First Affiliated Hospital of Xiamen University

Unexplained recurrent spontaneous abortion (URSA) is a prevalent reproductive issue but its etiology remains obscure. Male exposure to environmental chemicals is suggested to elevate URSA risk in female partners. Herein, a case-control design set out to investigate associations between metal levels in human seminal plasma with URSA risk, plus to determine evidence of mediating effects by oxidative stress. Levels of 15 metal elements and oxidative stress marker malondialdehyde (MDA) in seminal plasma were measured in 125 male spouses of URSA cases compared to 108 male partners of women with successful pregnancy outcomes. The associations of single or mixed metals on URSA risk were analyzed using logistic regression and Bayesian kernel machine regression (BKMR), respectively. BKMR analyses reveal a joint effect of metal co-exposures on URSA risk. Through multiple statistical approaches, titanium (Ti), cadmium (Cd) or magnesium (Mg) were major contributors to metal mixtures elevating URSA risk. MDA was significantly and positively associated with URSA risk. Mediation analysis shows that the associations of Ti, Cd or Mg with URSA risk appear to be mediated by MDA at rates of 23.30%, 16.26% or 34.48%, respectively. In vitro experiments confirmed the seminal plasma relevant dose Ti, Cd or Mg exposure induced male mouse spermatocyte-derived GC-2 cells oxidative stress. Metal mixtures in seminal plasma are associated with increased URSA risk in female spouses, with Ti, Cd or Mg being significant contributors, potentially via oxidative stress, providing further insights into URSA etiology.

Hepatitis B virus (HBV) infection remains a leading etiological driver of hepatocellular carcinoma (HCC). Cuproptosis is a recently defined copper-dependent form of regulated cell death that selectively eliminates mitochondria-dependent cells; whether HBV rewires this vulnerability remains unknown. Here we unveil a novel HBV X protein (HBx)-driven mechanism of cuproptosis evasion. Integrative analysis of clinical specimens, HBx-transgenic (HBx-Tg) mice, and multi-omics datasets revealed marked downregulation of STEAP4 (six-transmembrane epithelial antigen of prostate 4), a metalloreductase essential for cuproptosis sensitivity, in HBV-positive HCC. Mechanistically, HBx attenuates sirtuin 3 (SIRT3), impairing deacetylation of STEAP4 at lysine 404 and abolishing its mitochondrial targeting. Consequently, cells switch from the tricarboxylic acid (TCA) cycle respiration to glycolysis, reducing sensitivity to the copper ionophore elesclomol (ES). Restoring STEAP4 expression or pharmacological activation of SIRT3 with honokiol (HKL) re-instated mitochondrial STEAP4 localization and re-sensitized HBV-related HCC cells to cuproptosis; combination with ES produced synergistic tumor suppression in vitro and in orthotopic models. Collectively, our findings establish the SIRT3-STEAP4 axis as a novel regulator of cuproptosis resistance in HBV-related HCC. HBx-mediated repression of SIRT3 disrupts STEAP4 deacetylation and mitochondrial targeting, fostering metabolic reprogramming and evasion of copper-induced cell death. The results provide a pre-clinical rationale for copper-directed combination strategies in HBV-associated HCC.

Germline pathogenic alleles predispose carriers to malignancies; failure to recognize the underlying cancer susceptibility and subsequent delayed diagnosis may lead to severe health impairment. It remains largely undetermined what the somatic mutation characteristics are in colorectal cancer (CRC) patients with pathogenic/likely pathogenic (P/LP) germline mutations and whether, and how, these germline mutations typically located in non-mismatch repair genes, are associated with CRC tumorigenesis. From 8,676 Chinese patients with CRC, we initially screened those who had undergone both germline and somatic mutation testing. We analyzed the relationship between germline mutations and the somatic mutational landscape in this cohort. Germline alterations were examined with a 556- or 105- gene next-generation sequencing panel, and somatic alterations were examined with a 556-gene panel. Overall, 80 CRC patients were identified as carriers of P/LP germline mutations. After excluding 6 patients lacking somatic mutation testing data, 74 patients with P/LP germline mutations and 100 patients without germline mutations were finally enrolled in this study. Twenty-one germline genes were detected in the 74 patients. Compared with patients without P/LP mutations (non-P group), those in the P/LP mutations (P group) had significantly lower age and a higher ratio of microsatellite instability. Patients harboring P/LP germline mutations in MMR genes (P-MMR) were significantly younger and more frequently exhibited high tumor mutational burden. The most frequent somatic variations were KRAS and TP53. The somatic mutational landscape revealed a significantly higher mutational frequency in the P group than in the non-P group, and in the P-MMR group than in the P-non-MMR group. The MAPK pathway was significantly enriched in the P and P-MMR groups. Our data showed lower mutation rate of MSH2 among all MMR genes than in the Western population. Population-based risk analysis indicated that the odds ratio of BRCA2 and ATM mutations exceeded 10. Our findings offer a comprehensive overview of genetic susceptibility in Chinese CRC, which may help to shape a more comprehensive understanding of genetic structure of CRC and generate accurate individualized risk management strategies for mutation carriers.

ABSTRACT Aims The tolerance of patients with compensated hepatitis B cirrhosis to interferon (IFN) therapy remains controversial. Therefore, this study aimed to evaluate the safety of pegylated interferon‐alpha in chronic hepatitis B (CHB) patients with compensatory cirrhosis. Methods Data from two prospective cohorts (the OASIS Project and CHESS 2306) from January 2018 to January 2024 were synthesized and analyzed. Patients with Child‐Pugh Class A hepatitis B cirrhosis who received IFN‐based therapy ( n = 920) were included. The control groups included patients with compensated hepatitis B receiving nucleos(t)ide analog (Nuc) monotherapy ( n = 714) and patients without cirrhosis receiving IFN‐based therapy ( n = 4111), respectively. Propensity score matching was used to control for confounding factors; 566 versus 566 cases were analyzed among patients with cirrhosis treated with IFN‐based therapy or Nuc monotherapy, and 785 versus 785 cases were analyzed among patients with and without cirrhosis treated with IFN‐based therapy. Primary outcomes included decompensation events, and secondary outcomes included severe adverse events, overall adverse events, and treatment‐related hospitalizations or deaths. Results In patients with hepatitis B virus‐related cirrhosis, the incidence of decompensation events was similar between IFN‐based therapy and Nuc monotherapy (6/566 [1.1%] vs. 3/566 [0.5%], p = 0.506). No hospitalizations or deaths were associated with adverse events during the observation period (48 weeks). The incidences of severe adverse events were similar in patients with cirrhosis under IFN‐based therapy or Nuc monotherapy (severe neutropenia: 1/450 [0.2%] vs. 0/378 [0], p = 0.999; severe thrombocytopenia: 4/435 [0.9%] vs. 0/296 [0], p = 0.153; severe alanine aminotransferase level elevation: 1/523 [0.2%] vs. 1/458 [0.2%], p = 0.999; and severe total bilirubin [TBIL] level elevation: 5/419 [1.2%] vs. 3/385 [0.8%], p = 0.727). The incidences of severe adverse events were similar between patients with and without cirrhosis receiving IFN‐based therapy, except that severe TBIL level elevation was more frequent in patients with cirrhosis who already had mildly to moderately elevated TBIL levels at baseline than in those without (6/153 [3.9%] vs. 0/118 [0], p = 0.040). Conclusion IFN‐based therapy demonstrates favorable safety in Child‐Pugh A compensated cirrhosis. It did not increase decompensation events or severe adverse events compared to Nuc monotherapy, and adverse event profiles were largely similar between cirrhotic and non‐cirrhotic patients, except for a higher risk of severe hyperbilirubinemia in those with pre‐existing TBIL elevation. ClinicalTrials.gov identifier: NCT04896255. Chinese Clinical Trial Registry number: ChiCTR2500107592.

To investigate symptom clusters and their longitudinal trajectories in patients undergoing maintenance hemodialysis (MHD). A convenience sample of 510 MHD patients was enrolled between June 2022 and June 2023. Symptom assessments were conducted at four time points: baseline (T1), 4months (T2), 8months (T3), and 12months (T4), using a general information questionnaire and the dialysis symptom index (DSI). Exploratory factor analysis was applied to identify symptom clusters, and latent class growth modeling was used to examine the longitudinal trajectories of these symptom clusters over the one-year follow-up period. Exploratory factor analysis revealed seven symptom clusters: emotional symptoms, water-electrolyte imbalances, gastrointestinal symptoms, uremia-related symptoms, sleep disturbances, sexual symptoms, and sexual-emotional symptoms. The first five clusters-emotional, water-electrolyte imbalances, gastrointestinal, uremia-related, and sleep disturbances-exhibited common patterns over time. Latent class growth models identified 3 distinct trajectories within each symptom cluster, reflecting heterogeneous patterns of symptom progression. This one-year longitudinal study revealed heterogeneous developmental trajectories across symptom clusters in MHD patients. These findings underscore the importance of continuous symptom assessment and monitoring, particularly in patients with persistently high symptom severity. Tailored intervention strategies should be developed to address the specific needs of different patient subgroups, thereby alleviating symptom burden and enhancing the effectiveness of nursing care. Symptom management efforts may be prioritized based on the severity and trajectory of symptom clusters.