Transactions of the American Clinical and Climatological Association最新文献

Despite significant improvement in overall cancer mortality (>30% since 1991), these survival benefits have not been experienced by all groups uniformly especially in those of diverse heritage. Drivers of cancer health inequity are multi-factorial including more adverse social determinants of health, later stage cancer presentation, decreased health care access, decreased health literacy, and cultural barriers to prompt cancer care. Adding to these disparities is the historical inclusion of primarily well-insured Caucasian patients into cancer clinical trials leading to deep gaps in understanding both the efficacy and safety of new therapies in the actual populations for which these medications will be used. The need for trial accruals to reflect the U.S. population (i.e., diverse) is essential across diseases, but especially those in which certain minority populations are overrepresented (Latinos and hepatocellular carcinoma, African Americans and myeloma and prostate cancer). Strategies and new legislation to increase diversity in trial accruals are outlined and discussed.

Dr. Chi-yuan Hsu describes controversies surrounding the race coefficient ("if African American") in widely used kidney function estimating equations. He outlines recent research results on this topic by himself and others and comments on the relationship between activists and the academic medical community.

Glucose toxicity is central to the myriad complications of diabetes and is now believed to encompass neurodegenerative diseases and cancer as well as microvascular and macrovascular disease. Due to the widespread benefits of SGLT2 inhibitors, which affect glucose uptake in the kidney proximal tubular cell, a focus on cell metabolism in response to glucose has important implications for overall health. We previously found that a -Warburg-type effect underlies diabetic kidney disease and involves metabolic reprogramming. This is now supported by quantitative measurements of superoxide measurement in the diabetic kidney and systems biology analysis of urine metabolites in patients. Further exploration of mechanisms underlying mediators of mitochondrial suppression will be critical in understanding the chronology of glucose-induced toxicity and developing new therapeutics to arrest the systemic glucose toxicity of diabetes.

Voltage gated Na channels (Na_V) are essential for excitation of tissues. Mutations in Na_Vs cause a spectrum of human disease from autism and epilepsy to cardiac arrhythmias to skeletal myotonias. The carboxyl termini (CT) of Na_V channels are hotspots for disease-causing mutations and are richly invested with protein interaction sites. We have focused on the regulation of Na_V by two proteins that bind in this region: calmodulin (CaM) and non-secreted fibroblast growth factors (iFGF or FHF). CaM regulates Na_V gating, mediating Ca²⁺-dependent inactivation (CDI) in a channel isoform-specific manner, while Ca²⁺-free CaM (apo-CaM) binding broadly regulates Na_V opening and suppresses the arrhythmogenic late Na current (I_Na-L). FHFs inhibit CDI, in Na_V isoforms that exhibit this property, and potently suppress I_Na-L, the latter requiring the amino terminus of the FHF. A peptide comprised of the first 39 amino acids of FHF1_A is sufficient to inhibit I_Na-L, constituting a credible specific antiarrhythmic.