Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism.

Breast adipose tissue is an important contributor to the obesity-breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long-term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O-EVs) results in increased proliferation. RNA-seq analysis of O-EV-educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O-EV-induced cell proliferation. Several miRNAs-miR-155-5p, miR-10a-3p, and miR-30a-3p-which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing metabolic reprogramming of breast cancer cells.

Effectiveness of Repetitive Transcranial Magnetic Stimulation in Depression, Schizophrenia, and Obsessive-Compulsive Disorder: An Umbrella Meta-Analysis.

Objective: To analyze the safety and efficacy of repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder, schizophrenia, and obsessive-compulsive disorder (OCD) via umbrella meta-analysis.Data Sources: Meta-analysis studies were searched in PubMed from inception to May 2021 using the keywords anxiety, depression, ADHD, schizophrenia, mood disorder, OCD, psychiatric disorders, GAD, bipolar disorders, ASD, PTSD, transcranial magnetic stimulation, transcranial, magnetic, stimulation. PRISMA guidelines were followed.Study Selection: Abstracts and full-length articles were reviewed for meta-analysis studies with data on the safety and efficacy of rTMS and sham and were collected for quantitative analysis. The full texts of all identified studies were independently screened and assessed to determine eligibility. Any disagreement was resolved through consensus.Data Extraction: The descriptive variables extracted included the author names, study year, sample size, studies included in the meta-analysis, study period, and type of intervention.Results: 28 meta-analyses were included; 13 were on treatment-resistant depression, 9 on schizophrenia, and 6 on OCD. In treatment-resistant depression, the rTMS group had higher odds of response compared to sham (odds ratio [OR] = 3.27; 95% CI, 2.76-3.87; P < .00001) and higher odds of remission (secondary outcome) (OR = 2.83; 95% CI, 2.33-3.45; P < .00001). rTMS was superior to sham in the reduction of negative symptoms of schizophrenia (mean difference [MD]: 0.47; 95% CI, 0.23-0.7; P < .0001). However, no significant difference was found between the effects of rTMS and sham on auditory hallucinations (MD: 0.24; 95% CI, 0.26-0.74; P = .35), which resulted in 94% heterogeneity. TMS was better than sham in reducing the severity of OCD symptoms (MD: 0.81; 95% CI, 0.53-1.10; P < .00001).Conclusions: The effectiveness of rTMS for symptom reduction in various psychiatric disorders is associated with differences in neuropathology, disease-specific target site, and frequency of rTMS.Prim Care Companion CNS Disord 2023;25(5):22r03423. Author affiliations are listed at the end of this article.

Breast adipose tissue-derived extracellular vesicles from women with obesity stimulate mitochondrial-induced dysregulated tumor cell metabolism.

Breast adipose tissue is an important contributor to the obesity-breast cancer link. Dysregulated cell metabolism is now an accepted hallmark of cancer. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we found that long-term education of breast cancer cells (MCF7, T47D) with EVs from breast adipose tissue of women who are overweight or obese (O-EVs) leads to sustained increased proliferative potential. RNA-Seq of O-EV-educated cells demonstrates increased expression of genes, such as ATP synthase and NADH: ubiquinone oxidoreductase, involved in oxidative phosphorylation. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. Mitochondrial complex I inhibitor, metformin, reverses O-EV-induced cell proliferation. Several miRNAs, miR-155-5p, miR-10a-3p, and miR-30a-3p, which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing the metabolic reprogramming of ER+ breast cancer cells.

Mental health disparities amongst sexual-minority adolescents of the US - A national survey study of YRBSS-CDC.

OBJECTIVE: We aimed to evaluate the prevalence and trend of identifying as a sexual minority among the American adolescent population. Additionally, we aimed to evaluate the prevalence and odds of substance abuse, hopelessness, and suicidality among the sexual minority adolescents compared to their heterosexual peers. METHODS: We performed a retrospective cross-sectional study using Youth Risk Behavior Surveillance System (YRBSS) data from 2015 to 2019. YRBSS divides "Sexual identity" into three groups: heterosexuals, sexual minorities (gay or lesbian or bisexual), and unsure. We identified "hopelessness and suicidality" using the survey questions exploring if participants felt sad or hopeless for >2 weeks, considered suicide, made a suicide plan, and attempted suicide requiring medical care. Univariate and multivariable survey logistic regression analyses were performed to establish an association between hopelessness, suicidality, substance abuse, and identifying as a sexual minority. RESULTS: Out of 41,377 adolescents, 4055 (9.8%) identified as a sexual minority. An increasing percentage of adolescents identified themselves as a sexual minority between 2015 to 2019 (8% to 11.2%) (pTrend<0.0001). The sexual minority had a higher prevalence of feeling sad and hopeless (63.4 vs. 28.6%), considering suicide (46 vs. 14.2%), planning suicide (38.9 vs. 11.5%), attempting suicide, and having injurious suicide attempts compared to heterosexuals. (p<0.0001) Amongst sexual minorities, the prevalence of substance abuse was higher compared to their heterosexual peers, which includes cigarettes (15 vs 7.8%), e-cigarette (27.2 vs 23.2%), inhalants (14.1 vs 5.3%), cocaine (8.4 vs 3.9%), marijuana (31.2 vs 20.2%), alcohol (36.9 vs 30.3%), steroids (6.4 vs 2.2%), heroin (4.4 vs 1.2%), and injectable drugs (4.0 vs 1.1%) (p<0.0001). In regression analysis, the sexual minority had higher odds of substance abuse, feeling sad and hopeless (aOR:4.6; 95%CI:4.0-5.2; p<0.0001), considering suicide (3.2; 2.8-3.7; p<0.0001), planning suicide (2.0; 1.7-2.3; p<0.0001) compared to heterosexual. CONCLUSION: Sexual minorities not only have higher prevalence and odds of hopelessness and suicidality but also have higher prevalence and odds of substance abuse like cigarettes, marijuana, cocaine, heroin, inhalants, and steroids. Hence, early identification, risk stratification, and interventions to reduce mental health disparities are needed.

Deletion of Mechanosensory ß1-integrin From Bladder Smooth Muscle Results in Voiding Dysfunction and Tissue Remodeling.

The bladder undergoes large shape changes as it fills and empties and experiences complex mechanical forces. These forces become abnormal in diseases of the lower urinary tract such as overactive bladder, neurogenic bladder, and urinary retention. As the primary mechanosensors linking the actin cytoskeleton to the extracellular matrix (ECM), integrins are likely to play vital roles in maintaining bladder smooth muscle (BSM) homeostasis. In a tamoxifen-inducible smooth muscle conditional knockout of ß1-integrin, there was concomitant loss of α1- and α3-integrins from BSM and upregulation of αV- and ß3-integrins. Masson's staining showed a reduction in smooth muscle with an increase in collagenous ECM. Functionally, mice exhibited a changing pattern of urination by voiding spot assay up to 8 wk after tamoxifen. By 8 wk, there was increased frequency with reductions in voided volume, consistent with overactivity. Cystometrograms confirmed that there was a significant reduction in intercontractile interval with reduced maximal bladder pressure. Muscle strip myography revealed a loss of contraction force in response to electrical field stimulation, that was entirely due to the loss of muscarinic contractility. Quantitative western blotting showed a loss of M3 receptor and no change in P2X1. qPCR on ECM and interstitial genes revealed loss of Ntpd2, a marker of an interstitial cell subpopulation; and an upregulation of S100A4, which is often associated with fibroblasts. Collectively, the data show that the loss of appropriate mechanosensation through integrins results in cellular and extracellular remodeling, and concomitant bladder dysfunction that resembles lower urinary tract symptoms seen in older people.