hTERT mediates gastric cancer metastasis partially through the indirect targeting of ITGB1 by microRNA-29a.

Human telomerase reverse transcriptase (hTERT) plays a key role in tumor invasion and metastasis, but the mechanism of its involvement in these processes is not clear. The purpose of this study is to investigate the possible molecular mechanism of hTERT in the promotion of gastric cancer (GC) metastasis. We found that the up-regulation of hTERT in gastric cancer cells could inhibit the expression of miR-29a and enhance the expression of Integrin β1 (ITGB1). In addition, the invasive capacity of gastric cancer cells was also highly increased after hTERT overexpression. Our study also found that the restoration of miR-29a suppressed the expression of ITGB1 and inhibited GC cell metastasis both in vitro and in vivo. Taken together, our results suggested that hTERT may promote GC metastasis through the hTERT-miR-29a-ITGB1 regulatory pathway

Withdrawal of life-support in paediatric intensive care - a study of time intervals between discussion, decision and death

<p>Abstract</p> <p>Background</p> <p>Scant information exists about the time-course of events during withdrawal of life-sustaining treatment. We investigated the time required for end-of-life decisions, subsequent withdrawal of life-sustaining treatment and the time to death.</p> <p>Methods</p> <p>Prospective, observational study in the ICU of a tertiary paediatric hospital.</p> <p>Results</p> <p>Data on 38 cases of withdrawal of life-sustaining treatment were recorded over a 12-month period (75% of PICU deaths). The time from the first discussion between medical staff and parents of the subject of withdrawal of life-sustaining treatment to parents and medical staff making the decision varied widely from immediate to 457 hours (19 days) with a median time of 67.8 hours (2.8 days). Large variations were subsequently also observed from the time of decision to actual commencement of the process ranging from 30 minutes to 47.3 hrs (2 days) with a median requirement of 4.7 hours. Death was apparent to staff at a median time of 10 minutes following withdrawal of life support varying from immediate to a maximum of 6.4 hours. Twenty-one per cent of children died more than 1 hour after withdrawal of treatment. Medical confirmation of death occurred at 0 to 35 minutes thereafter with the physician having left the bedside during withdrawal in 18 cases (48%) to attend other patients or to allow privacy for the family.</p> <p>Conclusions</p> <p>Wide case-by-case variation in timeframes occurs at every step of the process of withdrawal of life-sustaining treatment until death. This knowledge may facilitate medical management, clinical leadership, guidance of parents and inform organ procurement after cardiac death.</p

Cytogenetic and histological studies of the brook trout, Salvelinus fontinalis (Mitchill), and the Arctic char, S-alpinus (L.) hybrids

Although brook trout and the Arctic char hybrids are able to reproduce, individuals with decreased fertility or even fish that are unable to produce any gametes have been also described. Abnormal gonadal development and disturbances in the gamete production in the char hybrid offspring may be triggered by the odd chromosome number and disturbances in their pairing during meiosis. To verify this hypothesis, cytogenetic examination and the gonadal histology analysis of the brook trout x Arctic char hybrids were carried out. Diploid chromosome number in the studied char (F-1) hybrids varied from 82 to 84 (FN = 99-102). Among 28 hybrids, 12 males, three females, nine intersex individuals and two sterile specimens were described. In the case of two individuals, gonads were not found. Diploid chromosome numbers in the males and intersex individuals varied from 82 to 84. Chromosome numbers in the females were 82 and 83 chromosomes. Two sterile fish exhibited karyotypes composed of 82 and 84 chromosomes. Predominance of the ovarian component in the intersex gonads and gonadal sex ratio distortion towards the males suggested hybrid females had problems with gonadal differentiation. However, the lack of the clear relationship between chromosome number and gonadal development in the studied hybrids did not support our hypothesis that odd chromosome number may be responsible for such reproductive disturbances in the hybrid individuals. We have presumed that sterility and intersexual development of the gonads may be caused by interactions between brook trout and Arctic char genes on the sex chromosomes and autosomes rather than unpairing of the parental chromosomes.Polish National Science Center (NCN) [N N311 525240]info:eu-repo/semantics/publishedVersio

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders

Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Forgoing life support: How the decision is made in European pediatric intensive care units

Purpose: To determine how decisions to forgo life support are made in European pediatric intensive care units (PICUs). Methods: A multicenter, prospective study, the Eurydice II study, among 45 PICUs: 20 in France, 21 in Northern/Western (N/W) European countries and 4 in Eastern/Central (E/C) Europe. Data were collected between November 2009 and April 2010 through a questionnaire. Results: The decision to forgo life-sustaining treatment was made in 166 (40.6%) out of 409 deceased children (median 42.9%, France 38.2%, N/W European countries 60.0%, E/C European countries 0%; P < 0.001). In the E/C group, more patients died after cardiopulmonary resuscitation (CPR) failure than after forgoing life support (P < 0.001). In all PICUs, caregivers discussed the decision during a formal meeting, after which the medical staff made the final decision. The decision was often documented in the medical record (median 100%). The majority of the parents were informed of the final decision and were at the bedside during their child's death (median 100%). Decision to forgo life-sustaining treatment occurred in 40.6% of children, compared with 33% in Eurydice I. A high percentage of parents from France were now informed about the meeting and its conclusion as compared with Eurydice I (median 100%). Conclusions: The results of this study and comparison with the Eurydice I study (2002) show a trend towards standardization of end-of-life practices across N/W European countries and France in the past decade