tbuckley/cabot-search huggingface dataset:
Air Pollution and Mortality in the Medicare Population
Authors: Qian Di, Yan Wang, Antonella Zanobetti, Yun Wang, Petros Koutrakis, Christine Choirat, Francesca Dominici, Joel D. Schwartz
Journal: New England Journal of Medicine (2017)

Studies have shown that long-term exposure to air pollution increases mortality. However, evidence is limited for air-pollution levels below the most recent National Ambient Air Quality Standards. Previous studies involved predominantly urban populations and did not have the statistical power to estimate the health effects in underrepresented groups.We constructed an open cohort of all Medicare beneficiaries (60,925,443 persons) in the continental United States from the years 2000 through 2012, with 460,310,521 person-years of follow-up. Annual averages of fine particulate matter (particles with a mass median aerodynamic diameter of less than 2.5 μm [PM2.5]) and ozone were estimated according to the ZIP Code of residence for each enrollee with the use of previously validated prediction models. We estimated the risk of death associated with exposure to increases of 10 μg per cubic meter for PM2.5 and 10 parts per billion (ppb) for ozone using a two-pollutant Cox proportional-hazards model that controlled for demographic characteristics, Medicaid eligibility, and area-level covariates.Increases of 10 μg per cubic meter in PM2.5 and of 10 ppb in ozone were associated with increases in all-cause mortality of 7.3% (95% confidence interval [CI], 7.1 to 7.5) and 1.1% (95% CI, 1.0 to 1.2), respectively. When the analysis was restricted to person-years with exposure to PM2.5 of less than 12 μg per cubic meter and ozone of less than 50 ppb, the same increases in PM2.5 and ozone were associated with increases in the risk of death of 13.6% (95% CI, 13.1 to 14.1) and 1.0% (95% CI, 0.9 to 1.1), respectively. For PM2.5, the risk of death among men, blacks, and people with Medicaid eligibility was higher than that in the rest of the population.In the entire Medicare population, there was significant evidence of adverse effects related to exposure to PM2.5 and ozone at concentrations below current national standards. This effect was most pronounced among self-identified racial minorities and people with low income. (Supported by the Health Effects Institute and others.).
Retinoblastoma and Neuroblastoma Predisposition and Surveillance
Authors: Junne Kamihara, Franck Bourdeaut, William D. Foulkes, Jan J. Molenaar, Yaël P. Mossé, Akira Nakagawara, Andreu Parareda, Sarah R. Scollon, Kami Wolfe Schneider, Alison H. Skalet, Lisa J. States, Michael F. Walsh, Lisa R. Diller, Garrett M. Brodeur
Journal: Clinical Cancer Research (2017)

Abstract Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Approximately 40% of retinoblastomas are hereditary and due to germline mutations in the RB1 gene. Children with hereditary RB are also at risk for developing a midline intracranial tumor, most commonly pineoblastoma. We recommend intensive ocular screening for patients with germline RB1 mutations for retinoblastoma as well as neuroimaging for pineoblastoma surveillance. There is an approximately 20% risk of developing second primary cancers among individuals with hereditary RB, higher among those who received radiotherapy for their primary RB tumors. However, there is not yet a clear consensus on what, if any, screening protocol would be most appropriate and effective. Neuroblastoma (NB), an embryonal tumor of the sympathetic nervous system, accounts for 15% of pediatric cancer deaths. Prior studies suggest that about 2% of patients with NB have an underlying genetic predisposition that may have contributed to the development of NB. Germline mutations in ALK and PHOX2B account for most familial NB cases. However, other cancer predisposition syndromes, such as Li–Fraumeni syndrome, RASopathies, and others, may be associated with an increased risk for NB. No established protocols for NB surveillance currently exist. Here, we describe consensus recommendations on hereditary RB and NB from the AACR Childhood Cancer Predisposition Workshop. Clin Cancer Res; 23(13); e98–e106. ©2017 AACR. See all articles in the online-only CCR Pediatric Oncology Series.
Abstract 126: High Efficiency Reprogramming of Fibroblasts Into Cardiomyocytes Requires Suppression of Pro-fibrotic Signaling
Authors: Kunhua Song, Yuanbiao Zhao, Pilar Londono, Emily Sharpe, Joshua R Clair, Catherine Proenza, Rebecca O’Rourke, Kenneth L Jones, Mark Y Jeong, Lori A Walker, Peter M Buttrick, Timothy A McKinsey, Yingqiong Cao
Journal: Circulation Research (2015)

The mammalian heart is composed of ~30% cardiomyocytes which have limited capacity to regenerate and ~70% non-cardiomyocytes including endothelial cells and cardiac fibroblasts. Direct reprogramming of fibroblasts into cardiomyocytes by forced expression of cardiomyogenic transcription factors, GMT (GATA4, Mef2C, Tbx5) or GHMT (GATA4, Hand2, Mef2C, Tbx5), has recently been demonstrated, suggesting a novel therapeutic strategy for cardiac repair. Despite extensive efforts, the efficiency of direct reprogramming of embryonic or adult fibroblasts into cardiomyocytes has yet to exceed 20%, or 0.1% respectively, leading many in the field to question the clinical translatability of this method. Here, we demonstrate that pro-fibrotic signaling events governed by transforming growth factor-β (TGF-β) and Rho kinase (ROCK) are concomitantly activated in GHMT-expressing fibroblasts, leading to potent suppression of cardiac reprogramming ( Figure 1 ). Remarkably, pharmacological inhibition of TGF-β, or ROCK leads to conversion of ≥ 60% of fibroblasts into highly functional cardiomyocytes, displaying global cardiac gene expression, spontaneous contractility, action potentials and calcium transients. Furthermore, inhibition of TGF-β, or ROCK dramatically enhances the kinetics of cardiac reprogramming, with spontaneously contracting cardiomyocytes emerging in less than two weeks, as opposed to 4 weeks with GHMT alone. These findings provide new insights into the molecular mechanisms underlying cardiac conversion of fibroblasts, and should enhance efforts to generate cardiomyocytes for clinical applications.
Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis
Authors: Samra Turajlic, Kevin Litchfield, Hang Xu, Rachel Rosenthal, Nicholas McGranahan, James L Reading, Yien Ning S Wong, Andrew Rowan, Nnennaya Kanu, Maise Al Bakir, Tim Chambers, Roberto Salgado, Peter Savas, Sherene Loi, Nicolai J Birkbak, Laurent Sansregret, Martin Gore, James Larkin, Sergio A Quezada, Charles Swanton
Journal: The Lancet Oncology (2017)

The focus of tumour-specific antigen analyses has been on single nucleotide variants (SNVs), with the contribution of small insertions and deletions (indels) less well characterised. We investigated whether the frameshift nature of indel mutations, which create novel open reading frames and a large quantity of mutagenic peptides highly distinct from self, might contribute to the immunogenic phenotype.
Government is in dark about scale of mental health problems in prisons, says NAO
Authors: Matthew Limb
Journal: BMJ (2017)

Urgent action is needed to tackle record rates of suicide and self harm in prisons under pressure from staffing and funding cuts, the public spending watchdog has warned.

Ministers have ambitious plans to improve prisoners’ mental health but have yet to grasp the scale of the problems, the National Audit Office said in a report on mental health in prisons.1

Amyas Morse, head of the agency, said, “The data on how many people in prison have mental health problems and how much government is spending to address this is poor. Consequently, government do not know the base they are starting from, what they need to improve, or how realistic it is for them to meet their objectives. Without this understanding it is hard to see how government can be achieving value for …
Impact of a pre-operative exercise intervention on Ki-67 and metabolic markers in women with early breast cancer.
Authors: Jennifer A. Ligibel, Anita Giobbie-Hurder, Laura Shockro, Esther Rhei, Susan Troyan, Laura Stewart Dominici, Anees B. Chagpar, Elizabeth S. Frank, Anne McTiernan, Rachel Lynn Yung, Rachel A. Freedman, Sara M. Tolaney, Keelin O'Connor, Kelly Stecker, Deborah Dillon, Melinda L Irwin
Journal: Journal of Clinical Oncology (2016)

564 Background: Women who exercise after breast cancer diagnosis have a lower risk of recurrence and mortality, but the biological mechanisms through which exercise impacts breast cancer are unclear. The Pre-Operative Health and Body (PreHAB) Study was a randomized window of opportunity trial designed to test the impact of exercise on tissue and serum biomarkers in women with early breast cancer. Methods: Inactive women with newly diagnosed Stage I-III breast cancer were enrolled through Dana-Farber Cancer Institute and Yale University prior to surgery. Participants were randomized 1:1 to an exercise intervention or Mind-Body control intervention and participated in the interventions between enrollment and the time of surgery. Tumor tissue and serum were collected at enrollment and surgery. Results: A total of 49 women were randomized (27 exercise and 22 control). At baseline, mean age was 52.6, BMI was 30.2kg/m2 and exercise was 49 min/wk. Mean time between enrollment and surgery was 4.2 weeks. Exercise participants significantly increased minutes of weekly exercise vs. controls (203 vs. 23, p<0.0001). Tumor expression of insulin receptor (IR) decreased significantly in the exercise group vs. controls (Table). There was no difference in change in Ki-67. Exercise participants experienced a significant decrease in serum leptin and a trend toward a decrease in IGF-1 compared to controls. Conclusions: A brief pre-operative exercise intervention led to alterations in metabolic but not proliferative markers in serum and breast tumor tissue. This study provides some of the first data regarding the impact of exercise on human breast cancer, offering insight into the biologic basis of the protective effect of exercise on breast cancer. Clinical trial information: NCT01516190.Changes in tissue and serum markers (baseline to post-intervention).* Exercise Control P value Tissue markers Ki-67, % staining (n=40) -1.1 (12.9) -0.7 (8.1) 0.77 IR, Allred (n=17) -0.7 (1.4) 0.8 (1.0) 0.05 Serum markers (n=44) Insulin, μu/ml -1.6 (2.9) -0.8 (4.0) 0.26 Leptin, pg/ml -41.6 (81.3) 2.1 (41.8) 0.008 Adiponectin, ng/ml -3.3 (14.3) -2.2 (14.5) 0.97 IGF-1, ng/ml -0.1 (0.3) 0.0 (0.1) 0.08 CRP, ng/ml -0.4 (12.7) -1.5 (7.5) 0.33 All changes reported as mean (SD)
Abstract 46: Identification of Novel Alternate Splicing Events in Humans With RBFOX2 Mutations and Hypoplastic Left Heart Syndrome
Authors: Craig C Benson, David McKean, Jason Homsy, Richard Kim, Josh Gorham, Jon Seidman, Christine Seidman
Journal: Circulation Research (2015)

Alternative splicing (AS) of protein isoforms is an integral mechanism for cardiac development. RNA Binding Protein, Fox-1 Homolog (C. Elegans) 2 (RBFOX2) is an RNA binding protein preferentially expressed in muscle and neuronal cells and regulates tissue-specific alternate exon splicing in ~2,100 target genes by binding the conserved RNA sequence motif (U)GCAUG. RBFOX2 was recently implicated in the pathogenesis of abnormal cardiac and cerebral development via loss-of-function studies in zebrafish and mouse. However, convincing evidence remains incomplete, as the full complement of RBFOX2 target genes and differential exon usage (DEU) in human cardiovascular cell lines are incompletely defined. We identified de novo mutations in RBFOX2 from four human cases of congenital heart disease (CHD) with hypoplastic left heart syndrome (HLHS) via whole exome sequencing. To test the hypothesis that RBFOX2 mutations alter DEU in known target genes, we performed RNA-seq on ductus arteriosus tissue from human CHD cases with and without RBFOX2 mutation. Analysis of RNA-seq for DEU was performed with DEXSeq. To limit the effect of differential gene expression, we restricted analysis to subjects with high global gene expression correlation (r2 &gt; 0.9, case=1 vs. control=5). DEU in known RBFOX2 target genes were highly enriched compared to all known genes (115/2,100 vs. 589/26,310, p=5.78e-15). A high percentage of the DEU genes (60.0%, 69/115) have high heart expression (HHE) in the developing mouse (mean expression of four cardiac chambers at e14.5). DEU genes with HHE include VCL, TPM1, FN1, ACTN1, and CALD1. Functional annotation clustering reveals enrichment for several actin, cytoskeletal, and contractile Gene Ontology terms, suggesting a possible role in the epithelial-mesenchymal transition (EMT) developmental processes active during early cardiac formation. We also identified enrichment from genes implicated in CHD by allelic specific expression or de novo mutations (44/1,263 vs. 589/26,310, p=0.007). These results are the first in humans to identify differentially expressed exons associated with RBFOX2 mutations in CHD and suggests RBFOX2-mediated alternate splicing may influence EMT pathways implicated in the pathogenesis of HLHS.
3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release
Authors: Mary Kyobula, Aremu Adedeji, Morgan R. Alexander, Ehab Saleh, Ricky Wildman, Ian Ashcroft, Paul R. Gellert, Clive J. Roberts
Journal: Journal of Controlled Release (2017)

A hot melt 3D inkjet printing method with the potential to manufacture formulations in complex and adaptable geometries for the controlled loading and release of medicines is presented. This first use of a precisely controlled solvent free inkjet printing to produce drug loaded solid dosage forms is demonstrated using a naturally derived FDA approved material (beeswax) as the drug carrier and fenofibrate as the drug. Tablets with bespoke geometries (honeycomb architecture) were fabricated. The honeycomb architecture was modified by control of the honeycomb cell size, and hence surface area to enable control of drug release profiles without the need to alter the formulation. Analysis of the formed tablets showed the drug to be evenly distributed within the beeswax at the bulk scale with evidence of some localization at the micron scale. An analytical model utilizing a Fickian description of diffusion was developed to allow the prediction of drug release. A comparison of experimental and predicted drug release data revealed that in addition to surface area, other factors such as the cell diameter in the case of the honeycomb geometry and material wettability must be considered in practical dosage form design. This information when combined with the range of achievable geometries could allow the bespoke production of optimized personalised medicines for a variety of delivery vehicles in addition to tablets, such as medical devices for example.
Subtype specific differences in genetic alterations and drug response in breast cancer cell lines
Authors: Carol O'Brien, Heidi Savage, Jill Spoerke, Xiaolan Hu, Guy Cavet, Lukas Amler, Mark Lackner
Journal: Clinical Cancer Research (2007)

B6  The emerging picture of breast cancer is of a heterogeneous disease with distinct molecular subtypes that respond differentially to both targeted and chemotherapeutic agents. Pharmacogenomic studies that link compound activity with specific molecular features are a useful tool that may help predict whether a given tumor will respond to a particular agent. In order to facilitate such an approach we have conducted extensive characterization of a panel of 45 breast cancer cell lines using immunohistochemistry, gene expression microarrays, microRNA microarrays, and sequencing of >80 key cancer genes. Among the findings to be discussed are subtype specific differences in copy number alterations and mutation frequency in the different subtypes and the implications for targeted therapies. In particular, data showing high rates of PTEN loss and overall genomic instability in basal-like cell lines will be discussed. We also present in vitro drug sensitivity data showing differential activity of both chemotherapeutic and commercially available targeted agents in cell lines representing different subtypes.
Role of Repeat Endoscopy to Assess the Healing of Endoscopically and Histologically Benign Gastric Ulcers. Is it Necessary?
Authors: M Ali, N Yahya, A Rafeh Khan, B Javaid
Journal: Endoscopy (2006)

Aims: Follow-up Endoscopy to assess the healing of even benign gastric ulcer is generally recommended as a standard practice. The purpose of this study was to evaluate the effectiveness and necessity of follow up endoscopy in patients with benign gastric ulcers to demonstrate healing and to minimise the risk of missing malignancy.
Consideration of Dental, Vision, and Hearing Services to Be Covered Under Medicare
Authors: Amber Willink, Cathy Schoen, Karen Davis
Journal: JAMA (2017)

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Efficacy and Toxicity of Single Daily Doses of Amikacin and Ceftriaxone versus Multiple Daily Doses of Amikacin and Ceftazidime for Infection in Patients with Cancer and Granulocytopenia
Authors: The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer.
Journal: Annals of Internal Medicine (1993)

Objective: To compare the efficacy and toxicity of single daily dosing of amikacin and ceftriaxone with that of multiple daily dosing of amikacin and ceftazidime for febrile episodes in patients with cancer and granulocytopenia. Design: A prospective, randomized, unblinded, multicenter trial. Setting: Twenty-one tertiary care or university medical centers. Patients: Six hundred seventy-seven patients with cancer and granulocytopenia (858 febrile episodes). Interventions: Random assignment to empirical therapy with a single daily dose of amikacin (20 mg/kg) and ceftriaxone (adults, 30 mg/kg; children, 80 mg/kg) (24-hour group) or with multiple daily doses of amikacin (6.5 mg/kg every 8 hours) and ceftazidime (33 mg/kg every 8 hours) (8-hour group). Measurements: Percentage response to each regimen and occurrence of nephrotoxicity and ototoxicity. Results: Single daily dosing of amikacin and ceftriaxone was as effective as multiple daily dosing of amikacin and ceftazidime (71% compared with 74%; difference, 3%;95% CI, 10% to 3%; P > 0.2). Equivalent responses also were noted for each category of infection. Median peak (30 minutes after a 60-minute infusion) serum concentrations of amikacin were higher in the 24-hour group than in the 8-hour group (45.6 compared with 21 g/mL, P < 0.001), whereas trough (preinfusion) levels were lower (0.9 compared with 2 g/mL, P < 0.001). Nephrotoxicity was 3% in the 24-hour group and 2% in the 8-hour group (difference, 1%; CI, 1% to 4%). Increases in serum creatinine, however, were delayed (P = 0.048) and smaller (P = 0.06) in the 24-hour group than in the 8-hour group and occurred almost exclusively after other nephrotoxic drugs were added. Audiometry was only done in 144 patients (21%). Ototoxicity was 9% in the 24-hour group and 7% in the 8-hour group (difference, 2%; CI, 7% to 11%; P > 0.2). Further infections developed in 15% and 12% of patients, respectively (difference, 3%; CI, 2% to 9%). The overall mortality rate was 11% in both treatment groups (difference, 0%; CI, 5% to 5%). Conclusions: Single daily dosing of amikacin and ceftriaxone was as effective and no more toxic than multiple daily dosing of amikacin and ceftazidime for the empirical therapy of infection in patients with cancer and granulocytopenia.
Adjuvant capecitabine for biliary tract cancer: The BILCAP randomized study.
Authors: John Neil Primrose, Richard Fox, Daniel H. Palmer, Raj Prasad, Darius Mirza, David Alan Anthoney, Philippa Corrie, Stephen Falk, Harpreet Singh Wasan, Paul J. Ross, Lucy R. Wall, Jonathan Wadsley, T.R. Jeffry Evans, Deborah Stocken, Raaj Praseedom, David Cunningham, O James Garden, Clive Stubbs, Juan W. Valle, John A. Bridgewater
Journal: Journal of Clinical Oncology (2017)

4006 Background: Despite improvements in multidisciplinary management, BTC has a poor outcome. Approximately 20% of cases are suitable for surgical resection with a 5 year survival of &lt; 10%. BILCAP aimed to determine whether capecitabine (Cape) improves overall survival (OS) compared to observation (Obs) following radical surgery. Methods: Patients with completely-resected cholangiocarcinoma (CCA) or gallbladder cancer (including liver and pancreatic resection, as appropriate), with adequate biliary drainage, no ongoing infection, adequate renal, haematological and liver function, and ECOG PS ≤2, were randomized 1:1 to Cape (1250 mg/m 2 D1-14 every 21 days, for 8 cycles) or Obs. Randomization was minimized on tumor site, resection status, ECOG PS and surgical center. The primary outcome was OS in the intention to treat (ITT) population. 410 patients were needed to detect a hazard ratio (HR) of 0.69 (2-sided α = 0.05 and 80% power). HR was estimated by Cox survival model with adjustment for the minimization factors. Primary analysis performed with at least 24 months (m) follow-up. Results: 447 participants were randomized to Cape (n = 223) or Obs (n = 224) from 44 UK sites between 2006-2014. Median age was 63y (IQR 55, 69) and 201 (45%), 232 (52%), and 14 (3%) patients were ECOG PS 0, 1 and 2 respectively. Primary site: 84 (19%) intrahepatic, 128 (28%) hilar, 156 (35%) extrahepatic CCA and 79 (18%) muscle-invasive gallbladder cancers. Resection margins: R0 in 279 (62%) and R1 in 168 (38%); 207 (46%) were node-negative. Follow up was at least 36m in &gt; 80% of surviving patients. By ITT analysis (n = 447), median OS was 51m (95%CI 35, 59) for Cape and 36m (95%CI 30, 45) for Obs, HR 0.80 (95%CI 0.63, 1.04; p = 0.097). Sensitivity analyses with adjustment for nodal status, grade of disease and gender indicated HR 0.71 (95%CI 0.55, 0.92 p &lt; 0.01). In the per-protocol analysis (Cape n = 210, Obs n = 220) median OS was 53m (95%CI 40, NR) for Cape and 36m (95%CI 30, 44) for Obs, HR 0.75 (95%CI 0.58, 0.97; p = 0.028). Median RFS (ITT) was 25m (95%CI 19, 37) for Cape and 18m (95%CI 13, 28) for Obs. Grade 3-4 toxicity was less than anticipated. Conclusions: Cape improves OS in BTC when used as adjuvant and should become standard of care. Clinical trial information: ISRCTN72785446.