Transactions of the American Clinical and Climatological Association最新文献

The only Food and Drug Administration (FDA)-approved biomarker for prediction of acute kidney injury (AKI) in adults has a false positive rate (FPR) of 50%. We identified insulin-like growth factor-binding protein 1 (IGFBP-1) as a good but not great predictor of severe AKI. IGFBP-1 was cleaved by an enzyme in the urine. We tested the ability of IGFBP-1 cleavage to predict progression to dialysis. Urine from all 12 patients with stage 1 AKI that progressed to require dialysis cleaved the protein (100% sensitivity). FPR was 0% among healthy controls. FPRs among patients with stage 1 AKI at the time of collection were 11% for patients who did not progress beyond stage 1, 15% for patients who progressed to stage 2, and 50% for patients who progressed to stage 3 but did not require dialysis. The sensitivity of a test with these characteristics would be 100% in a typical intensive care unit (ICU) population, and the FPR would be 6%.

A critical adaptation required for successful extrauterine life is the onset of respiration. The production of pulmonary surfactant by alveolar type II (AT2) cells is required for functional ventilation. Pulmonary surfactant is produced in lamellar bodies in AT2 cells. Key components of pulmonary surfactant include phospholipids and surfactant proteins B (SP-B) and C (SP-C). Phospholipids are transported into lamellar bodies by ATP-binding cassette subfamily A member 3 (ABCA3) where they combine with SP-B and -C to form surfactant that is secreted into alveoli. Recessive loss of function mutations in surfactant protein B (SFTPB) and ABCA3, or monoallelic dominant mutations in surfactant protein C (SFTPC), can cause severe respiratory distress in term newborns, later-onset childhood interstitial lung disease (ChILD), or adult-onset ILD. Currently, no specific treatments for these diseases are available. Genetic therapies, including gene addition and gene editing strategies, offer the possibility to correct these defects in AT2 progenitor cells.

Otto Warburg sparked the field of cancer metabolism in the 1920s through his observations that human and animal cancer tissues converted significant amounts of glucose to lactate with an elusive underlying mechanism. The discovery of oncogenes led to the notion that neoplasia results from deregulated cell division control with metabolism at the margin, standing by to support cell growth. Studies over the past several decades have linked oncogenes to the direct regulation of metabolism, such as the myelocytomatosis (MYC) oncogene, driving glycolysis and other central metabolic pathways, necessary for cell growth and proliferation. Deregulated oncogenic drive of metabolism renders tumor cells addicted to glucose and other nutrients, such that nutrient deprivation can trigger cancer cell death. The revelation of this addiction stimulated pharmaceutical companies to target metabolism for cancer therapy, but due to several failed clinical studies, this exuberance fizzled commercially. However, the transformative impact of cancer immunotherapy ushered in an interest in understanding the hostile metabolic tumor microenvironment that limits the function of anti-tumor T cells and clinical responses to immunotherapy. This interest drives the convergence of immunometabolism and cancer cell metabolism research to provide a richer understanding of tumor metabolic vulnerability. Herein, I discuss the historical and current context of opportunities and challenges to targeting cancer metabolism.

Calcium-permeable transient receptor potential cation channel subfamily V member 4 (TRPV4) channels, first described in 2000, are activated by osmotic, mechanical, thermal, actinic, and chemical cues; play multiple roles in multiple physiologic processes, organ systems, and diseases; and are expressed in diverse cell lineages, with channel function-expression regulated by metabolic and endocrine state, inflammation, mechanical microenvironment, and other forms of cellular stress. Here, I will focus on TRPV4's role in endothelia, citing three examples that can guide translational efforts and development of TPRV4-focused therapeutics. (i) Peroxynitrite-dependent impairment of endothelial TRPV4 drives obesity-related hypertension. (ii) Blood-brain barrier in MS: TRPV4 drives endothelial inflammation and pro-inflammatory interaction between endothelia and microglia in active lesions. (iii) Gain-of-function spinal cord endothelial TRPV4 causes spinal muscular atrophy via developmental barrier impairment, leakage, and subsequent motoneuron injury. Thus, different pathophysiologic mechanisms need to be met with different strategies when selectively targeting endothelial TRPV4, namely restoration of impaired function (i), versus inhibition of excessive function (ii)-(iii).

As the state's land-grant research institution, we implemented a transdisciplinary research strategy in the College of Medicine (COM) forming multiple research teams selected with criteria for success and progress. To assess for key factors, we reviewed the literature and data from studies conducted at the University of Kentucky (UK) that included a quantitative study with a mixed-methods approach to assess team dynamics, collaboration, and research outcomes, as well as a qualitative study (1,2). Team interactions were positively associated with scholarly products. We also experienced an approximate doubling of the COM National Institutes of Health (NIH) funding over four years. Based on these data and experiences, we developed a process for future team building. In summary, we describe a team-based model with consideration of evidential criteria for structure, monitoring, and success metrics, and we developed a process that could be used by leadership to develop transdisciplinary teams across the university for research, education, or service.