AURKA knockdown inhibits esophageal squamous cell carcinoma progression through ferroptosis.

Aurora kinase A, as a pro-carcinogenic in gastric cancer and glioma kinase, is enhanced in several human tumors. However, it's regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remains unclear. Thus, this study aimed to investigate the expression status, functional roles, and molecular mechanisms of AURKA in ESCC development. AURKA expression was analyzed by the screening of the GEO database and detected using an immunohistochemical method. The biological function of AURKA on ESCC was evaluated in vitro and in vivo. Western blot assay, malondialdehyde (MDA), iron, and glutathione (GSH) kits were utilized to assess changes in ferroptosis. Database analysis results showed that AURKA was a differential gene in ESCC and was highly expressed in human ESCC tissues. Functionally, AURKA knockdown decreased ESCC cell proliferation, invasion, and metastasis both in vitro and in vivo. Moreover, when AURKA was knockdown, cells were more correctly blocked in the G2/M phase, and the ferroptosis-related MDA and Fe increased, whereas the GSH reduced. Consistently, Glutathione peroxidase 4 (GPX4) and solute carrier family 7a member 11 (SLC7A11) expression were downregulated by AURKA knockdown. However, ferroptosis inhibitor partially restore ESCC cell proliferation, invasion, and metastasis caused by AURKA knockdown. AURKA knockdown enhances ferroptosis and acts against cancer progression in ESCC. AURKA acts as a tumor-promoting gene and may serve as potential target for ESCC treatment.

Salpingectomy for ectopic pregnancy reduces ovarian cancer risk-a nation-wide study.

Recent studies propose fallopian tubes as the tissue origin for many ovarian epithelial cancers. To further support this paradigm, we assessed whether salpingectomy for treating ectopic pregnancy had a protective effect using the Taiwan Longitudinal National-Health-Research Database. We identified 316,882 women with surgical treatment for ectopic pregnancy and 3,168,820 age- and index-date-matched controls from 2000-2016. In a nested cohort, 91.5% of cases underwent unilateral salpingectomy, suggesting that most surgically managed patients have salpingectomy. Over a follow-up period of 17 years, the ovarian carcinoma incidence was 0.0069 (95%CI : 0.0060-0.0079) and 0.0089 (95%CI : 0.0086-0.0092) in the ectopic pregnancy and the control groups, respectively (p < .001). After adjusting the events to per 100-person years, the hazard ratio in the ectopic pregnancy group was 0.70 (95%CI : 0.61-0.80). The risk reduction occurred only in epithelial ovarian cancer (HR : 0.73, CI : 0.63-0.86) and not in non-epithelial subtypes. These findings show a decrease in ovarian carcinoma incidence following salpingectomy for treating ectopic pregnancy.

MRE11A: a novel negative regulator of human DNA mismatch repair.

BACKGROUND: DNA mismatch repair (MMR) is a highly conserved pathway that corrects DNA replication errors, the loss of which is attributed to the development of various types of cancers. Although well characterized, MMR factors remain to be identified. As a 3'-5' exonuclease and endonuclease, meiotic recombination 11 homolog A (MRE11A) is implicated in multiple DNA repair pathways. However, the role of MRE11A in MMR is unclear. METHODS: Initially, short-term and long-term survival assays were used to measure the cells' sensitivity to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Meanwhile, the level of apoptosis was also determined by flow cytometry after MNNG treatment. Western blotting and immunofluorescence assays were used to evaluate the DNA damage within one cell cycle after MNNG treatment. Next, a GFP-heteroduplex repair assay and microsatellite stability test were used to measure the MMR activities in cells. To investigate the mechanisms, western blotting, the GFP-heteroduplex repair assay, and chromatin immunoprecipitation were used. RESULTS: We show that knockdown of MRE11A increased the sensitivity of HeLa cells to MNNG treatment, as well as the MNNG-induced DNA damage and apoptosis, implying a potential role of MRE11 in MMR. Moreover, we found that MRE11A was largely recruited to chromatin and negatively regulated the DNA damage signals within the first cell cycle after MNNG treatment. We also showed that knockdown of MRE11A increased, while overexpressing MRE11A decreased, MMR activity in HeLa cells, suggesting that MRE11A negatively regulates MMR activity. Furthermore, we show that recruitment of MRE11A to chromatin requires MLH1 and that MRE11A competes with PMS2 for binding to MLH1. This decreases PMS2 levels in whole cells and on chromatin, and consequently comprises MMR activity. CONCLUSIONS: Our findings reveal that MRE11A is a negative regulator of human MMR.

Disparities in Survival Outcomes Between Locally Advanced Cervical Squamous Cell Carcinoma and Adenocarcinoma Treated with Chemoradiotherapy.

Purpose: To determine the disparities in survival outcomes between stage IIB-IVA cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) treated with chemoradiotherapy. Methods: Patients diagnosed between 2004 and 2015 were retrospectively included from the Surveillance, Epidemiology, and End Results databases. Propensity score matching (PSM) was used in this study. The primary endpoints were cervical cancer-specific survival (CCSS) and overall survival (OS). Results: A total of 2752 patients were identified, including 87.5% (n=2408) were SCC and 12.5% (n=344) were AC. Patients with AC had inferior 5-year CCSS (67.5% vs 54.8%, P<0.001) and OS (58.4% vs 47.2%, P<0.001) compared to those with the SCC subtype. The hazard curve of cervical cancer-related death in AC peaked at 2 years (19%) and still small peaks in the 7 and 11 years of follow-up. Regarding SCC, cervical cancer-related deaths peaked at 2 years (15%) and the hazard rate was 2.0% during the six years of follow-up. The multivariate Cox regression analyses indicated that histology was an independent prognostic factor associated with survival outcomes. Patients with AC had significantly poor CCSS (P<0.001) and OS (P<0.001). Similar results were found after PSM. Conclusion: Our study demonstrates a significantly better prognosis for cervical SCC patients compared to those with cervical AC undergoing chemoradiotherapy. These results highlight the importance of histological subtyping in predicting treatment outcomes and tailoring therapeutic strategies.

Associations of perceived stress with loneliness and depressive symptoms: the mediating role of sleep quality.

BACKGROUND: Whether perceived stress is associated with loneliness and depressive symptoms in general adults, and to what extent sleep quality mediates the associations, remains unknown. The aim of this study was to estimate the associations of perceived stress with loneliness and depressive symptoms, and the mediating role of sleep quality in these associations. METHODS: Cross-sectional data on 734 participants (aged 18-87 years) were analyzed. Perceived stress was assessed using the 10-item Perceived Stress Scale (PSS-10; range 0-40). Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI; range 0-21). Loneliness was assessed using the three-item short form of the Revised University of California, Los Angeles (UCLA) loneliness scale (range 3-9). Depressive symptoms were assessed using the 10-item Center for Epidemiologic Studies Depression (CESD-10) Scale (range 0-30). General linear regression models, multivariable logistic regression models, and formal mediation analysis were performed. RESULTS: After adjustment for age and sex, we found that with each 1-point increment in the perceived stress score, both the loneliness score (ß = 0.07; 95% confidence interval [CI]: 0.06, 0.08) and depression score (ß = 0.45; 95% CI: 0.40, 0.49) increased significantly. Robust results were observed when adjusting for more confounders. Furthermore, sleep quality mediated 5.3% (95% CI: 1.3%, 10.0%; P = 0.014) and 9.7% (95% CI: 6.2%, 14.0%; P < 0.001) of the associations of perceived stress score with loneliness score and depression score, respectively. CONCLUSIONS: In general Chinese adults, perceived stress was positively associated with loneliness and depressive symptoms, and sleep quality partially mediated these associations. The findings reveal a potential pathway from perceived stress to mental health through sleep behaviors, and highlight the importance of implementing sleep intervention programs for promoting mental health among those who feel highly stressed.

Synergistic interaction between hyperlipidemia and obesity as a risk factor for stress urinary incontinence in Americans.

Urinary incontinence is a common disease among middle-aged and elderly women, which not only affects the physical and mental health of patients, but also brings a great medical burden to society. Obesity is a known risk factor for urinary incontinence and is the most common secondary cause of hyperlipidemia. Most obese patients also suffer from hyperlipidemia in the clinic. However, few studies have explored the role of hyperlipidemia in women with urinary incontinence. Using data from the 2005-2018 National Health and Nutrition Examination Survey (NHANES), we aimed to evaluated the independent associations of high body mass index and hyperlipidemia with urinary incontinence in Americans by conducting a weighted multivariate logistic regression model. Additive interactions were also assessed using the relative excess risk due to interaction (RERI), attributed proportion of interaction (AP) and synergy index (S). This study demonstrated that hyperlipidemia was associated with a higher risk of stress urinary incontinence among women with obesity (OR = 1.52, 95% CI = 1.03-2.25), and there was a significant synergistic effect of hyperlipidemia and obesity on stress urinary incontinence(adjusted RERI: 3.75, 95% CI 0.30-7.20; adjusted AP: 0.67, 95% CI 0.54-0.80; adjusted S: 5.49, 95% CI 4.15-7.27). Moreover, fasting serum triglyceride lipids were the most relevant blood lipid indicator for the risk of stress urinary incontinence, especially among obese women younger than 50 years old, which contributes to the development of more refined lipid control protocols for patients with urinary incontinence in different age groups.

Impact of blood lipid levels on venous thromboembolism in acute stroke patients.

BACKGROUND: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common complication of stroke with a high incidence of underdiagnosis. The relationship between dyslipidemia and VTE remains uncertain. Therefore, this study aimed to explore this connection in acute stroke patients to enhance diagnostic and preventative strategies. METHODS: Retrospective data from 7854 acute stroke patients admitted to Dongyang Hospital, Affiliated with Wenzhou Medical University, between 2010 and 2020 were extracted. Differential tests were compared among various blood lipid parameters and the presence or absence of venous thrombosis. Logistic regression analysis was employed to estimate associations. RESULTS: The prevalences of DVT and PE were 3.9 % and 1.1 %, respectively. Additionally, 43 cases (0.5 %) exhibited combined DVT and PE. A high triglyceride (TG) level was associated with a decreased risk of VTE (adjusted odd ratio [aOR] = 0.69, 95 % confidence interval [CI]: 0.54-0.89, P = 0.004), whereas a high low-density lipoprotein cholesterol (LDL-C) level was associated with an increased risk of VTE (aOR = 1.51, 95 % CI: 1.16-1.97, P = 0.002), after adjusting for confounding factors. No significant associations were observed for high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC) levels with VTE risk. Subgroup analyses revealed that these associations were significant in ischemic stroke patients. CONCLUSION: Low TG levels and high LDL-C levels were found to be associated with an increased risk of VTE in acute stroke patients, offering valuable insights for the early identification and management of high-risk individuals.

Epidemiological investigation and ß-lactam antibiotic resistance of Riemerella anatipestifer isolates with waterfowl origination in Anhui Province, China.

Riemerella anatipestifer (R. anatipestifer) is a highly pathogenic and complex serotypes waterfowl pathogen with inherent resistance to multiple antibiotics. This study was aimed to investigate the antibiotic resistance characteristics and genomic features of R. anatipestifer isolates in Anhui Province, China in 2023. A total of 287 cases were analysed from duck farms and goose farms, and the R. anatipestifer isolates were subjected to drug resistance tests for 30 antimicrobials. Whole genome sequencing (WGS) and bioinformatics analysis were performed on the bacterial genomes, targeting the ß-lactam resistance genes. The results showed that a total of 74 isolates of R. anatipestifer were isolated from 287 cases, with a prevalence of 25.8%. The antimicrobial susceptibility testing (AST) revealed that all the 74 isolates were resistant to multiple drugs, ranging from 13 to 26 kinds of drugs. Notably, these isolates showed significant resistance to aminoglycosides and macrolides, which are also commonly used in clinical practices. Data revealed the presence of several ß-lactamase-related genes among the isolates, including a novel blaRASA-1 variant (16.2%), the class A extended-spectrum ß-lactamase blaRAA-1 (12.2%), and a blaOXA-209 variant (98.6%). Functional analysis of the variants blaRASA-1 and blaOXA-209 showed that the blaRASA-1 variant exhibited activity against various ß-lactam antibiotics while their occurrence in R. anatipestifer were not common. The blaOXA-209 variant, on the other hand, did not perform any ß-lactam antibiotic resistance. Furthermore, we observed that blaRAA-1 could undergo horizontal transmission among different bacteria via the insertion sequence IS982. In conclusion, this study delves into the high prevalence of R. anatipestifer infection in waterfowl in Anhui, China. The isolated strains exhibit severe drug resistance issues, closely associated with the prevalence of antibiotic resistance genes (ARG). Additionally, our research investigates the ß-lactam antibiotic resistance mechanism in R. anatipestifer.

Efficacy of acupuncture therapy on cancer-related insomnia: a systematic review and network meta-analysis.

Objectives: Cancer-related insomnia (CRI) takes a toll on many cancer survivors, causing distressing symptoms and deteriorating the quality of life. Acupuncture therapy has been used for CRI already. However, it is still uncertain which acupuncture regime is best for CRI. The primary objective of this review is to conduct a comparative evaluation and ranking of the effectiveness of different acupuncture therapies for CRI. Methods: Randomized controlled trials (RCTs) that were published up to July 31, 2023, from 8 databases (PubMed, Embase, Cochrane library, Web of Science, China National Knowledge Infrastructure, Wanfang Database, VIP Database, and China Biology Medicine disc) were integrated in this study. Trials that met the inclusion criteria were evaluated the risk of bias. Pittsburgh sleep quality index (PSQI) was used to assess the efficacy of different acupuncture therapies as the primary outcome. Then, STATA 15, R, and OpenBUGS were applied to perform the network meta-analysis. PRISMA statements were followed in this network meta-analysis. Results: A total of 37 studies were included in this review, involving 16 interventions with 3,246 CRI participants. Auriculotherapy + moxibustion [surface under the cumulative ranking curve (SUCRA) 98.98%] and auriculotherapy (SUCRA 77.47%) came out top of the ranking, which were more effective than control, medicine, usual care and sham acupuncture. Conclusion: Auriculotherapy + moxibustion and auriculotherapy + acupuncture emerged as the top two acupuncture regimes for CRI and future studies should pay more attention to CRI. Clinical trial registration: https://clinicaltrials.gov/, identifier INPLASY202210095.

Microplastics alter soil structure and microbial community composition.

Microplastics (MPs), including conventional hard-to-biodegrade petroleum-based and faster biodegradable plant-based ones, impact soil structure and microbiota in turn affecting the biodiversity and functions of terrestrial ecosystems. Herein, we investigated the effects of conventional and biodegradable MPs on aggregate distribution and microbial community composition in microhabitats at the aggregate scale. Two MP types (polyethylene (PE) and polylactic acid (PLA) with increasing size (50, 150, and 300 µm)) were mixed with a silty loam soil (0-20 cm) at a ratio of 0.5 % (w/w) in a rice-wheat rotation system in a greenhouse under 25 °C for one year. The effects on aggregation, bacterial communities and their co-occurrence networks were investigated as a function of MP aggregate size. Conventional and biodegradable MPs generally had similar effects on soil aggregation and bacterial communities. They increased the proportion of microaggregates from 17 % to 32 %, while reducing the macroaggregates from 84 % to 68 %. The aggregate stability decreased from 1.4 mm to 1.0-1.1 mm independently of MP size due to the decline in the binding agents gluing soil particles (e.g., microbial byproducts and proteinaceous substances). MP type and amount strongly affected the bacterial community structure, accounting for 54 % of the variance. Due to less bioavailable organics, bacterial community composition within microaggregates was more sensitive to MPs addition compared to macroaggregates. Co-occurrence network analysis revealed that MPs exacerbated competition among bacteria and increased the complexity of bacterial networks. Such effects were stronger for PE than PLA MPs due to the higher persistence of PE in soils. Proteobacteria, Bacteroidetes, Chloroflexi, Actinobacteria, and Gemmatimonadetes were the keystone taxa in macroaggregates, while Actinobacteria and Chloroflexi were the keystone taxa in microaggregates. Proteobacteria, Actinobacteria, and Chloroflexi were the most sensitive bacteria to MPs addition. Overall, both conventional and biodegradable MPs reduced the portion of large and stable aggregates, altering bacterial community structures and keystone taxa, and consequently, the functions.

PET evaluation of myocardial perfusion function after percutaneous coronary intervention in patients with chronic total occlusion: a systematic review and meta-analysis.

Objective. The benefit of percutaneous coronary intervention (PCI) in chronic complete coronary artery occlusion (CTO) remains controversial. PCI is currently indicated only for symptom and myocardial ischemia abolition, but large chronically occluded vessels with extensive afferent myocardial territories may benefit most from this procedure. The noninvasive evaluation of myocardial perfusion is critical before and after revascularization, and positron emission tomography (PET) can determine absolute myocardial perfusion. Here, we aimed to explore and compare myocardial perfusion in CTO territories and their remote associated areas before and after PCI. Design. We searched for relevant articles published before November 28, 2022, in the Cochrane Library and PubMed. We calculated 95% confidence intervals (CIs) and standardized mean differences (SMDs) for parameters related to myocardial perfusion in CTO territories and remote areas in CTO patients before and after PCI. Results. We included five studies published between 2017 and 2022, with a total of 592 patients. Stress myocardial blood flow (MBF) was increased in CTO territories after PCI when compared to pre-PCI (mean difference [MD]: 1.70, 95% confidence interval [CI] 1.33-2.08, p < 0.001). Coronary flow reserve (CFR) in CTO regions was also higher after PCI (MD 1.37,95% [CI]1.13-1.61, p < 0.001). Stress MBF in remote regions was also increased after PCI (MD 0.27,95% [CI]0.99 ∼ 0.45, p = 0.004), as was CFR in remote regions (MD 0.32,95% [CI] 0.14-0.5, p = 0.001). Conclusions. According to our pooled analysis of current literature, there was an increase in stress MBF and CFR in both CTOs and remote regions after PCI, suggesting that patients with CTO have widespread recovery of blood perfusion after the procedure. These results provide evidence that patients with CTO arteries and high ischemic burdens would indeed benefit from CTO-PCI. Future research on the correlation of ischemia burden reduction with hard clinical endpoints would contribute to a clearer demarcation of the role of CTO PCI with prognostic potential.

Attitudes and health behaviors of middle-aged and older adults with elevated tumor markers in China.

Objectives: To understand the attitudes and health behaviors of middle-aged and older adults in China after receiving elevated results of tumor markers (TMs) test in the annual health examinations (AHEs) and explore the influencing factors. Methods: A three-section online questionnaire survey was conducted from March 1 to April 30, 2020 in Hangzhou, China, to people who were aged 45 and older and had at least one elevated result of TMs test. Clinical information was collected from the online survey and medical records. Descriptive statistics were carried out followed by regression analyses. Results: Of 380 participants, 76.1% were unwilling to quit the TMs test in AHEs, whereas 75.3% would take the doctor's advice and quit unnecessary TMs test; 67.4% felt stressed about their TMs. Among participants with elevated TMs, 76.8% changed lifestyle to keep healthy, 74.2% sought health information, 58.9% requested a TMs retest, and 50.3% did further tests to confirm a diagnosis. Family history of cancer was associated with lifestyle changing; education level, area of residence and health insurance were associated with health information seeking; comorbidity were associated with retests and sequential confirming tests. Conclusion: The application of the TMs test in AHEs among Chinese people may lead to positive and negative behavioral consequences and psychological distress. Doctors have a significant impact on patients' health behaviors. Accurate indications and adequate communication with patients before and after the TMs test are in great need.

LncRNA KTN1-AS1 facilitates esophageal squamous cell carcinoma progression via miR-885-5p/STRN3 axis.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies and frequent cause of cancer-related death worldwide. Long non-coding RNAs (lncRNAs) play regulatory roles and serve as biomarkers of multiple cancers, including ESCC. Our previous studies have confirmed that lncRNA Kinectin 1 antisense RNA 1 (KTN1-AS1) is highly expressed in ESCC and exerts oncogene function through RBBP4/HDAC1 complex. OBJECTIVE: Our present study focused on exploring a novel molecular mechanism of KTN1-AS1 in ESCC. METHODS: In this study, qRT-PCR assay, Western blot assay, Luciferase reporter assay, and RNA immunoprecipitation assay were conducted. RESULTS: We found that KTN1-AS1 could bind to miR-885-5p in ESCC cells, and miR-885-5p was low expressed in ESCC. Overexpression of miR-885-5p inhibited esophageal cancer cells proliferation and invasion in vitro. Mechanistic analysis demonstrated that miR-885-5p specifically targeted striatin 3 (STRN3), and KTN1-AS1/miR-885-5p promoted the EMT process by Hippo pathway in STRN3/YAP1 dependent manner. CONCLUSION: To sum up, KTN1-AS1 facilitates ESCC progression by acting as a ceRNA for miR-885-5p to regulate STRN3 expression and the Hippo pathway, and KTN1-AS1 maybe used as a promising therapeutic target for ESCC.

Fine-Regional Role of the Claustrum in Anxiety and Higher Sensitivity to Cocaine in Adolescent Cocaine-Exposed Male Mice during Adulthood.

Adolescent cocaine exposure (ACE) induces anxiety and higher sensitivity to substances abuse during adulthood. Here, we show that the claustrum is crucial for controlling these psychiatric problems in male mice. In anxiety-like behavioral tests, the CaMKII-positive neurons in the median portion of the claustrum (MClaustrum) were triggered, and local suppression of these neurons reduced the anxiety-like behavior in ACE mice during adulthood. In contrast, the CaMKII-positive neurons in the anterior portion of the claustrum (AClaustrum) were more activated in response to subthreshold dose of cocaine induced conditioned place preference (CPP), and local suppression of these neurons blocked the acquisition of cocaine CPP in ACE mice during adulthood. Our findings for the first time identified the fine-regional role of the claustrum in regulating the anxiety and susceptibility to cocaine in ACE mice during adulthood, extending our understanding of the claustrum in substance use disorder.

Transformational leadership competency: a cross-sectional study of medical university graduates in China.

PURPOSE: To explore the transformational leadership competency of graduates from one medical university in China and its influencing variables. METHOD: From 2020 to 2021, 851 medical graduates from seven hospitals affiliated with the Capital Medical University participated in this survey. The authors conducted a cross-sectional study to assess transformational leadership competency, particularly from three aspects, including values, Emotional Intelligence (EI) abilities, and behaviors using the socially responsible leadership scale (SRLS), emotionally intelligent leadership, and student leadership practices inventory (EILI and SLPI). RESULTS: The SRLS scores were medium except for 'controversy with civility'. The EILI scores were medium. The SLPI scores were high except for 'enable others to act' and 'encourage the heart'. The influencing variables of SRLS, EILI, and SLPI were serving as student cadres, serving longer than two semesters (p = 0.01, 0.02 in EILI and SLPI), joining student organizations, participating in social practice, voluntary service (p = 0.001 in SLPI), in training classes for student cadres (p = 0.02, 0.01, 0.02 in SRLS, EILI, and SLPI), and attending lectures on leadership (except for indicated, p < 0.001). Regression analysis showed that attending lectures on leadership was associated with high SRLS, EILI, and SLPI scores (p = 0.04, SRLS; p < 0.001, others), and SRLS and EILI scores could affect SLPI score (F = 2674.44, p < 0.001, R2 = 0.86). CONCLUSIONS: Medical graduates' transformational leadership competency at the Capital Medical University was medium measured from values, EI abilities, and behaviors. Group analysis indicated that knowledge learning, organizational involvement, and social/community involvement were associated with leadership capacity building, meanwhile, leaders' values and EI abilities would affect their behaviors, suggesting medical graduates should undertake leadership training from both knowledge learning and practicing.

Identification of Key Genes for Pyroptosis-Induced Salivary Gland Inflammation in Sjogren's Syndrome Based on Microarray Data and Immunohistochemistry Analysis.

Purpose: Sjogren's Syndrome (SS) is a systemic autoimmune disease primarily characterized by dysfunction of the exocrine glands. Research into the etiology and pathogenesis of salivary glands (SG) inflammation of SS is very limited. The aim of this study was to identify potential pyroptosis-related genes in SG inflammation through bioinformatics analysis and validation of the SG in SS. Methods: GSE157159 dataset and GSE159574 dataset were downloaded from Gene Expression Omnibus (GEO). Differentially Expressed Genes (DEGs) analysis was used to screen DEGs from SS and non-SS SG samples. Pyroptosis-related genes were obtained from GeneCards. After intersecting DEGs with pyroptosis-related genes, the pyroptosis-related DEGs in SS were obtained. Subsequently, ClueGO enrichment analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis, Protein-protein Interaction (PPI), and identification and co-expression analysis of hub genes were performed. Subsequently, we collected SG samples from 17 SS patients and 17 non-SS patients and validated the expression of two hub genes (GZMA, GBP1) and characteristic genes (GSDMD) of pyroptosis through immunohistochemistry. The accuracy of hub genes as biomarkers for predicting SS was evaluated by receiver operating characteristic (ROC) curve. Results: 834 DEGs were selected from the GSE157159 dataset, and a total of 39 pyroptosis-related DEGs were obtained. Functional analysis showed that these DEGs were significantly enriched in some inflammatory signaling pathways. Through the intersection of seven algorithms proposed by CytoHubba and validation using the GSE159574 dataset, 11 hub genes were identified, including IL18, AIM2, CCL5, CD274, GBP1, GBP5, GZMA, GZMB, TLR8, TNFS13B, and ICAM1. Finally, the results of immunohistochemistry showed that GSDMD, GZMA and GBP1 were all significantly highly expressed in SG from SS. And ROC analysis showed a high combined diagnostic value of the 3 genes (AUC=0.8858). Conclusion: Our study revealed enhanced levels of pyroptosis in the SS. GZMA and GBP1 were identified as candidate genes for pyroptosis-induced inflammation of the SG in SS, which may be used as biomarkers or potential therapeutic targets for SS.

The landscape of investigator-initiated oncology trials conducted in mainland China during the past decade (2010-2019).

The number of clinical trials conducted in mainland China, including investigator-initiated trials (IITs), has increased rapidly in recent years. However, there are few data on the characteristics of cancer-related IITs. We performed a comprehensive analysis of the landscape of cancer-related IITs in mainland China in the past decade. All cancer-related IITs registered on two clinical trial registries in the United States (www.clinicaltrials.gov, CT.gov) and mainland China (www.chictr.org.cn, ChiCTR) from 2010 to 2019 were identified. IITs were reviewed manually to validate classification, subcategorized by cancer type, and stratified by design characteristics to facilitate comparison across cancer types and with other specialties. A total of 8199 cancer-related IITs were identified. The number of trials registered annually increased over time, especially in the last 5 years. Although interventional studies were predominant, randomized double-blind studies accounted for only 8% of IITs. In the past decade, the trend for interventional studies conducted with different drugs increased year on year, although the increase in hormonal therapy IITs was not significant. Additionally, cancer-related IITs were unevenly geographically distributed, with half concentrated in the economically developed cities Shanghai, Beijing, and Guangdong. We also found an increase in registration before participant enrollment (64.9% for trials in conducted in 2015-2019 vs. 40.2% in 2010-2014, p < 0.001) and data monitoring committee use (44.5% vs. 40.0%, p = 0.001) and a decrease in randomization (51.5% vs. 62.7%, p < 0.001) and funding (36.4% vs. 56.3%, p < 0.001) between these periods. We also observed changes in intervention type (decrease in cytotoxic drug therapy [34.8% vs. 48.9%, p < 0.001]; increase in targeted therapy [17.8% vs. 14.2%, p = 0.004], immune checkpoint inhibitor therapy [6.6% vs. 0.0%, p < 0.001], and immune cell therapy [9.6% vs. 4.5%, p < 0.001]). Details of cancer-related IITs conducted during the past decade illustrate the merits of oncology research in mainland China. Although the increased quantity of IITs is encouraging, limitations remain regarding the quality of clinical trials, regional imbalances, and funding allocation.

METH exposure alters sperm DNA methylation in F0 mice and mPFC transcriptome in male F1 mice.

RATIONALE: Methamphetamine (METH) exposure has toxicity in sperm epigenetic phenotype and increases the risk for developing addiction in their offspring. However, the underlying transgenerational mechanism remains unclear. OBJECTIVES: The current study aims to investigate the profiles of sperm epigenetic modifications in male METH-exposed mice (F0) and medial prefrontal cortex (mPFC) transcriptome in their male first-generation offspring (F1). METHODS: METH-related male F0 and F1 mice model was established to investigate the effects of paternal METH exposure on reproductive functions and sperm DNA methylation in F0 and mPFC transcriptomic profile in F1. During adulthood, F1 was subjected to a conditioned place preference (CPP) test to evaluate sensitivity to METH. The gene levels were verified with qPCR. RESULTS: METH exposure obviously altered F0 sperms DNA methylated profile and male F1 mPFC transcriptomic profile, many of which being related to neuronal system and brain development. In METH-sired male F1, subthreshold dose of METH administration effectively elicited CPP, along with more mPFC activation. After qPCR verification, Sort1 and Shank2 were at higher levels in F0 sperm and F1 mPFC. CONCLUSIONS: Our findings put new insights into paternal METH exposure-altered profiles of F0 sperm DNA methylation and male F1 mPFC transcriptomics. Several genes, such as Sort1 and Shank2, might be used as potential molecules for further research on the transgenerational vulnerability to drug addiction in offspring by paternal drug exposure.

Prescriptions for Buprenorphine in Michigan Following an Education Intervention.

Importance: Buprenorphine is an underused treatment for opioid use disorder (OUD) that can be prescribed in general medical settings. Founded in 2017, the Michigan Opioid Collaborative (MOC) is an outreach and educational program that aims to address clinician and community barriers to buprenorphine access; however, the association between the MOC and buprenorphine treatment is unknown. Objective: To evaluate the association between MOC service use and county-level temporal trends of density of buprenorphine prescribers and patients receiving buprenorphine. Design, Setting, and Participants: This cohort study exploited staggered implementation of MOC services across all Michigan counties. Difference-in-difference analyses were conducted by applying linear fixed-effects regression across all counties to estimate the overall association of MOC engagement with outcomes and linear regression for each MOC-engaged county separately to infer county-specific results using data from May 2015 to August 2020. Analyses were conducted from September 2021 to November 2023. Exposures: MOC engagement. Main Outcomes and Measures: County-level monthly numbers of buprenorphine prescribers and patients receiving buprenorphine (per 100 000 population). Results: Among 83 total counties, 57 counties (68.7%) in Michigan were engaged by MOC by 2020, with 3 (3.6%) initiating engagement in 2017, 19 (22.9%) in 2018, 27 (32.5%) in 2019, and 8 (9.6%) in 2020. Michigan is made up of 83 counties with a total population size of 9 990 000. A total of 5 070 000 (50.8%) were female, 1 410 000 (14.1%) were African American or Black, 530 000 (5.3%) were Hispanic or Latino, and 7 470 000 (74.7%) were non-Hispanic White. The mean (SD) value of median age across counties was 44.8 (6.4). The monthly increases in buprenorphine prescriber numbers in the preengagement (including all time points for nonengaged counties) and postengagement periods were 0.07 and 0.39 per 100 000 population, respectively, with the absolute difference being 0.33 (95% CI, 0.12-0.53) prescribers per 100 000 population (P = .002). The numbers of patients receiving buprenorphine increased by an average of 0.6 and 7.15 per 100 000 population per month in preengagement and postengagement periods, respectively, indicating an estimated additional 6.56 (95% CI, 2.09-11.02) patients receiving buprenorphine per 100 000 population (P = .004) monthly increase after engagement compared with before. Conclusions and Relevance: In this cohort study measuring buprenorphine prescriptions in Michigan over time, counties' engagement in OUD-focused outreach and clinician education services delivered by a multidisciplinary team was associated with a temporal increase in buprenorphine prescribers and patients receiving buprenorphine.