Blocking the mineralocorticoid receptor prevents cardiac and mitochondrial dysfunction through the activation of NOX-4 in female hormone deprivation rats

Aim: Young women exhibit lower rates of cardiovascular disease (CVD) than age-matched men, a protective effect often attributed to estrogen\u27s influence on cardiac and mitochondrial function. The risk of CVD increases in post-menopausal women, likely due to estrogen deficiency and aldosterone\u27s negative effects, including those on mitochondria and other cellular targets. This study aimed to explore the link between estrogen deficiency and mitochondrial dysfunction in cardiac health. We hypothesized that in estrogen-deprived conditions, aldosterone could stimulate NADPH oxidase, leading to mitochondrial dysfunction, and reduced cardiac contractility. Methods: Wistar rats were divided into four groups: Sham, Ovariectomy-induced hormone deprivation (Ovx), Ovx with apocynin treatment, and Ovx with spironolactone treatment for 60 days. Results: Both apocynin and spironolactone countered the adverse effects of hormone deprivation by preserving myocardial contractility, improving cellular responses to calcium and isoproterenol, and normalizing the expression of key mitochondrial proteins. These compounds also attenuated the increase in reactive oxygen species (ROS) and maintained mitochondrial respiration rates. Conclusion: We concluded that estrogen deficiency contributes to cardiac oxidative stress via the NADPH oxidase and mitochondrial pathways. Apocynin and spironolactone offer significant protective effects, opening new avenues for treating cardiac issues related to estrogen deficiency

DHX16-Associated Neuromuscular Oculoauditory Syndrome: A Novel Case

DHX16, a member of the DexD/H-box RNA helicase family, facilitates ATP-dependent unwinding of RNA secondary structures. Pathogenic variants cause poor functioning of the spliceosome complex leading to intron retention in gene transcripts. Clinically, it is associated with neuromuscular oculoauditory syndrome (MIM #618733). To date, there are nine published cases. We report a tenth case: a 3-year-old female, initially presented at 7 months of age, with mild developmental delay, ocular anomalies, dysmorphia, and increased infections. An inherited retinal disorder panel identified nondiagnostic variants of uncertain significance. Trio exome sequencing revealed a de novo Likely Pathogenic DHX16 variant, c.692G\u3eC; p.R231P. Published cases of DHX16-related disorders report developmental delay/intellectual disability, seizures, myopathy, retinal anomalies, myopia, nystagmus, and hearing loss. No published variants to date are located upstream of the start of the helicase domain, and little is known about upstream domains. In silico analysis demonstrates evidence of pathogenicity, while Missense3D modeling demonstrates no structural damage to the protein. These findings are consistent with current literature, suggesting a mechanism of pathogenicity that is difficult to assess via modeling. This case illustrates a DHX16 variant in an unknown domain displaying a mild phenotype

Neoadjuvant Therapy for Mucosal Head and Neck Squamous Cell Carcinoma: A Review From the American Head and Neck Society

IMPORTANCE: While neoadjuvant chemotherapy for head and neck squamous cell carcinoma dates to the earliest multidisciplinary approaches, the introduction of immune checkpoint inhibitors (ICIs) has renewed enthusiasm and research into its use. Although neoadjuvant therapy has remained mostly investigative through single-institutional clinical trials for mucosal head and neck squamous cell carcinoma, new data have emerged to support its use. OBSERVATIONS: A narrative review was conducted by the American Head and Neck Society to address current literature, evolving research, and gaps in knowledge surrounding neoadjuvant therapy. Neoadjuvant ICIs, most notably agents targeting anti-programmed cell death protein 1 (anti-PD-1), are a promising approach for bolstering antitumor immunity prior to ablating local structures. While neoadjuvant therapy may allow for an individualized approach, biomarkers to guide patient selection are limited. Potential benefits include de-escalation of subsequent treatment, but neoadjuvant therapy for curable disease also carries a small but real risk of progression and compromise of curative options. Measures of response include pathologic, clinical, and radiographic, but there are rapidly expanding capabilities in new diagnostics, such as circulating tumor DNA, with the emerging potential to provide objective quantification of disease burden. Further neoadjuvant strategies include response adaptive therapy, such as treatment selection/bioselection or modification of surgery, adjuvant therapy, or definitive treatment. Neoadjuvant ICI trials are summarized in this review. Optimized trial designs and additional research are needed to standardize surrogate outcomes and compare survival to standard treatment. CONCLUSIONS AND RELEVANCE: Neoadjuvant therapy can be an effective option for precision head and neck oncology bolstered by the advent of anti-PD-1 immunotherapy. However, tools for predicting and assessing treatment response remain limited. Further trials are evaluating adaptive strategies, combinations to increase efficacy, and comparisons to standard approaches

Riding the Wave of Progress: Examining the Current Landscape and Future Potential of MicroRNAs in Cancer Gene Therapy

MicroRNAs, commonly referred to as miRNAs, exert a significant impact on cellular processes by coordinating post-transcriptional gene regulation. These non-coding RNAs, which are only 22 nucleotides long, form a part of the RNA-induced silencing complex (RISC) and play a crucial role in regulating gene expression. Their complex participation in cell proliferation, differentiation, and death highlights their crucial role in maintaining cellular balance. MicroRNAs have become significant contributors in the complex field of cancer biology, operating beyond the usual tasks of cells. Their dysregulation is closely intertwined with cancer initiation and development. miRNAs act as cellular regulators and regulate complex processes of gene expression. Disruption of this regulation can result in tumor development. This review article explores the intricate process of miRNA biosynthesis and its mechanisms, providing insights into its complex interactions with cancer. It also discusses the exciting field of miRNA-based cancer treatment. Exploring the therapeutic possibilities of these small RNA molecules presents opportunities for precision medicine, introducing a new age where miRNAs can be utilized to create targeted therapeutic interventions that mainly address the abnormal genetic characteristics that cause tumor formation. miRNAs provide a harmonious balance between understanding their biology and utilizing their therapeutic potential in cancer treatment. However, they also serve as conductors and possible therapeutic instruments in the symphony of molecular biology for gene therapy

Assessing the State of Published Research Concerning COVID-19 and Transgender and Nonbinary People in the United States via a Scoping Review: Lessons Learned for Future Public Health Crises

Purpose: Transgender and nonbinary people (TNB) experienced a disproportionate burden of poor health and socioeconomic outcomes resulting from the coronavirus disease 2019 (COVID-19) pandemic, largely driven by increased vulnerability due to pervasive structural discrimination. To characterize the extent and nature of TNB inclusivity within COVID-19 research, we conducted a scoping review of studies published in English from 2019-2022 reporting COVID-19 pandemic impacts on TNB individuals in the United States. Methods: We searched PubMed (PubMed.gov), Embase (Elsevier), PsycInfo (EBSCO), Sociological Abstracts (ProQuest), and CINAHL (EBSCO), and TNB-focused organizational websites using search concepts 1) COVID-19, 2) TNB people. Studies were systematically reviewed for inclusion. Findings were extracted then summarized using systematic narrative synthesis. Results: Our search identified 1518 studies; 80 articles (65 peer-reviewed, 15 gray literature) met eligibility criteria. Most studies collected data early in the pandemic (69%) utilizing quantitative methods (79%), survey data (81%), and convenience sampling methods (65%); geographic foci varied. Many studies lacked transparent reporting on TNB involvement (80%), race/ethnicity of TNB subsamples (67%), and gender measurement (30%). The findings addressed COVID-19 (39%), mental health (29%), socioeconomics (26%), health care access (24%), physical health (13%), substance use (11%), violence/discrimination (8%), resiliency/coping (5%), gender identity/expression (5%), and sexual health (4%). Conclusions: A substantial amount of COVID-19 research inclusive of TNB people was conducted during the initial 2.5 years of the pandemic. However, there were key methodological (e.g., standardized measurement, enhanced community involvement) and topical gaps (e.g., social and structural resiliencies), which should be addressed in future research and practice to reduce TNB health disparities related to COVID-19 and future public health crises

Environmental Aromatic Amine Induces Pulmonary Arterial Hypertension Associated With Estrogen Signaling and Serpine1

4,4′-Diaminodiphenylmethane (DAPM) is an aromatic amine used in the industrial synthesis of polyurethane. In rats, acute DAPM exposure induces biliary epithelial cell injury in the liver, but subchronic exposure promotes a female-specific pulmonary arterial hypertension (PAH). PAH in humans is four times more prevalent in women than men. To shed light on mechanisms explaining the female selectivity of PAH in humans, we examined molecular pathways underlying DAPM-induced PAH in female rats. Intersections between DAPM-mediated hepatic injury and DAPM-induced PAH were also interrogated. Intact compared to ovariectomized female rats were gavaged once weekly for 12 weeks with DAPM or vehicle. Morphometric analysis in lung sections was used to quantify PAH pathology. mRNA from liver were assessed for DAPM-induced alterations in genes associated with aryl hydrocarbon receptor, estrogen response, and endothelin-1 signaling. mRNA from pulmonary arteries were subjected to transcript profiling, and pathways associated with differentially expressed genes were mapped. First, DAPM-induced PAH was exacerbated by ovariectomy. Although DAPM-mediated liver injury per se was not correlated with its induction of PAH, increases in levels of the potent vasoconstrictor endothelin-1 were exacerbated by ovariectomy and were correlated with increased expression of Edn1 in the liver. In pulmonary arteries, transcript profiling revealed that DAPM and ovariectomy interacted to dysregulate estrogen receptor, VEGF, PI3K/AKT, endothelin-1, glucocorticoid receptor, IL-17A, and idiopathic pulmonary fibrosis signaling. One of the most dysregulated genes associated with both DAPM and estrogen status was Serpine1