Protection of murine bone marrow by dexamethasone during cytotoxic chemotherapy

Corticosteroids have the ability to suppress the production of growth factors and cytokines and are thus implicated in the negative regulation of hematopoiesis. We have shown that the corticosteroids, prednisolone and dexamethasone, were able to effectively protect progenitor cells in four strains of mice against cell-cycle-specific antimetabolic chemotherapy agents. The highest levels of protection against 5-fluorouracil (FU; 200 mg/kg) were achieved when two or three intraperitoneal injections of dexamethasone were administered between - 7 and +3 hours at a dose of 7.5 mg/kg/injection (optimal dose) or by continuous infusion between -4 and +20 hours. This protective effect is manifested as an increase in the number of high proliferative potential colony-forming cells that survive in the bone marrow 3 days after treatment with FU from between 0.5% and 11% to between 10% and 34% of normal. The bone marrow progenitors and blood cell numbers return to normal from 3 to 5 days and 1 to 2 days earlier, respectively. Less dexamethasone than prednisolone is required to give an equivalent protective effect, which is consistent with their anti-inflammatory potency. These findings are further evidence of the negative regulatory role played by corticosteroids, and indicate that the treatment schedules of corticosteroids during cancer therapy need to be reexamined to obtain the maximum benefit from their use.     

Plasma Renin Activity and Its Association With Ischemic Heart Disease,Congestive Heart Failure,and Cerebrovascular Disease in a Large Hypertensive Cohort

Plasma renin activity (PRA) may be a surrogate for vascular damage. The authors hypothesize that PRA is associated with cardiovascular and cerebrovascular disease (CED). A cross‐sectional study (January 1, 1998, to December 31, 2009) was performed on hypertensive individuals 18 years and older using multivariable logistic regression models to estimate odds ratios (ORs) for ischemic heart disease (IHD), congestive heart failure (CHF), and CED based on PRA quartiles controlling for age, sex, race, diabetes mellitus (DM), and medication use. Among 7887 individuals (60% women; 34% whites, 23% blacks, and 19% Hispanics; and 29% with DM), the adjusted ORs (95% CI) for IHD were 0.94 (0.80–1.10), 1.09 (0.92–1.29), and 1.18 (1.00–1.39); for CHF were 1.23 (0.99–1.53), 1.27 (1.01–1.61), and 1.41 (1.13–1.77); and for CED were 0.95 (0.78–1.17), 0.77 (0.61–0.97), and 0.97 (0.78–1.20) for the second, third, and fourth quartiles compared with the first quartile. Higher PRA was associated with greater likelihood for prevalent IHD and CHF but not CED in this large ethnically diverse population of hypertensive individuals.     

Xenophagy in Helicobacter pylori‐ and Epstein–Barr virus‐induced gastric cancer

Helicobacter pylori and Epstein–Barr virus (EBV) account for roughly 80% and 10%, respectively, of gastric carcinomas worldwide. Autophagy is an evolutionarily conserved and intricately regulated cellular process that involves the sequestration of cytoplasmic proteins and organelles into double‐membrane autophagosomes that eventually fuse with lysosomes for degradation of the engulfed content. Emerging evidence indicates that xenophagy, a form of selective autophagy, plays a crucial role in the pathogenesis of H. pylori‐ and EBV‐induced gastric cancer. Xenophagy specifically recognizes intracellular H. pylori and EBV and physically targets these pathogens to the autophagosomal–lysosomal pathway for degradation. In this connection, H. pylori or EBV‐induced dysregulation of autophagy may be causally linked to gastric tumourigenesis and therefore can be exploited as therapeutic targets. This review will discuss how H. pylori and EBV infection activate autophagy and how these pathogens evade recognition and degradation by the autophagic pathway. Elucidating the molecular aspects of H. pylori‐ and EBV‐induced autophagy will help us better understand the pathogenesis of gastric cancer and promote the development of autophagy modulators as antimicrobial agents. Published by John Wiley & Sons, Ltd     

Atomic layout of an orthodontic titanium mini-implant in human tissue: Insights into the possible mechanisms during osseointegration

Objectives:To evaluate nanoscale molecular interactions in the interface between human bone and orthodontic titanium implants.Materials and Methods:An orthodontic implant (sandblasted with large grit and with an acid-etched surface treated with Ti6A14V alloy) retrieved from the mandible of human after 2 months of healing was used to analyze the molecular interactive mechanism between the implant and the surrounding bone tissue. To preserve the natural state of the sample as much as possible, cryofixation and scanning electron microscope/focused ion beam milling without any chemical treatment were used during sample preparation. Atom probe tomography was used to investigate the chemical composition and structure at the interface between the implant and human bone tissue.Results:Three-dimensional (3D) reconstruction of the whole sample revealed a 20 × 50-nm² plate-like bony element diffusion layer in the sample. The iso concentration analysis of the diffusion layer indicated that the bony element, calcium, and the implant element, titanium oxide, were interspersed with each other. Detailed ionic distribution was illustrated by 3D reconstruction with partial region of interest and one-dimensional concentration profiles of the implant-bone interface.Conclusions:The study results advance nanoscale understanding of osseointegration and suggest a potential nanostructure for increasing bond strength of biomaterials to bone.