Novel patient-derived xenograft mouse model for pancreatic acinar cell carcinoma demonstrates single agent activity of oxaliplatin

Additional file 4: Figure S3. Integrated genomic viewer (IGV) of BRCA2 gene. IGV displays genomic data of the PA-018 PAAC PDTX model. Chromosome 13 (Chr 13) is shown and 5bp deletions are found after position 32907365 (c.1755_1759del5), this region resides on exon 10 of BRCA2. The bottom of the image shows the nucleotides and amino acids that correspond to the reference sequence of the BRCA2 gene and protein

Cost-Effectiveness Analysis of Four Simulated Colorectal Cancer Screening Interventions, North Carolina

Colorectal cancer (CRC) screening rates are suboptimal, particularly among the uninsured and the under-insured and among rural and African American populations. Little guidance is available for state-level decision makers to use to prioritize investment in evidence-based interventions to improve their population’s health. The objective of this study was to demonstrate use of a simulation model that incorporates synthetic census data and claims-based statistical models to project screening behavior in North Carolina

Tracking Antigen-Specific T-Cells during Clinical Tolerance Induction in Humans

Allergen immunotherapy presents an opportunity to define mechanisms of induction of clinical tolerance in humans. Significant progress has been made in our understanding of changes in T cell responses during immunotherapy, but existing work has largely been based on functional T cell assays. HLA-peptide-tetrameric complexes allow the tracking of antigen-specific T-cell populations based on the presence of specific T-cell receptors and when combined with functional assays allow a closer assessment of the potential roles of T-cell anergy and clonotype evolution. We sought to develop tools to facilitate tracking of antigen-specific T-cell populations during wasp-venom immunotherapy in people with wasp-venom allergy. We first defined dominant immunogenic regions within Ves v 5, a constituent of wasp venom that is known to represent a target antigen for T-cells. We next identified HLA-DRB1*1501 restricted epitopes and used HLA class II tetrameric complexes alongside cytokine responses to Ves v 5 to track T-cell responses during immunotherapy. In contrast to previous reports, we show that there was a significant initial induction of IL-4 producing antigen-specific T-cells within the first 3–5 weeks of immunotherapy which was followed by reduction of circulating effector antigen-specific T-cells despite escalation of wasp-venom dosage. However, there was sustained induction of IL-10-producing and FOXP3 positive antigen-specific T cells. We observed that these IL-10 producing cells could share a common precursor with IL-4-producing T cells specific for the same epitope. Clinical tolerance induction in humans is associated with dynamic changes in frequencies of antigen-specific T-cells, with a marked loss of IL-4-producing T-cells and the acquisition of IL-10-producing and FOXP3-positive antigen-specific CD4+ T-cells that can derive from a common shared precursor to pre-treatment effector T-cells. The development of new approaches to track antigen specific T-cell responses during immunotherapy can provide novel insights into mechanisms of tolerance induction in humans and identify new potential treatment targets

The Primary Prevention of PTSD in Firefighters: Preliminary Results of an RCT with 12-Month Follow-Up

AIM: To develop and evaluate an evidence-based and theory driven program for the primary prevention of Post-traumatic Stress Disorder (PTSD). DESIGN: A pre-intervention / post-intervention / follow up control group design with clustered random allocation of participants to groups was used. The "control" group received "Training as Usual" (TAU). METHOD: Participants were 45 career recruits within the recruit school at the Department of Fire and Emergency Services (DFES) in Western Australia. The intervention group received a four-hour resilience training intervention (Mental Agility and Psychological Strength training) as part of their recruit training school curriculum. Data was collected at baseline and at 6- and 12-months post intervention. RESULTS: We found no evidence that the intervention was effective in the primary prevention of mental health issues, nor did we find any significant impact of MAPS training on social support or coping strategies. A significant difference across conditions in trauma knowledge is indicative of some impact of the MAPS program. CONCLUSION: While the key hypotheses were not supported, this study is the first randomised control trial investigating the primary prevention of PTSD. Practical barriers around the implementation of this program, including constraints within the recruit school, may inform the design and implementation of similar programs in the future. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12615001362583

Internet Daters’ Body Type Preferences: Race–Ethnic and Gender Differences

Employing a United States sample of 5,810 Yahoo heterosexual internet dating profiles, this study finds race–ethnicity and gender influence body type preferences for dates, with men and whites significantly more likely than women and non-whites to have such preferences. White males are more likely than non-white men to prefer to date thin and toned women, while African-American and Latino men are significantly more likely than white men to prefer female dates with thick or large bodies. Compatible with previous research showing non-whites have greater body satisfaction and are less influenced by mainstream media than whites, our findings suggest Latinos and African Americans negotiate dominant white idealizations of thin female bodies with their own cultures’ greater acceptance of larger body types

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Lactate Produced by Glycogenolysis in Astrocytes Regulates Memory Processing

When administered either systemically or centrally, glucose is a potent enhancer of memory processes. Measures of glucose levels in extracellular fluid in the rat hippocampus during memory tests reveal that these levels are dynamic, decreasing in response to memory tasks and loads; exogenous glucose blocks these decreases and enhances memory. The present experiments test the hypothesis that glucose enhancement of memory is mediated by glycogen storage and then metabolism to lactate in astrocytes, which provide lactate to neurons as an energy substrate. Sensitive bioprobes were used to measure brain glucose and lactate levels in 1-sec samples. Extracellular glucose decreased and lactate increased while rats performed a spatial working memory task. Intrahippocampal infusions of lactate enhanced memory in this task. In addition, pharmacological inhibition of astrocytic glycogenolysis impaired memory and this impairment was reversed by administration of lactate or glucose, both of which can provide lactate to neurons in the absence of glycogenolysis. Pharmacological block of the monocarboxylate transporter responsible for lactate uptake into neurons also impaired memory and this impairment was not reversed by either glucose or lactate. These findings support the view that astrocytes regulate memory formation by controlling the provision of lactate to support neuronal functions

Simulation-based Estimation Methods for Financial Time Series Models

Published in Handbook of computational finance, 2010, https://doi.org/10.1007/978-3-642-17254-0_15</p