Targeting maternal gut microbiome to improve mental health outcomes—a pilot feasibility trial

BackgroundPerinatal depression and anxiety (PDA) is prevalent in new and expectant mothers, affecting millions of women worldwide. Those with a history of mood and anxiety disorders are at the greatest risk of experiencing PDA in a subsequent pregnancy. Current safety concerns with pharmacological treatments have led to a greater need for adjunctive treatment options for PDA. Changes in the composition of the microbiome have been associated with various diseases during pregnancy, and these changes are thought to play some role in perinatal mood disorders. While the relationship between PDA and the microbiome has not been explored, evidence suggests that nutritional interventions with fiber, fish oils, and probiotics may play a favorable role in neuropsychiatric outcomes during and after pregnancy. The primary objective of the present study is to assess the feasibility and acceptability of a combination of nonpharmacological interventions to maintain stability in pregnant women who have a history of depression and/or anxiety. This study will also aim to understand ease of recruitment and protocol adherence in this cohort.MethodsThis is a single-centered, partially randomized, placebo-controlled, double-blind feasibility trial. One hundred pregnant women with a history of depression and/or anxiety/PDA will be recruited and randomized into one of four arms, which could include the following: receiving a daily dose of both investigational products and dietary counseling on increasing dietary fiber, receiving a daily dose of both investigational drugs only, receiving fish oil investigational product and placebo, and a control arm with no intervention. The study involves six study visits, all of which can be conducted virtually every 3 months from the time of enrollment. At all study visits, information on diet, mental health, physical activity, and sleep quality will be collected. Additionally, all participants will provide a stool sample at each visit.DiscussionIt is anticipated that pregnant women with a history of depression and anxiety will be particularly interested in partaking in this trial, resulting in favorable recruitment rates. Given the positive findings of omega-3 fatty acids (O3FAs) and probiotic supplements on mental health symptoms in nonpregnant adults, we expect a similar trend in PDA symptoms, with a low likelihood of adverse events. This study will build the foundation for larger powered studies to further contribute evidence for the efficacy of this potential preventative treatment option.Trial registrationThis trial was registered at ClinicalTrials/gov on October 6, 2023; NCT06074250. Trial Sponsor: The Canadian College of Naturopathic Medicine, 1255 Sheppard Ave E, Toronto, ON M2K 1E2, 416-498-1255

The effect of telephone-based interpersonal psychotherapy for the treatment of postpartum depression: study protocol for a randomized controlled trial

BACKGROUND: Substantial data indicate potential health consequences of untreated postpartum depression (PPD) on the mother, infant, and family. Studies have evaluated interpersonal psychotherapy (IPT) as treatment for PPD; however, the results are questionable due to methodological limitations. A comprehensive review of maternal treatment preferences suggests that mothers favor ‘talking therapy’ as a form of PPD treatment. Unfortunately, IPT is not widely available, especially in rural and remote areas. To improve access to care, telepsychiatry has been introduced, including the provision of therapy via the telephone. METHODS/DESIGN: The purpose of this randomized controlled trial is to evaluate the effect of telephone-based IPT on the treatment of PPD. Stratification is based on self-reported history of depression and province. The target sample is 240 women. Currently, women from across Canada between 2 and 24 weeks postpartum are able to either self-identify as depressed and refer themselves to the trial or they may be referred by a health professional based on a score >12 on the Edinburgh Postnatal Depression Scale (EPDS). Following contact by the trial coordinator, a detailed study explanation is provided. Women who fulfill the eligibility criteria (including a positive diagnostic assessment for major depression) and consent to participate are randomized to either the control group (standard postpartum care) or intervention group (standard postpartum care plus 12 telephone-based IPT sessions within 12 to 16 weeks, provided by trained nurses). Blinded research nurses telephone participants at 12, 24, and 36 weeks post-randomization to assess for PPD and other outcomes including depressive symptomatology, anxiety, couple adjustment, attachment, and health service utilization. Results from this ongoing trial will: (1) develop the body of knowledge concerning the effect of telephone-based IPT as a treatment option for PPD; (2) advance our understanding of training nurses to deliver IPT; (3) provide an economic evaluation of an IPT intervention; (4) investigate the utility of the EPDS in general clinical practice to identify depressed mothers; and (5) present valuable information regarding PPD, along with associated couple adjustment, co-morbid anxiety and self-reported attachment among a mixed rural and urban Canadian population. TRIAL REGISTRATION: Current Controlled Trials Ltd. ISRCTN88987377

Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial

Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative ‘BRCAness’ subgroups—tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes—may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker–treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection

Meta-analyses of genome-wide association studies for postpartum depression

Objective: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. Method: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)–based heritability (), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. Results: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. Conclusions: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone)

Genomic–transcriptomic evolution in lung cancer and metastasis

Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic–transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary–metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response