m6A-modified RIPK4 facilitates proliferation and cisplatin resistance in epithelial ovarian cancer.

BACKGROUND: Cisplatin (DDP)-based chemotherapy is a common chemotherapeutic regimen for the treatment of advanced epithelial ovarian cancer (EOC). However, most patients rapidly develop chemoresistance. N6-methyladenosine (m6A) is a pervasive RNA modification, and its specific role and potential mechanism in the regulation of chemosensitivity in EOC remain unclear. METHODS: The expression of RIPK4 and its clinicopathological impact were evaluated in EOC cohorts. The biological effects of RIPK4 were investigated using in vitro and in vivo models. RNA m6A quantification was used to measure total m6A levels in epithelial ovarian cancer cells. Luciferase reporter, MeRIP-qPCR, RIP-qPCR and actinomycin-D assays were used to investigate RNA/RNA interactions and m6A modification of RIPK4 mRNA. RESULTS: We demonstrated that RIPK4, an upregulated mRNA in EOC, acts as an oncogene in EOC cells by promoting tumor cell proliferation and DDP resistance at the clinical, database, cellular, and animal model levels. Mechanistically, METTL3 facilitates m6A modification, and YTHDF1 recognizes the specific m6A-modified site to prevent RIPK4 RNA degradation and upregulate RIPK4 expression. This induces NF-κB activation, resulting in tumor growth and DDP resistance in vitro and in vivo. CONCLUSIONS: Collectively, the present findings reveal a novel mechanism underlying the induction of DDP resistance by m6A-modified RIPK4, that may contribute to overcoming chemoresistance in EOC.

Exosomal YB-1 facilitates ovarian restoration by MALAT1/miR-211-5p/FOXO3 axis.

Premature ovarian failure (POF) affects many adult women less than 40 years of age and leads to infertility. Mesenchymal stem cells-derived small extracellular vesicles (MSCs-sEVs) are attractive candidates for ovarian function restoration and folliculogenesis for POF due to their safety and efficacy, however, the key mediator in MSCs-sEVs that modulates this response and underlying mechanisms remains elusive. Herein, we reported that YB-1 protein was markedly downregulated in vitro and in vivo models of POF induced with H2O2 and CTX respectively, accompanied by granulosa cells (GCs) senescence phenotype. Notably, BMSCs-sEVs transplantation upregulated YB-1, attenuated oxidative damage-induced cellular senescence in GCs, and significantly improved the ovarian function of POF rats, but that was reversed by YB-1 depletion. Moreover, YB-1 showed an obvious decline in serum and GCs in POF patients. Mechanistically, YB-1 as an RNA-binding protein (RBP) physically interacted with a long non-coding RNA, MALAT1, and increased its stability, further, MALAT1 acted as a competing endogenous RNA (ceRNA) to elevate FOXO3 levels by sequestering miR-211-5p to prevent its degradation, leading to repair of ovarian function. In summary, we demonstrated that BMSCs-sEVs improve ovarian function by releasing YB-1, which mediates MALAT1/miR-211-5p/FOXO3 axis regulation, providing a possible therapeutic target for patients with POF.

M6A demethylase FTO-stabilized exosomal circBRCA1 alleviates oxidative stress-induced granulosa cell damage via the miR-642a-5p/FOXO1 axis.

BACKGROUND: Premature ovarian insufficiency (POI) is an important cause of female infertility and seriously impacts the physical and psychological health of patients. Human umbilical cord mesenchymal stem cell-derived exosomes (HucMSCs-Exs, H-Exs) have exhibited protective effects on ovarian function with unclear mechanisms. METHODS: A comprehensive analysis of the Gene Expression Omnibus (GEO) database were used to identify POI-associated circRNAs and miRNAs. The relationship between HucMSC-derived exosomal circBRCA1/miR-642a-5p/FOXO1 axis and POI was examined by RT-qPCR, Western blotting, reactive oxygen species (ROS) staining, senescence-associated ß-gal (SA-ß-gal) staining, JC-1 staining, TEM, oxygen consumption rate (OCR) measurements and ATP assay in vivo and in vitro. RT-qPCR detected the expression of circBRCA1 in GCs and serum of patients with normal ovarian reserve function (n = 50) and patients with POI (n = 50); then, the correlation of circBRCA1 with ovarian reserve function indexes was analyzed. RESULTS: Herein, we found that circBRCA1 was decreased in the serum and ovarian granulosa cells (GCs) of patients with POI and was associated with decreased ovarian reserve. H-Exs improved the disorder of the estrous cycles and reproductive hormone levels, reduced the number of atretic follicles, and alleviated the apoptosis and senescence of GCs in rats with POI. Moreover, H-Exs mitigated mitochondrial damage and reversed the reduced circBRCA1 expression induced by oxidative stress in GCs. Mechanistically, FTO served as an eraser to increase the stability and expression of circBRCA1 by mediating the m6A demethylation of circBRCA1, and exosomal circBRCA1 sponged miR-642a-5p to block its interaction with FOXO1. CircBRCA1 insufficiency aggravated mitochondrial dysfunction, mimicking FTO or FOXO1 depletion effects, which was counteracted by miR-642a-5p inhibition. CONCLUSION: H-Exs secreted circBRCA1 regulated by m6A modification, directly sponged miR-642a-5p to upregulate FOXO1, resisted oxidative stress injuries in GCs and protected ovarian function in rats with POI. Exosomal circBRCA1 supplementation may be a general prospect for the prevention and treatment of POI.

Clinicopathological characteristics and prognostic significance of casting-type calcifications in patients with invasive breast cancer presenting with microcalcification.

To explore the clinicopathological characteristics and prognostic significance of casting-type calcification (CC) in patients with breast cancer presenting with microcalcification on mammography. Data on patients with invasive breast cancer who had mammographic calcification was retrospectively analyzed. The chi-square test was utilized to assess the clinicopathological characteristics of two forms of CC-related breast cancer. The examination of prognostic variables was conducted using Kaplan-Meier and Cox regression analyses. A total of 427 eligible patients were included in this study. Chi-square analysis indicated that the presence of CC was associated with estrogen receptor (ER) negativity (P = 0.005), progesterone receptor (PR) negativity (P < 0.001), and epidermal growth factor receptor 2 (HER-2) positivity (P < 0.001); among these, the association was stronger with the CC-predominant type. After a median follow-up of 82 months, those with CC had a worse 5-year recurrence-free survival (RFS) (77.1% vs. 86.9%, p = 0.036; hazard ratio [HR], 1.86; 95% confidence interval [CI] 1.04-3.31) and overall survival (OS) (84.0% vs. 94.4%, p = 0.007; HR, 2.99; 95% CI 1.34-6.65) rates. In COX regression analysis, such differences were still observed in HER-2 positive subgroups (RFS: HR: 2.45, 95% CI 1-5.97, P = 0.049; OS: HR: 4.53, 95% CI 1.17-17.52, P = 0.029). In patients with invasive breast cancer exhibiting calcifications on mammography, the presence of CC, especially the CC-predominant type, is linked to a higher frequency of hormone receptor negativity and HER-2 positivity. The presence of CC is associated with an unfavorable 5-year RFS and OS rates.

Clinical Efficacy of Ulinastatin Combined with Azithromycin in the Treatment of Severe Pneumonia in Children and the Effects on Inflammatory Cytokines and Oxidative Stress: A Retrospective Cohort Study.

Purpose: This retrospective cohort study aimed to evaluate the clinical efficacy of ulinastatin (UTI) and azithromycin (AZM) combination therapy in treating severe pneumonia in children and its impact on inflammatory cytokines and oxidative stress. Patients and Methods: This retrospective cohort study was conducted from January 1, 2019, to January 1, 2021, involving pediatric patients diagnosed with severe mycoplasma pneumonia (SMPP). The pediatric patients were divided into two groups: those receiving UTI and AZM combination therapy (treatment group) and those receiving azithromycin alone (control group). We compared the two groups regarding clinical data, disease outcomes, inflammatory cytokines, and oxidative stress levels. Results: Baseline characteristics did not significantly differ between the two groups. UTI, in combination with AZM, significantly improved blood oxygen levels, inflammatory infection markers, and relevant clinical symptoms in patients with SMPP on the 3rd day of treatment. Additionally, it significantly reduced the levels of inflammatory cytokines TNF-a, IL-6, IL-1ß, and IL-10, as well as oxidative stress markers GSH and SOD. Conclusion: Combining UTI and AZM can rapidly alleviate clinical symptoms and effectively control the progression of patients with SMPP. Therefore, this treatment approach deserves consideration for clinical promotion and utilization.

Human amniotic membrane as a delivery vehicle for stem cell-based therapies.

Stem cell-based therapy is known as a regenerative approach for a variety of diseases and tissue injuries. These cells exert their therapeutic effects through paracrine secretions namely extracellular vesicles. To achieve higher therapeutic potential, a variety of delivery routes have been tested in clinical and preclinical studies. Direct cell injection, intra-venous administration, and intra-arterial infusion are widely used methods of stem cells delivery but these methods are associated with several complications. As one of the most popular biological delivery systems, amniotic membrane has been widely utilized to support cell proliferation and differentiation therefore facilitating tissue regeneration without endangering the stem cells' viability. It is composed of several extracellular matrix components and growth factors. Due to these characteristics, amniotic membrane can mimic the stem cell's niche and can be an ideal carrier for stem cell transplantation. Here, we provide an overview of the recent progress, challenges, and future perspectives in the use of amniotic membrane as a delivery platform for stem cells.

The Impact of Young Age for Prognosis by Subtype in Women with Early Breast Cancer.

Young age (≤40 years) use to be considered an independent risk factor for the prognosis of women with early-stage breast cancer. We conducted a retrospective analysis to investigate this claim in a population of young patients who were stratified by molecular subtype. We identified 2,125 women with stage I to III breast cancer from the Fujian Medical University Union Hospital. Multivariable Cox proportional hazards models were used to analyze the relationship between age groups stratified by molecular subtype and 5-year disease-free survival (DFS), 5-year distant metastasis-free survival (DMFS), and 5-year breast cancer-specific survival (BCSS). Median follow-up time was 77 months. Patients ≤40 years of age presented with a significantly worse 5-year DFS and 5-year DMFS. In stratified analyses, young women with luminal A subtype disease were associated with a worse 5-year DFS, 5-year DMFS, and 5-year BCSS. Women with luminal B (Her2-) tumors showed a decrease in 5-year DFS and 5-year DMFS. Our findings support the hypothesis that young age seems to be an independent risk factor for the prognosis for breast cancer patients with the luminal A and luminal B (Her2-) subtypes but not in those with luminal B (Her2+), Her2 over-expression, and triple-negative disease.

Evaluating the benefits and adverse effects of an enthracycline-taxane-capecitabine combined regimen in patients with early breast cancer.

Capecitabine in addition to anthracycline-taxane based regimens for patients with early breast cancer (EBC) has been reported in previous clinical trials, but the reported efficacy of this regimen remained inconsistent. In order to clarify the survival benefit of this regimen, a meta-analysis was performed. The systematic literature search was conducted in PubMed, the Cochrane library and Google scholar. The hazard ratios (HRs) were used to evaluate the efficacy and adverse events. The result indicated that capecitabine combine with an anthracycline-taxane based regimen would significantly improve DFS (HR = 0.87, 95% CI 0.77-0.97) and OS (HR = 0.78, 95% CI 0.66-0.91) compared with the controls. In subgroup analysis, we found that capecitabine improved the DFS in hormone receptor negative (HR = 0.72, 95% CI 0.53-0.92) and triple negative (HR = 0.67, 95% CI 0.49-0.86) EBC patients. However, adding capecitabine might also increase the occurrence of some side-effects, such as hand-foot syndrome, stomatitis and diarrhea. Capecitabine combined with an anthracycline-taxane based regimen maybe effective and well-tolerated by patients with EBC, especially for triple negative breast cancer, and might be a good clinical choice.

The precision relationships between eight GWAS-identified genetic variants and breast cancer in a Chinese population.

Some of the new breast cancer susceptibility loci discovered in recent Genome-wide association studies (GWASs) have not been confirmed in Chinese populations. To determine whether eight novel Single-Nucleotide Polymorphisms (SNPs) have associations with breast cancer risk in women from southeast China, we conducted a case-control study of 1,156 breast cancer patients and 1,256 healthy controls. We first validated that the SNPs rs12922061, rs2290203, and rs2981578 were associated with overall breast cancer risk in southeast Chinese women, with the per-allele OR of 1.209 (95%CI: 1.064-1.372), 1.176 (95%CI: 1.048-1.320), and 0.852 (95%CI: 0.759-0.956), respectively. Rs12922061 and rs2290203 even passed the threshold for Bonferroni correction (P value: 0.00625). In stratified analysis, we found another three SNPs were significantly associated within different subgroups. However, after Bonferroni correction (P value: 0.000446), there were no statistically significant was observed. In gene-environment interaction analysis, we observed gene-environment interactions played a potential role of in the risk of breast cancer. These findings provide new insight into the associations between the genetic susceptibility and fine classifications of breast cancer. Based on these results, we encourage further large series studies and functional research to confirm these finding.