Tuttlebuckley1805

Ciclopirox (CPX) modulates multiple cellular pathways involved in the growth of a variety of tumor cell types. However, the effects of CPX on colorectal cancer (CRC) and the underlying mechanisms for its antitumor activity remain unclear. Herein, we report that CPX exhibited strong antitumorigenic properties in CRC by inducing cell cycle arrest, repressing cell migration, and invasion by affecting N-cadherin, Snail, E-cadherin, MMP-2, and MMP-9 expression, and disruption of cellular bioenergetics contributed to CPX-associated inhibition of cell growth, migration, and invasion. Interestingly, CPX-induced reactive oxygen species (ROS) production and impaired mitochondrial respiration, whereas the capacity of glycolysis was increased. CPX (20 mg/kg, intraperitoneally) substantially inhibited CRC xenograft growth in vivo. Mechanistic studies revealed that the antitumor activity of CPX relies on apoptosis induced by ROS-mediated endoplasmic reticulum (ER) stress in both 5-FU-sensitive and -resistant CRC cells. Our data reveal a novel mechanism for CPX through the disruption of cellular bioenergetics and activating protein kinase RNA-like endoplasmic reticulum kinase (PERK)-dependent ER stress to drive cell death and overcome drug resistance in CRC, indicating that CPX could potentially be a novel chemotherapeutic for the treatment of CRC.Many empirical networks incorporate higher order relations between elements and therefore are naturally modelled as, possibly directed and/or weighted, hypergraphs, rather than merely as graphs. In order to develop a systematic tool for the statistical analysis of such hypergraph, we propose a general definition of Ricci curvature on directed hypergraphs and explore the consequences of that definition. The definition generalizes Ollivier's definition for graphs. It involves a carefully designed optimal transport problem between sets of vertices. While the definition looks somewhat complex, in the end we shall be able to express our curvature in a very simple formula, [Formula see text]. This formula simply counts the fraction of vertices that have to be moved by distances 0, 2 or 3 in an optimal transport plan. We can then characterize various classes of hypergraphs by their curvature.Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC.An amendment to this paper has been published and can be accessed via a link at the top of the paper.Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases. We recently showed decreased SIRT7 expression in lung tissues and fibroblasts from patients with pulmonary fibrosis compared to controls. To gain insight into aging-related mechanisms in ALI, we investigated the effects of SIRT7 depletion on lipopolysaccharide (LPS)-induced inflammatory responses and endothelial barrier permeability in human primary pulmonary endothelial cells. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuated LPS-induced increases in ICAM1, VCAM1, IL8, and IL6 and induced endomesenchymal transition (EndoMT) with decreases in VE-Cadherin and PECAM1 and increases in collagen, alpha-smooth muscle actin, TGFβ receptor 1, and the transcription factor Snail. Loss of endothelial adhesion molecules was accompanied by increased F-actin stress fibers and increased endothelial barrier permeability. Together, these results show that an aging phenotype induced by SIRT7 deficiency promotes EndoMT with impaired inflammatory responses and dysfunction of the lung vascular barrier.

Cross-sectional pilot study on spinal cord injury (SCI) among in- and outpatients.

To evaluate the challenges faced by individuals with SCI during Clean Intermittent Catheterisation (CIC).

Kilimanjaro Christian Medical Center (KCMC), a tertiary referral hospital in Moshi, Tanzania.

A questionnaire was sent to individuals with SCI who were either admitted to the Orthopedic Rehabilitation Unit or attended the Outpatient clinic between January and April 2018. Navitoclax mouse Inpatients were less than 1 year post-injury and outpatients were one to 3 years post-injury.

In total, 48 individuals responded 28 outpatients and 20 inpatients. Among the inpatient group, 80% were performing CIC as compared with 25% of outpatient group. Of the entire cohort, 35.4% reported doing well without catheter-based management. Failure to perform CIC was present in 16.7% of all individuals. CIC-equipment was unavailable in local villages for 58.3% of all patients. The most frequent complications of CIC were urinary tract infections (20.8%) and mild bleeding (14.6%). The majority of individuals (79.2%) reported satisfaction with their situation, regardless of the severity.

Some individuals performed CIC upon discharge, but the majority discontinued use, for which unavailability of CIC-equipment was a major determinant. While all individuals reported concerns prior to CIC, only a small minority actually experienced anxiety, pain or shame. Through targeted counselling and enhanced regular follow-up we will likely improve compliance to CIC.

We are grateful to the International Network of SCI Nurses in collaboration with Wellspect Health Care for funding this study.

We are grateful to the International Network of SCI Nurses in collaboration with Wellspect Health Care for funding this study.