Nutrition and Physical Activity in British Army Officer Cadet Training Part 2-Daily Distribution of Energy and Macronutrient Intake.

Dietary intake and physical activity impact performance and adaptation during training. The aims of this study were to compare energy and macronutrient intake during British Army Officer Cadet training with dietary guidelines and describe daily distribution of energy and macronutrient intake and estimated energy expenditure. Thirteen participants (seven women) were monitored during three discrete periods of military training for 9 days on-camp, 5 days of field exercise, and 9 days of a mixture of the two.

Discovery of a Thiadiazole-Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models.

Tumors have evolved a variety of methods to reprogram conventional metabolic pathways to favor their own nutritional needs, including glutaminolysis, the first step of which is the hydrolysis of glutamine to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor could potentially target certain cancers by blocking the tumor cell's ability to produce glutamine-derived nutrients. Starting from the known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide, we describe the medicinal chemistry evolution of a series from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic properties to cell potent examples with reduced molecular weight and lipophilicity, leading to compounds with greatly improved oral exposure that demonstrate in vivo target engagement accompanied by activity in relevant disease models.

Rapid activation of epithelial-mesenchymal transition drives PARP inhibitor resistance in -mutant mammary tumours.

Tumours defective in the DNA homologous recombination repair pathway can be effectively treated with poly (ADP-ribose) polymerase (PARP) inhibitors; these have proven effective in clinical trials in patients with gene function-defective cancers. However, resistance observed in both pre-clinical and clinical studies is likely to impact on this treatment strategy. Over-expression of phosphoglycoprotein (P-gp) has been previously suggested as a mechanism of resistance to the PARP inhibitor olaparib in mouse models of -mutant breast cancer.

Long-term psychological distress of Bosnian war survivors: an 11-year follow-up of former displaced persons, returnees, and stayers.

Background: Research on the long-term mental health consequences of war and displacement among civilians who live in post-conflict countries is rare. The aim of this study was to examine the developmental trajectories and predictors of general psychological distress in three samples of Bosnian war survivors over an 11-year period.

Methods: In 1998/99, about three years after the war in Bosnia and Herzegovina, a representative sample of 299 adult Sarajevo citizens was examined in three subsamples: individuals who had stayed in Sarajevo throughout the siege, individuals who had been internally displaced, and refugees who had returned.

Irreversible Inhibition of EGFR: Modeling the Combined Pharmacokinetic-Pharmacodynamic Relationship of Osimertinib and Its Active Metabolite AZ5104.

Osimertinib (AZD9291) is a potent, selective, irreversible inhibitor of EGFR-sensitizing (exon 19 and L858R) and T790M-resistant mutation. In vivo, in the mouse, it is metabolized to an active des-methyl metabolite, AZ5104. To understand the therapeutic potential in patients, this study aimed to assess the relationship between osimertinib pharmacokinetics, the pharmacokinetics of the active metabolite, the pharmacodynamics of phosphorylated EGFR reduction, and efficacy in mouse xenograft models of EGFR-driven cancers, including two NSCLC lines.

AZD9496: An Oral Estrogen Receptor Inhibitor That Blocks the Growth of ER-Positive and ESR1-Mutant Breast Tumors in Preclinical Models.

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a nonsteroidal small-molecule inhibitor of ERα, which is a potent and selective antagonist and downregulator of ERα in vitro and in vivo in ER-positive models of breast cancer.

Inhibition of PI3Kβ signaling with AZD8186 inhibits growth of PTEN-deficient breast and prostate tumors alone and in combination with docetaxel.

Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kβ isoform. Inhibitors of PI3Kβ have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kβ and PI3Kδ (AZD8186) and assessed its antitumor activity across a panel of cell lines.

Dialogical Exposure with Traumatically Bereaved Bosnian Women: Findings from a Controlled Trial.

Objective: In this trial, we compared the relative efficacy of dialogical exposure group treatment using Gestalt empty-chair method with a supportive group in the treatment of symptoms stemming from traumatic loss in a post-war society.

Methods: One-hundred and nineteen women whose husbands were either killed or registered as missing during the war in Bosnia and Herzegovina were quasi-randomized to seven sessions of group treatment with dialogical exposure or to an active control condition.

Results: Both interventions resulted in significant improvement from baseline to post-treatment for both kinds of loss, in terms of post-traumatic symptoms, general mental health and grief reactions, with the exception of depression and traumatic grief in the control condition.

Recruitment of participants to a multiple sclerosis trial: the CombiRx experience.

Background: and purpose Participant recruitment is central to all clinical trials. Any delay in recruitment affects the completion and ultimate success of the trial. We report our experience with patient screening and randomization in CombiRx, which may inform the design of other trials.

RNA-Seq Differentiates Tumour and Host mRNA Expression Changes Induced by Treatment of Human Tumour Xenografts with the VEGFR Tyrosine Kinase Inhibitor Cediranib.

Pre-clinical models of tumour biology often rely on propagating human tumour cells in a mouse. In order to gain insight into the alignment of these models to human disease segments or investigate the effects of different therapeutics, approaches such as PCR or array based expression profiling are often employed despite suffering from biased transcript coverage, and a requirement for specialist experimental protocols to separate tumour and host signals. Here, we describe a computational strategy to profile transcript expression in both the tumour and host compartments of pre-clinical xenograft models from the same RNA sample using RNA-Seq.

Sedative techniques for endoscopic retrograde cholangiopancreatography.

Background: Endoscopic retrograde cholangiopancreatography (ERCP) is an uncomfortable therapeutic procedure that cannot be performed without adequate sedation or general anaesthesia. A considerable number of ERCPs are performed annually in the UK (at least 48,000) and many more worldwide.

Objectives: The primary objective of our review was to evaluate and compare the efficacy and safety of sedative or anaesthetic techniques used to facilitate the procedure of ERCP in adult (age > 18 years) patients.

Expression of stromal genes associated with the angiogenic response are not differentiated between human tumour xenografts with divergent vascular morphologies.

Human tumour xenografts have commonly been used to explore the mechanisms of tumour angiogenesis and the interaction of tumour cells with their microenvironment, as well as predict potential utility of anti-angiogenic inhibitors across different tumour types. To investigate how well human tumour xenografts can be used to differentiate the effects of stromal targeting agents we performed a comparative assessment of the murine angiogenic response across a panel of pre-clinical tumour xenografts. By analysing a panel of 22 tumour xenografts with a range of vascular morphologies, micro-vessel densities and levels of fibroblast and inflammatory infiltrate, we have examined the relationship between angiogenic stroma and human tumour models.

Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types.

Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.

Induction of heart valve lesions by small-molecule ALK5 inhibitors.

Aberrant signaling by transforming growth factor-β (TGF-β) and its type I (ALK5) receptor has been implicated in a number of human diseases and this pathway is considered a potential target for therapeutic intervention. Transforming growth factor-β signaling via ALK5 plays a critical role during heart development, but the role of ALK5 in the adult heart is poorly understood. In the current study, the preclinical toxicology of ALK5 inhibitors from two different chemistry scaffolds was explored.

Early phase TGFβ receptor signalling dynamics stabilised by the deubiquitinase UCH37 promotes cell migratory responses.

TGFβ signals through serine/threonine kinase receptors and intracellular Smad transcription factors. An important regulatory step involves ubiquitination of Smads and/or TGFβ receptors by specific ubiquitin ligases, in a process that can be reversed by the deubiquitinating enzyme UCH37. Here, to explore the physiological role of UCH37 in TGFβ signalling we have generated stable and inducible HaCAT keratinocyte and Colo-357 pancreatic carcinoma cell lines mis-expressing UCH37.

The use of intravascular ultrasound imaging to improve use of inferior vena cava filters in a high-risk bariatric population.

Objective: Pulmonary embolism is the leading cause of death after gastric bypass procedures for obesity, approximating 0.5% to 4%. All bariatric patients, but especially the super-obese, which have a body mass index (BMI) >50 kg/m(2), are at significant risk for postoperative venous thromboembolism (VTE).

Somatic mutations of GUCY2F, EPHA3, and NTRK3 in human cancers.

Tyrosine kinases are major regulators of signal transduction cascades involved in cellular proliferation and have important roles in tumorigenesis. We have recently analyzed the tyrosine kinase gene family for alterations in human colorectal cancers and identified somatic mutations in seven members of this gene family. In this study we have used high-throughput sequencing approaches to further evaluate this subset of genes for genetic alterations in other human tumors.

The Bosnian version of the international self-report measure of posttraumatic stress disorder, the Posttraumatic Stress Diagnostic Scale, is reliable and valid in a variety of different adult samples affected by war.

Background: The aim of the present study was to assess the internal consistency and discriminant and convergent validity of the Bosnian version of a self-report measure of posttraumatic stress disorder (PTSD), the Posttraumatic Stress Diagnostic Scale (PTDS). The PTDS yields both a PTSD diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) and a measure of symptom severity.

Methods: 812 people living in Sarajevo or in Banja Luka in Bosnia-Herzegovina, of whom the majority had experienced a high number of traumatic war events, were administered the PTDS and other measures of trauma-related psychopathology.