tbuckley/cabot-search huggingface dataset:
Quality of Life in Patients With Low-Risk Prostate Cancer Treated With Hypofractionated vs Conventional Radiotherapy
Authors: Deborah W. Bruner, Stephanie L. Pugh, W. Robert Lee, William A. Hall, James J. Dignam, Daniel Low, Gregory P. Swanson, Amit B. Shah, Shawn Malone, Jeff M. Michalski, Ian S. Dayes, Samantha A. Seaward, Paul L. Nguyen, Thomas M. Pisansky, Yuhchyau Chen, Howard M. Sandler, Benjamin Movsas
Journal: JAMA Oncology (2019)

Hypofractionated radiotherapy (HRT) would be more convenient for men with low-risk prostate cancer and cost less than conventional radiotherapy (CRT) as long as HRT is noninferior to CRT in terms of survival and quality of life (QOL) is not found to be worse.To assess differences in QOL between men with low-risk prostate cancer who are treated with HRT vs CRT.In this phase 3 randomized clinical trial, men with low-risk prostate cancer were enrolled from sites within the National Cancer Institute's National Clinical Trials Network in the United States, Canada, and Switzerland.Random assignment to CRT (73.8 Gy in 41 fractions over 8.2 weeks) or to HRT (70 Gy in 28 fractions over 5.6 weeks).Quality of life was assessed using the Expanded Prostate Index Composite questionnaire measuring bowel, urinary, sexual, and hormonal domains; the 25-item Hopkins Symptom Checklist measuring anxiety and depression; and the EuroQol-5 Dimension questionnaire measuring global QOL. All data were collected at baseline and 6, 12, 24, and 60 months. Change scores were compared between treatment arms using the Wilcoxon signed rank test. A significance level of .0125 to adjust for multiple comparisons was used for an overall 2-sided type 1 error of .05. Clinical significance was determined for the Expanded Prostate Index Composite change scores by an effect size of 0.5.Of 1092 patients analyzable for the primary end point, 962 (mean [SD] age, 66.6 [7.4] years) consented to the QOL component. No statistically significant differences with regard to baseline characteristics nor any of the QOL baseline domains were measured between arms. There were no differences in change score between arms with respect to any of the Expanded Prostate Index Composite questionnaire domain scores except at 12 months when the HRT arm had a larger decline than the CRT arm in the bowel domain (mean score, -7.5 vs -3.7, respectively; P<.001), but it did not reach clinical significance (effect size = 0.29). There were no differences between arms at any time point for the Hopkins Symptom Checklist nor EuroQol-5 Dimension questionnaire.Treatment with HRT is noninferior to CRT in men with low-risk prostate cancer in terms of disease-free survival and, as shown in the present study, in prostate cancer-specific (eg, bowel, bladder, sexual) and general QOL, as well as in anxiety and depression. This study provides evidence to affirm that HRT is a practice standard for men with low-risk prostate cancer.ClinicalTrials.gov identifier: NCT00331773.
Abstract P328: Association of Functional and Structural Social Network Components With Medication Adherence Among Participants With Coronary Heart Disease Risk Factors: the REasons for Geographic and Racial Differences in Stroke Study
Authors: Favel L Mondesir, April P Carson, Raegan W Durant, Marquita W Lewis, Monika M Safford, Emily B Levitan
Journal: Circulation (2017)

Prior research suggests that functional (e.g., practical support) social network components are more strongly associated with chronic disease health outcomes than structural (e.g., social network size, frequency of social contacts) components. Yet, it is unclear whether strong social networks help improve health outcomes by promoting medication adherence, particularly among those with coronary heart disease (CHD) risk factors. We included 17,133 black and white adults aged ≥45 years from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes, hypertension, dyslipidemia, or prevalent CHD and used medications for these conditions. Functional (i.e., someone to care for you while sick or disabled vs no-one available) and structural (i.e., presence vs absence of adults in household, married/in a marriage-like relationship vs not partnered, number of close friends and relatives, and number of close friends and relatives seen at least monthly) social network components were self-reported and medication adherence was assessed using the Morisky scale. A weighted composite score was created using the structural components and participants were categorized as reporting high vs low structural support based on the median. Multi-variable adjusted logistic regression models adjusted for demographics, CHD risk factors and cumulative number of medications, were used to estimate the association between functional and structural social network components and medication adherence. Prevalence of high medication adherence was 68.9%. Compared to participants who reported that they had no one to care for them while sick or disabled, participants who reported that someone was available had higher prevalence of medication adherence [OR=1.15 (95% CI: 1.04, 1.26)]. Participants who reported higher structural support (composite score above median) had similar prevalence of medication adherence compared to participants who reported lower structural support [OR=1.09 (95% CI: 0.87, 1.37)]. In conclusion, interventions aimed at providing social support for people with CHD risk factors may need to consider preferentially focusing on enhancing functional aspects of individuals’ social networks as a means of potentially improving medication adherence and ultimately cardiovascular health.
Abstract 17230: Impact of Preoperative Statin Use on Ascending Aortic Aneurysm Repair Outcomes
Authors: Robert B Hawkins, J Hunter Mehaffey, Abra Guo, Clifford Fonner, Alan Speir, Jeffrey Rich, Leora Yarboro, Ravi Ghanta, Gorav Ailawadi
Journal: Circulation (2016)

Objectives: Statins have potent pleiotropic effects that have been correlated with improved perioperative cardiovascular surgery outcomes. Additionally, statins are protective in murine aortic aneurysm models. Hypothesis: We hypothesize that statins may improve short-term morbidity and mortality after ascending aortic surgery. Methods: A total of 2,781 patients who underwent ascending aortic aneurysm repair in a multi-institution database (2004-2015) were stratified by preoperative statin administration. Patients with endocarditis or aortic dissection were excluded. To account for baseline differences, patients were propensity matched (1:1) across 41 preoperative and procedural characteristics, resulting in a well matched cohort of 1682 patients. Patient characteristics and outcomes were analyzed by univariate analysis and logistic regression. Results: In the total cohort, patients taking statins were older with more comorbid disease, yet had less extensive surgery performed. Composite major morbidity and...
GPs should have doctors’ messes too
Authors: Simon E Atkins
Journal: BMJ (2019)

Rimmer’s article about doctors’ messes emphasises the importance and benefits to hospital colleagues of having a “space to breathe” in the middle of busy, stressful days.1

This type of space is just as important in general practice. Our days on the front line of patient care are equally pressurised. And primary care has the …
Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure–Guided Strategy vs an Empirical High PEEP-F<scp>io</scp><sub>2</sub> Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome
Authors: Jeremy R. Beitler, Todd Sarge, Valerie M. Banner-Goodspeed, Michelle N. Gong, Deborah Cook, Victor Novack, Stephen H. Loring, Daniel Talmor
Journal: JAMA (2019)

Adjusting positive end-expiratory pressure (PEEP) to offset pleural pressure might attenuate lung injury and improve patient outcomes in acute respiratory distress syndrome (ARDS).To determine whether PEEP titration guided by esophageal pressure (PES), an estimate of pleural pressure, was more effective than empirical high PEEP-fraction of inspired oxygen (Fio2) in moderate to severe ARDS.Phase 2 randomized clinical trial conducted at 14 hospitals in North America. Two hundred mechanically ventilated patients aged 16 years and older with moderate to severe ARDS (Pao2:Fio2 ≤200 mm Hg) were enrolled between October 31, 2012, and September 14, 2017; long-term follow-up was completed July 30, 2018.Participants were randomized to PES-guided PEEP (n = 102) or empirical high PEEP-Fio2 (n = 98). All participants received low tidal volumes.The primary outcome was a ranked composite score incorporating death and days free from mechanical ventilation among survivors through day 28. Prespecified secondary outcomes included 28-day mortality, days free from mechanical ventilation among survivors, and need for rescue therapy.Two hundred patients were enrolled (mean [SD] age, 56 [16] years; 46% female) and completed 28-day follow-up. The primary composite end point was not significantly different between treatment groups (probability of more favorable outcome with PES-guided PEEP: 49.6% [95% CI, 41.7% to 57.5%]; P = .92). At 28 days, 33 of 102 patients (32.4%) assigned to PES-guided PEEP and 30 of 98 patients (30.6%) assigned to empirical PEEP-Fio2 died (risk difference, 1.7% [95% CI, -11.1% to 14.6%]; P = .88). Days free from mechanical ventilation among survivors was not significantly different (median [interquartile range]: 22 [15-24] vs 21 [16.5-24] days; median difference, 0 [95% CI, -1 to 2] days; P = .85). Patients assigned to PES-guided PEEP were significantly less likely to receive rescue therapy (4/102 [3.9%] vs 12/98 [12.2%]; risk difference, -8.3% [95% CI, -15.8% to -0.8%]; P = .04). None of the 7 other prespecified secondary clinical end points were significantly different. Adverse events included gross barotrauma, which occurred in 6 patients with PES-guided PEEP and 5 patients with empirical PEEP-Fio2.Among patients with moderate to severe ARDS, PES-guided PEEP, compared with empirical high PEEP-Fio2, resulted in no significant difference in death and days free from mechanical ventilation. These findings do not support PES-guided PEEP titration in ARDS.ClinicalTrials.gov Identifier NCT01681225.
On the Lipophilic Nature of Autoreactive IgE in Chronic Spontaneous Urticaria
Authors: Elisa Lakin, Martin K. Church, Marcus Maurer, Oliver Schmetzer
Journal: Theranostics (2019)

Chronic spontaneous urticaria (CSU) is a skin disease related to autoreactive IgE in at least a subgroup of patients.However, the nature of this autoreactive IgE remains poorly characterized.This investigation had three objectives: first, to quantity CSU autoreactive IgE; second, to recognize the patterns of CSU autoreactive IgE compared with healthy control IgE; and third, to investigate the physiochemical nature of CSU autoreactive IgE.Methods: IgE autoreactivity was assessed in sera from 7 CSU and 7 healthy individuals.Autoantigen recognition patterns were assessed using principal component analysis (PCA) and heatmap visualization.Lipophilicity was assessed using NanoOrange reagent.Results: First, although total IgE levels did not differ significantly, the autoreactive proportion of IgE of CSU patients was 62% ± 37%, 1000-fold higher than that of healthy controls 0.03% ± 0.008% (P = 0.0006).Second, CSU autoreactive IgE differed from healthy control IgE by recognizing more and different autoantigens (226 vs. 34; P = 0.01).Third, the median (with 10-90% percentiles) serum level of lipophilic IgE was 39% (38-40%) in 232 CSU patients, 1.4-fold higher than the 28% (26-29%) of 173 healthy controls (P < 0.0001).Furthermore, lipophilicity correlated with autoreactivity (r = 0.8; P < 0.0001), connecting these two observed features. Conclusion:We believe that these novel observations about CSU autoreactive IgE, particularly the finding that it is more lipophilic than that of IgE from healthy individuals, will lead to the development of new diagnostic tests and therapies for autoreactive IgE-mediated diseases.
Calcium/Calmodulin Dependent Protein Kinase 2 Gamma Is Identified As a Potential Therapeutic Target of Myelofibrosis Using Disease-Specific Induced Pluripotent Stem Cells
Authors: Masashi Miyauchi, Ken Sasaki, Kazuki Taoka, Yosuke Masamoto, Sho Yamazaki, Shunya Arai, Mineo Kurokawa
Journal: Blood (2018)
Loss of FOXP3 and TSC1 Accelerates Prostate Cancer Progression through Synergistic Transcriptional and Posttranslational Regulation of c-MYC
Authors: Lianpin Wu, Baozhu Yi, Shi Wei, Dapeng Rao, Youhua He, Gurudatta Naik, Sejong Bae, Xiaoguang M. Liu, Wei-Hsiung Yang, Guru Sonpavde, Runhua Liu, Lizhong Wang
Journal: Cancer Research (2019)

Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here, we characterize the functional cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both FOXP3 and TSC1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR-4EBP1-c-MYC and FOXP3-c-MYC pathways. In mice, Tsc1 and Foxp3 double deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic antitumor effects of cotreating mice with inhibitors of mTOR and c-MYC in prostate cancer cells and in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Because loss of FOXP3 transcriptionally induces c-Myc expression and loss of TSC1 activates mTOR signaling, these data suggest cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling that converges on c-MYC to regulate tumor progression. Coadministration of c-MYC and mTOR inhibitors may overcome the resistance to mTOR inhibition commonly observed in prostate cancer cells. SIGNIFICANCE: These results establish the principle of a synergistic action of TSC1 and FOXP3 during prostate cancer progression and provide new therapeutic targets for patients who have prostate cancer with two signaling defects.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/7/1413/F1.large.jpg.
Abstract 18992: Targeted Temperature Management and Acute Kidney Injury in Cardiac Arrest
Authors: Abhishek Bhardwaj, David G Buckler, Benjamin S Abella
Journal: Circulation (2017)

Introduction: Acute kidney injury (AKI) after cardiac arrest (CA) results from hypoperfusion/ischemia. Previous studies have shown an AKI incidence of up to 50% post CA. The impact of targeted temp...
Unmanipulated Haploidentical Marrow Transplantation with a Modified Post-Transplant Cyclophosphamide (PT-CY) Regimen: An Update on 444 Patients
Authors: Andrea Bacigalupo, Anna Maria Raiola, Alida Dominietto, Carmen Di Grazia, Stefania Bregante, Francesca Gualandi, Maria Teresa Van Lint, Patrizia Chiusolo, Luca Laurenti, Federica Sora, Sabrina Giammarco, Simona Sica, Emanuele Angelucci
Journal: Blood (2018)
Distribution of neuroendocrine marker-positive cells in colorectal cancer tissue and adjacent mucosa.
Authors: Takashi Ogimi, Sotaro Sadahiro, Hiroshi Miyakita, Gota Saito, Lin Fung Chan, Kazutake Okada, Akira Tanaka, Toshiyuki Suzuki, Hiroshi Kajiwara
Journal: Journal of Clinical Oncology (2019)

617 Background: Neuroendocrine carcinoma (NEC) is a rare disease and has been reported to most frequently arise in the right side of the colon. In the 2010 WHO classification, mixed adenoneuroendocrine carcinoma (MANEC) was defined as a neoplasm consisting of NEC and adenocarcinoma components. To clarify the histogenesis of NEC, we attempted to detect neuroendocrine marker-positive cells in cancer tissue and in the adjacent mucosa in patients with adenocarcinoma. Methods: The study group comprised 390 patients with Stage II or III colorectal adenocarcinoma between 2007 and 2012. Immunostaining was performed with anti chromogranin A, synaptophysin, and CD56 antibodies. Cases with positively stained cells in cancer tissue were defined as positive. In the adjacent mucosa, at least 5 cm from the tumor, the numbers of positive cells per 15 HPF were measured. Results: Tumor location was right side in 181 patients, left side in 173, and the rectum in 36 patients. Positive rates of Chromogranin A in cancer tissues were 23.7% in the right colon, 13.2% in the left colon, and 19.4% in the rectum. Those of synaptopysin were 35.3%, 21.9%, and 30.6%, respectively. Those of CD56 were 22.6%, 8.0%, and 16.7%, respectively. Positive rates of these three markers in right colon were significantly higher than those in left colon and rectum. (p = 0.0115, p = 0.0054, p = 0.0062). In the adjacent mucosa, the mean numbers of positive cells for chromogranin A were 62.2 ± 20.5 in the right colon, 131.9 ± 44.7 in the left colon, and 243.7 ± 60.2 in the rectum (p &lt; 0.001). Those for synaptophysin were 47.7 ± 23.5, 95.3 ± 35.1, and 156.9 ± 56.8, respectively. (p &lt; 0.001). There were no significant differences in the number of positive cells for CD56 among the sites (p = 0.295). Conclusions: In cancer tissue, the rate of positive staining for neuroendocrine marker-positive cells was higher in the right side of the colon, whereas in normal mucosa the rates of positive staining for these cells were higher in the sigmoid colon and the rectum. These results suggest that neuroendocrine marker-positive cells are an acquired characteristic of cancer tissue.
Abstract 20863: Inferring Transcription Factor Variation of Murine Cardiogenesis From Single Cell RNA-seq Data
Authors: Wuming Gong, Naoko Koyano-Nakagawa, Wei Pan, Mary G Garry, Daniel J Garry
Journal: Circulation (2017)

Background: The RNA-seq analysis at the single cell level emerges as a powerful tool to study the complex transcriptional dynamics of heart development. However, the understanding of the epigenetic dynamics at the single cell level is required to further discover the cis-regulatory elements and trans-acting factors that drive the expression changes and the lineage differentiation. Though single cell ATAC-seq and ChIP-seq have been invented to analyze individual cells, signals from these experiments are intrinsically discrete and cannot be used to accurately describe the continuum of chromatin accessibility and histone modifications. Results: Using the publicly available sequencing data, we successfully built a statistical model to predict various histone marks such as H3K4me3, H3K27me3, H3K27ac and chromatin accessibility signals from corresponding RNA-seq data. We found a high correlation coefficient (0.86 on average) between observed and predicted epigenomic data. Applying this method on a combined data...
Association of All-Cause and Cardiovascular Mortality With High Levels of Physical Activity and Concurrent Coronary Artery Calcification
Authors: Laura F. DeFina, Nina B. Radford, Carolyn E. Barlow, Benjamin L. Willis, David Leonard, William L. Haskell, Stephen W. Farrell, Andjelka Pavlovic, Katelyn Abel, Jarett D. Berry, Amit Khera, Benjamin D. Levine
Journal: JAMA Cardiology (2019)

Few data are available to guide clinical recommendations for individuals with high levels of physical activity in the presence of clinically significant coronary artery calcification (CAC).
Impact of Peanut Allergy on Quality of Life: Baseline Results from PALISADE, a Phase 3, Double-Blind, Placebo-Controlled Trial for AR101 Oral Immunotherapy
Authors: Julie Wang, Douglas T. Johnston, Jay A. Lieberman, Christine Birchwood, Sarah Acaster, Jane de Vries, Andrea Vereda, Rezi Zawadzki, Steve Hass, Nadine Zawadzki, Audrey DunnGalvin, Anthony E.J. Dubois, Karin Rosén, Jonathan O'B. Hourihane
Journal: Journal of Allergy and Clinical Immunology (2019)
Light Chain Amyloidosis and Non-Hodgkin's Lymphomas: A Peculiar Association with Distinct Clinical Features and Outcome
Authors: Marco Basset, Irene Defrancesco, Paolo Milani, Sara Rattotti, Andrea Foli, Marzia Varettoni, Alessandro Corso, Marco Paulli, Giampaolo Merlini, Luca Arcaini, Giovanni Palladini
Journal: Blood (2018)
Abstract P2-02-03: FASN inhibition as a potential treatment for therapy of endocrine resistant breast cancer
Authors: A Gruslova, GR Sareddy, RK Vadlamudi, S Viswanadhapalli, A Brenner
Journal: Cancer Research (2019)

Abstract INTRODUCTION: Fatty acid synthase (FASN) is a key enzyme in tumor cell biology controlling endogenous lipid biosynthesis. It is overexpressed in a biologically aggressive subset of tumors, including breast carcinoma. We previously reported prolonged stabilization of disease with TVB-2640 in patients with advanced metastatic breast cancer, including some endocrine resistant ER+ tumors. Using in vitro and in vivo models, we assessed the role of FASN inhibition by TVB-3166 (preclinical version of TVB-2640) for treatment of endocrine resistant breast cancer. METHODS: Breast tumor cells were incubated with TVB-3166 (200nM), imaged and analyzed by automated Live-Cell analysis system (IncuCyte). For tumor growth inhibition, cells (2X106)were subcutaneously injected into SCID mice implanted with estrogen pellets. Once tumors were measurable, mice were divided into treatment groups: tamoxifen (4mg/kg), TVB-3166 (60mg/kg) and the combination. Patient tumor explants were incubated for 72h on gelatin sponges in culture medium in the absence or presence of 200nM TVB-3166. Tissue were fixed in 10% formalin and processed into paraffin blocks. Sections were stained with H&amp;E, ERα and Ki67. RESULTS: The effectiveness of FASN inhibition on the growth of tumor cells has been confirmed in a number of breast cancer cell lines such as MCF7, ZR75, MDA-MB-231 and others. TVB-3166 leads to a marked inhibition of growth in tamoxifen resistant (TamR) cells, which 15% greater than in the parent line. IHC and Western blot showed FASN inhibition leads to significantly reduction of ERα levels. Immunofluorescent confocal microscopy showed inhibition of FASN by TVB-3166 alters subcellular localization of ERα. TVB-3166 was able to significantly inhibit tamoxifen resistant breast tumor growth in mice (p&amp;lt;0.05). Additionally, TVB-3166 treatment of primary tumor explants decreased their proliferation (Ki67) compared to untreated controls (21% vs 38%, p&amp;lt;0.01). CONCLUSION: Our preclinical data provide evidence that FASN inhibition by TVB-3166 presents a promising therapeutic strategy for treating of endocrine resistant breast cancer. RNA sequencing of tumor explants is being performed to evaluate FASN inhibition impact on canonical and non-canonical ERα signaling pathways. Citation Format: Gruslova A, Sareddy GR, Vadlamudi RK, Viswanadhapalli S, Brenner A. FASN inhibition as a potential treatment for therapy of endocrine resistant breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-03.
Lawrence Peter Ormerod
Authors: Pauline Ormerod
Journal: BMJ (2019)

A form of childhood tuberculosis at age 7 made Lawrence Peter Ormerod decide to become a doctor. After training in respiratory and general medicine in Manchester and Birmingham, he was appointed as consultant in Blackburn in 1980, with a remit to tackle TB, in the district that then had the fourth highest incidence of the infection in the UK. He devised a full …