In a randomised controlled trial (RCT), we compared the effects of treatment with furosemide + small volumes of hypertonic saline solution (HSS) with those of furosemide alone in patients with decompensated heart failure (HF), and their effects on inflammatory and remodelling markers and epigenetic signatures.

Large-scale randomized trials have found that multivitamin-multimineral (MVM) supplements and cocoa flavanols may benefit several age-related chronic conditions among older adults, but it remains unclear whether these two supplements directly slow the biological aging process. This prespecified ancillary study evaluated the 2-year effect of a daily MVM (Centrum Silver) and cocoa extract (500 mg cocoa flavanols per day, including 80 mg (-)-epicatechin) on five DNA methylation measures of biological aging (PCHannum, PCHorvath, PCPhenoAge, PCGrimAge and DunedinPACE) among 958 participants (482 women and 476 men) in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Compared with placebo, daily MVM supplementation modestly reduced the rate of increase of second-generation epigenetic clocks, with a between-group difference in yearly change of -0.113 years (95% confidence interval (CI) -0.205 to -0.020; P = 0.017) for PCGrimAge and -0.214 years (-0.410 to -0.019; P = 0.032) for PCPhenoAge. MVM had a stronger effect on PCGrimAge among those with accelerated biological aging at baseline (-0.236 [-0.380 to -0.091]) compared with those with normal or decelerated biological aging (-0.013 [-0.130 to 0.104]; P = 0.018 for interaction). Cocoa extract did not have an effect on the five epigenetic clocks tested. Although the statistically significant but small effects of daily MVM supplementation on slowing biological aging are encouraging, additional studies are needed to determine the clinical relevance of daily MVM supplementation on epigenetic clocks and whether such effects can help explain the beneficial effects of MVM supplementation on aging-related chronic conditions.

Dravet syndrome is a severe developmental and epileptic encephalopathy caused primarily by SCN1A haploinsufficiency. Risks of sudden unexpected death in epilepsy and cognitive deficits are higher among patients with this syndrome than in the general population with epilepsy. The effects of zorevunersen, an antisense oligonucleotide designed to up-regulate NaV1.1 sodium channels, in patients with Dravet syndrome are not known.

Endometriosis is a chronic, multifactorial disorder. Reactive oxygen species (ROS) and oxidative stress (OS) contribute to the development of endometriosis by affecting apoptosis-related genes in granulosa cells. N-acetylcysteine (NAC) is an antioxidant that reduces OS. This randomized controlled trial aimed to investigate the effects of NAC on serum levels of superoxide dismutase (SOD) and total antioxidant capacity (TAC), as well as the expression of apoptotic genes in granulosa cells. Infertile women with endometriosis were enrolled and administered either NAC (1200 mg/day; n = 11) or placebo (n = 14). Enzyme-linked immunosorbent assay (ELISA) was used to measure serum SOD and TAC levels. The expression of Bcl-2, Bax, and Caspase-3 genes in granulosa cells was evaluated by Real-Time Polymerase Chain Reaction. NAC treatment increased serum SOD and TAC levels. Additionally, the expression of pro-apoptotic genes Bax and Caspase-3 in granulosa cells decreased compared to the placebo group, while the expression of the anti-apoptotic gene Bcl-2 increased. We conclude that administration of N-acetylcysteine (NAC) can reduce apoptosis in granulosa cells of women with infertility due to endometriosis.

Immune checkpoint inhibitors (ICI) have transformed cancer therapy, but their efficacy in sarcomas remains limited. A seven-gene predictive signature (CD86, CHI3L1, CXCL10, CXCL9, LAG3, NR4A1, and VCAM1) was previously identified as a biomarker for response to combined antiangiogenic and PD-1 inhibitor therapy in soft-tissue sarcomas. This study aimed to externally validate the predictive utility of this signature [SIGNature for immuno-oncology PD-1 inhibitors in sarcoma (SIGNIOS)] in an independent cohort of patients with sarcoma treated with ICIs.

Paediatric acute-onset neuropsychiatric syndrome (PANS) is a syndrome of infection-provoked abrupt-onset obsessive-compulsive disorder (OCD) or eating restriction. Based on the hypothesis that PANS is an epigenetic disorder of immune and brain function, a full-spectrum medicinal cannabinoid-rich low-THC cannabis (NTI164) was selected for its known epigenetic and immunomodulatory properties. This open-label trial of 14 children with chronic-relapsing PANS (mean age 12·1 years; range 4-17; 71 % male) investigated the safety and efficacy of 20 mg/kg/day NTI164 over 12 weeks. Clinical outcomes were assessed using gold standard tools. To define the biological effects of NTI164, blood samples were collected pre- and post-treatment for bulk and single-cell transcriptomics, proteomics, phosphoproteomics, and DNA methylation. NTI164 was well-tolerated, and 12 weeks of treatment decreased the mean Clinical Global Impression-Severity (CGI-S) score from 4·8 to 3·3 (p = 0·002). Significant improvements were observed in emotional regulation (RCADS-P, p < 0·0001), obsessive-compulsive disorder (CYBOCS-II, p = 0·0001), tics (YGTSS, p < 0·0001), attention-deficit hyperactivity disorder (Conner's, p = 0·028), and overall quality of life (EQ-5D-Y, p = 0·011). At baseline, the multi-omic approach revealed that leucocytes from patients with PANS had dysregulated epigenetic (chromatin structure, DNA methylation, histone modifications, transcription factors), ribosomal, mRNA processing, immune, and signalling pathways. These pathways were significantly modulated by NTI164 treatment. NTI164 shows promise as a disease-modifying therapeutic for PANS. Multi-omics reveal broad epigenetic and immune dysregulation in patients, which was modified by NTI164, presenting epigenetic machinery as a therapeutic target in PANS.

Lowering mutant huntingtin (HTT) gene products is a promising approach for slowing the progression of Huntington's disease (HD), a monogenic neurodegenerative disease caused by an expansion mutation in the HTT gene (NCBI Gene ID: 3064). Branaplam, an orally available HTT messenger RNA splicing modulator, reduces HTT protein levels in vitro and in animal models, and is the first splicing modulator to be evaluated in individuals with HD. Here we present the design and results of VIBRANT-HD, a randomized phase 2b study of branaplam in HD, along with preclinical findings in nonhuman primates. VIBRANT-HD utilized an innovative study design informed by our preclinical data, including targeted safety monitoring measures (for example, neurofilament light chain measurements in blood, nerve conduction studies), and staggered cohorts to capture potential neurotoxic effects early. Of the 21 participants in the initial cohort receiving branaplam 56 mg weekly, 18 (85.7%) showed at least one sign or symptom of peripheral neuropathy. This safety signal, along with dose-modeling results triggered the early termination of VIBRANT-HD. The primary outcome, a decrease in cerebrospinal fluid mutant HTT levels versus placebo, was summarized descriptively, making branaplam the first splicing modulator to lower mutant HTT levels in the cerebrospinal fluid of individuals with HD. Increased neurofilament light chain levels observed in most participants reversed after treatment discontinuation. ClinicalTrials.gov identifier: NCT05111249.

DNA methylation plays an important role in systemic lupus erythematosus (SLE) pathogenesis by regulating immune cell function and disease progression. Dietary factors, particularly methyl-donor micronutrients such as folic acid and vitamin B12, may influence DNA methylation patterns and autoimmune responses. However, their specific effects in SLE, especially in adipose tissue that is a key modulator of systemic inflammation, remain unclear. Given the high prevalence of obesity in SLE and its impact on disease severity, understanding the interaction between nutritional status, epigenetics, and immune dysregulation is crucial. This study examines whether folic acid and vitamin B12 supplementation modulate adipose tissue DNA methylation in female SLE patients, considering their nutritional status, to uncover potential mechanisms influencing disease progression and therapeutic response. This is a randomized, double-blind, placebo-controlled trial with premenopausal women with inactive SLE, classified as normal weight (NW, n = 23) or excess body weight (EBW, n = 27). Participants received daily supplementation of folic acid (400 mcg) and vitamin B12 (2000 mcg) or placebo for 12 weeks. Phenotypic characteristics and adipose tissue DNA methylation profiles were assessed before and after intervention using the Illumina EPIC BeadChip platform.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors, primarily used to treat type 2 diabetes, exhibit cardioprotective effects by improving myocardial energy metabolism, reducing oxidative stress, and modulating inflammation and fibrosis, which are critical in the context of acute myocardial infarction (AMI). Our research aims to explore the molecular mechanisms of SGLT2 inhibitors, with a focus on their influence on non-coding RNAs through sirtuins pathways, to identify novel biomarkers and therapeutic strategies for preventing heart failure following AMI.

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by the activation of the JAK-STAT pathway. Previous evidence showed that metformin might be a possible therapeutic option for treating JAK2-mediated myeloproliferative neoplasms. In vitro and in vivo studies demonstrated that metformin inhibits the JAK-STAT pathway, induces apoptosis in JAK2V617F-positive cell lines and reduces tumor burden and splenomegaly in Jak2V617F knock-in-induced mice. The FIBROMET trial, an open label phase II study, evaluated metformin effects on 10 primary myelofibrosis patients over 2 years of treatment. Primary endpoint was bone marrow fibrosis reduction. Secondary endpoints were constitutional symptoms, blood counts, spleen size modulation and exploratory evaluation of protein and gene expression. Metformin treatment reduced bone marrow collagen deposits, downregulated the STAT pathway and reduced the p85 subunit of PI3K enzymatic complex, together with endothelial maintenance genes, in PMF patients. These results raise new evidence regarding metformin, a cheap and widely available drug, as a possible adjuvant for the treatment of PMF patients.

In the phase I/II Study 22 (NCT02519348) trial, objective response rates were 24.0% with STRIDE (single tremelimumab regular-interval durvalumab), 21.3% with durvalumab plus bevacizumab (D + B), and 11.5% with durvalumab monotherapy in unresectable hepatocellular carcinoma (uHCC). Increased proliferating CD8+ T cells were associated with improved efficacy of STRIDE versus durvalumab monotherapy. Here, analyses of changes in T-cell clonal expansion and gene expression signatures (GES) in peripheral blood were performed to explore the mechanisms of action associated with the anticancer activity of STRIDE and D + B versus durvalumab monotherapy.

The NeoRHEA was a single-arm phase 2 study that included patients with estrogen receptor positive / human epidermal factor receptor 2 negative early breast cancer that received 4 cycles of neoadjuvant palbociclib and endocrine therapy. The primary outcome was baseline biomarkers of treatment resistance and secondary outcome was post-treatment transcriptional and epigenetic changes of tumor, immune and stromal cells. E2F targets and G2M checkpoint proliferation-related genes gene sets were enriched in baseline samples from resistant patients., Downregulation of E2F targets and G2M checkpoint post treatment was observed in tumor, endothelial and T cells. Gene Set Enrichment Analyses (GSEA) based on genes residing in the differentially accessible peaks revealed similar effects,. Moreover, decreases in CD8 + CD103+ tissue-resident memory cell marker genes were observed post-treatment and validated by multiplex immunohistochemistry. Our data reveal that treatment with palbociclib and endocrine therapy diminishes adaptive anti-tumor immunity by decreasing T cell proliferation and the presence of tissue-resident memory T cells NCT03065621.

MicroRNAs (miRNAs), which are non-coding RNAs of approximately 20 nucleotides in length, have attracted attention for their involvement in various biological processes and the regulation of diseases. However, the effects of foods and supplements on miRNA expression in vivo remain unclear. Onion extract tablets (OET) alleviate male menopausal symptoms and stress; however, their effects on miRNA expression in vivo are unknown. Herein, we investigated the effects of OET on miRNA expression in vivo. A randomized, double-blind, placebo-controlled study was conducted on 19 healthy Japanese participants (men and women) aged 30-65 years. Participants consumed either a placebo tablet (PT) or OET which included 30 mg of sulfur-containing amino acids daily for 2 weeks. MiRNAs prepared from plasma samples before and after intake were comprehensively analyzed using next-generation sequencing. A comparison of the variation before and after intake showed that the expression levels of three miRNAs, miR-106b-5p, miR-339-3p, and miR-181b-5p, were significantly increased in the OET group than in the PT group. Receiver operating characteristic analysis of these miRNAs also showed that miR-106b-5p had the highest discriminatory power. To our knowledge, this study is the first to show that consumption of onion extract can modulate miRNA expression in humans.

Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are debilitating psychiatric conditions associated with poor health outcomes similarly observed in non-pathological aging. Ketamine is a dissociative anesthetic and NMDA receptor antagonist with demonstrated rapid reduction in symptoms associated with Treatment Resistant Depression (TRD) and PTSD. Ketamine's effects on biological aging have not been extensively studied among patients with moderate to severe symptoms of depression and/or trauma. To address this gap, this study looked at the changes in non-epigenetic measures, DNA methylation levels, immune cell composition, and biological age based on various epigenetic biomarkers of aging, of 20 participants at baseline and after completion of a course of six ketamine 0.5 mg/kg infusions in individuals with MDD or PTSD. As expected, depression and PTSD scores decreased in participants following ketamine infusion treatments as measured by the PHQ-9 and PCL-5. We observed a reduction in epigenetic age in the OMICmAge, GrimAge V2, and PhenoAge biomarkers. In order to better understand the changes in epigenetic age, we also looked at the underlying levels of various Epigenetic Biomarker Proxies (EBPs) and surrogate protein markers and found significant changes following ketamine treatment. The results are consistent with existing literature on ketamine's effects on different biomarkers. These results underline the ability of GrimAge V2, PhenoAge, and OMICmAge in particular, to capture signals associated with key clinical biomarkers, and add to the growing body of literature on ketamine's epigenetic mechanisms and their effect on biological aging. Clinical Trial Code. NCT05294835.

Subasumstat (TAK-981) is a first-in-class inhibitor of SUMOylation that can engage innate and adaptive immune responses in tumors by enhancing type I IFN (IFNI) production. We conducted a phase I/II dose-escalation/-expansion study (NCT03648372) to investigate the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of subasumstat as a single agent in patients with advanced/metastatic solid tumors and relapsed/refractory hematologic malignancies.

To investigate the impact of glucocorticoid (GC) exposure on clock gene expression in human skeletal muscle and fat, circadian variations in peripheral interstitial glucose levels, blood pressure, total and bioactive GC levels, and sleep quality.

This study aimed to assess the efficacy of ezetimibe in combination with metformin versus metformin alone in patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and type 2 diabetes mellitus. Patients were randomly divided into two groups: one receiving ezetimibe and metformin (Met + EZY) and the other receiving metformin alone (Met group) for six months. Parameters were measured at baseline (T1), after three months (T2), and after six months (T3). The findings indicated that insulin levels and HOMA-IR exhibited a significant decrease from T1 to T2 in the Met + EZY group (p < 0.05). Malondialdehyde (MDA) and triglycerides levels also demonstrated significant decreases from T1 to T2 in the Met + EZY group (p < 0.05). The expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) and adiponectin (ADIPO) showed a significant increase from T1 to T2 in the Met + EZY group (p < 0.01). Additionally, ADIPO expression showed a significant increase from T1 to T3 (p < 0.001) in both groups. When comparing the two treatment groups, PPAR-γ and ADIPO expression were significantly higher in the Met + EZY group during T2 and T3 compared to the Met group (p < 0.001). Combination therapy appears to be more effective than metformin treatment alone and should be used cautiously.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially the only curative option for high-risk acute myeloid leukemia (AML) patients. However, disease relapse remains the principal cause of treatment failure of these patients, and outcomes of salvage treatments are poor. This research seeks to evaluate the efficacy and safety of a dual epigenetic targeting maintenance therapy with chidamide and azacitidine (AZA) in patients with high-risk AML post-allo-HSCT.

Purpose Recent studies have investigated intraperitoneal paclitaxel (IP PTX) combined with systemic chemotherapy for the treatment of gastric cancer peritoneal metastases (GCPM). This clinical trial integrated translational study was conducted to identify biomarkers that can predict patient responses to IP PTX plus systemic systemic S-1 plus oxaliplatin (SOX) chemotherapy. Materials and methods Patients from the PIPS-GC phase Ib/II clinical trial, enrolled at the Korea University Guro Hospital, were included in analyses. Whole exome and transcriptome sequencing were performed on formalin-fixed, paraffin-embedded gastric tumor, normal gastric, and peritoneal tumor tissues. A metastatic tumor-specific gene set was analyzed using The Cancer Genome Atlas (TCGA) gastric cancer data and publicly available single-cell RNA sequencing (scRNA-seq) datasets. Spatial transcriptomic analysis of primary and peritoneal tumors from a non-responder was performed to validate candidate biomarkers. Results Nine patients with gastric cancer were enrolled; six in the response group and three in the non-response group. Candidate genes for predicting IP PTX plus systemic SOX chemotherapy response were identified and compared with TCGA-GC and scRNA-seq datasets. Spatial transcriptomics revealed higher expression of thrombospondin type 1 domain-containing protein 4 (THSD4) in peritoneal tumors, which was associated with chemotherapy resistance via midkine and epithelial-mesenchymal transition pathways. Conclusion This PIPS-GC clinical trial identified THSD4 as a potential biomarker for predicting IP PTX plus systemic SOX response in gastric cancer peritoneal metastasis. Further research is required to elucidate the mechanism of action by which THSD4 affects GCPM and validate its clinical utility as a predictive biomarker for IP PTX response.

IL-13 has been implicated as a key contributor to the pathogenesis of eosinophilic esophagitis (EoE) partly on the basis of the finding that cendakimab (a humanized monoclonal anti-IL-13 antibody) significantly improved esophageal eosinophils, endoscopic severity, histology grade and stage, and clinician's assessment of severity in the HEROES phase 2 trial.