Conjugated Linoleic Acid-induced Hepatotoxicity Requiring Liver Transplant.

Acute liver failure (ALF) typically presents with encephalopathy and impairment in the synthetic function of the liver. Weight loss supplements have been associated with ALF, and their use has only been increasing in the United States. We report a case of a 42-year-old woman with a history of Gilbert's syndrome who presented to the hospital with ALF secondary to weight loss supplements, who ultimately required liver transplantation. This is the first known case of conjugated linoleic acid (CLA) toxicity requiring liver transplantation in the United States.

Risk Factors for Early Treatment Discontinuation Due to Toxicity Among Patients With Metastatic Castration-resistant Prostate Cancer Receiving Androgen Receptor-targeted Therapy.

OBJECTIVES: Androgen receptor-targeted therapies (ARTs) improve survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC); however, a significant portion of patients discontinue treatment for various reasons including treatment-related toxicity. We aim to describe reasons for ART treatment discontinuation and identify predictors associated with increased risk of treatment discontinuation due to toxicity. METHODS: We performed a single-institution retrospective review of patients with mCRPC receiving ART between 2010 and 2021. Our primary aim was to identify risk factors for treatment discontinuation due to toxicity. Our secondary aim was to describe ART discontinuation patterns among patients with mCRPC. RESULTS: One hundred thirty-three patients with mCRPC started and discontinued ARTs. Fourteen patients (10.5%) discontinued treatment due to toxicity. Common reasons for treatment discontinuation include Prostate Specific Antigen test progression, radiographic progression, toxicity, and death. Significant predictors of treatment discontinuation due to toxicity on bivariate analysis and multivariate analysis included patient-reported falls (odds ratio [OR]: 7.67, CI: [1.31-40.42]; P =0.016), rash (OR: 13.4, CI: [1.35-134.81]; P =0.026), and weakness (OR: 4.16, CI: [1.15-15.0]; P =0.019). CONCLUSIONS: Our work presents the first description of ART treatment discontinuation and its causes in the real-world setting, as well as patient-reported side effects. Most patients with mCRPC discontinued treatment due to the progression of disease and a minority of patients discontinued secondary to treatment toxicity. Initial multivariable analysis suggests that patient-reported weakness, falls, and rash were associated with a higher likelihood of treatment discontinuation due to toxicity. Early monitoring of this population can prolong the duration of treatment and prevent unnecessary treatment burden.

Performance Status and End-of-Life Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Androgen Receptor Targeted Therapy.

OBJECTIVES: Androgen receptor targeted therapies (ARTs) are widely preferred over taxane chemotherapy due to their good tolerability and similar efficacy. However, there is a paucity of data that support the use of ART therapy or describe end-of-life (EOL) outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) with reduced performance status (PS) (European Cooperative Oncology Group [ECOG] ≥2). METHODS: We performed a retrospective, single-institution study of 142 patients with mCRPC who received ART therapy between 2010 and 2021. We assessed each record for baseline demographic and clinical information, ART treatment course, and survival and EOL outcomes. Our primary aim was to compare overall survival (OS) between the two groups (ECOG ≥2 vs 0 to 1), and our secondary aim was to describe EOL outcomes. Fisher exact tests and Wilcoxon signed-rank tests were used to compare baseline characteristics. Cox regression was used to compare OS for patients with ECOG ≥2 at the start of treatment with those who had an ECOG of 0 or 1. Descriptive analyses were performed to assess EOL outcomes between the groups. RESULTS: Patients with mCRPC and decreased PS experienced shorter OS on ART compared with those with higher PS. Moreover, when examining EOL outcomes, a near majority of these patients died in the hospital, with a greater percentage among those with an ECOG ≥2. CONCLUSION: These findings highlight the need for continual assessment of PS, improved shared decision-making in ART treatment, and additional research exploring the association between PS and EOL outcomes.

Astronauts Plasma-Derived Exosomes Induced Aberrant EZH2-Mediated H3K27me3 Epigenetic Regulation of the Vitamin D Receptor.

There are unique stressors in the spaceflight environment. Exposure to such stressors may be associated with adverse effects on astronauts' health, including increased cancer and cardiovascular disease risks. Small extracellular vesicles (sEVs, i.e., exosomes) play a vital role in intercellular communication and regulate various biological processes contributing to their role in disease pathogenesis. To assess whether spaceflight alters sEVs transcriptome profile, sEVs were isolated from the blood plasma of 3 astronauts at two different time points: 10 days before launch (L-10) and 3 days after return (R+3) from the Shuttle mission. AC16 cells (human cardiomyocyte cell line) were treated with L-10 and R+3 astronauts-derived exosomes for 24 h. Total RNA was isolated and analyzed for gene expression profiling using Affymetrix microarrays. Enrichment analysis was performed using Enrichr. Transcription factor (TF) enrichment analysis using the ENCODE/ChEA Consensus TF database identified gene sets related to the polycomb repressive complex 2 (PRC2) and Vitamin D receptor (VDR) in AC16 cells treated with R+3 compared to cells treated with L-10 astronauts-derived exosomes. Further analysis of the histone modifications using datasets from the Roadmap Epigenomics Project confirmed enrichment in gene sets related to the H3K27me3 repressive mark. Interestingly, analysis of previously published H3K27me3-chromatin immunoprecipitation sequencing (ChIP-Seq) ENCODE datasets showed enrichment of H3K27me3 in the VDR promoter. Collectively, our results suggest that astronaut-derived sEVs may epigenetically repress the expression of the VDR in human adult cardiomyocytes by promoting the activation of the PRC2 complex and H3K27me3 levels.

Emerging Role of Exosomal Long Non-coding RNAs in Spaceflight-Associated Risks in Astronauts.

During spaceflight, astronauts are exposed to multiple unique environmental factors, particularly microgravity and ionizing radiation, that can cause a range of harmful health consequences. Over the past decades, increasing evidence demonstrates that the space environment can induce changes in gene expression and RNA processing. Long non-coding RNA (lncRNA) represent an emerging area of focus in molecular biology as they modulate chromatin structure and function, the transcription of neighboring genes, and affect RNA splicing, stability, and translation. They have been implicated in cancer development and associated with diverse cardiovascular conditions and associated risk factors. However, their role on astronauts' health after spaceflight remains poorly understood. In this perspective article, we provide new insights into the potential role of exosomal lncRNA after spaceflight. We analyzed the transcriptional profile of exosomes isolated from peripheral blood plasma of three astronauts who flew on various Shuttle missions between 1998-2001 by RNA-sequencing. Computational analysis of the transcriptome of these exosomes identified 27 differentially expressed lncRNAs with a Log2 fold change, with molecular, cellular, and clinical implications.