Background and aims As a ferroptosis inducer, sorafenib, a first-line treatment for hepatocellular carcinoma (HCC), has a significant antitumor effect. Nonetheless, HCC patients frequently develop sorafenib resistance. Here, we investigated the impacts of progestagen-associated endometrial protein (PAEP), which controls sorafenib resistance and tumorigenesis in HCC. Furthermore, we investigated the function of PAEP and the underlying molecular mechanisms that cause HCC ferroptosis when sorafenib is applied. Methods Western blot analysis, cell proliferation, colony formation and animal experiments were performed to investigate the function of PAEP in sorafenib resistance and tumorigenesis in HCC. We detected the levels of reactive oxygen species, iron, and malondialdehyde and preformed transmission electron microscopy to investigate the relationship between PAEP and ferroptosis. Co-immunoprecipitation (co-IP) assay was performed to investigate the underlying molecular mechanisms of PAEP that cause HCC ferroptosis. Results PAEP was significantly overexpressed in HCC tissues, and this was associated with a poor clinical prognosis. PAEP silencing dramatically reduced HCC cells’ malignant phenotype. We found that sorafenib-induced ferroptosis was more sensitive to HCC cells with PAEP knockdown. Furthermore, the orthotopic cell line-derived xenograft mouse model results showed that sorafenib sensitivity can be effectively increased in vivo by PAEP knockdown. We determined that transferrin (TF) was a PAEP target using the String database, and we further supported this finding with Co-IP analysis. Additionally, on sorafenib-induced ferroptosis in HCC cells, TF partially reversed the effects of PAEP knockdown. Conclusions Our research indicates that PAEP may be a potential biomarker for predicting sorafenib resistance in HCC and disruption of PAEP expression may be a potential cancer-directed therapeutic option for HCC.

Objective:To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia.Methods:A retrospective study was conducted on 7 patients diagnosed by Yangjiang People′s Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People′s Hospital of Yangjiang (Ethics No: 20240001).Results:For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A 2, whilst another had significantly decreased Hb A and Hb A 2, in addition with the appearance of a Hb H band. The content of Hb Bart′s in four neonates was ≥0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c. 2delT, HBA2: c. 1A>G, HBA2: c. 1A>T, and HBA1: c. 2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c. 427T>C (Hb CS) and HBA2: c. 2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c. 1A>G and Southeast Asian type deletion. Conclusion:Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c. 1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.

Objective:To explore the impact of a three-dimensional management based on a perinatal one-day clinic on pregnancy outcomes in overweight and obese pregnant women.Methods:It was a randomized controlled trial. A simple random sampling method was used to select 460 singleton pregnant women with a pre-pregnancy body mass index≥24 kg/m2 who had regular prenatal check-ups at the Obstetrics and Gynecology Center of the Third Affiliated Hospital of Chongqing Medical University from June 1, 2018, to December 31, 2022. The women were randomly divided into an experimental group and a control group (230 cases each) using a computer-generated random number table. The control group received regular prenatal check-ups according to the pregnancy care guidelines (once every 4 weeks during mid-pregnancy, once every 2 weeks during late pregnancy, with additional frequency as needed based on the condition). The control group also received a one-time body composition analysis and dietary guidance from a nutritionist at the time of registration. In addition to the control group′s interventions, the experimental group received three-dimensional management based on a perinatal one-day clinic. It included an intensive one-day clinic session, a traditional plus internet-based re-education model (as needed based on the condition), individualized guidance from obstetrics and clinical nutrition clinics (once every 2 weeks), a free body composition test at 24 weeks of pregnancy, and weekly WeChat group push of health care knowledge during pregnancy. A total of 55 cases dropped out, leaving 200 cases in the experimental group and 205 cases in the control group for analysis. General information, pregnancy-related, and postpartum indicators were collected in the two groups. The effect of three-dimensional management based on a perinatal one-day clinic on pregnancy outcomes in overweight and obese pregnant women was analyzed using t-tests and chi-square tests. Results:There was no significant differences in baseline age, pre-pregnancy body mass index, initial blood glucose, initial glycated hemoglobin, or initial gestational age between the two groups (all P>0.05). The experimental group showed significantly lower gestational weight gain, neonatal weight, and proportion of excessive pregnancy weight gain compared to those in the control group [(11.41±5.23) vs (13.22±4.51) kg, (3 352.1±465.3) vs (3 489.5±464.0) g, 48.00% vs 73.17%] (all P<0.05). There were no significant differences in hospitalization days, gestational age at delivery, incidence of gestational diabetes, incidence of hypertensive disorders of pregnancy, incidence of premature rupture of membranes, incidence of preterm birth, incidence of macrosomia, vaginal delivery rate and rate of neonatal transfer to the pediatric department between the two groups (all P>0.05). Conclusion:Early intervention with the three-dimensional management based on the one-day perinatal clinic can effectively control gestational weight gain and neonatal weight in overweight and obese pregnant women.

Objective:To investigate the effects of apical periodontitis of mandibular primary molars on the development of mandibu-lar permanent premolars in children in Guangzhou.Methods:335 children aged 4-9 years with apical periodontitis of mandibular pri-molar at one side and normal healthy homologous tooth at another side were included and divided into 2 groups:Group A(n=200)in-cluded the first mandibular premolars and group B(n=135)included the second mandibular premolars.Subgroup A1 and B1 were the apical periodontitis groups,subgroup A2 and B2 were the normal healthy groups.The degree of root destruction of primary teeth,the degree of destruction and development of the dental follicle of permanent teeth,the mesial and distal direction changes,and the eruption height were observed and measured on the panoramic raidiographs,data were statistically analyzed.Results:In the 7-year-old children of A1 and the 6-year-old of B1 groups,the development degree of successor permanent teeth was lower than that of group A2 and group B2 of the same age children respectively(P＜0.05).In the 6-7-year-old children of group A1,the permanent teeth development of boys was slower than that of the girls(P＜0.05).There was no gender difference in dental follicle destruction and malposition of the perma-nent teeth in both A1 and B1 groups(P＞0.05).The proportion of malposition of the successor permanent teeth in group A1 increased with the primary teeth damage degree increace(P＜0.05),while the proportion of malposition of the successor permanent teeth in group B1 showed no significant difference(P＞0.05).Positive correlation between the damage degree of primary teeth and dental follicle of per-manent teeth was observed(rA1=0.41,rB1=0.21,P＜0.05).In boys aged 7-8 years,the succesor permanent teeth eruption in group A1 was higher than that in group A2(P＜0.05),and there was no significant difference between group B1 and group B2(P＞0.05).Conclusion:In the later stages of root stabilization of primary molars,periapical inflammation of primary teeth may cause developmen-tal delay of the succesor permanent teeth,and the delay degree is higher in boys than in girls.With the deterioration of the periapical tissue of primary teeth,the destruction of the dental follicle of permanent teeth may deepen,and the mandibular first premolar is more likely to have abnormal eruption.

OBJECTIVE: To analyze the correlation between variants in the start codon of the α-globin gene and phenotypes of thalassemia, so as to provide a basis for the diagnosis and prevention of α-thalassemia. METHODS: A retrospective study was conducted on 7 patients diagnosed by Yangjiang People's Hospital and Guangzhou Hybribio Co. Ltd., from June 2019 to October 2022. Routine blood tests and hemoglobin electrophoresis were carried out. Potential variants were identified through polymerase chain reaction (PCR) combined with Reverse dot blotting (RDB), Gap-PCR, and Sanger sequencing. This study has been approved by the Medical Ethics Committee of People's Hospital of Yangjiang (Ethics No: 20240001). RESULTS: For the 7 patients, results of blood routine test of one case was unknown, and that of another was normal. The remaining 5 cases had presented with microcytic hypochromic anemia. The results of hemoglobin electrophoresis showed that one case had normal Hb A and slightly lower Hb A2, whilst another had significantly decreased Hb A and Hb A2, in addition with the appearance of a Hb H band. The content of Hb Bart's in four neonates was ≥ 0.4%. The remaining one case had no result. Genetic testing has identified 4 rare start codon mutations, namely HBA2: c.2delT, HBA2: c.1A>G, HBA2: c.1A>T, and HBA1: c.2T>C. Among these, Patient 1 had harbored compound heterozygous variants of HBA2: c.427T>C (Hb CS) and HBA2: c.2delT. Patient 4 had harbored compound heterozygous variants of HBA2: c.1A>G and Southeast Asian type deletion. CONCLUSION Heterozygotes with HBA start codon variants usually present as silent or mild thalassemia, and the symptoms of anemia may deteriorate when combined with other α-thalassemia variant. The HBA2: c.1A>T start codon variant was unreported previously in China. The detection of start codon variants has helped to clarify the causes of anemia, genetic counseling, and guidance for reproduction.
Humans ; Phenotype ; Codon, Initiator/genetics* ; Female ; Male ; Retrospective Studies ; alpha-Globins/genetics* ; alpha-Thalassemia/genetics* ; Hemoglobin A/genetics* ; Adult ; Mutation

Objective To investigate the association between intraoperative dexamethasone administration and long-term survival outcomes.Methods A total of 1 629 NSCLC patients who underwent lung tumor resection between January 2008 and December 2014 were included in this study.A propensity score-matched cohort was generated at a ratio of 1∶2 to compare patients who received dexamethasone with those who did not.This matching process resulted in a cohort of 532 patients in the non-DEX group and 283 patients in the DEX group.Within this propensity score-matched cohort,disease-free survival(DFS)and overall survival(OS)were compared between the non-DEX and DEX groups using the Kaplan-Meier method.Additionally,Cox proportional hazards regression analysis was used to evaluate the associations between intraoperative administration of dexamethasone and high-risk factors for postoperative nausea and vomiting(PONV),as well as their impact on DFS and OS.Results After propensity score matching,intraoperative dexamethasone was significantly associated with worse OS(P=0.005),while no significant correlation was observed between intraoperative dexamethasone and DFS.Multivariate Cox regression analyses indicated that intraoperative dexamethasone was associated with poorer overall survival(HR=1.233,95%CI:1.002～1.516,P=0.048).In subgroup analyses,intraoperative dexamethasone was significantly associated with shorter OS in the female,video-assisted thoracoscopic surgery(VATS),prolonged anesthetic time,and inhalation anesthesia subgroups.Conclusions There was a significant correlation between intraopera-tive dexamethasone administration and overall survival in NSCLC patients following curative surgery.In high-risk subgroups for PONV,including females,those undergoing VATS,patients with prolonged anesthetic duration,and those under inhalation anesthesia,the administration of intraoperative dexamethasone was associated with a potentially poorer prognosis compared to patients who did not receive intraoperative dexamethasone.

Recent studies have shown that shorter periods of ejaculatory abstinence may enhance certain sperm parameters, but the molecular mechanisms underlying these improvements are still unclear. This study explored whether reduced abstinence periods could improve semen quality, particularly for use in assisted reproductive technologies (ART). We analyzed semen samples from men with normal sperm counts ( n = 101) and those with low sperm motility or concentration ( n = 53) after 3-7 days of abstinence and then after 1-3 h of abstinence, obtained from the Reproductive & Genetic Hospital of CITIC-Xiangya (Changsha, China). Physiological and biochemical sperm parameters were evaluated, and the dynamics of transfer RNA (tRNA)-derived fragments (tRFs) were analyzed using deep RNA sequencing in five consecutive samples from men with normal sperm counts. Our results revealed significant improvement in sperm motility and a decrease in the DNA fragmentation index after the 1- to 3-h abstinence period. Additionally, we identified 245 differentially expressed tRFs, and the mitogen-activated protein kinase (MAPK) signaling pathway was the most enriched. Further investigations showed significant changes in tRF-Lys-TTT and its target gene mitogen-activated protein kinase kinase 2 ( MAP2K2 ), which indicates a role of tRFs in improving sperm function. These findings provide new insights into how shorter abstinence periods influence sperm quality and suggest that tRFs may serve as biomarkers for male fertility. This research highlights the potential for optimizing ART protocols and improving reproductive outcomes through molecular approaches that target sperm function.
Male ; Humans ; Spermatozoa/metabolism* ; RNA, Transfer/genetics* ; Sperm Motility/genetics* ; Adult ; Semen Analysis ; Sexual Abstinence/physiology* ; Sperm Count ; DNA Fragmentation

The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating many physiological processes. Activating the AhR-CYP1A1 axis has emerged as a novel therapeutic strategy against various inflammatory diseases. Here, a practical in situ cell-based fluorometric assay was constructed to screen AhR-CYP1A1 axis modulators, via functional sensing of CYP1A1 activities in live cells. Firstly, a cell-permeable, isoform-specific enzyme-activable fluorogenic substrate for CYP1A1 was rationally constructed for in-situ visualizing the dynamic changes of CYP1A1 function in living systems, which was subsequently used for discovering the efficacious modulators of the AhR-CYP1A1 axis. Following screening of a compound library, LAC-7 was identified as an efficacious activator of the AhR-CYP1A1 axis, which dose-dependently up-regulated the expression levels of both CYP1A1 and AhR in multiple cell lines. LAC-7 also suppressed macrophage M1 polarization and reduced the levels of inflammatory factors in LPS-induced bone marrow-derived macrophages. Animal tests showed that LAC-7 could significantly mitigate DSS-induced ulcerative colitis and LPS-induced acute lung injury in mice, and markedly reduced the levels of multiple inflammatory factors. Collectively, an optimized fluorometric cell-based assay was devised for in situ functional imaging of CYP1A1 activities in living systems, which strongly facilitated the discovery of efficacious modulators of the AhR-CYP1A1 axis as novel anti-inflammatory agents.

Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.