Enhanced osteogenesis and physicochemical properties of PMMA bone cement with SrBG/HA porous core-shell microspheres.

Artificial bone graft with osteoconductivity, angiogenesis, and immunomodulation is promising clinical therapeutics for the reluctant healing process of bone defects. Among various osteogenic substitutes, polymethyl methacrylate (PMMA) bone cement is a quit competitive platform due to its easy deployment to the bone defects with irregular shape and biomimetic mechanical properties. However, the biologically inert essence of PMMA is reliant on the passive osseointegration and cannot provide sufficient biologic cues to induce fast bone repair. Bioactive glass could serve as an efficient platform for the active osteogenesis of PMMA via ionic therapy and construction of alkaline microenvironment. However, the direct of deployment of bioactive glass into PMMA may trigger additional cytotoxicity and hinder cell growth on its surface. Hence we incorporated ionic therapy as osteogenic cue into the PMMA to enhance the biomedical properties. Specifically, we synthesized core-shell microspheres with a strontium-doped bioactive glass (SrBG) core and hydroxyapatite (HA) shell, and then composited them with PMMA to introduce multifunctional effects of HA incorporation, alkaline microenvironment construction, and functional ion release by adding microsphere. We preparedxSrBG@HA/PMMA cements (x= 30, 40, 50) with varied microsphere content and evaluated impacts on mechanical/handling properties, ion release, and investigated the impacts of different composite cements on proliferation, osteogenic differentiation, angiogenic potential, and macrophage polarization. These findings provide new perspectives and methodologies for developing advanced bone biomaterials to promote tissue regeneration.

Factors associated with the persistence of human papillomavirus after surgery in patients with cervical cancer.

OBJECTIVE: To determine the rate of human papillomavirus (HPV) persistence after surgery in patients with cervical cancer, and to analyze the factors associated with HPV persistence and viral load after surgery. METHODS: Medical records of women who underwent surgery for treatment of cervical cancer between 1 January 2018 and 30 June 2019 at Obstetrics and Gynecology Hospital of Fudan University in Shanghai, China, were retrospectively analyzed. Patients with persistent HPV infection after 2 years of follow-up were identified. Univariate and multivariate analyses were employed to determine the impact of various factors including patient age, menopausal status, parity, and surgical margin status on HPV persistence. The Wilcoxon test was used to analyze the factors that influenced postoperative HPV viral load. RESULTS: Altogether, 607 women were eligible for the final analysis. The persistence rates of HPV at 6 months, 1 year, and 2 years after surgery were 17.3, 13.7, and 10.2 %, respectively. In univariate analysis, the factors that were predictive of the persistence of HPV infection were old age, postmenopausal status, and positive vaginal incision margin with cancer. In multivariate analysis, the significant independent predictive factors were postmenopausal status and positive vaginal incision margin with cancer (P < 0.05, odds ratio (OR) = 2.289, 95 % confidence interval (CI): 1.262-4.150 and OR = 3.271, 95 % CI: 1.253-8.537, respectively). A vaginal lesion with cancer or squamous intraepithelial lesion (SIL) and positive vaginal incision margin influenced HPV viral load at 6 months after surgery (P < 0.05). CONCLUSIONS: Postmenopausal patients and those with positive vaginal incision margin with cancer are at an increased risk of HPV persistence after surgical treatment for cervical cancer. Vaginal lesions with cancer or SILs and positive vaginal incision margin are risk factors for high HPV viral load after surgery.

Enhanced ·OH-Scavenging Activity of Cu-CeOx Nanozyme via Resurrecting Macrophage Nrf2 Transcriptional Activity Facilitates Diabetic Wound Healing.

Diabetic wounds are a prevalent and devastating complication of diabetes, which may impede their healing and regeneration. In diabetic wounds, excess reactive oxygen species (ROS) activate the nuclear factor kappa-B pathway, leading to transcriptional silencing of nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in a vicious cycle of oxidative stress and inflammation. Conventional nanozymes have limitations in preventing the continuous production of ROS, including the most oxidizing reactive hydroxyl radical (·OH), although they can remove pre-existing ROS. Herein, a novel antioxidant nanoplatform addresses this challenge by incorporating JSH-23 into the mesoporous of cupric-doped cerium oxide nanozymes. Additionally, for rapid wound adaptability and durable tissue adhesion, a nanozyme hydrogel spray consisting of oxidized sodium alginate and methacrylate gelatin is constructed, named OG@CCJs. This platform resurrects Nrf2 transcriptional activity of macrophages in vitro, curbing the production of ROS at its source, particularly ·OH, while enabling the nanozymes to scavenge previously generated ROS. OG@CCJs significantly alleviate oxidative stress in diabetic wounds in vivo, promoting wound healing. Overall, the proposed nanozyme-hydrogel spray with enhanced ·OH-scavenging activity uses a "two-track" antioxidant strategy to rebuild the antioxidant defense barrier of macrophages. This pioneering approach highlights the tremendous potential of OG@CCJs for facilitating diabetic wound healing.

Machine learning combined with single-cell analysis reveals predictive capacity and immunotherapy response of T cell exhaustion-associated lncRNAs in uterine corpus endometrial carcinoma.

BACKGROUND: The exhaustion of T-cells is a primary factor contributing to immune dysfunction in cancer. Long non-coding RNAs (lncRNAs) play a significant role in the advancement, survival, and treatment of Uterine Corpus Endometrial Carcinoma (UCEC). Nevertheless, there has been no investigation into the involvement of lncRNAs associated with T-cell exhaustion (TEXLs) in UCEC. The goal of this work is to establish predictive models for TEXLs in UCEC and study their related immune features. METHODS: Using transcriptome and single-cell sequencing data from The Cancer Genome Atlas and Gene Expression Omnibus databases, we employed co-expression analysis and univariate Cox regression to identify prognostic-associated TEXLs (pTEXLs). The prognostic model was developed using the Least Absolute Contraction and Selection Operator. The immunotherapy characteristics of the prognostic model risk score were studied. Then molecular subgroups were identified through non-negative Matrix Factorization based on pTEXLs. The identification of co-expressed genes was done using a weighted correlation network analysis. Subsequently, a diagnostic model for UCEC was created. In-depth investigations, both in vitro and in vivo, were carried out to elucidate the molecular mechanism of the key gene within the diagnostic model. RESULTS: Receiver operating characteristic curve, calibration curve, and decision curve analysis proved the validity of the predictive models established according to pTEXLs. The subgroup with lower risk scores in the prognostic model has better responses to blocking immune checkpoint therapy. Single-cell analysis suggests that the expression level of MIEN1 is relatively high in immune cells among diagnostic genes. Furthermore, the targeted suppression of MIEN1 via sh-MIEN1 diminishes the proliferative, migratory, and invasive capacities of UCEC cells, potentially associated with CD8+ T cell exhaustion. CONCLUSIONS: The association between TEXLs and UCEC was methodically elucidated by our investigation. A stable pTEXLs risk prediction model and a diagnosis model for UCEC were also established.

Application of a diagnosis flow draft based on appearance impression for detection of vulvar disease.

OBJECTIVES: The aims of this retrospective study were to evaluate the clinical applicability of the latest International Society for the Study of Vulvovaginal Disease (ISSVD) and International Federation for Cervical Pathology and Colposcopy (IFCPC) terminology for vulvar diseases, and to explore a new evaluation flow to optimize decision-making on diagnosis. METHODS: A total of 1,068 patients with 5,340 qualified vulvar images were evaluated by observers using 2011 ISSVD and 2011 IFCPC terminology systems. The sensitivity, specificity, positive predictive value, negative predictive value, Youden Index and Overall Diagnostic Value (ODV) were calculated for each finding in the two systems. Then the disease diagnosis order and a diagnosis flow draft (DFD) were obtained. RESULTS: A total of 15 kinds of vulvar diseases were diagnosed. The proportion of patients accompanied with cervical or vaginal intraepithelial neoplasia was highest (83.3 %) in vulvar Paget's disease group (p<0.001). Total area of lesions was larger in vulvar Paget's disease, lichen simplex chronicus and lichen sclerosus group (p<0.001). Among the top five findings of ODV, some findings inferred several (≥6) kinds of diseases, while some findings only exist in a certain disease. When the DFD was used, the agreement between the initial impression and histopathology diagnosis was 68.8 %, higher than those when ISSVD an IFCPC terminology systems used (p=0.028), and it didn't change with the experience of the observer (p=0.178). CONCLUSIONS: Based on the findings in ISSVD and IFCPC terminology systems, we explored a DFD for observers with different experience on the detection of vulvar disease.

Anoikis Patterns in Cervical Cancer: Identification of Subgroups and Construction of a Novel Risk Model for Predicting Prognosis and Immune Response.

BACKGROUND: Cervical cancer has high morbidity and intratumor heterogeneity. Anoikis, a form of programmed cell death preventing detached cancer cells from readhering, may serve as a potential prognostic signature for cervical cancer. This study aimed to assess the predictive performance of anoikis patterns in cervical cancer prognosis. METHODS: Differentially expressed anoikis-related genes (DEARGs) were identified between normal and cancer samples using data from the Gene Expression Omnibus database with the elucidation of mutation status and bio-function. Novel anoikis molecular subtypes were defined in The Cancer Genome Atlas (TCGA) cohort with consensus clustering analysis. A multigene prognostic signature was constructed through least absolute shrinkage and selection operator (LASSO) Cox analysis with internal and external validation. The nomogram-based survival probability of cervical cancer over 3 and 5 years was predicted and assessed with calibration, receiver operating characteristic, decision curve analysis, and Kaplan-Meier curves. Additionally, mutation, function, and immune analysis were conducted among different risk groups. RESULTS: We identified 77 DEARGs between normal and cervical cancer tissues and explored their mutation status and functions. The TCGA cohort could be categorized into two subtypes based on these genes. Furthermore, seven prognostic signature genes were constructed, and the nomogram involving DEARGs and clinicopathological characteristics showed satisfactory predictive performance. Functional analysis indicated that immune-related genes were enriched, and immune status, as well as sensitivity of chemotherapies and targeting drugs, were correlated with the risk model. CONCLUSIONS: Anoikis patterns play important roles in tumor immunity and can be used to predict the prognosis of cervical cancers.

Hypoxic Microenvironment Reconstruction with Synergistic Biofunctional Ions Promotes Diabetic Wound Healing.

Chronic hypoxia and ischemia make diabetic wounds non-healing. Cellular functions of diabetic chronic wounds are inhibited under a pathological environment. Therefore, this work develops a composite hydrogel system to promote diabetic wound healing. The composite hydrogel system consists of ε-poly-lysine (EPL), calcium peroxide (CP), and borosilicate glass (BG). The hydrogel supplies continuous dissolved oxygen molecules to the wound that can penetrate the skin tissue to restore normal cellular function and promote vascular regeneration. Biofunctional ions released from BGs can recruit more macrophages through neovascularization and modulate macrophage phenotypic transformation. Combining oxygen-mediated vascular regeneration and ion-mediated inflammatory regulation significantly accelerated diabetic wound healing. These findings indicate that this composite hydrogel system holds promise as a novel tissue engineering material.

Effect of B/Si molar ratio on the structure and properties of borosilicate bioactive glasses assessed using molecular dynamics simulations.

Due to the improvement and innovation of theoretical methods and the increasing enhancement of high performance computing, computer simulations provide a new method and strategy for optimizing complex composition of novel bioactive glass. In this work, molecular dynamics simulations were used to analyze the effect of B/Si molar ratio on the structure of borosilicate bioactive glass (BBG) and to investigate the effect of structural alterations on its ions release and biological effects. Structural descriptor a theoretical structural descriptor that estimates the overall strength of the glass network (Fnet) was calculated from the simulated data, and the linear relationships ofFnetwith B and Mg releasing rate in deionized water and simulated body fluid were built.In vitromineralization experiments showed that all three BBGs could generate hydroxyapatite and the release of some network modifier ions such as Mg would be regulated by the B/Si ratio.In vitrocellular experiments revealed that the BBG sample with a composition of 1.25B (6Na2O-8K2O-8MgO-22CaO-22.5B2O3-2P2O5-31.5SiO2) promoted the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells, and significantly enhanced the expression of osteogenesis-related genes such as osteopontin, which might be related to the release of Mg at an early stage.

The biological roles of CD24 in ovarian cancer: old story, but new tales.

CD24 is a glycosylphosphatidylinositol linked molecular which expressed in diverse malignant tumor cells, particular in ovarian carcinoma cells and ovarian carcinoma stem cells. The CD24 expression is associated with increased metastatic potential and poor prognosis of malignancies. CD24 on the surface of tumor cells could interact with Siglec-10 on the surface of immune cells, to mediate the immune escape of tumor cells. Nowadays, CD24 has been identified as a promising focus for targeting therapy of ovarian cancer. However, the roles of CD24 in tumorigenesis, metastasis, and immune escape are still not clearly demonstrated systematically. In this review, we i) summarized the existing studies on CD24 in diverse cancers including ovarian cancer, ii) illustrated the role of CD24-siglec10 signaling pathway in immune escape, iii) reviewed the existing immunotherapeutic strategies (targeting the CD24 to restore the phagocytic effect of Siglec-10 expressing immune cells) based on the above mechanisms and evaluated the priorities in the future research. These results might provide support for guiding the CD24 immunotherapy as the intervention upon solid tumors.

Impacts of ovarian preservation on the prognosis of neuroendocrine cervical carcinoma: a retrospective analysis based on machine learning.

BACKGROUND: Neuroendocrine cervical carcinoma (NECC) is a rare but aggressive malignancy with younger patients compared to other common histology types. This study aimed to evaluate the impacts of ovarian preservation (OP) on the prognosis of NECC through machine learning. METHODS: Between 2013 and 2021, 116 NECC patients with a median age of 46 years received OP or bilateral salpingo-oophorectomy (BSO) and were enrolled in a retrospective analysis with a median follow-up of 41 months. The prognosis was estimated using Kaplan-Meier analysis. Random forest, LASSO, stepwise, and optimum subset prognostic models were constructed in training cohort (randomly selected 70 patients) and tested in 46 patients through receiver operator curves. Risk factors for ovarian metastasis were identified through univariate and multivariate regression analyses. All data processing was carried out in R 4.2.0 software. RESULTS: Among 116 patients, 30 (25.9%) received OP and showed no significantly different OS compared with BSO group (p = 0.072) and got better DFS (p = 0.038). After construction of machine learning models, the safety of OP was validated in lower prognostic risk group (p > 0.05). In patients ≤ 46 years, no impacts of OP were shown for DFS (p = 0.58) or OS (p = 0.67), and OP had no impact on DFS in different relapse risk population (p > 0.05). In BSO group, regression analyses showed that later stage, para-aortic LNM, and parametrial involvement were associated with ovarian metastasis (p < 0.05). CONCLUSIONS: Preserving ovaries had no significant impact on prognosis in patients with NECC. OP should be considered cautiously in patients with ovarian metastasis risk factors.

Regulated contribution of local and systemic immunity to new bone regeneration by modulating B/Sr concentration of bioactive borosilicate glass.

The local immune response induced by bioactive borosilicate glass (BG) plays a vital role in bone regeneration, but its effect in the systemic immune response of distal tissues, such as spleen, remains unknown. In this study, the network structures and the relative theoretical structural descriptors (Fnet) of the novel BG composition containing boron (B) and strontium (Sr) were calculated and stimulated by molecular dynamics (MD) simulation, and the linear relationships of Fnet and B and Sr releasing rate in pure water and simulate body fluid were built. Next, the synergistic effects of the released B and Sr on promoting osteogenic differentiation, angiogenesis, and macrophage polarization were analyzed in vitro and convinced in rats skull models in vivo. Results show that the optimal synergistic effects of B and Sr both in vitro and in vivo released from 1393B2Sr8 BG increased vessel regeneration, modulated M2 macrophages polarization and promoted new-bone formation. Interestingly, the 1393B2Sr8 BG was found to mobilize monocytes from the spleen to the defects and subsequently modulate them into M2 macrophages. Then, these modulated cells cycled from the bone defects back to the spleen. To analyze the necessity of spleen-derived immune cells in bone regeneration, two contrasting rat models (with/without spleen) of skull defects were furtherly established. As results, rats without spleen had fewer M2 macrophages surrounding skull defects and the bone tissues recovered more slowly, indicating the beneficial effects on bone regeneration of circulating monocytes and polarized macrophages provided by spleen. The present study provides a new approach and strategy in optimizing complex composition of novel BG and sheds light on the importance of spleen through modulating systemic immune response to contribute to local bone regeneration.

Comparison of Sheares vaginoplasty, vaginoplasty using acellular porcine small intestinal submucosa graft and laparoscopic peritoneal vaginoplasty in patients with Mayer-Rokitansky-Küster-Hauser syndrome.

INTRODUCTION AND HYPOTHESIS: The aim of this study is to compare the perioperative, anatomical and functional outcomes of patients with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), undergoing Sheares vaginoplasty, vaginoplasty using acellular porcine small intestinal submucosa (SIS) graft or laparoscopic peritoneal (Davydov) vaginoplasty. METHODS: In this retrospective study, a total of 117 patients with MRKHS undergoing creation of a neovagina from 2017 to 2020 were retrospectively investigated. Comparisons between continuous variables were performed using Student's t-test and between qualitative variables using chi-squared tests. RESULTS: The operative time, return of bowel activity and return to work were the longest in the laparoscopic Davydov group (P < 0.001). The total cost was the highest in the SIS graft group (P < 0.001). The length of the neovagina was 7.9 ± 1.2 cm in the Sheares group, 7.1 ± 0.8 cm in the SIS graft group and 8.1 ± 1.1 cm in the laparoscopic Davydov group. The difference in the length of the neovagina was significant (P < 0.001). There was significant difference in the duration of continuous mould wearing (P < 0.001). There were no significant differences in the total female sexual function index (FSFI) scores or in the satisfaction scores of the male partner among the three groups. CONCLUSION: Sheares vaginoplasty and the vaginoplasty using SIS graft caused less trauma and provided similar functional results to laparoscopic peritoneal vaginoplasty. However, the patients in the Sheares group and SIS graft group needed to wear the mould for a longer duration post-surgery. Sheares vaginoplasty can provide a valuable and economic alternative method for the creation of a neovagina in patients with MRKHS.

Comparison of two different methods for cervicovaginal reconstruction: a long-term follow-up.

INTRODUCTION AND HYPOTHESIS: As a consequence of the evolution of surgery in reconstructive techniques, cervicovaginal reconstruction has become an option for patients diagnosed with congenital cervical and vaginal atresia. This study was aimed at comparing long-term clinical and anatomical results in patients who had cervicovaginal reconstruction with either a small intestinal submucosa (SIS) graft or a split-thickness skin (STS) graft. METHODS: This was a retrospective study of 34 patients who underwent cervicovaginal reconstruction using SIS or STS grafts between January 2012 and August 2017. The patients' postoperative resumption of menstruation, vaginal length, body image satisfaction, and sexual satisfaction were assessed. Quantitative and categorical variables were compared using Student's t test and Chi-squared test respectively. RESULTS: The mean follow-up time was 81.29 ± 20.69 months. The SIS group had a shorter surgery time, an earlier return to work, and a higher cost (p < 0.05). All patients resumed menstruation, but 4 patients were diagnosed with cervical stricture. There was no significant difference in the length of the neovagina, and the satisfaction score of the sexual life of patients and their sexual partners was similar in both groups. Patients in the SIS group showed greater satisfaction with their bodies (p < 0.001). One patient in the SIS group got pregnant via assisted-reproduction techniques. CONCLUSIONS: Cervicovaginal reconstruction using SIS or STS grafts is an effective treatment for patients diagnosed with congenital cervical and vaginal atresia. The method of SIS graft is simpler, with less surgical injury and greater body satisfaction, but it is more expensive.

An Investigation of Depressive Symptoms in Patients with Congenital Cervical and Vaginal Aplasia: A Cross-Sectional Study.

Purpose: Congenital cervical and vaginal aplasia is a rare condition that has a great impact on patients physically and psychologically. The present study was designed to assess depressive symptoms related to congenital cervical vaginal aplasia and provide a scientific basis for formulating psychological intervention measures. Patients and Methods: This was a cross-sectional study of forty-six patients who were diagnosed with congenital cervical and vaginal aplasia and underwent cervicovaginal reconstruction surgery between January 2018 and December 2020. Patients were required to complete a demographic questionnaire, the Patient Health Questionnaire-9 (PHQ-9), the Generalized Anxiety Disorder-7 (GAD-7), and the Symptom Checklist-90 (SCL-90). When patients had sexual activity, their sexual function was evaluated by the Female Sexual Function Index (FSFI) questionnaire. The main outcome was the depressive symptoms screened by PHQ-9, and the factors affecting depressive symptoms were analyzed. Quantitative and categorical variables were compared using Student's t-test and chi-squared test, respectively. Results: Of all patients diagnosed with congenital cervical and vaginal aplasia, 58.7% (27/46) presented moderate to severe depressive symptoms. Some factors were related to the patient's depressive symptoms, such as age, parental attitudes, family disharmony, being teased by peers, sexual dysfunction, fertility anxiety, and feeling uncomfortable while wearing the vaginal mold. Conclusion: Half of patients with congenital cervical and vaginal aplasia have depressive symptoms. These findings stress that psychotherapy should be regarded as an independent treatment for patients with congenital cervical and vaginal aplasia.

Single-port laparoscopy versus conventional laparoscopy of benign adnexal masses during pregnancy: a retrospective case-control study.

OBJECTIVE: To compare operative outcomes between single-port laparoscopy (SPL) and conventional laparoscopy (CL) to remove adnexal masses during pregnancy. METHODS: This retrospective case-control study included all patients who had undergone laparoscopic removal of benign adnexal masses during pregnancy between October 2010 and January 2020. Multiple clinical characteristics and operative outcomes were retrospectively analysed and compared between patients who had undergone SPL versus CL, including cosmetic satisfaction with the scar, measured on a 10-point scale (10 indicating very satisfied). RESULTS: A total of 64 patients were included (SPL, n = 22; and CL, n = 42). Overall scar satisfaction scores significantly favoured SPL versus CL (9.1 ± 1.7 versus 8.1 ± 1.3, respectively), however, surgery duration was significantly longer for SPL than CL (69.2 ± 21.0 min versus 54.7 ± 20.7 min). No incisional hernia was detected in the study. Operative blood loss, decrease in estimated haemoglobin level, length of hospital stay, and hospitalization expenses were comparable between the two groups. Pregnancy and fetal outcomes were not remarkably different. CONCLUSION: For removal of benign adnexal masses during pregnancy, SPL may offer superior cosmetic satisfaction versus CL, and was not associated with additional perioperative danger, economic burden, or adverse pregnancy and neonatal outcomes.

Vaginal Microbial Environment Skews Macrophage Polarization and Contributes to Cervical Cancer Development.

As a common female reproductive system malignancy, cervical cancer (CC) disturbs numerous women's health. This study demonstrates the role of the vaginal microbial environment (Peptostreptococcus anaerobius) in cervical cancer. Functional assays, including cell proliferation assay, tube formation assay, and immunofluorescence staining, revealed the effect of Peptostreptococcus anaerobius-treated macrophages on cell proliferation and the angiogenesis process. The tube formation assay disclosed the function of Peptostreptococcus anaerobius-treated macrophages on angiogenesis. In vivo assays were also established to explore the impact of Peptostreptococcus anaerobius-treated macrophages on tumor migration. The results revealed that Peptostreptococcus anaerobius-induced macrophages boosted cervical cancer migration and angiogenesis both in vitro and in vivo. Then, this study unveiled that Peptostreptococcus anaerobius-induced macrophage secreted VEGF to stimulate the angiogenesis in cervical cancer. As a whole, Peptostreptococcus anaerobius-induced macrophage facilitates cervical cancer development through modulation of VEGF expression.

Life Modifications and PCOS: Old Story But New Tales.

Polycystic ovary syndrome (PCOS) is defined as a kind of endocrine and metabolic disorder that affects female individuals of reproductive age. Lifestyle modifications, including diet modifications, exercise, and behavioral modification, appear to alleviate the metabolic dysfunction and improve the reproductive disorders of PCOS patients (particularly in obese women). Therefore, lifestyle modifications have been gradually acknowledged as the first-line management for PCOS, especially in obese patients with PCOS. However, the mechanism of lifestyle modifications in PCOS, the appropriate composition of diet modifications, and the applicable type of exercise modifications for specific female populations are rarely reported. We conducted a systematic review and enrolled 10 randomized controlled trials for inclusion in a certain selection. In this review, we summarized the existing research on lifestyle modifications in PCOS. We aimed to illustrate the relationship between lifestyle modifications and PCOS (referring to hyperandrogenism, insulin resistance as well as obesity) and also considered the priorities for future research. These results might be an invaluable tool to serve as a guide in lifestyle modifications as the intervention for PCOS and other related endocrine disorders.

Exosome Mediated Cytosolic Cisplatin Delivery Through Clathrin-Independent Endocytosis and Enhanced Anti-cancer Effect via Avoiding Endosome Trapping in Cisplatin-Resistant Ovarian Cancer.

Background: Ovarian carcinoma is one of the most common gynecologic malignancies, cisplatin resistance has become a key obstacle to the successful treatment of ovarian cancer because ovarian carcinomas are liable to drug resistance. To find an effective drug carrier is an urgent need. Methods: Exosomes and loading-cisplatin exosomes are isolated using differential centrifugation and characterized by transmission, electron, nanoparticle tracking analysis. The anti-cancer effect of cisplatin was detected under the circumstance of delivered by exosomes or without exosomes in vitro and in vivo. Using proteome analysis and bioinformatics analysis, we further discovered the pathways in exosomes delivery process. We employed a con-focal immunofluorescence analysis, to evaluate the effects of milk-exosomes deliver the cisplatin via avoiding endosomal trapping. Results: Exosomes and exosome-cisplatin were characterized including size, typical markers including CD63, Alix and Tsg101. The anti-cancer effect of cisplatin was enhanced when delivered by exosome in vitro and in vivo. Mechanistic studies shown that exosomes deliver cisplatin mostly via clathrin-independent endocytosis pathway. Exosomes deliver cisplatin into cisplatin-resistant cancer cells clathrin-independent endocytosis and enhance the anti-cancer effect through avoiding endosome trapping. Conclusion: Cisplatin could be delivered by exosome through clathrin-independent endocytosis, and could evade the endosome trapping, diffused in the cytosol evenly. Our study clarifies the mechanism of exosomes mediated drug delivery against resistant cancer, indicates that exosomes can be a potential nano-carrier for cisplatin against cisplatin resistant ovarian cancer, which validates and enriches the theory of intracellular exosome trafficking.

Ubiquitin C-terminal hydrolase L1 promotes lymph node metastasis in small cell neuroendocrine carcinomas of the cervix.

OBJECTIVE: To screen for specific differentially expressed genes in small cell neuroendocrine carcinoma of the cervix (SCNEC) and to further explore their roles and mechanisms in tumor progression. METHODS: Differentially expressed genes in SCNEC compared with squamous cell carcinoma (SCC) and adenocarcinoma (AC) were screened by microarray and immunohistochemical analyses. The biological functions of the identified genes were examined in a SCNEC cell line using RNA interference and over-expression plasmid-transfection technologies. Co-expression network analysis and immunoprecipitation technology were used to explore the potential mechanisms. RESULTS: Compared with SCC and AC, UCHL1 (encoding ubiquitin C-terminal hydrolase L1) was identified as a specific differentially expressed gene in SCNEC, which was positively related to lymph node metastasis (LNM). Migration and invasion of SCNEC tumor cells were induced by UCHL1 over-expression and suppressed by UCHL1 down-regulation, as shown by scratch and transwell invasion assays. Co-expression network analysis suggested that Prospero homeobox protein 1 (PROX1) might interact with UCHL1, and in vivo immunoprecipitation and western blots verified that levels of ubiquitinated PROX1 were significantly decreased following UCHL1 overexpression. CONCLUSION: UCHL1 is a potential biomarker of LNM in SCNEC. UCHL1 might promote SCNEC cell migration and invasion by reducing PROX1 ubiquitination.

Gut and Vaginal Microbiomes in PCOS: Implications for Women's Health.

PCOS is defined as a kind of endocrine and metabolic disorder which affects females at reproductive ages, is becoming much more common, nowadays. Microbiomes are known as microorganisms that inhabit the body to play a vital role in human health. In recent years, several basic and clinical studies have tried to investigate the correlation between the reproductive health/disorder and microbiomes (gut microbiomes and vaginal microbiomes). However, the mechanism is still unclear. In this review, we reviewed the relationship between PCOS and microbiomes, including gut/vaginal microbiomes compositions in PCOS, mechanism of microbiomes and PCOS, and then collectively focused on the recent findings on the influence of microbiomes on the novel insight regarding the therapeutic strategies for PCOS in the future clinical practice.