The Werner Syndrome Protein Suppresses Telomeric Instability Caused by Chromium (VI) Induced DNA Replication Stress

Telomeres protect the chromosome ends and consist of guanine-rich repeats coated by specialized proteins. Critically short telomeres are associated with disease, aging and cancer. Defects in telomere replication can lead to telomere loss, which can be prevented by telomerase-mediated telomere elongation or activities of the Werner syndrome helicase/exonuclease protein (WRN). Both telomerase and WRN attenuate cytotoxicity induced by the environmental carcinogen hexavalent chromium (Cr(VI)), which promotes replication stress and DNA polymerase arrest. However, it is not known whether Cr(VI)-induced replication stress impacts telomere integrity. Here we report that Cr(VI) exposure of human fibroblasts induced telomeric damage as indicated by phosphorylated H2AX (γH2AX) at telomeric foci. The induced γH2AX foci occurred in S-phase cells, which is indicative of replication fork stalling or collapse. Telomere fluorescence in situ hybridization (FISH) of metaphase chromosomes revealed that Cr(VI) exposure induced an increase in telomere loss and sister chromatid fusions that were rescued by telomerase activity. Human cells depleted for WRN protein exhibited a delayed reduction in telomeric and non-telomeric damage, indicated by γH2AX foci, during recovery from Cr(VI) exposure, consistent with WRN roles in repairing damaged replication forks. Telomere FISH of chromosome spreads revealed that WRN protects against Cr(VI)-induced telomere loss and downstream chromosome fusions, but does not prevent chromosome fusions that retain telomere sequence at the fusion point. Our studies indicate that environmentally induced replication stress leads to telomere loss and aberrations that are suppressed by telomerase-mediated telomere elongation or WRN functions in replication fork restoration

Survey of Confidence and Knowledge to Manage Patellofemoral Pain in Readers Versus NonReaders of the Physical Therapy Clinical Practice Guideline

Objectives: To compare beliefs of physical therapists (PTs) who read the clinical practice guideline (CPG) for the management of individuals with patellofemoral pain (PFP) to those who have not read the CPG. Design: Cross-sectional study. Setting: Online survey. Participants: 494 currently licensed/registered PTs or physiotherapists. Main Outcome Measures: Respondents answered Likert-based or open-ended questions regarding the diagnosis, prognosis, risk factors, and management of individuals with PFP, as well as confidence for managing individuals with PFP, especially the ability to identify beneficial and non-beneficial interventions. We dichotomized responses into participants who read (READERS) and did not read (NonREADERS) the CPG. Results: Most respondents held inaccurate beliefs about risk factors and prognosis; however, READERS\u27 beliefs better aligned with the CPG than NonREADERS (P \u3c 0.01). Most respondents correctly agreed that hip and knee exercise was the recommended treatment strategy; yet NonREADERS believed in implementing unsupported passive treatments (P \u3c 0.01). READERS reported greater confidence in managing individuals with PFP, delivering evidence-based interventions, identifying less beneficial treatments, and locating evidence-based resources than NonREADERS (P \u3c 0.01). Conclusions: While READERS and NonREADERS held accurate beliefs for exercise-based treatment for PFP, greater knowledge translation is needed to counter inaccurate beliefs regarding risk factors, prognostic factors, and passive treatments

Validity of Devices That Assess Body Temperature During Outdoor Exercise in the Heat

Context: Rectal temperature is recommended by the National Athletic Trainers' Association as the criterion standard for recognizing exertional heat stroke, but other body sites commonly are used to measure temperature. Few authors have assessed the validity of the thermometers that measure body temperature at these sites in athletic settings

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

10.1186/s12943-023-01827-6Molecular Cancer221138