Gastrointestinal toxicities of proteasome inhibitor therapy.

PURPOSE: Proteasome inhibitors (PIs), which cause cell death via tumor suppressor and pro-apoptotic proteins, are integral to treatment of many hematologic malignancies but are limited by their gastrointestinal adverse effects. Evidence regarding these PI-related adverse effects is scant. In this study, we evaluated gastrointestinal adverse events caused by PIs and compared gastrointestinal toxicities between bortezomib, carfilzomib, and ixazomib. METHODS: We conducted a retrospective study of cancer patients treated with PIs at a tertiary care cancer center to investigate the clinical characteristics of PI-related gastrointestinal adverse events. RESULTS: Our sample comprised 973 patients with PI exposure and stool studies ordered between January 2017 and December 2022. Of these, 193 patients (20%) had PI-related gastrointestinal toxicity based on clinical symptoms and stool study results. The most common symptom was diarrhea, present in 169 (88% of those with gastrointestinal toxicity). Twenty-two (11%) required hospitalization, and 71 (37%) developed recurrence of symptoms. Compared to bortezomib or carfilzomib, ixazomib had a longer interval from PI initiation to the onset of gastrointestinal symptoms (313 days vs 58 days vs 89 days, p = 0.002) and a significantly lower percentage of diarrhea-predominant presentation of gastrointestinal toxicity (71% vs 96% vs 91%, p = 0.048). CONCLUSION: While PI-related gastrointestinal toxicities have various presentations and courses based on different regimens, the vast majority of patients presented with milder disease behavior. Despite a considerably high rate of hospitalization and recurrence after treatment necessitating optimization of clinical management, our cohort demonstrates favorable outcomes without long-term consequences.

Cost Barriers to More Widespread Use of Peritoneal Dialysis in the United States.

The United States Department of Health and Human Services launched the Advancing American Kidney Health Initiative in 2019, which included a goal of transforming dialysis care from an in-center to a largely home-based dialysis program. A substantial motivator for this transition is the potential to reduce costs of ESKD care with peritoneal dialysis. Studies demonstrating that peritoneal dialysis is less costly than in-center hemodialysis have often focused on the perspective of the payer, whereas less consideration has been given to the costs of those who are more directly involved in treatment decision making, including patients, caregivers, physicians, and dialysis facilities. We review comparisons of peritoneal dialysis and in-center hemodialysis costs, focusing on costs incurred by the people and organizations making decisions about dialysis modality, to highlight the financial barriers toward increased adoption of peritoneal dialysis. We specifically address misaligned economic incentives, underappreciated costs for key stakeholders involved in peritoneal dialysis delivery, differences in provider costs, and transition costs. We conclude by offering policy suggestions that include improving data collection to better understand costs in peritoneal dialysis, and sharing potential savings among all stakeholders, to incentivize a transition to peritoneal dialysis.

Optogenetic control of Bacillus subtilis gene expression.

The Gram-positive bacterium Bacillus subtilis exhibits complex spatial and temporal gene expression signals. Although optogenetic tools are ideal for studying such processes, none has been engineered for this organism. Here, we port a cyanobacterial light sensor pathway comprising the green/red photoreversible two-component system CcaSR, two metabolic enzymes for production of the chromophore phycocyanobilin (PCB), and an output promoter to control transcription of a gene of interest into B. subtilis. Following an initial non-functional design, we optimize expression of pathway genes, enhance PCB production via a translational fusion of the biosynthetic enzymes, engineer a strong chimeric output promoter, and increase dynamic range with a miniaturized photosensor kinase. Our final design exhibits over 70-fold activation and rapid response dynamics, making it well-suited to studying a wide range of gene regulatory processes. In addition, the synthetic biology methods we develop to port this pathway should make B. subtilis easier to engineer in the future.