Transactions of the American Clinical and Climatological Association最新文献

Anthracyclines have been integral to cancer therapy for over 50 years, but their clinical use is constrained by dose-dependent cardiotoxicity. These agents target topoisomerase 2a, a critical enzyme for DNA replication, to exert their anticancer effects. Notably, while adult cardiomyocytes lack topoisomerase 2a, they do express topoisomerase 2b. Using genetic models, we demonstrated that deleting topoisomerase 2b in cardiomyocytes prevents anthracycline-induced DNA double-strand breaks, ROS production, mitochondrial dysfunction, and heart failure. These findings identify topoisomerase 2b as the key mediator of anthracycline-induced cardiotoxicity. Dexrazoxane, a Food and Drug Administration (FDA)-approved agent for preventing doxorubicin-induced cardiotoxicity, acts as a catalytic inhibitor of topoisomerases. However, this activity could potentially diminish doxorubicin's anticancer efficacy. New evidence, discovered serendipitously, shows that dexrazoxane selectively induces degradation of topoisomerase 2b without affecting topoisomerase 2a. A promising alternative approach involves pretreating with dexrazoxane prior to doxorubicin infusion. This strategy is supported by preclinical studies and is being tested in the PHOENIX trial.

Scientific fraud, particularly within medical journals, is a critical and complex issue due to the potential consequences for public health. Medical research plays a crucial role in informing scientific innovation, guiding clinical practice, and driving advancements in treatments. False or misleading research can influence future discovery, lead to ineffective or harmful treatments, waste valuable resources, and erode public trust. A troubling increase in misconduct, including data fabrication and falsification, has been recently noted, although it's unclear whether this partially reflects the development of better methods of detection. Addressing the issue of scientific fraud in medical journals requires a concerted effort from all stakeholders involved, including researchers, journal editors, peer reviewers, funding agencies, and regulatory bodies. Implementing robust measures for detecting and preventing fraud, promoting transparency and accountability in research practices, and fostering a culture of integrity and ethical conduct are all essential steps toward safeguarding the integrity of medical research.

Phosphorus metabolism disorders are independent risk factors for cardiovascular disease, kidney disease, and mortality. Given that excessive dietary phosphorus intake is prevalent in the general population and significantly contributes to disruptions in phosphorus balance, there is growing interest in limiting phosphorus intake as a potential strategy to enhance cardiovascular and kidney health. Socioeconomic status is a major determinant of phosphorus intake, as extensive epidemiological research indicates a direct correlation between income, education, and diet quality. Beyond individual socioeconomic indicators like income and education, built environment factors such as the availability of and access to healthy food outlets, as well as the density of fast-food restaurants in certain areas, greatly affect individuals' ability to moderate phosphorus consumption. Given the strong link between the built environment and diet quality, any effective strategy to reduce excess phosphorus intake and improve health outcomes must address built environmental challenges in accessing healthy foods.

In aggregate, autoimmune diseases affect at least 8% of the U.S. population, making them a significant health problem. Multiple lines of evidence accumulated over the last 20+ years have clearly demonstrated that the pathophysiology leading to autoimmune tissue damage and organ dysfunction occurs over a lengthy and clinically silent time period. As with other chronic diseases, this preclinical phase is an opportunity to identify people at risk and to develop medical and/or lifestyle interventions that can lessen the impact of disease or prevent it entirely. This will require movement away from historical disease definitions that emphasize the clinical features of tissue damage and toward more precise molecular definitions. It is a daunting task that requires large-scale epidemiological studies of immune dysfunction. Ultimately, it creates the opportunity to describe disease "stages" that give patients more clarity about their health and provide researchers, industry, and regulators with a path forward to autoimmune disease prevention.

Given that low testosterone levels predict type 2 diabetes mellitus (T2DM) in men, we sought to dissect the relationship between testosterone and insulin sensitivity in men. We showed a positive correlation between serum testosterone levels and insulin sensitivity in men across the full spectrum of glucose tolerance. Men with hypogonadal testosterone levels were twice as insulin resistant as eugonadal controls. By dissecting the hypothalamic-pituitary-gonadal axis, we demonstrated that the cause of low testosterone was a decrease in testicular responsiveness to luteinizing hormone (LH). Using functional and genetic studies, we provided evidence that hypogonadism may induce insulin resistance by causing mitochondrial dysfunction. We also showed that weight loss can increase testosterone levels and reverse hypogonadism in over 50% of obese men with impaired glucose tolerance. We concluded that the relationship between testosterone and insulin resistance in men is bidirectional. Our data emphasized the importance of lifestyle modification as a key therapeutic step in the management of the hypogonadal male.

Programmed death 1 (PD-1) pathway inhibitors have transformed cancer therapy, leading to durable responses in some patients. However, many patients do not benefit from PD-1 blockade therapy, which highlights the critical need to identify new therapeutic targets to complement PD-1 pathway inhibitors. To address this need, we have developed an in vivo clustered regularly interspaced short palindromic repeats (CRISPR)-based screening platform to discover novel regulators of anti-tumor immunity. In this article, I will first discuss the biology of the PD-1 pathway and its role in regulating anti-tumor immunity. Next, I will introduce our innovative CRISPR-based platforms designed for conducting gene screens in mature immune cell lineages and for enabling gene perturbation without stimulating or manipulating immune cells, two approaches that can affect immune cell development and function. In addition, I will illustrate how these platforms facilitate discovery of new targets that can promote anti-tumor immunity and their potential to lead to more effective cancer therapies.

Aging is a recent development in human history with nearly half of all median life expectancy gains occurring in the last two to three centuries. Aging is the strongest risk factor for medical conditions that predominately account for morbidity, mortality, and health care costs: cancer, heart disease, stroke, arthritis, and neurodegenerative disease. The geroscience hypothesis postulates that mechanisms of aging simultaneously drive multiple chronic illnesses and functional decline/disability, and intervening in the rate of aging can prevent multiple diseases. Geroscience now relies on 12 identified "hallmarks" or "pillars" of aging that involve alterations in genomic stability/repair, telomere length, epigenetics, proteostasis, macroautophagy, nutrient-sensing, mitochondrial function, cellular senescence, stem cell regeneration, intercellular communication, inflammation, and the microbiome. These pillars are mechanisms/pathways associated with aging, and evidence for causal associations is rapidly becoming more robust. Geroscience-based interventions may reduce illness burden-preserving function and independence-to a greater degree than addressing illnesses one by one. However, the pathway from promise to success is riddled with obstacles and potential pitfalls. Even success can have negative impacts on human populations and our planet that will require major shifts in society. Both the promises and perils of geroscience are likely to shape medical research and ethical debate for years to come.