatment-related AE was decreased neutrophil count (53% all grade; 41% Gr 3-4). No DLTs or related deaths occurred. 24 pts (dosed by June 1, 2015) were efficacy evaluable (Table). 3 pts developed new lesions with PR in target lesions that were scored as RECIST PD, but remained on treatment with prolonged biologic response. Responses occurred in pts whose tumors expressed PD-L1 and in those with little to no PD-L1 expression. Nab-pac did not affect atezo-induced proliferation of circulating activated CD8+ T cells. Conclusions: These results are the first to demonstrate that atezo + nab-pac is tolerable with promising activity in mTNBC. Updated results and tissue correlates will be presented. An ongoing Phase III trial is evaluating this regimen in previously untreated mTNBC pts. Clinical trial information: NCT01633970.Best Response, % 1L n = 9 2L n = 8 3L+ n = 7 All pts N = 24 Confirmed ORR (95% CI) 67 (30, 93) 25 (3, 65) 29 (4, 71) 42 (22, 63) ORRa (95% CI) 89 (52, 100) 75 (35, 97) 43 (10, 82) 71 (49, 87) CR 11 0 0 4 PR 78 75 43 67 SD 11 25 29 21 a Including investigator-assessed unconfirmed responses.
Cost-effectiveness of Intensive Glycemic Control, Intensified Hypertension Control, and Serum Cholesterol Level Reduction for Type 2 Diabetes
Authors: None The CDC Diabetes Cost-effectiveness Group
Journal: JAMA (2002)

ContextSeveral treatment interventions can reduce complications of type 2 diabetes, but their relative cost-effectiveness is not known.ObjectiveTo estimate the incremental cost-effectiveness of intensive glycemic control (relative to conventional control), intensified hypertension control, and reduction in serum cholesterol level for patients with type 2 diabetes.Design, Setting, and PatientsCost-effectiveness analysis of a hypothetical cohort of individuals living in the United States, aged 25 years or older, who were newly diagnosed as having type 2 diabetes. The results of the United Kingdom Prospective Diabetes Study (UKPDS) and other studies were used to create a model of disease progression and treatment patterns. Costs were based on those used in community practices in the United States.InterventionsInsulin or sulfonylurea therapy for intensive glycemic control; angiotensin-converting enzyme inhibitor or β-blocker for intensified hypertension control; and pravastatin for reduction of serum cholesterol level.Main Outcome MeasuresCost per quality-adjusted life-year (QALY) gained. Costs (in 1997 US dollars) and QALYs were discounted at a 3% annual rate.ResultsThe incremental cost-effectiveness ratio for intensive glycemic control is $41 384 per QALY; this ratio increased with age at diagnosis from $9614 per QALY for patients aged 25 to 34 years to $2.1 million for patients aged 85 to 94 years. For intensified hypertension control the cost-effectiveness ratio is −$1959 per QALY. The cost-effectiveness ratio for reduction in serum cholesterol level is $51 889 per QALY; this ratio varied by age at diagnosis and is lowest for patients diagnosed between the ages of 45 and 84 years.ConclusionsIntensified hypertension control reduces costs and improves health outcomes relative to moderate hypertension control. Intensive glycemic control and reduction in serum cholesterol level increase costs and improve health outcomes. The cost-effectiveness ratios for these 2 interventions are comparable with those of several other frequently adopted health care interventions.
Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses
Authors: Spencer W. Stonier, Andrew S. Herbert, Ana I. Kuehne, Ariel Sobarzo, Polina Habibulin, Chen V. Abramovitch Dahan, Rebekah M. James, Moses Egesa, Stephen Cose, Julius Julian Lutwama, Leslie Lobel, John M. Dye
Journal: The Journal of Experimental Medicine (2017)

Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity.
Endothelial Cells: Mechanical Adaptability of the MMP-Responsive Film Improves the Functionality of Endothelial Cell Monolayer (Adv. Healthcare Mater. 14/2017)
Authors: Mi Hu, Hao Chang, He Zhang, Jing Wang, Wen-xi Lei, Bo-chao Li, Ke-feng Ren, Jian Ji
Journal: Advanced Healthcare Materials (2017)

Endothelial cells (EC) play key physiologic and pathologic roles. In article 1601410, Ke-feng Ren and co-workers report a surface with mechanical adaptability based on the thin polyelectrolyte film that can respond to cell-secreted matrix metalloproteinases. The data demonstrates that such system showed distinguished superiority to promote EC growth and functionality.
Unintended Consequences of Machine Learning in Medicine
Authors: Federico Cabitza, Raffaele Rasoini, Gian Franco Gensini
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity
Authors: E Liu, Y Tong, G Dotti, H Shaim, B Savoldo, M Mukherjee, J Orange, X Wan, X Lu, A Reynolds, M Gagea, P Banerjee, R Cai, M H Bdaiwi, R Basar, M Muftuoglu, L Li, D Marin, W Wierda, M Keating, R Champlin, E Shpall, K Rezvani
Journal: Leukemia (2017)
The c.1085A&amp;gt;G Genetic Variant of <i>CSF1R</i> Gene Regulates Tumor Immunity by Altering the Proliferation, Polarization, and Function of Macrophages
Authors: Yu-Min Yeh, Shan-Ju Hsu, Peng-Chan Lin, Keng-Fu Hsu, Pei-Ying Wu, Wu-Chou Su, Jang-Yang Chang, Meng-Ru Shen
Journal: Clinical Cancer Research (2017)

Purpose: Targeting tumor-associated macrophages with colony-stimulating factor 1 receptor (CSF-1R) inhibition reveals a strategy for cancer therapy. Here, we studied the impact of CSF1R germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.Experimental designs:CSF1R germline genetic variants were studied in 140 cancer patients. CSF-1R phosphorylation, endocytosis, and macrophage polarization were measured as the response to CSF-1 stimulation. Tumor-associated macrophages in surgical specimens and sensitivity to CSF-1R inhibitors were used to determine macrophage function.Results: A CSF1R c.1085A>G genetic variant causing the change of histidine to arginine in the domain of receptor dimerization was identified as a high allele frequency in Eastern Asian population. Cancer patients with this variant allele had less M2-like tumor-associated macrophages accompanied by low VEGF expression in tumor tissues. Importantly, CSF1R genetic variant was significantly associated with disease-free survival in colorectal, endometrial, and ovarian cancer. In terms of differentiation, macrophages with CSF1R c.1085A>G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC50 of 0.1 to 1 nmol/L range. On contrast, CSF-1 induced a prominent phosphorylation and rapid endocytosis of CSF-1R, leading to an M2-like dominant polarization in macrophages with CSF1R c.1085 genotype A_A, in which CSF-1R inhibitors of PLX3397, BLZ945, and GW2580 inhibited macrophage survival with IC50 of 10 to 100 nmol/L range.Conclusions: The CSF1R c.1085A>G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment. Clin Cancer Res; 23(20); 6021-30. ©2017 AACR.
Improving Accrual of Adolescents and Young Adults and Underrepresented Minorities with Leukemia to Children's Oncology Group Clinical Trials: A Novel Collaborative Approach to Address Disparities in Leukemia
Authors: Nupur Mittal, Mario Martinez, Johnathan Davidson, Paul Kent, Lisa Giordano, Dipti Dighe, Daniel K. Choi, Rey Sanchez, John G. Quigley, Rosalind Catchatorian, Cathleen Kiely, Kathleen Breen, Jennifer Misasi, Nitin Sane, Michael Buraglio, Mary Lou Schmidt
Journal: Blood (2016)
Association of Coronary Artery Calcium Score vs Age With Cardiovascular Risk in Older Adults
Authors: Yuichiro Yano, Christopher J. O’Donnell, Lewis Kuller, Maryam Kavousi, Raimund Erbel, Hongyan Ning, Ralph D’Agostino, Anne B. Newman, Khurram Nasir, Albert Hofman, Nils Lehmann, Klodian Dhana, Ron Blankstein, Udo Hoffmann, Stefan Möhlenkamp, Joseph M. Massaro, Amir-Abbas Mahabadi, Joao A. C. Lima, M. Arfan Ikram, Karl-Heinz Jöckel, Oscar H. Franco, Kiang Liu, Donald Lloyd-Jones, Philip Greenland
Journal: JAMA Cardiology (2017)

Besides age, other discriminators of atherosclerotic cardiovascular disease (ASCVD) risk are needed in older adults.To examine the predictive ability of coronary artery calcium (CAC) score vs age for incident ASCVD and how risk prediction changes by adding CAC score and removing only age from prediction models.We conducted an analysis of pooled US population-based studies, including the Framingham Heart Study, the Multi-Ethnic Study of Atherosclerosis, and the Cardiovascular Health Study. Results were compared with 2 European cohorts, the Rotterdam Study and the Heinz Nixdorf Recall Study. Participants underwent CAC scoring between 1998 and 2006 using cardiac computed tomography. The participants included adults older than 60 years without known ASCVD at baseline.Coronary artery calcium scores.Incident ASCVD events including coronary heart disease (CHD) and stroke.The study included 4778 participants from 3 US cohorts, with a mean age of 70.1 years; 2582 (54.0%) were women, and 2431 (50.9%) were nonwhite. Over 11 years of follow-up (44 152 person-years), 405 CHD and 228 stroke events occurred. Coronary artery calcium score (vs age) had a greater association with incident CHD (C statistic, 0.733 vs 0.690; C statistics difference, 0.043; 95% CI of difference, 0.009-0.075) and modestly improved prediction of incident stroke (C statistic, 0.695 vs 0.670; C statistics difference, 0.025; 95% CI of difference, -0.015 to 0.064). Adding CAC score to models including traditional cardiovascular risk factors, with only age being removed, provided improved discrimination for incident CHD (C statistic, 0.735 vs 0.703; C statistics difference, 0.032; 95% CI of difference, 0.002-0.062) but not for stroke. Coronary artery calcium score was more likely than age to provide higher category-free net reclassification improvement among participants who experienced an ASCVD event (0.390; 95% CI, 0.312-0.467 vs 0.08; 95% CI -0.001 to 0.181) and to result in more accurate reclassification of risk for ASCVD events among these individuals. The findings were similar in the 2 European cohorts (n = 4990).Coronary artery calcium may be an alternative marker besides age to better discriminate between lower and higher CHD risk in older adults. Whether CAC score can assist in guiding the decision to initiate statin treatment for primary prevention in older adults requires further investigation.
The key components of survivorship care plans: Results from an ASCO multidisciplinary consensus conference.
Authors: Claire Frances Snyder, Larissa Nekhlyudov, Janette Merrill, Sweatha Katta, Dana Wollins, Lawrence N Shulman, Deborah Mayer
Journal: Journal of Clinical Oncology (2014)

e20604 Background: In response to the Institute of Medicine cancer survivorship report, ASCO and others developed survivorship care plan (SCP) templates, incorporating treatment summaries and follow up care needs. Various factors (eg., time needed to complete SCPs, lack of data regarding users' needs) have limited uptake. ASCO aimed to address these issues by identifying the key components of SCPs. Methods: A Steering Group and ASCO staff planned a 1-day consensus meeting with attendees from medical, surgical, radiation and nurse oncology, primary care, patient navigators, social work, cancer survivors, and insurers. To inform meeting discussions, meeting attendees and relevant stakeholder groups completed a pre-meeting survey with 94 items (61 treatment summary, 33 follow up care) recommended and/or included on SCPs. All survey respondents rated each SCP element as essential, desirable, or not necessary; oncology providers rated the feasibility of completing each SCP item (easy, some effort, extensive effort, do not know). At the consensus meeting, 3 breakout groups with members from the different stakeholders reviewed each item from the survey and independently determined whether it was essential. The full assembly reviewed each group's list of key components, and areas of disagreement were discussed. The final list of key components informed revisions to the ASCO templates. Results: The consensus meeting included 28 attendees, informed by 301 pre-meeting survey responses. Consensus was easily reached within and across the 3 breakout groups, with few exceptions. Key components for the treatment summary (n=8) included contact information, diagnosis, stage, treatments received, ongoing toxicity/side effects, and as needed, predisposing conditions/genetic testing. Key components for the follow up care plan (n=9) included contact information, ongoing therapy, schedule for visits/testing, cancer screening/surveillance tests, symptoms of recurrence, late/long-term effects, and psychosocial concerns. Conclusions: The revised ASCO templates require substantially less detail with the goal of improving uptake. Evaluation of whether they are more feasible and useful to recipients is planned.
Reanalysis of the Crystalloid versus Hydroxyethyl Starch Trial (CHEST)
Authors: Anushka Patel, Karen Pieper, John A Myburgh, Vlado Perkovic, Simon Finfer, Qinghong Yang, Qiang Li, Laurent Billot
Journal: New England Journal of Medicine (2017)

This reanalysis of the Crystalloid versus Hydroxyethyl Starch Trial (CHEST), which compared 6% hydroxyethyl starch with 0.9% saline for fluid resuscitation in critically ill patients, confirms no significant difference in 90-day mortality between the trial groups.
Abstract 149: Effect of Pentraxin 3 on Pressure Overload--Induced Left Ventricular Hypertrophy
Authors: Satoshi Suzuki, Tetsuro Shishido, Akira Funayama, Shunsuke Netsu, Yasuchika Takeishi
Journal: Circulation Research (2012)

Backgrounds: Left ventricular (LV) adverse remodeling is enhanced by inflammatory cytokines. Pentraxin 3 (PTX3), which is one of the pentraxin superfamily same as C-reactive protein, is rapidly produced in response to inflammatory signals, and plasma PTX3 levels are increased in patients with heart failure. Previously we reported that PTX3 deficient mice demonstrated the suppression of hypertrophic cardiac remodeling after pressure overload. This study aimed to examine the cardiac specific influence of PTX3 on LV hypertrophy and dysfunction in response to pressure overload. Methods and Results: We created transgenic (TG) mice with cardiac-specific overexpression of PTX3 using alpha-myosin heavy chain promoter. We performed transverse aortic constriction (TAC) or sham operation on TG and wild type (WT) littermate mice. Expression of PTX3 was increased after TAC in WT mice, and immunohistochemistry proved that PTX3 was produced mainly from the interstitial tissue of the heart and infiltrating macrophages. Activation of extracellular signal-regulated kinase (ERK) and nuclear factor kappa-B was enhanced in TG mice compared to WT mice after TAC. Interleukin-6 production in heart tissue was augmented in TG mice compared to WT mice. Echocardiography and cardiac catheterization revealed that adverse remodeling with LV dysfunction was enhanced with increased interstitial fibrosis in TG mice compared to WT mice. Real time RT-PCR demonstrated that gene expressions related to cardiac hypertrophy and fibrosis were augmented in TG mice compared to WT mice. Next we isolated neonatal rat cardiomyocytes and fibroblasts. PTX3 expressions were increased after H 2 O 2 stimulation in cardiomyocytes and fibroblasts. Phosphorylation of ERK by recombinant PTX3 stimulation was more potent in cardiac fibroblasts than in cardiomyocytes. Conclusions: The local inflammatory mediator PTX3 directly modulates the hypertrophic response and LV dysfunction following increased afterload, and cardiac fibroblast might be important target cells of PTX3 stimulation.
Association of History of Dizziness and Long-term Adverse Outcomes With Early vs Later Orthostatic Hypotension Assessment Times in Middle-aged Adults
Authors: Stephen P. Juraschek, Natalie Daya, Andreea M. Rawlings, Lawrence J. Appel, Edgar R. Miller, B. Gwen Windham, Michael E. Griswold, Gerardo Heiss, Elizabeth Selvin
Journal: JAMA Internal Medicine (2017)

Guidelines recommend assessing orthostatic hypotension (OH) 3 minutes after rising from supine to standing positions. It is not known whether measurements performed immediately after standing predict adverse events as strongly as measurements performed closer to 3 minutes.To compare early vs later OH measurements and their association with history of dizziness and longitudinal adverse outcomes.This was a prospective cohort study of middle-aged (range, 44-66 years) participants in the Atherosclerosis Risk in Communities Study (1987-1989).Orthostatic hypotension, defined as a drop in blood pressure (BP) (systolic BP ≥20 mm Hg or diastolic BP ≥10 mm Hg) from the supine to standing position, was measured up to 5 times at 25-second intervals.We determined the association of each of the 5 OH measurements with history of dizziness on standing (logistic regression) and risk of fall, fracture, syncope, motor vehicle crashes, and all-cause mortality (Cox regression) over a median of 23 years of follow-up (through December 31, 2013).In 11 429 participants (mean age, 54 years; 6220 [54%] were women; 2934 [26%] were black) with at least 4 OH measurements after standing, after adjustment OH assessed at measurement 1 (mean [SD], 28 [5.4] seconds; range, 21-62 seconds) was the only measurement associated with higher odds of dizziness (odds ratio [OR], 1.49; 95% CI, 1.18-1.89). Measurement 1 was associated with the highest rates of fracture, syncope, and death at 18.9, 17.0, and 31.4 per 1000 person-years. Measurement 2 was associated with the highest rate of falls and motor vehicle crashes at 13.2 and 2.5 per 1000 person-years. Furthermore, after adjustment measurement 1 was significantly associated with risk of fall (hazard ratio [HR], 1.22; 95% CI, 1.03-1.44), fracture (HR, 1.16; 95% CI, 1.01-1.34), syncope (HR, 1.40; 95% CI, 1.20-1.63), and mortality (HR, 1.36; 95% CI, 1.23-1.51). Measurement 2 (mean [SD], 53 [7.5] seconds; range, 43-83 seconds) was associated with all long-term outcomes, including motor vehicle crashes (HR, 1.43; 95% CI, 1.04-1.96). Measurements obtained after 1 minute were not associated with dizziness and were inconsistently associated with individual long-term outcomes.In contrast with prevailing recommendations, OH measurements performed within 1 minute of standing were the most strongly related to dizziness and individual adverse outcomes, suggesting that OH be assessed within 1 minute of standing.