Vitamin D regulates microbiome-dependent cancer immunity.

A role for vitamin D in immune modulation and in cancer has been suggested. In this work, we report that mice with increased availability of vitamin D display greater immune-dependent resistance to transplantable cancers and augmented responses to checkpoint blockade immunotherapies. Similarly, in humans, vitamin D-induced genes correlate with improved responses to immune checkpoint inhibitor treatment as well as with immunity to cancer and increased overall survival. In mice, resistance is attributable to the activity of vitamin D on intestinal epithelial cells, which alters microbiome composition in favor of Bacteroides fragilis, which positively regulates cancer immunity. Our findings indicate a previously unappreciated connection between vitamin D, microbial commensal communities, and immune responses to cancer. Collectively, they highlight vitamin D levels as a potential determinant of cancer immunity and immunotherapy success.

High-risk and silent clonal hematopoietic genotypes in patients with nonhematologic cancer.

ABSTRACT: Clonal hematopoiesis (CH) identified by somatic gene variants with variant allele fraction (VAF) ≥ 2% is associated with an increased risk of hematologic malignancy. However, CH defined by a broader set of genotypes and lower VAFs is ubiquitous in older individuals. To improve our understanding of the relationship between CH genotype and risk of hematologic malignancy, we analyzed data from 42 714 patients who underwent blood sequencing as a normal comparator for nonhematologic tumor testing using a large cancer-related gene panel. We cataloged hematologic malignancies in this cohort using natural language processing and manual curation of medical records. We found that some CH genotypes including JAK2, RUNX1, and XPO1 variants were associated with high hematologic malignancy risk. Chronic disease was predicted better than acute disease suggesting the influence of length bias. To better understand the implications of hematopoietic clonality independent of mutational function, we evaluated a set of silent synonymous and noncoding mutations. We found that silent CH, particularly when multiple variants were present or VAF was high, was associated with increased risk of hematologic malignancy. We tracked expansion of CH mutations in 26 hematologic malignancies sequenced with the same platform. JAK2 and TP53 VAF consistently expanded at disease onset, whereas DNMT3A and silent CH VAFs mostly decreased. These data inform the clinical and biological interpretation of CH in the context of nonhematologic cancer.

Lifestyle interventions for bipolar disorders: A systematic review and meta-analysis.

This review and meta-analysis aimed to describe the existing literature on interventions for bipolar disorder (BD) targeting the 6 pillars of Lifestyle Psychiatry: diet, physical activity (PA), substance use (SU), sleep, stress management, and social relationships (SR). Randomized Controlled Trials that examined the efficacy of lifestyle interventions targeting improvement in depressive/(hypo)manic symptom severity, lifestyle patterns, functioning, quality of life, and/or circadian rhythms were included. The systematic review included 18 studies, while the meta-analysis included studies targeting the same lifestyle domains and outcomes. Sleep (n = 10), PA (n = 9), and diet (n = 8) were the most targeted domains, while SU, SM and SR were least targeted (n = 4 each). Combined diet and PA interventions led to significant improvements in depressive symptoms (SMD: -0.46; 95%CI: -0.88, -0.04; p = 0.03), and functioning (SMD: -0.47; 95%CI: -0.89, -0.05; p = 0.03). Sleep interventions also led to significant improvements in depressive symptoms (SMD: -0.80; 95%CI: -1.21, -0.39; p < 0.01). Future research should focus on developing more multidimensional lifestyle interventions for a potentially greater impact on clinical and functional outcomes of BD.

Bipolar disorder and frontotemporal dementia: A systematic review.

OBJECTIVES: To detail the biological, clinical and neurocognitive characteristics differentiating bipolar disorder (BD) from frontotemporal dementia (FTD) and to investigate whether BD is a risk factor for FTD. METHODS: A total of 16 studies were included in this systematic review. Five studies described biological and/or neurocognitive characteristics between patients with BD and FTD, and 11 studies investigated whether BD was a risk factor for FTD. RESULTS: Individuals with FTD presented higher levels of serum neurofilament light chain, greater grey matter reduction in frontal, parietal and temporal lobes, and increased slow wave oscillations in channels F3, F4, T3, T5, T4 and T6 within an electroencephalogram (EEG), relative to individuals with BD. Patients with FTD presented greater deficits in executive function and theory of mind compared to patients with BD in a euthymic state, and more deficits in verbal fluency compared to patients with BD in a current mood episode. Patients with BD in a current mood episode showed greater impairment in attention, working memory, verbal memory and executive function relative to individuals with FTD. In addition, retrospective studies showed that 10.2%-11.6% of patients with behavioural variant FTD (bvFTD) had a preceding history of BD. CONCLUSION: Biological and neurocognitive characteristics help to distinguish between BD and FTD, and it may help to reach a more precise diagnosis. In addition, individuals with BD are at higher risk of developing FTD. More studies are needed to identify the predictors of the conversion between BD to FTD.