SLC25A48 influences plasma levels of choline and localizes to the inner mitochondrial membrane.

Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.

Statin use in older adults with cancer - Experience from a dedicated geriatric oncology service.

INTRODUCTION: The increase in statin use, since their introduction, has been rapid and the broadening of indications has occurred seemingly without restriction. Once established on statin therapy, there is sparse research on discontinuation. Trials do not often address benefit in later life, or the impact of a life-limiting diagnosis. Data on primary prevention suggest that 100 patients need treatment for 2.5 years to prevent one major adverse cardiovascular event. Acknowledging this, we sought to determine the use of statins in a cohort of older adults with cancer, to highlight prevalence, and suggest a role for deprescribing. MATERIALS AND METHODS: Data were retrospectively collected from a prospectively maintained database of patients attending a single centre Geriatric Oncology clinic. Data collected included sex, age, cancer type and stage, systemic anti-cancer therapy (SACT) recommendation, comorbidities, non-SACT medications, and overall survival. For those receiving statin therapy, data were separated into primary prevention and stage IV cancer. RESULTS: In the group studied (n = 230), 135 (59%) were prescribed a statin, with 79 (58%) for primary prevention. Ninety-three (40%) had stage IV cancer. Of the 230 patients, 134 (58%) were recommended SACT. Within the primary prevention group, the median age was 79 years. Twenty-seven patients (34%) had stage III disease, while 36 (46%) had stage IV disease. Thirteen (16%) had diabetes mellitus. The median number of medications was seven (Interquartile range 5). Fifty patients (63%) were recommended SACT. In terms of survival, 31 (50%) were alive at one year, 18 (29%) alive at two years, and 14 (23%) alive beyond two and a half years. Within the stage IV disease group, 59 out of 93 (63%) were receiving statin therapy; 35 (59%) for primary prevention and seven (8%) for diabetes mellitus. Fifty-eight (63%) were recommended SACT. Twenty-four (29%) were alive at one year, 17 (21%) alive at two years, and 13 (16%) alive beyond two and a half years. DISCUSSION: Statin therapy is prevalent and continues into older age. Available data regarding statin therapy in older adults and survival seen in this study support deprescribing in primary prevention and life-limiting illness, such as stage IV cancer.

Vitamin B12 status and folic acid supplementation influence mitochondrial heteroplasmy levels in mice.

One-carbon metabolism is a complex network of metabolic reactions that are essential for cellular function including DNA synthesis. Vitamin B12 and folate are micronutrients that are utilized in this pathway and their deficiency can result in the perturbation of one-carbon metabolism and subsequent perturbations in DNA replication and repair. This effect has been well characterized in nuclear DNA but to date, mitochondrial DNA (mtDNA) has not been investigated extensively. Mitochondrial variants have been associated with several inherited and age-related disease states; therefore, the study of factors that impact heteroplasmy are important for advancing our understanding of the mitochondrial genome's impact on human health. Heteroplasmy studies require robust and efficient mitochondrial DNA enrichment to carry out in-depth mtDNA sequencing. Many of the current methods for mtDNA enrichment can introduce biases and false-positive results. Here, we use a method that overcomes these limitations and have applied it to assess mitochondrial heteroplasmy in mouse models of altered one-carbon metabolism. Vitamin B12 deficiency was found to cause increased levels of mitochondrial DNA heteroplasmy across all tissues that were investigated. Folic acid supplementation also contributed to elevated mitochondrial DNA heteroplasmy across all mouse tissues investigated. Heteroplasmy analysis of human data from the Framingham Heart Study suggested a potential sex-specific effect of folate and vitamin B12 status on mitochondrial heteroplasmy. This is a novel relationship that may have broader consequences for our understanding of one-carbon metabolism, mitochondrial-related disease and the influence of nutrients on DNA mutation rates.

Hospitalisation and adverse drug events in a geriatric oncology setting: A systematic review of the literature.

BACKGROUND: Geriatric Oncology is a specialty where a multidisciplinary approach can address the unmet needs of older adults with cancer. Older adults are at increased risk of adverse drug events (ADE) due to age-related changes in pharmacokinetics and pharmacodynamics, increasing treatment complexity, and medication burden. OBJECTIVES: To review the literature to determine the incidence of unplanned hospitalisation due to ADE for all medications, both systemic anticancer therapy (SACT) and non-SACT medications. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The search included the following databases: PubMed, CINAHL, and Embase. A manual search of Scopus was then performed. Study quality was assessed using the Cochrane Handbook for Systematic Reviews of Interventions, Mixed Methods Appraisal Tool (MMAT) and Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. RESULTS: Overall, three studies were included. One observational study reported 19 % of unplanned hospital admissions due to ADE in patients aged ≥70 years with cancer. The first retrospective study reported 24 % of unplanned hospital admissions are due to ADE in patients aged ≥70 years with cancer, and the second retrospective study reported 26 % of patients with metastatic melanoma treated with immune checkpoint inhibitors had an unplanned hospital admission due to an ADE. CONCLUSION: There is a paucity of studies assessing unplanned hospitalisation due to ADE in older adults with cancer. Future studies are needed and should account for the reporting of potential ADE relative to supportive care, ancillary medications, and indeed chronic medications used to treat long-standing comorbidities.

Ageing-related considerations for medication used in supportive care in cancer.

Both randomized controlled trials (RCTs) and retrospective studies have shown that a comprehensive geriatric assessment (CGA) prior to a patient commencing systemic anti-cancer therapy (SACT) results in improved quality of life outcomes and is associated with a decreased risk of grade 3-5 toxicity; however, data are lacking in relation to adverse drug events (ADE) associated with supportive care medications. Supportive care medications are prescribed as prophylactic agents in a SACT regimen, for management of treatment related toxicity and for symptoms caused by the disease itself. While necessary, the commencement of SACT and supportive medications may cause, or exacerbate, a significant drug burden in older patients, some of whom may have existing comorbidities. For many medications, older adults are underrepresented in pharmacokinetic and pharmacodynamic modelling studies. In this article we will review ageing-related changes in pharmacokinetics and pharmacodynamics, as well as how these changes may impact supportive care medications. Additional considerations for prescribing these medications in older adults with cancer, such as polypharmacy, potentially inappropriate medications, drug-drug interactions, and anticholinergic burden, as well as ageing-related considerations and recommendations for supportive care medications commonly used in older adults with cancer are also reviewed.