University of Tennessee Health Science Center

About: University of Tennessee Health Science Center is a education organization based out in Memphis, Tennessee, United States. It is known for research contribution in the topics: Population & Medicine. The organization has 15716 authors who have published 26884 publications receiving 1176697 citations.

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis.

Abstract: Importance Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice. Objective To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types. Data Sources PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018. Study Selection Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included. Data Extraction and Synthesis Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis. Main Outcomes and Measures Incidences of treatment-related adverse events and differences between different drugs and cancer types. Results This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54). Conclusions and Relevance Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.

Genetic/familial high-risk assessment: Breast, ovarian, and pancreatic, version 2.2021

Abstract: The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

CFTR regulates phagosome acidification in macrophages and alters bactericidal activity

Abstract: Acidification of phagosomes has been proposed to have a key role in the microbicidal function of phagocytes. Here, we show that in alveolar macrophages the cystic fibrosis transmembrane conductance regulator Cl- channel (CFTR) participates in phagosomal pH control and has bacterial killing capacity. Alveolar macrophages from Cftr-/- mice retained the ability to phagocytose and generate an oxidative burst, but exhibited defective killing of internalized bacteria. Lysosomes from CFTR-null macrophages failed to acidify, although they retained normal fusogenic capacity with nascent phagosomes. We hypothesize that CFTR contributes to lysosomal acidification and that in its absence phagolysosomes acidify poorly, thus providing an environment conducive to bacterial replication.

A Theoretical Analysis of Intracavitary Blood Mass Influence on the Heart-Lead Relationship

Abstract: As a result of theoretic advances made during the past 10 years, it is now feasible to record scalar and vector electrocardiograms in a manner which is independent of body shape and cardiac location. A similar independence of the body's electric inhomogeneities has not yet been achieved. On the contrary, the evidence presented here shows that inhomogeneity phases in the body, especially the intracavitary blood mass, exert a powerful influence on the heart-lead relationship. The particular effect of the intracavitary phase is to augment the manifest strength of normal components of myocardial doublets, and to reduce the manifest strength of tangential components. This augmentation-reduction effect is quantitatively predictable under conditions of simple idealization, and has been confirmed by experiments on electrocardiograpic models. The net effect of the intracavitary phase is probably to produce quasi-vectorial registration of the electromotive forces of the heart, at least during the normal depolarizat...