Role and species-specific expression of colon T cell homing receptor GPR15 in colitis.

Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon.

Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche.

Hereditary mixed polyposis syndrome (HMPS) is characterized by the development of mixed-morphology colorectal tumors and is caused by a 40-kb genetic duplication that results in aberrant epithelial expression of the gene encoding mesenchymal bone morphogenetic protein antagonist, GREM1. Here we use HMPS tissue and a mouse model of the disease to show that epithelial GREM1 disrupts homeostatic intestinal morphogen gradients, altering cell fate that is normally determined by position along the vertical epithelial axis. This promotes the persistence and/or reacquisition of stem cell properties in Lgr5-negative progenitor cells that have exited the stem cell niche.

Fluid therapy in critical illness.

Major surgery and critical illnesses such as sepsis and trauma all disturb normal physiological fluid handling. Intravenous fluid therapy for resuscitation and fluid maintenance is a central part of medical care during these conditions, yet the evidence base supporting practice in this area lacks answers to a number of important questions. Recent research developments include a refinement of our knowledge of the endothelial barrier structure and function and a focus on the potential harm that may be associated with intravenous fluid therapy.

Evidence that breast cancer risk at the 2q35 locus is mediated through IGFBP5 regulation.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data.

A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer.

Complex focal chromosomal rearrangements in cancer genomes, also called "firestorms", can be scored from DNA copy number data. The complex arm-wise aberration index (CAAI) is a score that captures DNA copy number alterations that appear as focal complex events in tumors, and has potential prognostic value in breast cancer. This study aimed to validate this DNA-based prognostic index in breast cancer and test for the first time its potential prognostic value in ovarian cancer.

Putative cis-regulatory drivers in colorectal cancer.

The cis-regulatory effects responsible for cancer development have not been as extensively studied as the perturbations of the protein coding genome in tumorigenesis. To better characterize colorectal cancer (CRC) development we conducted an RNA-sequencing experiment of 103 matched tumour and normal colon mucosa samples from Danish CRC patients, 90 of which were germline-genotyped. By investigating allele-specific expression (ASE) we show that the germline genotypes remain important determinants of allelic gene expression in tumours.

Skeletal muscle adiposity is associated with physical activity, exercise capacity and fibre shift in COPD.

Quadriceps muscle phenotype varies widely between patients with chronic obstructive pulmonary disease (COPD) and cannot be determined without muscle biopsy. We hypothesised that measures of skeletal muscle adiposity could provide noninvasive biomarkers of muscle quality in this population. In 101 patients and 10 age-matched healthy controls, mid-thigh cross-sectional area, percentage intramuscular fat and skeletal muscle attenuation were calculated using computed tomography images and standard tissue attenuation ranges: fat -190- -30 HU; skeletal muscle -29-150 HU.

Nocturnal pulse rate and symptomatic response in patients with obstructive sleep apnoea treated with continuous positive airway pressure for one year.

Background: Obstructive sleep apnoea (OSA) is the most common form of sleep-disordered breathing and a known risk factor for cardiovascular disease. We hypothesised that in patients with OSA the characteristics of nocturnal pulse rate (PR) are associated with changes in blood pressure and daytime sleepiness, following commencement of continuous positive airway pressure (CPAP) therapy.

Methods: Pulse oximetry data, demographics, daytime sleepiness and blood pressure were recorded at baseline and at one year follow up.

Usefulness of new imaging methods for assessment of type B aortic dissection.

While the medical management of uncomplicated type B aortic dissection has good outcomes in the short term, the longer term mortality can be in the region of 50% at 5 years. Up to 40% of the survivors can have significant dilatation of the false lumen with the risk of aneurysm formation and death due to rupture. The results of the randomized controlled trials ADSORB and INSTEAD-XL have shown that beneficial aortic remodelling occurs after endoluminal stent graft placement, but these trials were underpowered to show any effect on survival.

Pathology specific early outcome after thoracic endovascular aortic repair.

Objectives: Endovascular intervention is established for treatment of thoracic aortic dissection and aneurysm. The aim of this study was to compare the incidence of all-cause and aortic-related in-hospital mortality, stroke, spinal cord ischaemia, and major adverse event rate for patients undergoing thoracic aortic endovascular intervention to see if there is a pathology-specific effect.

Methods: Data were collected prospectively and analysed retrospectively for a cohort of 309 consecutive patients with either thoracic aortic dissection or aneurysm over a 14-year period.

Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium.

Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression.

Optimising pre- and postoperative imaging for thoracic aortic pathology.

Thoracic aortic pathology carries significant morbidity and mortality, which requires prompt and accurate clinical and radiological evaluation. Advances in imaging technologies have improved our knowledge of the mechanisms of growth and rupture and our understanding of endovascular repair. Computed tomography has become a crucial component in this process, replacing catheter-based angiography as the most commonly used pre- and postoperative imaging modality for the thoracic aorta.

Genetic variation at CYP3A is associated with age at menarche and breast cancer risk: a case-control study.

Introduction: We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years.

Methods: We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium.

Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP.

The presence of multiple (5-100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.

Uncomplicated type B dissections: which patients should be treated? Lessons learned from the recent literature.

The management of type B aortic dissection is complex and decision-making is often based on physician experience and subjective clinical judgment. Thoracic endovascular aortic repair is considered first-line therapy for complicated type B aortic dissection but whether this should be performed in uncomplicated cases has been a matter of debate. Randomized controlled trials have demonstrated the long-term benefit of endovascular treatment to prevent aortic-related mortality, however pre-emptive surgery may not be the solution for all patients because of the occurrence of adverse events such death, stroke and paraplegia.

Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden.

Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations and chromosomal changes in 14 bladder cancers of different grades and stages.

Functional electrical stimulation with cycling in the critically ill: a pilot case-matched control study.

Purpose: The purpose was to determine (a) safety and feasibility of functional electrical stimulation (FES)-cycling and (b) compare FES-cycling to case-matched controls in terms of functional recovery and delirium outcomes.

Materials And Methods: Sixteen adult intensive care unit patients with sepsis ventilated for more than 48 hours and in the intensive care unit for at least 4 days were included. Eight subjects underwent FES-cycling in addition to usual care and were compared to 8 case-matched control individuals.

Association analysis using next-generation sequence data from publicly available control groups: the robust variance score statistic.

Motivation: Sufficiently powered case-control studies with next-generation sequence (NGS) data remain prohibitively expensive for many investigators. If feasible, a more efficient strategy would be to include publicly available sequenced controls. However, these studies can be confounded by differences in sequencing platform; alignment, single nucleotide polymorphism and variant calling algorithms; read depth; and selection thresholds.

A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS.

Objective: Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS).

Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis.

Purpose: Fluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain.

Patients And Methods: We tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2).

Replicative DNA polymerase mutations in cancer.

Three DNA polymerases - Pol α, Pol δ and Pol ɛ - are essential for DNA replication. After initiation of DNA synthesis by Pol α, Pol δ or Pol ɛ take over on the lagging and leading strand respectively. Pol δ and Pol ɛ perform the bulk of replication with very high fidelity, which is ensured by Watson-Crick base pairing and 3'exonuclease (proofreading) activity.

A randomized controlled trial of angiotensin-converting enzyme inhibition for skeletal muscle dysfunction in COPD.

Background: Skeletal muscle impairment is a recognized complication of COPD, predicting mortality in severe disease. Increasing evidence implicates the renin-angiotensin system in control of muscle phenotype. We hypothesized that angiotensin-converting enzyme (ACE) inhibition would improve quadriceps function and exercise performance in COPD.

Beyond poiseuille: preservation fluid flow in an experimental model.

Poiseuille's equation describes the relationship between fluid viscosity, pressure, tubing diameter, and flow, yet it is not known if cold organ perfusion systems follow this equation. We investigated these relationships in an ex vivo model and aimed to offer some rationale for equipment selection. Increasing the cannula size from 14 to 20 Fr increased flow rate by a mean (SD) of 13 (12)%.

Enhanced and persistent levels of interleukin (IL)-17⁺ CD4⁺ T cells and serum IL-17 in patients with early inflammatory arthritis.

Prognosis of patients with early inflammatory arthritis (EIA) is highly variable. The aim of this study was to compare, longitudinally and cross-sectionally, the levels of cytokine-expressing cells in peripheral blood (PB) from patients with EIA to those in established rheumatoid arthritis (RA) and healthy controls (HC). PB mononuclear cells from HC (n = 30), patients with EIA (n = 20) or RA (n = 38) were stimulated with phorbol myristate acetate (PMA)/ionomycin for 3 h, and stained for cell markers and cytokines.