Search

Abstract Autophagy, a conserved catabolic process implicated in a diverse array of human diseases, requires efficient fusion between autophagosomes and lysosomes to function effectively. Recently, SNAP47 has been identified as a key component of the dual-purpose SNARE complex mediating autophagosome-lysosome fusion in both bulk and selective autophagy. However, the spatiotemporal regulatory mechanisms of this SNARE complex remain unknown. In this study, we found that SNAP47 undergoes acetylation followed by deacetylation during bulk autophagy and mitophagy. The acetylation status of SNAP47 is regulated by the acetyltransferase CBP and the deacetylase HDAC2. Notably, the spatiotemporal regulatory dynamics of SNAP47 acetylation differ between bulk autophagy and mitophagy due to distinct regulation on the activity of acetyltransferase and deacetylase. Acetylated SNAP47 inhibits autophagosome-lysosome fusion by indirectly impeding SNARE complex assembly. Mechanistically, deacetylated SNAP47 recruits HOPS components to autophagic vacuoles independently of STX17 and STX17-SNAP47 interaction, while acetylated SNAP47 inhibits this recruitment, consequently leading to the failure of SNARE complex assembly. Taken together, our study uncovers a SNAP47 acetylation-dependent regulatory mechanism governing autophagosome-lysosome fusion by modulating the recruitment of HOPS to autophagic vacuoles without involving STX17, SNAP47-STX17 interaction and ternary SNARE complex formation.

Abstract Uterine sarcoma (US) is a rare malignant tumor that has various pathological types and high heterogeneity in the female reproductive system. Its subtle early symptoms, frequent recurrence, and resistance to radiation and chemotherapy make the prognosis for US patients very poor. Therefore, understanding the molecular mechanisms underlying tumorigenesis and progression is essential for an accurate diagnosis and targeted therapy to improve patient outcomes. Recent advancements in high-throughput molecular sequencing have allowed for a deeper understanding of diseases through multi-omics technologies. In this review, the latest progress and future potential of multi-omics technologies in US research is examined, and their roles in biomarker discovery and their application in the precise diagnosis and treatment of US are highlighted.

ABSTRACT Vaginitis is the most common problem afflicting women of childbearing age. However, the underlying etiological factors remain poorly understood, leading to recurrent vaginitis and constraining clinical management. Here, we explored whether the gut microbiota influences the risk of vaginitis by performing a two-sample Mendelian randomization analysis using the largest genome-wide association studies to date. Four gut taxa in genus levels were identified related to vaginitis: Candidatus Soleaferrea (inverse-variance weighted [IVW] odds ratio [OR] = 2.20, P = 0.026), Dialister (IVW OR = 2.62, P = 0.029), Lachnospiraceae UCG-008 (IVW OR = 0.41, P = 0.0067), and Ruminiclostridium 5 (IVW OR = 0.080, P = 1.42 × 10−5). We further explored the mediation effect of the plasma metabolites by two-step Mendelian randomization (MR) and multivariable MR. The findings indicated that 3-phosphoglycerate and lysophosphatidylcholine antagonistically act against the two identified risk factors (Candidatus Soleaferrea and Dialister, respectively) of vaginitis, thus appearing to confer protective effects against vaginitis. On the contrary, the elevation of arachidonate/pyruvate ratio and reduction in palmitate/myristate ratio mediated the protective effects of Lachnospiraceae UCG-008 against vaginitis. These findings support a potential causal role for gut microbiota in the development of vaginitis, thereby providing potential strategies for its prevention and intervention.IMPORTANCEVaginitis is the most common problem afflicting women of childbearing age. However, the underlying etiological factors remain poorly understood, leading to recurrent vaginitis and constraining clinical management. Besides, the human gut and vagina are important organs that are both colonized by thousands of microorganisms impacting human physiology and health. Whether there is an interplay between the microecosystems is intriguing and unclear. This study evaluated the potential causal relationship between the gut microbiota and vaginitis and suggested that specific types of gut microbiota may be the potential risk or protective factors of vaginitis mediated or suppressed by certain plasma metabolites. These findings provide treatment insights for vaginitis.

To effectively recover low/mid-grade waste flue gas and provide larger refrigeration capacity, an efficient combined power and refrigeration cycle only using ammonia water as the working fluid is proposed and studied in this paper. Parametric analysis is conducted from the perspectives of thermodynamics, exergoeconomics, and environment, the results demonstrate that the low/mid-grade waste flue gas within a wide temperature range can be sufficiently recovered by the proposed cycle, and the cycle performance is significantly affected by the turbine inlet pressure, work/basic concentration and separation temperature of work solution. Based on the heat source condition of 300 °C/10 kg·s−1, the results of single-objective optimization show that the maximum effective exergy efficiency, reduction amount of CO2 emission and waste heat recovery ratio that can be achieved are 0.5989, 262 kg/h and 0.97 respectively, and the achievable minimum unit cost of produced exergy is 8.432 $·GJ−1. Besides, the multi-objective optimization indicates that the optimal comprehensive thermodynamic efficiency is 0.5458 with net power output of 372.5 kW and larger refrigeration capacity of 545.7 kW, and the associated effective exergy efficiency, unit cost of produced exergy, reduction amount of CO2 emission and waste heat recovery ratio are 0.5701, 9.187 $/GJ, 258.3 kg/h and 0.9574, respectively.

High-fat diet (HFD) has been linked to female infertility. However, the specific age at which HFD impacts ovarian function and the underlying mechanisms remain poorly understood. Here, we administered a HFD to female mice at various developmental stages: pre-puberty (4 weeks old), post-puberty (6 weeks old), young adult (9 weeks old), and middle age (32 weeks old). Our observations indicated that ovarian function was most significantly compromised when HFD was initiated at post-puberty. Consequently, post-puberty mice were chosen for further investigation. Through transplantation of fecal bacteria from the HFD mice to the mice on a normal diet, we confirmed that gut microbiota dysbiosis contributed to HFD-induced deteriorated fertility and disrupted estradiol synthesis. Utilizing untargeted and targeted metabolomics analyses, we identified L-saccharopine as a key metabolite, which was enriched in the feces, serum, and ovaries of HFD and HFD-FMT mice. Subsequent in vitro and in vivo experiments demonstrated that L-saccharopine disrupted mitochondrial homeostasis by impeding AMPKα/MFF-mediated mitochondrial fission. This disruption ultimately hindered estradiol synthesis and compromised oocyte quality. AICAR, an activator of AMPKα, ameliorated L-saccharopine induced mitochondrial damage in granulosa cells and oocytes, thereby enhancing E2 synthesis and improving oocyte quality. Collectively, our findings indicate that the accumulation of L-saccharopine may play a pivotal role in mediating HFD-induced ovarian dysfunction. This highlights the potential therapeutic benefits of targeting the gut microbiota-metabolite-ovary axis to address HFD-induced ovarian dysfunction.

Abstract Tumour cell senescence can be induced by various factors, including DNA damage, inflammatory signals, genetic toxins, ionising radiation and nutrient metabolism. The senescence‐associated secretory phenotype (SASP), secreted by senescent tumour cells, possesses the capacity to modulate various immune cells, including macrophages, T cells, natural killer cells and myeloid‐derived suppressor cells, as well as vascular endothelial cells and fibroblasts within the tumour microenvironment (TME), and this modulation can result in either the promotion or suppression of tumorigenesis and progression. Exploring the impact of SASP on the TME could identify potential therapeutic targets, yet limited studies have dissected its functions. In this review, we delve into the causes and mechanisms of tumour cell senescence. We then concentrate on the influence of SASP on the tumour immune microenvironment, angiogenesis, extracellular matrix and the reprogramming of cancer stem cells, along with their associated tumour outcomes. Last, we present a comprehensive overview of the diverse array of senotherapeutics, highlighting their prospective advantages and challenge for the treatment of cancer patients. Key points Senescence‐associated secretory phenotype (SASP) secretion from senescent tumour cells significantly impacts cancer progression and biology. SASP is involved in regulating the remodelling of the tumour microenvironment, including immune microenvironment, vascular, extracellular matrix and cancer stem cells. Senotherapeutics, such as senolytic, senomorphic, nanotherapy and senolytic vaccines, hold promise for enhancing cancer treatment efficacy.

Abstract With increasing proportion of the elderly in the population, age-related diseases (ARD) lead to a considerable healthcare burden to society. Prevention and treatment of ARD can decrease the negative impact of aging and the burden of disease. The aging rate is closely associated with the production of high levels of reactive oxygen species (ROS). ROS-mediated oxidative stress in aging triggers aging-related changes through lipid peroxidation, protein oxidation, and DNA oxidation. Antioxidants can control autoxidation by scavenging free radicals or inhibiting their formation, thereby reducing oxidative stress. Benefiting from significant advances in nanotechnology, a large number of nanomaterials with ROS-scavenging capabilities have been developed. ROS-scavenging nanomaterials can be divided into two categories: nanomaterials as carriers for delivering ROS-scavenging drugs, and nanomaterials themselves with ROS-scavenging activity. This study summarizes the current advances in ROS-scavenging nanomaterials for prevention and treatment of ARD, highlights the potential mechanisms of the nanomaterials used and discusses the challenges and prospects for their applications. Graphical Abstract

Not available.

BackgroundWhile previous research has established an association between inflammatory bowel disease (IBD) and osteoporosis (OP), the nature of this association in different populations remains unclear.ObjectiveOur study used linkage disequilibrium scores(LDSC) regression analysis and Mendelian randomization(MR) to assess the genetic correlation and causal relationship between IBD and OP in European and East Asian populations.MethodsWe performed separate genetic correlation and causal analyses for IBD and OP in European and East Asian populations, used the product of coefficients method to estimate the mediating effect of nutritional status on the causal relationship, and used multi-trait analysis to explore the biological mechanisms underlying the IBD-nutrition-OP causal pathway.ResultsOur analysis revealed a significant genetic correlation and causal relationship between IBD and OP in the European population. Conversely, no such correlation or causal relationship was observed in the East Asian population. Mediation analysis revealed a significant mediating effect of nutritional status on the causal pathway between IBD and OP in the European population. Multi-trait analysis of the IBD-nutrition-OP causal pathway identified MFAP2, ATP13A2, SERPINA1, FTO and VCAN as deleterious variants.ConclusionOur findings establish a genetic correlation and causal relationship between IBD and OP in the European population, with nutritional status playing a crucial mediating role.

Abstract For decades, most studies of ovarian aging have focused on its functional units, known as follicles, which include oocytes and granulosa cells. However, in the ovarian stroma, there are a variety of somatic components that bridge the gap between general aging and ovarian senescence. Physiologically, general cell types, microvascular structures, extracellular matrix, and intercellular molecules affect folliculogenesis and corpus luteum physiology alongside the ovarian cycle. As a result of damage caused by age-related metabolite accumulation and external insults, the microenvironment of stromal cells is progressively remodeled, thus inevitably perturbing ovarian physiology. With the established platforms for follicle cryopreservation and in vitro maturation and the development of organoid research, it is desirable to develop strategies to improve the microenvironment of the follicle by targeting the perifollicular environment. In this review, we summarize the role of stromal components in ovarian aging, describing their age-related alterations and associated effects. Moreover, we list some potential techniques that may mitigate ovarian aging based on their effect on the stromal microenvironment.

Abstract Comprehensively understanding the female reproductive system is crucial for safeguarding fertility and preventing diseases concerning women's health. With the capacity to simulate the intricate physio- and patho-conditions, and provide diagnostic platforms, microfluidic chips have fundamentally transformed the knowledge and management of female reproductive health, which will ultimately promote the development of more effective assisted reproductive technologies, treatments, and drug screening approaches. This review elucidates diverse microfluidic systems in mimicking the ovary, fallopian tube, uterus, placenta and cervix, and we delve into the culture of follicles and oocytes, gametes’ manipulation, cryopreservation, and permeability especially. We investigate the role of microfluidics in endometriosis and hysteromyoma, and explore their applications in ovarian cancer, endometrial cancer and cervical cancer. At last, the current status of assisted reproductive technology and integrated microfluidic devices are introduced briefly. Through delineating the multifarious advantages and challenges of the microfluidic technology, we chart a definitive course for future research in the woman health field. As the microfluidic technology continues to evolve and advance, it holds great promise for revolutionizing the diagnosis and treatment of female reproductive health issues, thus propelling us into a future where we can ultimately optimize the overall wellbeing and health of women everywhere. Graphical Abstract

Abstract Recurrence is the main cause of death in patients with endometrial cancer (EC). This study aimed to construct and validate a nomogram to predict the recurrence-free survival of patients with EC. This was a multicenter retrospective study. A total of 812 patients from Wuhan Tongji Hospital were divided into training and validation cohorts, and 347 and 580 patients from People’s Hospital of Peking University and Qilu Hospital of Shandong, respectively, were used for validation. Univariate and multivariate Cox regression analyses were used to construct a nomogram for predicting recurrence-free survival of EC. Calibration curves, receiver operating characteristic (ROC) curves, and consistency indexes (C-indexes) were used to estimate the performance of the model. Decision curve analysis (DCA) curves were used to assess the clinical utility of the model. Age (P = 0.013), cancer antigen 125 level (P = 0.014), lymphovascular space invasion (P = 0.004), International Federation of Gynecology and Obstetrics stage (P = 0.034), and P53 (P

Abstract The aim of assisted reproductive technology (ART) is to select the high‐quality sperm, oocytes, and embryos, and finally achieve a successful pregnancy. However, functional evaluation is hindered by intra‐ and inter‐operator variability. Microfluidic chips emerge as the one of the most powerful tools to analyze biological samples for reduced size, precise control, and flexible extension. Herein, a systematic search was conducted in PubMed, Scopus, Web of Science, ScienceDirect, and IEEE Xplore databases until March 2023. We displayed and prospected all detection strategies based on microfluidics in the ART field. After full‐text screening, 71 studies were identified as eligible for inclusion. The percentages of human and mouse studies equaled with 31.5%. The prominent country in terms of publication number was the USA (n = 13). Polydimethylsiloxane (n = 49) and soft lithography (n = 28) were the most commonly used material and fabrication method, respectively. All articles were classified into three types: sperm (n = 38), oocytes (n = 20), and embryos (n = 13). The assessment contents included motility, counting, mechanics, permeability, impedance, secretion, oxygen consumption, and metabolism. Collectively, the microfluidic chip technology facilitates more efficient, accurate, and objective evaluation in ART. It can even be combined with artificial intelligence to assist the daily activities of embryologists. More well‐designed clinical studies and affordable integrated microfluidic chips are needed to validate the safety, efficacy, and reproducibility. Trial registration: The protocol was registered in the Open Science Frame REGISTRIES (identification: osf.io/6rv4a).

Senescent cells (SnCs) accumulate in multiple tissue types with the process of individual aging, hindering tissue renewal and driving multiple aging-related disorders. Aside from senescence-associated secretory phenotype (SASP) neutralization and senolytics, there is an emerging senolysis strategy to eliminate SnCs by mobilizing the immunosurveillance function of cytotoxic T lymphocytes (CTLs).

Premature ovarian insufficiency (POI) may lead to early menopause, fertility loss and birth defects without effective treatment. Here, we explored the efficacy and safety of gene therapy to rescue ovarian function in both natural ovarian aging and doxorubicin (Dox) induced POI mice. Sirt1 and Tgfbr2 were screened out and identified as key genes in both murine and human ovarian tissues. Then, adenovirus (AdV) was selected as a suited carrier for ovarian infection after comparison of multiple viral vectors. In both two models, murine fertility was significantly improved after AdV-Sirt1 and AdV-Tgfbr2 invention individually or in combination, without obvious side effects to themselves and their offspring. Compared with the control group, the successful pregnancy rate in the 9-month-old-AdV-Sirt1 group increased by 60 % (67 % vs 42 %). Meanwhile, the pregnancy rate in the AdV-Tgfbr2 + Dox group increased by 85 % (55.6 % vs 20 %). The biological process of ovarian follicle development and fibrosis was rescued. Our work demonstrated that AdV-Sirt1 and AdV-Tgfbr2 therapy alleviates natural ovarian aging and Dox-associated POI, which may be potentially applicable for female fertility protection.

Exposure to airborne fine particulate matter (PM2.5) is strongly associated with poor fertility and ovarian damage. However, the mechanism underlying this remains largely unclear. Here, we found that PM2.5 markedly impaired murine ovarian reserve, decreased hormone levels, and aggravated ovarian inflammation. Circulating interleukin-6 (IL-6) was elevated in PM2.5-exposed mice and was further confirmed to mediate this damage by IL-6 recombinant protein intervention. PM2.5 exposure led to increased alveolar macrophage infiltration in the lungs. However, alveolar macrophage clearance with clodronate liposomes could not fully reverse the elevated IL-6 levels and ovarian injury, suggesting that alveolar macrophages were probably not the only source of circulating IL-6. Further experiments indicated that IL-6 mainly targeted ovarian theca–interstitial cells and impaired testosterone synthesis via suppressing the peroxisome proliferator-activated receptor γ (PPARγ) pathway. In addition, apoptosis of granulosa cells and restriction of follicular growth were observed in co-cultures with IL-6-treated theca–interstitial cells, which could be further reversed by the PPARγ agonist. Moreover, IL-6-neutralizing antibodies ameliorated PM2.5-induced ovarian damage. Notably, increased levels of circulating IL-6 were observed in premature ovarian aging patients and were inversely associated with their ovarian function. In summary, our findings offer a mechanistic explanation for PM2.5-induced ovarian dysfunction and verify IL-6 as a biomarker and potential therapeutic target.

Abstract Objective The objective of this study is to study the adjunct role of combining DNA aneuploidy analysis with radial endobronchial ultrasound (R‐EBUS)‐guided sampling for diagnosis of peripheral lung lesions (PPLs). Method A single‐center prospective study was conducted in patients undergoing R‐EBUS‐guided sampling for PPLs. DNA image cytometry (DNA‐ICM) was used to analyze DNA aneuploidy in bronchial washing from the bronchial segment of the PPL. Clinical information, R‐EBUS data, pathology, DNA‐ICM results, and follow‐up data were analyzed. Sensitivity, specificity, and predictive values for R‐EBUS‐guided sampling, DNA‐ICM, and the two methods combined were measured. Binary logistic regression was performed to determine influencing factors on diagnostic positivity rate. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cutoff point for DNA‐ICM. Results A total of 101 patients were enrolled. Sixty‐four (63.4%) patients had confirmed malignant tumor, of whom 33 were confirmed by R‐EBUS‐guided sampling (biopsy and/or bronchial brush and wash cytology), and 31 by surgery or percutaneous lung biopsy. Thirty‐seven patients were finally considered to have benign lesions, based on clinical information and 1‐year follow‐up. The sensitivity for malignant disease was 51.6% by R‐EBUS, and specificity was 100%. DNA‐ICM had a sensitivity of 67.2% and a specificity of 86.5%. When combining the two methods, sensitivity increased to 78.1% and specificity was 86.5%. Lesion size and whether the R‐EBUS probe was located in the lesion were significantly associated with positivity rate of the combined methods. The optimal cutoff point for DNA‐ICM was 5c for max DNA content, and 1 for aneuploid cell count (sensitivity 67.2%, specificity 86.5%, accuracy 63.4%). Conclusion In malignant PPLs, DNA‐ICM combined with R‐EBUS‐guided sampling can improve diagnostic positivity compared with either method alone.

Objective To evaluate the hospitalised patients with uterine fibroids (UFs) and describe treatment patterns in hospital-treated patients in central China from 2018 to 2021.Design A retrospective analysis.Setting The gynaecology departments of class A and class B secondary and tertiary hospitals in Hubei Province, China.Participants 101 008 patients diagnosed with UFs from 1 January 2018 to 31 December 2021.Results The hospitalised patients with UFs increased with age, reaching a peak at ages 45–49 years and then gradually decreasing. Among these patients, 19.05% had anaemia symptoms. Women aged 25–29 years were more likely to be treated with laparoscopic myomectomy (62.22%), while women aged 20–24 years tend to choose open myomectomy (34.58%). Women over age 45 years who had entered perimenopause tended to be treated with laparoscopic hysterectomy (64.85% for those aged 65–69 years). Patients with fibroid with moderate-to-severe anaemia mostly chose hysterectomy. As a whole, the proportion of patients who chose laparoscopic hysterectomy was similar to that of patients who chose laparoscopic myomectomy (31.38% vs 31.14%). Only 2.08% of UFs were treated with high-frequency MRI-guided focused ultrasound surgery (MRgFUS). The number of patients who choose laparoscopic surgery or MRgFUS treatment was increasing year by year. After stratifying by hospital grade, we found that women treated at class A tertiary hospitals were more likely to have laparoscopic than open surgery (66.12% vs 31.26%). At class B secondary hospitals, 61.9% of the patients underwent myomectomy. By contrast, hysterectomy was used to treat the majority of patients at class A secondary hospitals and class B tertiary hospitals (57.79% and 57.57%, respectively). Use of MRgFUS was mainly concentrated within class A tertiary hospitals.Conclusion UFs affect mainly women in childbearing period. Most patients chose to receive treatment at class A tertiary hospitals, among which laparoscopic myomectomy was the mainstream surgical method for patients in Hubei Province.Trial registration number NCT05840042.

BackgroundThe impact of lipid metabolism on bone metabolism remains controversial, and the extent to which human traits mediate the effects of lipid metabolism on bone metabolism remains unclear.ObjectiveThis study utilized mendelian randomization to investigate the effects of blood lipids on bone mineral density (BMD) at various skeletal sites and examined the mediating role of human traits in this process.MethodsWe leveraged genetic data from large-scale genome-wide association studies on blood lipids (n=1,320,016), forearm bone mineral density (FA-BMD) (n=10,805), lumbar spine bone mineral density (LS-BMD) (n=44,731), and femoral neck bone mineral density (FN-BMD) (n=49,988) to infer causal relationships between lipid and bone metabolism. The coefficient product method was employed to calculate the indirect effects of human traits and the proportion of mediating effects.ResultsThe results showed that a 1 standard deviation(SD) increase in HDL-C, LDL-C and TC was associated with a decrease in LS-BMD of 0.039 g/cm2, 0.045 g/cm2 and 0.054 g/cm2, respectively. The proportion of mediating effects of systolic blood pressure (SBP) on HDL-C to LS-BMD was 3.17%, but suppression effects occurred in the causal relationship of LDL-C and TC to LS-BMD. Additionally, the proportion of mediating effects of hand grip strength (HGS) on the TC to LS-BMD pathway were 6.90% and 4.60% for the left and right hands, respectively.ConclusionIn conclusion, a negative causal relationship was established between lipid metabolism and bone metabolism. Our results indicated that SBP and HGS served as mediators for the effects of lipid metabolism on bone metabolism.

Purpose Since previous studies have shown a paradoxical relationship between acute kidney injury (AKI) and risk of cognitive impairment, there is an urgent need for a meta-analysis to assess the relationship between AKI and risk of cognitive impairment or dementia.Materials and methods From database inception to October 2023, we searched PubMed, OVID (Medline), Embase, Web of Science, and Cochrane Library. This study examined AKI and cognitive impairment or dementia observational studies. Two authors independently assessed cohort and cross-sectional study quality using the Newcastle–Ottawa Scale and AHRQ Scale. They also used ROBINS-I to assess bias. The meta-analysis used fixed effects. Sensitivity analysis verified results stability. The funnel plot, Egger test, and Begg test determined publication bias in the results.Results Seven studies with 423,876 patients were included in the meta-analysis. Patients with AKI were at higher risk of cognitive impairment or dementia compared to those who had not experienced AKI (OR = 1.87, 95% confidence interval [CI]: 1.77–1.98, I2=46.0%, p = 0.08). All subgroups showed a substantial connection between AKI and cognitive impairment. Compared to domestic research, the connection was stronger in overseas studies (OR = 2.18, 95% CI: 1.66–2.87). Both cognitive impairment and dementia outcomes showed a substantial connection between AKI and cognitive impairment, with OR values of 2.00 (95% CI: 1.44–2.76) and 2.04 (95% CI: 1.66–2.51).Conclusions We found that AKI significantly increases cognitive impairment or dementia risk. Thus, early interventions to delay cognitive impairment and prevent adverse outcomes in AKI patients are needed.

MicroRNA (miR)-145 is enriched in the follicular granulosa cells (GCs) of 3-week-old mice. Downregulating miR-145 inhibits the proliferation and differentiation of GCs and induces evident changes in their cytoskeleton. In this study, we examined how miR-145 induces cytoskeletal changes in mouse GCs and its potential mechanism in regulating GC steroidogenesis. We found that actin related protein 2/3 complex subunit 5 (Arpc5) is a target of miR-145. The miR-145 antagomir increased ARPC5 expression but not β-ACTIN, β-TUBULIN, and PAXILLIN expression. Arpc5 overexpression inhibited GC proliferation, differentiation, and progesterone synthesis. Furthermore, the expression of progesterone synthesis-associated enzymes was downregulated in the Arpc5 overexpression group, and the GC cytoskeleton exhibited evident changes. We conclude that Arpc5, a new target of miR-145, regulates primary GC proliferation and progesterone production by regulating the cytoskeleton remodeling.

Abstract Background Hysterectomy is one of the most frequently gynecologic surgeries performed in premenopausal women. Many premenopausal patients are unwilling to undergo hysterectomy due to the probable decreased ovarian function. The aim of this study is to determine the effect of hysterectomy on ovarian function. Methods A meta-analysis has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) guidelines. We mainly searched the Embase, PubMed and Web of Science databases for eligible studies. The outcomes were the levels of common indicators of ovarian function, such as anti-müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, estradiol (E2) and luteinizing hormone (LH). The evidence was synthesized using meta-analysis via fixed or random effect model according to heterogeneity. Subgroup analyses were performed to examine the potential sources of heterogeneity. Results The 14 included studies were conducted between 1989 and 2021, involving a total of 1,457 premenopausal women with 760 and 697 in the hysterectomy and control group, respectively. We found that hysterectomy damage ovarian function compared to the control group, with lower AMH level [Weighted mean difference (WMD) = -0.56, 95% confidence interval (95% CI): -0.72 to -0.39, P = 0.000], higher FSH levels (WMD = 2.96, 95% CI: 1.47 to 4.44, P = 0.000), lower inhibin B levels (WMD = -14.34, 95% CI: -24.69 to -3.99, P = 0.000) and higher LH levels (WMD = 4.07, 95% CI: 1.78 to 6.37, P = 0.000). In addition, E2 levels have a decreasing trend (WMD = -17.13, 95% CI: -35.10 to 0.85, P = 0.631) in the hysterectomy group but were not statistically significant. Conclusion Hysterectomy has a negative impact on ovarian function, especially in female patients over 40 years old. So, the older patients should closely monitor their ovarian function for early diagnosis and treatment of menopausal symptoms.

Abstract Background Studies have reported frailty as an independent risk factor of mortality in patients with inflammatory bowel disease (IBD). However, no systematic review and meta-analysis has been conducted to determine the relationship of frailty and IBD. We aimed to investigate the prevalence of frailty in patients with IBD and the impact of frailty on the clinical prognosis of these patients. Methods We systematically searched PubMed, Ovid (Medline), Embase, Web of Science, and Cochrane Library from database inception until October 2022. This systematic review included observational studies describing IBD and frailty. We performed meta-analysis for the frailty prevalence in patients with IBD. We analyzed primary outcomes (mortality) and secondary outcomes (infections, hospitalizations, readmission, and IBD-related surgery). Results Nine studies with a total of 1,495,695 participants were included in our meta-analysis. The prevalence of frailty was 18% in patients with IBD. The combined effect analysis showed that frail patients with IBD had a higher risk of mortality (adjusted hazard ratio = 2.25, 95% confidence interval: 1.11–4.55) than non-frail patients with IBD. The hazard ratio for infections (HR = 1.23, 0.94–1.60), hospitalizations (HR = 1.72, 0.88–3.36), readmission (HR = 1.21, 1.17–1.25) and IBD-related surgery (HR = 0.78, 0.66–0.91) in frail patients with IBD. Conclusions We demonstrated that frailty is a significant independent predictor of mortality in patients with IBD. Our work supports the importance of implementing frailty screening upon admission in patients with IBD. More prospective studies are needed to investigate the influence of frailty on patients with IBD and improve the poor prognosis of patients with frailty and IBD.

BackgroundOsteosarcopenia(OS) is a significant health concern resulting from the ageing process. Currently, as the population grows older, the prevalence of OS, a disease that entails the synchronous degeneration of muscles and bones, is mounting. This poses a serious threat to the health of the elderly while placing an enormous burden on social care. In order to comprehend the pathological mechanism of OS and develop clinical drugs, it is pertinent to construct an efficient animal model of OS. To investigate the modeling techniques of diverse experimental models of OS and elucidate their respective benefits and drawbacks, with the purpose of furnishing a theoretical foundation to advance experimental research on OS.MethodsWe searched PubMed, Embase database, China Knowledge Network, Wanfang data platform and Vipshop journal platform databases from 2000 through to September 1, 2023. We included animal studies on sarcopenia or osteoporosis or osteosarcopenia or sarcopenia-osteoporosis, modeling methods for osteosarcopenia. Two independently screened study abstracts and full reports and complete data extraction.ResultsEventually, Of 112, 106 citations screened. 4938 underwent full-text review and 38 met the inclusion criteria. we reviewed and analyzed the literature and categorized the animal models of OS into the following five categories: Aging OS models; Hormonal deficiency model of OS;Chemical injection to induce OS;Disuse OS models and Genetic engineering OS models.ConclusionThis review outlines animal modeling approaches for OS, providing a comprehensive summary of their advantages and disadvantages. The different models were evaluated and selected based on their respective strengths and weaknesses to enable higher quality research outcomes in various research directions. The most widely used and established approach is considered to be the ageing and chemical injection OS model, which has the advantages of excellent reproducibility and low cost.The translational potential of this articleTo gain a profound comprehension of the pathological mechanism of OS and to devise efficacious clinical treatments, it is imperative to establish a viable laboratory animal model of OS. This article surveys various modeling techniques assessing their benefits, drawbacks and areas of applicability while predominantly employing mice as the primary model animal. Additionally, the evaluation indicators of OS models are briefly described.

Clock synchronization is one of the popular research topics in Distributed Measurement and Control Systems (DMCSs). In most industrial fields, such as Smart Grid and Flight Test, the highest requirement for synchronization accuracy is 1 μs. IEEE 1588 Precision Time Protocol-2008 (PTPv2) can theoretically achieve sub-microsecond accuracy, but it relies on the assumption that the forward and backward delays of PTP packets are symmetrical. In practice, PTP packets will experience random queue delays in switches, making the above assumption challenging to satisfy and causing poor synchronization accuracy. Although using switches supporting the Transparent Clock (TC) can improve synchronization accuracy, these dedicated switches are generally expensive. This paper designs a PTP clock servo for compensating Queue-Induced Delay Asymmetry (QIDA), which can be implemented based on ordinary switches. Its main algorithm comprises a minimum window filter with drift compensation and a fuzzy proportional–integral (PI) controller. We construct a low-cost hardware platform (the cost of each node is within USD 10) to test the performance of the clock servo. In a 100 Mbps network with background (BG) traffic of less than 70 Mbps, the maximum absolute time error (max |TE|) does not exceed 0.35 μs, and the convergence time is about half a minute. The accuracy is improved hundreds of times compared with other existing clock servos.

Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, the authors report human papillomavirus features and genomic landscape in SCCC via high-throughput sequencing methods and identify MYC, SOX, NR4A, ANKRD and CEA family genes as HPV-integrated hotspots.

Abstract Background Zishen Yutai (ZSYT) pill, a patent Chinese medicine, has been widely used in the treatment of infertility, abortion, and adjunctive treatment of in vitro fertilization (IVF) for decades. Recently, the results of clinical observations showed that premature ovarian failure (POF) patients exhibited improved expression of steroids and clinical symptoms associated with hormone disorders after treatment with Zishen Yutai pills. However, the pharmacological mechanism of action of these pills remains unclear. Methods The compounds of Zishen Yutai pills found in blood circulation were identified via ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) technique in the serum of POF mice after oral administration of Zishen Yutai pills. The potential targets of compounds were screened using Traditional Chinese Medicine Systems Pharmacology Database, Traditional Chinese Medicine Database@Taiwan, Drugbank Database, PubChem, HIT, Pharmapper, and Swiss Target Prediction. The target genes associated with POF were collected from Online Mendelian Inheritance in Man Database, PharmGkb, Genecards, Therapeutic Target Database, and Genetic Association Database. The overlapping genes between the potential targets of Zishen Yutai pills’ compounds and the target genes associated with POF were clarified via protein-protein interaction (PPI), pathway, and network analysis. Results Nineteen compounds in Zishen Yutai pills were detected in the serum of POF mice after oral administration. A total of 695 Zishen Yutai (ZSYT) pill-related targets were screened, and 344 POF-related targets were collected. From the results of Zishen Yutai (ZSYT) pill-POF PPI analysis, CYP19A1, AKR1C3, ESR1, AR, and SRD5A2 were identified as key targets via network analysis, indicating their core role in the treatment of POF with Zishen Yutai pills. Moreover, the pathway enrichment results suggested that Zishen Yutai pills treated POF primarily by regulating neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis. Conclusions Via virtual screening, we found that regulation of neuroactive ligand-receptor interaction, steroid hormone biosynthesis, and ovarian steroidogenesis was the potential therapeutic mechanism of Zishen Yutai pills in treating POF. Our study suggested that combining the analysis of Zishen Yutai pills’ compounds in blood in vivo in the POF model and network pharmacology prediction might offer a tool to characterize the mechanism of Zishen Yutai pills in the POF.

Purpose: Uterine fibroids occur in 40%–60% of women and are symptomatic in 30% of the patients by causing abnormal uterine bleeding, pelvic pressure, pain, and infertility. The study aims to evaluate the long-term trend of uterine fibroids mortality and disability-adjusted life years (DALYs) in China and the relative risks of age, period, and birth cohort effects.Methods: The mortality and DALYs of uterine fibroids from 1990 to 2019 were derived from the Global Burden of Disease 2019. The annual percentage change and average annual percent change (AAPC) were assessed using the Joinpoint regression. The effects of age, period, and birth cohort on death and DALYs were analyzed by the Age–Period–Cohort framework.Results: The age-standardized rates were all on the ascending trend, with the greatest increase in the age-standardized mortality rate (AAPC, 1.53; 95% CI, 1.04–2.02). The net drift was found to be 3.51% (95% CI, 2.25%–4.78%) per year for mortality and 0.34% (95% CI, 0.14%–0.53%) per year for DALYs. Significant age, period, and birth cohort effects were found for mortality and DALYs (p < 0.001 for all). The mortality risk increased overall with age, but the DALYs risk increased first and then decreased with age. The period and birth cohort risks for mortality and DALYs showed different trends.Conclusion: These secular time trends and changes of mortality and DALYs reveal the socioeconomic alterations, reform of diagnosis and therapy, and changes in social lifestyles and behaviors. Uterine fibroids are still the most common benign gynecological tumors in women, and more epidemiological investigations and social health prevention and control should be applied.

Abstract Ovarian aging is characterized by a progressive decline in ovarian function. With the increase in life expectancy worldwide, ovarian aging has gradually become a key health problem among women. Over the years, various strategies have been developed to preserve fertility in women, while there are currently no clinical treatments to delay ovarian aging. Recently, advances in biomaterials and technologies, such as three-dimensional (3D) printing and microfluidics for the encapsulation of follicles and nanoparticles as delivery systems for drugs, have shown potential to be translational strategies for ovarian aging. This review introduces the research progress on the mechanisms underlying ovarian aging, and summarizes the current state of biomaterials in the evaluation and treatment of ovarian aging, including safety, potential applications, future directions and difficulties in translation. Graphical Abstract

Abstract Background Injury to the external iliac artery can have serious consequences and can be extremely challenging for surgeons. Here, we report a patient with bizarre disconnection of the external iliac artery during a laparoscopic operation. Case presentation On May 27, 2020, during a laparoscopic pelvic lymphadenectomy operation to treat endometrial stromal sarcoma, we encountered an unusual anatomy: abnormal disconnection of the left external iliac artery in a 26-year-old female patient. The proximal and distal ends of the left external iliac artery demonstrated old narrowing without active bleeding, and the distance between the two disconnected ends was more than 3 cm. The scenario was surprising to all the staff in the operating theater. After a comprehensive assessment of skin temperature, arterial pulsation and arterial blood flow, a multidisciplinary team determined that collateral circulation of the left lower limb had been established and could meet the blood supply of the lower limbs, which was also confirmed three times by computed tomography angiography and Doppler ultrasound of the blood vessels in the abdomen and lower limbs. Sixteen months after the operation, the patient had no obvious abnormality, and the daily activities of the left lower limb were not affected. Follow-up after treatment for the patient is still in progress. Conclusions We describe the details of the whole case of disconnection of the external iliac artery. We hope to summarize the experience and lessons learned through this case and a relevant literature review to improve the safety and orderliness of our future clinical work.

Abstract Although immunotherapy has achieved recent clinical success in antitumor therapy, it is less effective for solid tumors with large burdens. To overcome this challenge, herein, we report a new strategy based on platelet membrane‐camouflaged aggregation‐induced emission (AIE) luminogen (Plt‐M@P) combined with the anti‐programmed death ligand 1 (anti‐PD‐L1) for tumoral photodynamic‐immunotherapy. Plt‐M@P is prepared by using poly lactic‐co‐glycolic acid (PLGA)/PF3‐PPh3 complex as a nanocore, and then by co‐extrusion with platelet membranes. PF3‐PPh3 is an AIE‐active conjugated polyelectrolyte with photosensitizing capability for photodynamic therapy (PDT). Plt‐M@P exhibits superior tumor targeting capacity in vivo. When applied in small tumor‐bearing (~40 mm3) mice, Plt‐M@P‐mediated PDT significantly inhibits tumor growth. In tumor models with large burdens (~200 mm3), using Plt‐M@P‐mediated PDT or anti‐PD‐L1 alone is less effective, but the combination of both is effective in inhibiting tumor growth. Importantly, this combination therapy has good biocompatibility, as demonstrated by the absence of damage to the major organs, especially the reproductive system. In conclusion, we show that Plt‐M@P‐mediated PDT can improve anti‐PD‐L1 immunotherapy by enhancing antitumor effects, providing a promising strategy for the treatment of tumors with large burdens.

BackgroundEarly detection of ovarian aging is of huge importance, although no ideal marker or acknowledged evaluation system exists. The purpose of this study was to develop a better prediction model to assess and quantify ovarian reserve using machine learning methods.MethodsThis is a multicenter, nationwide population-based study including a total of 1,020 healthy women. For these healthy women, their ovarian reserve was quantified in the form of ovarian age, which was assumed equal to their chronological age, and least absolute shrinkage and selection operator (LASSO) regression was used to select features to construct models. Seven machine learning methods, namely artificial neural network (ANN), support vector machine (SVM), generalized linear model (GLM), K-nearest neighbors regression (KNN), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM) were applied to construct prediction models separately. Pearson’s correlation coefficient (PCC), mean absolute error (MAE), and mean squared error (MSE) were used to compare the efficiency and stability of these models.ResultsAnti-Müllerian hormone (AMH) and antral follicle count (AFC) were detected to have the highest absolute PCC values of 0.45 and 0.43 with age and held similar age distribution curves. The LightGBM model was thought to be the most suitable model for ovarian age after ranking analysis, combining PCC, MAE, and MSE values. The LightGBM model obtained PCC values of 0.82, 0.56, and 0.70 for the training set, the test set, and the entire dataset, respectively. The LightGBM method still held the lowest MAE and cross-validated MSE values. Further, in two different age groups (20–35 and >35 years), the LightGBM model also obtained the lowest MAE value of 2.88 for women between the ages of 20 and 35 years and the second lowest MAE value of 5.12 for women over the age of 35 years.ConclusionMachine learning methods combining multi-features were reliable in assessing and quantifying ovarian reserve, and the LightGBM method turned out to be the approach with the best result, especially in the child-bearing age group of 20 to 35 years.

Abstract Background To date, there is no approved blood‐based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker. Methods We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan‐cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre‐treatment serum SEMA4C levels, measured using optimized in‐house enzyme‐linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post‐surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities. Results We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900–0.941) and 0.932 (95%CI: 0.911–0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early‐stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916–0.946) and 0.879 (95%CI: 0.832–0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors. Conclusions Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted.

Objective. To evaluate whether postoperative adjuvant treatment is beneficial for patient survival after surgery for early stage endometrial cancer (EC). We analyzed the outcomes of patients treated with radiotherapy, chemotherapy, or progestagen combined with other adjuvant treatments. Methods. We analyzed the outcomes of patients treated with radiotherapy alone, chemotherapy alone, or progestagen treatment with other adjuvant treatments. Women without any adjuvant treatment after operation were used as controls. We retrospectively examined disease-free survival (DFS), overall survival (OS), and high-risk factors that affected the survival status of all patients who received different postoperative adjuvant therapies. Results. In all 192 patients, the total relapse and mortality rates were 5.57% and 1.68%, respectively. Fourteen patients (7.29%) developed isolated local recurrence, and 2 patients died (1.04%) of recurrence during the follow-up period. The 5-year DFS and OS rates of all patients were 95.83% and 93.75%, respectively. No significant differences were observed in the 5-year DFS, 5-year OS, OS, or DFS among the four groups of patients with FIGO stage I endometrial cancer (P=0.9849, 0.7430, 0.9754, and 0.4534, respectively). The differences in the log-rank test results of the estimates of the 5-year DFS, 5-year OS, DFS, and OS of patients with different disease stages and different ages were all significant, but no differences were observed in these parameters among patients with varying degrees of differentiation. Histologic grade, CA125 level, ER and PR status, and adjuvant therapy had no significant effect on the DFS and OS of all patients according to univariate and multivariate regression analyses, but a significant effect on DFS and OS was found when the patients were stratified by age. Conclusion. This retrospective study showed that adjuvant therapy after surgery was not significantly associated with improved DFS or OS in patients with early stage endometrial cancer. However, FIGO stage and age affected the survival of patients with stage I endometrial cancer.

Chemotherapy is often a cause of premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to the effects of chemotherapeutic agents. Different chemotherapeutic agents with varying mechanisms of action may damage ovarian function differently. Taxanes are widely used in clinical cancer treatment, but the specific reproductive toxicological information is still controversial. This review described the impact and duration of taxanes on ovarian function in women and analyzed the possible reasons for different conclusions. Furthermore, the toxicity of taxanes on ovarian function and its possible mechanisms were discussed. The potential protective strategies and agents against ovarian damage induced by taxanes are also reviewed.

Compound methyl salicylate liniment (Ammeltz) is composed of various components, such as methyl salicylate, menthol, camphor, chlorpheniramine maleate, and thymol. It was approved for listing in China in 2011. The purpose of this phase Ⅳ clinical trial was to evaluate the safety and efficacy of Ammeltz in a real-life environment in China. Adverse events and adverse drug reactions were used to assess the safety of the monitored drugs. Visual analog scale (VAS) scores were evaluated to assess the severity of pain and the pain relief rate was used to evaluate the efficacy of the study drug. Of 3,600 subjects enrolled, 3,515 (97.64%) subjects completed the study and 85 (2.36%) terminated the study prematurely. A total of 277 adverse events occurred in 258 subjects (7.28%). The most common adverse events included upper respiratory infections (130 cases, 3.67%), local pruritus (17 cases, 0.48%), and diarrhea (12 cases, 0.34%). A total of 50 (1.41%) subjects experienced 58 adverse drug reactions. The most common adverse drug reactions included local pruritus (17 cases, 0.48%), a burning sensation at the application site (10 cases, 0.28%), and irritation at the application site (local) (7 cases, 0.2%). No adverse reactions were identified as new adverse drug reactions. The majority of adverse drug reactions were mild (48 cases, 1.36%), and no severe adverse drug reactions occurred. The subjects experienced significant pain relief after using Ammeltz (mean VAS scores: 5.34 vs. 2.79; Day 7 ± 1 vs. Baseline; p < 0.0001). The pain relief rate was 47.11% ± 23.13%, and in 2,769 cases (78.31%) the drug was effective in pain relief. After excluding subjects who used drugs that could affect the efficacy of the study drug, the subgroups of subjects experienced significant pain relief after using Ammeltz (mean VAS scores: 5.31 vs 2.77; Day 7 ± 1 vs Baseline; p < 0.0001). The pain relief rate was 47.34% ± 23.00%, and 2,612 subjects (78.75%) experienced effective pain relief. In conclusion, Ammeltz is safe and effective in real-life use. It can significantly relieve soft tissue pain caused by shoulder and neck pain, back pain, or muscle pain. No new adverse drug reactions were found in our multicenter real-world study.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT05489939?cond=Safety+and+efficacy+of+compound+methyl+salicylate+liniment+for+topical+pain%3A+A+multicenter+real-world+study+in+China&draw=2&rank=1, identifier NCT05489939

Objective De novo CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) has different clinical characteristics compared with CD5-negative (CD5−) DLBCL. However, few studies have been reported in Chinese cohorts. We investigated the clinical features and prognosis of patients with CD5+ DLBCL and summarized the related literature. Methods Data from 245 patients with newly diagnosed DLBCL were retrospectively assessed. Results Thirty-one and 214 patients were diagnosed with CD5+ DLBCL or CD5− DLBCL, respectively. In the CD5+ DLBCL group, there were significantly higher proportions of patients with older age (≥60 years), International Prognostic Index (IPI) ≥3, Eastern Cooperative Oncology Group (ECOG) scores ≥ 2, bone marrow involvement, positive B-cell lymphoma 2 expression, and positive MYC expression. Survival analysis showed that CD5+ DLBCL had a markedly poorer 2-year progression-free survival than CD5− DLBCL (18.2% vs. 56.2%). Univariate analysis indicated that age ≥60 years, ECOG score ≥ 2, IPI ≥ 3, B symptoms, and no rituximab-based treatment were poor predictive factors for overall survival (OS). Multivariate analysis revealed that B symptoms and no rituximab-based treatment, but not positive CD5 expression, were independent factors for OS. Conclusions Patients with CD5+ DLBCL had heterogeneous clinical characteristics and poor survival. The development of more targeted and effective therapies is needed.

Carbon tetrachloride (CCL4) is widely used as a chemical intermediate and as a feedstock in the production of chlorofluorocarbons. CCL4 is highly toxic in the liver, kidney, testicle, brain and other tissues. However, the effect of CCL4 on ovarian function has not been reported. In this study, we found that the mice treated with CCL4 showed decreased ovarian function with disturbed estrus cycle, decreased serum level of 17β-estradiol and the reduced number of healthy follicles. Ovarian damage was accompanied by oxidative stress and the production of proinflammatory cytokines, especially interleukins. The indicators of oxidative stress, 4-Hydroxynonenal (4-HNE), 8-hydroxy-2´-deoxyguanosine (8-OHdG), 3-Nitrotyrosine (3-NT) and malondialdehyde (MDA), and the levels of proinflammatory cytokines IL-1α, IL-1β, IL-6 and IL-11 were increased, while the antioxidants, including superoxide dismutase (SOD), nuclear factor erythroid2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), were decreased in the CCL4 group. In the CCL4 treated group, the results of Sirius Red staining, immunohistochemistry and qPCR indicated that proinflammatory cytokines caused further ovarian fibrosis. And CCL4 could also promote ovarian thecal cells to secrete inflammatory cytokines, resulting in fibrosis in vitro. In addition, CCL4 inhibited oocyte development and triggered oocyte apoptosis. In conclusion, CCL4 exposure causes ovarian damage by strong oxidative stress and the high expression of the proinflammatory cytokine mediated ovarian fibrosis.

Abstract Background Interleukin-10 (IL-10) is an independent factor for predicting adverse outcomes in pediatric patients with hemophagocytic lymphohistiocytosis (HLH). However, little is known about its prognostic value in adult patients. Methods This single center retrospective study was conducted to explore the prognostic value of IL-10 in 101 adults newly diagnosed with HLH. The serum interleukin levels were quantitatively determined by chemiluminescence using cytokine profiling kits. Results Serum IL-10 levels were significantly increased in adult HLH patients. Elevated IL-10 levels was correlated with lower concentrations of hemoglobin (r = − 0.279, P = 0.005). IL-10 levels were significantly lower in patients with macrophage activation syndrome (MAS) than in those with infection-associated HLH (IAHS) and malignancy-associated HLH (MAHS) (P = 0.033, P = 0.012). Patients with MAS had relatively longer survival than those with IAHS and MAHS (P 1050 µg/L and IL-10 ≥ 129 pg/mL were poor prognostic factors for survival. However, multivariate analysis revealed that only high serum IL-10 levels (≥ 129 pg/mL) at diagnosis and high post-treatment ferritin levels (> 1050 µg/L) were independent risk factors for poor overall survival in adult HLH patients (HR: 4.087, 95% CI 2.064–8.090, P

Abstract Background Increasing evidence indicates that site-distant metastases are associated with survival outcomes in patients with epithelial ovarian cancer. This study aimed to investigate the prognostic values of site-distant metastases and clinical factors and develop a prognostic nomogram score individually predicting overall survival (OS, equivalent to all-cause mortality) and cancer specific survival (CSS, equivalent to cancer-specific mortality) in patients with epithelial ovarian cancer. Methods We retrospectively collected data on patients with epithelial ovarian cancer from the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2016. Multivariate Cox regression was performed to identify survival trajectories. A nomogram score was used to predict long-term survival probability. A comparison between the nomogram and the International Federation of Gynecology and Obstetrics (FIGO 2018) staging system was conducted using time-dependent receiver operating characteristic (tROC) curve. Results A total of 131,050 patients were included, 18.2, 7.8 and 66.1% had localized, regional and distant metastases, respectively. Multivariate analysis identified several prognostic factors for OS including race, grade, histology, FIGO staging, surgery, bone metastasis, liver metastasis, lung metastasis, and lymphatic metastasis. Prognostic factors for CSS included grade, site, FIGO staging, surgery, bone metastasis, brain metastasis, lung metastasis, lymphatic metastasis, and insurance. Following bootstrap correction, the C-index of OS and CSS was 0.791 and 0.752, respectively. These nomograms showed superior performance compared with the FIGO 2018 staging criteria (P

BackgroundAntimicrobial resistance to metronidazole has emerged after several decades of worldwide use of the drug. The purpose of this study was to evaluate the effectiveness, safety and population pharmacokinetics of morinidazole plus levofloxacin in adult women with pelvic inflammatory disease (PID).MethodsPatients in 30 hospitals received a 14-day course of 500 mg intravenous morinidazole twice daily plus 500 mg of levofloxacin daily. A total of 474 patients were included in the safety analysis set (SS); 398 patients were included in the full analysis set (FAS); 377 patients were included in the per protocol set (PPS); 16 patients were included in the microbiologically valid (MBV) population.ResultsThe clinical resolution rates in the FAS and PPS populations at the test of cure (TOC, primary effectiveness end point, 7–30 days post-therapy) visit were 81.91 and 82.49% (311/377), respectively. There were 332 patients who did not receive antibiotics before treatment, and the clinical cure rate was 82.83%. Among 66 patients who received antibiotics before treatment, 51 patients were clinically cured 7–30 days after treatment, with a clinical cure rate of 77.27%. The bacteriological success rate in the MBV population at the TOC visit was 87.5%. The minimum inhibitory concentration (MIC) values of morinidazole for use against these anaerobes ranged from 1 to 8 μg/mL. The rate of drug-related adverse events (AEs) was 27.43%, and no serious AEs or deaths occurred during the study.ConclusionsThe study showed that treatment with a 14-day course of intravenous morinidazole, 500 mg twice daily, plus levofloxacin 500 mg daily, was effective and safe. The results of this study were consistent with the results of a phase III clinical trial, which verified the effectiveness and safety of morinidazole.

Erythrocytes are often used for the development of cell membrane camouflaged nanoparticles (NPs) due to their wide range of sources. However, whether the difference between autologous and allogeneic sources for the erythrocyte membranes have an influence on the performance of camouflaged NPs, which is still inconclusive. To this end, we developed two aggregation-induced emission (AIE) photosensitizers camouflaged with erythrocyte membranes (E-M), named E-Mauto@P and E-Mallo@P, which were prepared using autologous- and allogeneic-derived erythrocytes, respectively. In vivo, E-M@P-mediated photodynamic therapy (PDT) effectively inhibited tumor growth, and this therapeutic effect did not differ between E-Mauto@P and E-Mallo@P. Importantly, there were no differences between E-Mauto@P and E-Mallo@P treated mice in terms of general condition, organ function or immune system. Both E-Mauto@P and E-Mallo@P have been shown not to cross the placental barrier and do not affect the development of the embryo, which could be a good platform for the treatment of pregnancy-related disorders. These findings provided more detailed evidences for erythrocyte membrane camouflaged NPs as a promising therapeutic platform, since there is no difference in efficacy or biosafety of either autologous or allogeneic erythrocyte-derived NPs.

Abstract Background The preservation of fertility and integrity of the reproductive organs has increasingly been of concern to most women with adenomyosis. Adenomyomectomy is conservative surgery that is now widely applied; however, relapse is a serious problem after the operation. Postoperative treatment, such as gonadotropin-releasing hormone agonist (GnRHa) has been suggested to result in reducing the rate of disease recurrence. However, there is still a lack of evidence from randomized clinical trials examining the efficacy of GnRHa in decreasing the postoperative recurrence rate. Method/design Relapse after conservative surgery combined with triptorelin acetate versus conservative surgery only in women with focal adenomyosis is a multicenter, prospective, randomized controlled trial. The primary outcome is relapse assessed using a visual analogue scale (VRS) and numeric rating scale (NRS), pictorial blood loss assessment chart (PBAC) score, and the size of the uterus and the lesion as measured by two/three-dimensional color doppler ultrasonography (2D/3D-CDUS) or magnetic resonance imaging (MRI). The secondary outcomes include quality of life, clinical pregnancy, ovarian reserve, adverse events, assessment by the Short Form (36) Health Survey and Female Sexual Function index, serum follicle-stimulating hormone, estradiol levels, and anti-Muellerian hormone and so on. All these indexes are measured at 3, 6, 12, 18, 24, 30, and 36 months after conservative surgery. Discussion The result of this large, multicenter randomized trial will provide evidence for one of the strategies of long-term management in focal adenomyosis after conservative operation. Trial registration Chinese Clinical Trial Registry: ChiCTR1800014340 . Registered on 6 January 2018.

Parabens, a type of endocrine-disrupting chemicals, are widely used as antibacterial preservatives in food and cosmetics in daily life. Paraben exposure has gained particular attention in the past decades, owing to its harmful effects on reproductive function. Whether low-dose paraben exposure may cause ovarian damage has been ignored recently. Here, we investigated the effects of chronic low-dose propylparaben (PrPB) exposure on ovarian function. Female C57BL/6J mice were exposed to PrPB at a humanly relevant dose for 8 months. Our results showed that chronic exposure to PrPB at a humanly relevant dose significantly altered the estrus cycle, hormone levels, and ovarian reserve, accelerating ovarian aging in adult mice. These effects are accompanied by oxidative stress enrichment, leading to steroidogenesis dysfunction and acceleration of primordial follicle recruitment. Notably, melatonin supplementation has been shown to protect against PrPB-induced steroidogenesis dysfunction in granulosa cells. Here, we report that daily chronic PrPB exposure may contribute to ovarian aging by altering oxidative stress-mediated JNK and PI3K-AKT signaling regulation, and that melatonin may serve as a pharmaceutical candidate for PrPB-associated ovarian dysfunction.

Purpose: Endometrial thickness is one of the most important indicators in endometrial disease screening and diagnosis. Herein, we propose a method for automated measurement of endometrial thickness from transvaginal ultrasound images.Methods: Accurate automated measurement of endometrial thickness relies on endometrium segmentation from transvaginal ultrasound images that usually have ambiguous boundaries and heterogeneous textures. Therefore, a two-step method was developed for automated measurement of endometrial thickness. First, a semantic segmentation method was developed based on deep learning, to segment the endometrium from 2D transvaginal ultrasound images. Second, we estimated endometrial thickness from the segmented results, using a largest inscribed circle searching method. Overall, 8,119 images (size: 852 × 1136 pixels) from 467 cases were used to train and validate the proposed method.Results: We achieved an average Dice coefficient of 0.82 for endometrium segmentation using a validation dataset of 1,059 images from 71 cases. With validation using 3,210 images from 214 cases, 89.3% of endometrial thickness errors were within the clinically accepted range of ±2 mm.Conclusion: Endometrial thickness can be automatically and accurately estimated from transvaginal ultrasound images for clinical screening and diagnosis.

Endometrial carcinoma (EC) is a common cause of cancer death in women, and having an early accurate prediction model to identify this disease is crucial. The aim of this study was to develop a new machine learning (ML) model-based diagnostic prediction model for EC. We collected data from consecutive patients between November 2012 and January 2021 at tertiary hospitals in central China. Inclusion criteria included women undergoing endometrial biopsy, dilation and curettage, or hysterectomy. A total of 9 features, including patient demographics, vital signs, and laboratory and ultrasound results, were selected in the final analysis. This new model was combined with three top optimal ML methods, namely, logistic regression, gradient-boosted decision tree, and random forest. A total of 1,922 patients were eligible for final analysis and modeling. The ensemble model, called TJHPEC, was validated in an internal validation cohort and two external validation cohorts. The results showed that the AUC values were 0.9346, 0.8341, and 0.8649 for the prediction of total EC and 0.9347, 0.8073, and 0.871 for prediction of stage I EC. Nine clinical features were confirmed to be highly related to the prediction of EC in TJHPEC. In conclusion, our new model may be accurate for identifying EC, especially in the early stage, in the general population of central China.

BackgroundWomen with ovarian cancer had the highest suicidal rate among all patients with gynecological malignancies, but no large studies about suicide and accidental death for women with ovarian cancers in detail were conducted. We aimed to determine the relative risk of suicide and accidental death among patients with ovarian cancer to that of the general population, and to identify risk factors associated with suicide and accidental death.MethodsData are from the SEER (surveillance, epidemiology, and end results) cancer registry of women diagnosed with ovarian cancer data from 18 registries for the years 1973–2016. The study population comprised 149,204 patients after inclusion and exclusion criteria were applied. Standardized mortality ratios (SMRs) were calculated and Fine-Gray models were fitted to identify risk factors associated with suicidal and accidental death among cancer patients, with stratifications on demographic and tumor-related characteristics.ResultsWomen with ovarian cancer had a higher risk of suicide and accidental death than the cancer-free group [SMR = 1.86; 95% CI (1.54–2.25) and SMR = 1.54; 95% CI (1.39–1.71)]. Subgroup analysis indicated that only patients with type II epithelial ovarian cancer [SMR = 2.31; 95% CI (1.83–2.91)] had an increased risk of suicide, and those with type I and type II epithelial ovarian cancer [SMR = 1.65; 95% CI (1.39–1.97) and SMR = 1.49; 95% CI (1.30–1.70)] were at a higher risk of accidental death. Patients with ovarian cancer who were younger, white, diagnosed with high-grade, non-metastatic cancer and pelvic exenteration were at a higher risk of suicide. The advanced age, earlier year of diagnosis, and non-metastatic cancer were associated with a higher risk of accidental death. Additionally, pelvic exenteration increased the risk of suicide but not the risk of accidental death among women with primary ovarian cancer.ConclusionsWomen with ovarian cancer had a higher risk of suicide and accidental death compared with the general population. The findings suggested that clinicians should identify high-risk subgroups of ovarian cancer patients for suicide and accidental death as early as possible, with appropriate prevention strategies.

ObjectivesTo reveal the characteristics of vaginal microbiota in premature ovarian insufficiency (POI) patients and their relationship with ovarian function.Materials and MethodsIn this case-control study, the vaginal bacterial composition of 30 POI patients and 26 healthy women of comparable age was assessed by 16S rRNA gene sequencing targeting the V3-V4 hypervariable regions. The metabolic functions of vaginal microflora were preliminarily predicted through the PICRUSt2 analysis. Redundancy analysis and Spearman’s correlation analyzed the relationships between vaginal microbiota and ovarian function indicators.ResultsActinobacteria, Atopobium, and Gardnerella were significantly increased in POI patients. Their increments were significantly negatively correlated with anti-müllerian hormone (AMH) and inhibin B, and positively correlated with follicle-stimulating hormone (FSH) and luteinizing hormone (LH). While Bifidobacterium was significantly decreased in POI patients. Its relative abundance was significantly positively correlated with AMH and negatively correlated with FSH and LH. Then, POI patients included in this study were divided into POI (25 < FSH ≤ 40) (n = 9) and premature ovarian failure (POF) (FSH > 40) (n = 21) subgroups according to serum FSH levels. Compared with the controls, Firmicutes and Lactobacillus were significantly decreased only in POF (FSH > 40) patients, while no difference was observed in POI (25 < FSH ≤ 40) patients. Lactobacillus was negatively correlated with FSH. Firmicutes was significantly reduced and Actinobacteria was significantly increased in POF (FSH > 40) patients compared with POI (25 < FSH ≤ 40) patients. The key bacterial taxa Gardnerella and Atopobium showed potency in predicting POI.ConclusionsHere we demonstrated significant changes in the vaginal microbiota of POI patients, and these changes were significantly correlated with reduced ovarian reserve, endocrine disruption, and symptoms of perimenopausal syndrome. Differences in vaginal microbiota between POI (25 < FSH ≤ 40) and POF (FSH > 40) patients were also identified. These findings may provide new evidence for the relationship between vaginal microbiota and ovarian function.

Our previous study demonstrated that ovarian wild-type P53-induced phosphatase 1 (WIP1) expression decreased with age. We hypothesized that WIP1 activity was related to ovarian aging. The role of WIP1 in regulating ovarian aging and its mechanisms remain to be elucidated. Adult female mice with or without WIP1 inhibitor (GSK2830371) treatment were divided into three groups (Veh, GSK-7.5, GSK-15) to evaluate the effect of WIP1 on ovarian endocrine and reproductive function and the ovarian reserve. In vitro follicle culture and primary granulosa cell culture were applied to explore the mechanisms of WIP1 in regulating follicular development. This study revealed that WIP1 expression in atretic follicle granulosa cells is significantly lower than that in healthy follicles. Inhibiting WIP1 phosphatase activity in mice induced irregular estrous cycles, caused fertility declines, and decreased the ovarian reserve through triggering excessive follicular atresia and primordial follicle activation. Primordial follicle depletion was accelerated via PI3K-AKT-rpS6 signaling pathway activation. In vitro follicle culture experiments revealed that inhibiting WIP1 activity impaired follicular development and oocyte quality. In vitro granulosa cell experiments further indicated that downregulating WIP1 expression promoted granulosa cell death via WIP1-p53-BAX signaling pathway-mediated apoptosis. These findings suggest that appropriate WIP1 expression is essential for healthy follicular development, and decreased WIP1 expression accelerates ovarian aging by promoting follicular atresia and primordial follicle activation.

Background: Population-based data on the risk assessment of newly diagnosed cervical cancer patients' bone metastasis (CCBM) are lacking. This study aimed to develop various predictive models to assess the risk of bone metastasis via machine learning algorithms.Materials and Methods: We retrospectively reviewed the CCBM patients from the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute to risk factors of the presence of bone metastasis. Clinical usefulness was assessed by Akaike information criteria (AIC) and multiple machine learning algorithms based predictive models. Concordance index (C-index) and receiver operating characteristic (ROC) curve were used to define the predictive and discriminatory capacity of predictive models.Results: A total of 16 candidate variables were included to develop predictive models for bone metastasis by machine learning. The areas under the ROC curve (AUCs) of the random forest model (RF), generalized linear model (GL), support vector machine (SVM), eXtreme Gradient Boosting (XGBoost), artificial neutral network (ANN), decision tree (DT), and naive bayesian model (NBM) ranged from 0.85 to 0.93. The RF model with 10 variables was developed as the optimal predictive model. The weight of variables indicated the top seven factors were organ-site metastasis (liver, brain, and lung), TNM stage and age.Conclusions: Multiple machine learning based predictive models were developed to identify risk of bone metastasis in cervical cancer patients. By incorporating clinical characteristics and other candidate variables showed robust risk stratification for CCBM patients, and the RF predictive model performed best among these predictive models.