SOCS3, Transcriptionally Activated by NR4A1, Induces Apoptosis and Extracellular Matrix Degradation of Vaginal Fibroblasts in Pelvic Organ Prolapse

Background: Pelvic organ prolapse (POP) is a common gynecological chronic disorder. Human vaginal fibroblasts (HVFs) that maintain the integrity of vaginal wall tissues are essential for keeping pelvic organs in place. Apoptosis and the degradation of the extracellular matrix in HVFs contribute to the progression of POP. The cytokine signal transduction inhibitor 3 (SOCS3) exerts significant regulatory effects on cell signal transduction pathways, thereby affecting various pathological processes. Aims: To explore the role and mechanism of SOCS3 on HVFs in the context of POP. Study Design: In vitro cell lines and human-sample study. Methods: Anterior vaginal wall tissues were obtained from POP or non-POP patients for the analysis of SOCS3 expression. HVFs were isolated from the vaginal tissues of POP patients, and SOCS3 was either overexpressed or knocked down in HVFs via lentivirus infection. Subsequently, the biological function and mechanism of SOCS3 in HVFs were investigated. Results: SOCS3 was highly expressed in the vaginal tissues of POP patients compared to non-POP patients. Functionally, the overexpression of SOCS3 suppressed cell viability while promoting cell apoptosis in HVFs. The overexpression of SOCS3 also accelerated extracellular matrix degradation (decreasing collagen I, collagen III, and elastin, and increasing MMP2 and MMP9). In terms of mechanism, NR4A1 transcriptionally activated SOCS3 by binding to its promoter. Furthermore, rescue experiments revealed that SOCS3 knockdown hindered NR4A1 overexpression-induced cell apoptosis and extracellular matrix degradation in HVFs. Conclusion: SOCS3 mediated the apoptotic and extracellular matrix degradation effects of NR4A1 on HVFs, underlining that the restraining of the SOCS3 expression may be a promising strategy for POP treatment.

Early growth response 2, a novel target of pelvic organ prolapse, is highly expressed in anterior vaginal wall tissues with pelvic organ prolapse.

Pelvic organ prolapse (POP) is a common disorder among women that negatively affects women's quality of life. Early growth response 2 (EGR2) is a transcription factor that regulates cell growth. The present study aimed to explore the role of EGR2 in POP progression and provided a new target for the treatment and prevention of POP. Firstly, we extracted primary vaginal anterior wall fibroblasts from POP tissues and non-POP tissues and then constructed an EGR2-silencing lentivirus for further study. Immunoblotting, qPCR, TUNEL assay, CCK-8 assay, dual luciferase assay, and ELISA assay were carried out. EGR2 expression was much higher in POP tissues than in control tissues, and EGR2 expression positively correlated with cytokine signaling 3 (SOCS3) expression. Knockdown of EGR2 increased cell proliferation, upregulated PCNA expression, and reduced apoptosis in POP fibroblasts. Moreover, we found that the knockdown of EGR2 increased COL1A1, COL3A1, and Elastin expression and decreased MMP2 and MMP9 activities, and knockdown of EGR2 increased TGF-ß/Smad pathway activity in POP fibroblasts. Interestingly, the results of dual luciferase assay demonstrated that EGR2 was able to increase SOCS3 transcriptional activity. EGR2 knockdown alleviated the apoptosis of POP fibroblasts by reducing SOCS3 expression and improving the proliferation and collagen synthesis of POP fibroblasts. Overall, our study illustrated that EGR2 was highly expressed in POP tissues, and knockdown of EGR2 alleviated apoptosis and reduced matrix degradation in POP fibroblasts. This study might provide a new insight into the pathogenesis of POP.

Extracellular vesicles targeting tumor microenvironment in ovarian cancer.

Ovarian cancer (OC) is a prevalent neoplastic condition affecting women. Extracellular vesicles (EVs), nano-sized membrane vesicles, are secreted by various cells in both physiological and pathological states. The profound interplay between EVs and the tumor microenvironment (TME) in ovarian cancer is crucial. In this review, we explores the pivotal role of EVs in facilitating intercellular communication between cancer cells and the TME, emphasizing the potential of EVs as promising diagnostic markers and innovative therapeutic targets for ovarian cancer. The comprehensive analysis outlines the specific mechanisms by which EVs engage in communication with the constituents of the TME, including the modulation of tumor growth through EVs carrying matrix metalloproteinases (MMPs) and EV-mediated inhibition of angiogenesis, among other factors. Additionally, the we discuss the potential clinical applications of EVs that target the TME in ovarian cancer, encompassing the establishment of novel treatment strategies and the identification of novel biomarkers for early detection and prognosis. Finally, this review identifies novel strategies for therapeutic interventions, such as utilizing EVs as carriers for drug delivery and targeting specific EV-mediated signaling pathways. In summary, this manuscript offers valuable insights into the role of EVs in ovarian cancer and highlights the significance of comprehending intercellular communication in the realm of cancer biology.

Circular RNAs in gynecologic cancers: mechanisms and implications for chemotherapy resistance.

Chemotherapy resistance remains a major challenge in the treatment of gynecologic malignancies. Increasing evidence suggests that circular RNAs (circRNAs) play a significant role in conferring chemoresistance in these cancers. In this review, we summarize the current understanding of the mechanisms by which circRNAs regulate chemotherapy sensitivity and resistance in gynecologic malignancies. We also discuss the potential clinical implications of these findings and highlight areas for future research. CircRNAs are a novel class of RNA molecules that are characterized by their unique circular structure, which confers increased stability and resistance to degradation by exonucleases. Recent studies have shown that circRNAs can act as miRNA sponges, sequestering miRNAs and preventing them from binding to their target mRNAs. This can lead to upregulation of genes involved in drug resistance pathways, ultimately resulting in decreased sensitivity to chemotherapy. We discuss several specific examples of circRNAs that have been implicated in chemoresistance in gynecologic cancers, including cervical cancer, ovarian cancer, and endometrial cancer. We also highlight the potential clinical applications of circRNA-based biomarkers for predicting chemotherapy response and guiding treatment decisions. Overall, this review provides a comprehensive overview of the current state of knowledge regarding the role of circRNAs in chemotherapy resistance in gynecologic malignancies. By elucidating the underlying mechanisms by which circRNAs regulate drug sensitivity, this work has important implications for improving patient outcomes and developing more effective therapeutic strategies for these challenging cancers.

Robot tool use: A survey.

Using human tools can significantly benefit robots in many application domains. Such ability would allow robots to solve problems that they were unable to without tools. However, robot tool use is a challenging task. Tool use was initially considered to be the ability that distinguishes human beings from other animals. We identify three skills required for robot tool use: perception, manipulation, and high-level cognition skills. While both general manipulation tasks and tool use tasks require the same level of perception accuracy, there are unique manipulation and cognition challenges in robot tool use. In this survey, we first define robot tool use. The definition highlighted the skills required for robot tool use. The skills coincide with an affordance model which defined a three-way relation between actions, objects, and effects. We also compile a taxonomy of robot tool use with insights from animal tool use literature. Our definition and taxonomy lay a theoretical foundation for future robot tool use studies and also serve as practical guidelines for robot tool use applications. We first categorize tool use based on the context of the task. The contexts are highly similar for the same task (e.g., cutting) in non-causal tool use, while the contexts for causal tool use are diverse. We further categorize causal tool use based on the task complexity suggested in animal tool use studies into single-manipulation tool use and multiple-manipulation tool use. Single-manipulation tool use are sub-categorized based on tool features and prior experiences of tool use. This type of tool may be considered as building blocks of causal tool use. Multiple-manipulation tool use combines these building blocks in different ways. The different combinations categorize multiple-manipulation tool use. Moreover, we identify different skills required in each sub-type in the taxonomy. We then review previous studies on robot tool use based on the taxonomy and describe how the relations are learned in these studies. We conclude with a discussion of the current applications of robot tool use and open questions to address future robot tool use.

Rapidly Learning Generalizable and Robot-Agnostic Tool-Use Skills for a Wide Range of Tasks.

Many real-world applications require robots to use tools. However, robots lack the skills necessary to learn and perform many essential tool-use tasks. To this end, we present the TRansferrIng Skilled Tool Use Acquired Rapidly (TRI-STAR) framework for task-general robot tool use. TRI-STAR has three primary components: 1) the ability to learn and apply tool-use skills to a wide variety of tasks from a minimal number of training demonstrations, 2) the ability to generalize learned skills to other tools and manipulated objects, and 3) the ability to transfer learned skills to other robots. These capabilities are enabled by TRI-STAR's task-oriented approach, which identifies and leverages structural task knowledge through the use of our goal-based task taxonomy. We demonstrate this framework with seven tasks that impose distinct requirements on the usages of the tools, six of which were each performed on three physical robots with varying kinematic configurations. Our results demonstrate that TRI-STAR can learn effective tool-use skills from only 20 training demonstrations. In addition, our framework generalizes tool-use skills to morphologically distinct objects and transfers them to new platforms, with minor performance degradation.

miR-19-3p Promotes Autophagy and Apoptosis in Pelvic Organ Prolapse Through the AKT/mTOR/p70S6K Pathway: Function of miR-19-3p on Vaginal Fibroblasts by Targeting IGF-1.

OBJECTIVE: Pelvic organ prolapse (POP) is a common condition in older women. A decrease in collagen 1 (Col-1) expression is one of the main causes of POP. Many microRNAs play an important role in regulating target genes. The relationship between miR-19-3p and POP is investigated in this study, and the molecular mechanism was also explored to find whether miR-19-3p may be a potential target for early diagnosis and prevention of POP. METHODS: A total of 60 patients with POP and 60 patients without POP were included in this study. Reverse transcription-polymerase chain reaction and Western blot were used to detect the expression of miR-19-3p, insulin-like growth factor 1 (IGF-1), and the Akt/mTOR/p70S6K pathway. Cell cycle was defined by flow cytometric analysis. The combination of miR-19-3p and IGF-1 was revealed by luciferase assays. RESULTS: The results of this study show that miR-19-3p was upregulated in the tissue of patients with POP, whereas COL-1 and IGF-1 expressions were lower in the POP group. miR-19-3p promoted excessive fibroblast autophagy and apoptosis. miR-19-3p negatively regulated the Akt/mTOR/p70S6K pathway and inhibited COL-1 secretion. Luciferase reporter assay showed that miR-19-3p regulated IGF-1 expression by direct target binding. CONCLUSIONS: miR-19-3p has negative associations with the expression of Col-1. Our study highlights that miR-19-3p may affect the synthesis of Col-1 by targeting IGF-1 and that it may play an vital role in POP.

Transforming Growth Factor Beta 1 and p44/42 Expression in Cardinal Ligament Tissues of Patients with Pelvic Organ Prolapse.

BACKGROUND Pelvic organ prolapse (POP) is a disease associated with collagen loss and decreased fibroblast proliferation. Transforming growth factor beta 1 (TGF-ß1) controls collagen synthesis and degradation in pelvic connective tissue. Although the p44/42 MAPK pathway has been implicated in collagen production and extracellular matrix disorders, its expression in POP remains unknown. This study aimed to investigate TGF-ß1 and p44/42 expression in cardinal ligament tissues in patients with POP. MATERIAL AND METHODS Cardinal ligament tissues were obtained from 30 patients with POP (POP group) and 30 patients with benign gynecological disorders who had undergone total hysterectomy (control group). The clinical characteristics of the 2 groups were summarized. Immunohistochemical staining and western blotting analysis were performed to measure the expression of TGF-ß1, p44/42, phospho-p44/42, MMP9, TIMP1, caspase 3, collagen I, and collagen III in the cardinal ligament tissues. RESULTS Patients with POP had significantly lower TGF-ß1 and phospho-p44/42 levels than did control patients (P<0.05). The expression of TIMP1, collagen I, and collagen III was significantly lower, and the expression of MMP9 and caspase 3 was significantly higher in the POP group than in the control group (P<0.05). Moreover, the expression of phospho-p44/42 was positively correlated with the expression of TGF-ß1, collagen I, and collagen III. CONCLUSIONS The expression levels of phospho-p44/42 and TGF-ß1 were decreased in patients with POP and were positively correlated with collagen expression. Low levels of TGF-ß1 and phospho-p44/42 expression in patients with POP may be associated with the occurrence of POP.

Improvement in Outlet Obstructive Constipation Symptoms After Vaginal Stent Treatment for Rectocele.

Objective. The objective is to determine the possible improvement in outlet obstructive constipation symptoms after vaginal stent treatment for rectocele. Methods. Female patients with rectocele (n = 156) accompanied with outlet obstructive constipation were selected in this study. Longo's obstructed defecation syndrome (ODS) questionnaire, rectoanal pressures, and rectal balloon expulsion (BET) were evaluated at baseline, 1 month follow-up, and 6 months follow-up. Moreover, the side effects and the potential reasons for giving up treatment were also detected. Results. Vaginal stent significantly decreased the straining intensity, shortened the straining extensity time, decreased the use of laxatives, and alleviated the symptoms of incomplete evacuation (P < .05). The vaginal stent also increased the rectal pressure and shortened the balloon expulsion time (P < .05). Conclusions. As an effective, feasible, and safe procedure, the vaginal stent can be recommended as a treatment of choice for rectocele combined with outlet obstructive constipation.

Subjective and Objective Evaluation of Total Pelvic Floor Reconstruction with Six-Arm Mesh in Patients with Severe Pelvic Organ Prolapse: A 1-Year Retrospective Study.

PURPOSE: To investigate the effect of total pelvic floor reconstruction with a six-arm mesh in the treatment of pelvic organ prolapse. PATIENTS AND METHODS: This is a retrospective observational cohort study. A total of 368 patients with pelvic organ prolapse underwent pelvic floor reconstruction surgery. Patients were categorized by the type of surgical mesh: 176 patients received a six-arm mesh and 192 patients received an anteroposterior approach mesh. The 1-year effect of the two groups was compared. The Pelvic Floor Distress Inventory Questionnaire (PFDI-20), Colorectal-Anal Distress Inventory (CRADI-8) and the Pelvic Organ Prolapse Quantitation (POP-Q) staging were used for evaluation. The incidence of complications was recorded. A cure standard was registered by a POP-Q score of grade I or below. A P value <0.05 indicates the difference is statistically significant. RESULTS: There was no recurrence documented in the patients; the cure rate was 100% in both groups. After surgery, the length of the vagina in the six-arm mesh group was longer than that of the control group at 6 months and 12 months, respectively (P < 0.05). The six-arm mesh group had lower PFDI-20 and CRADI-8 scores after surgery than those of the control group at 6 and 12 months, respectively (P < 0.05). Pelvic floor and rectal dysfunction symptom improvement were superior in the six-arm mesh group compared with the control group. After surgery, the Female Sexual Function Inventory (FSFI) score of the six-arm mesh group was superior to that of the control group at 6 and 12 months, respectively (P < 0.05). The incidence of complications in the six-arm mesh group was lower than that of the control group (P < 0.05). CONCLUSION: The total pelvic floor reconstruction using six-arm mesh has the same healing rate as anteroposterior approach mesh surgery, and it is better than traditional surgery in improving subjective symptoms and reducing postoperative complications.

Three-Dimensional Transperineal Ultrasonography for Diagnosis of Female Occult Stress Urinary Incontinence.

BACKGROUND We evaluated the utility of three-dimensional transperineal ultrasonography in detecting occult stress urinary incontinence in women undergoing anterior pelvic floor reconstruction surgery for severe cystocele. MATERIAL AND METHODS We enrolled 207 women with stage III-IV cystocele without urinary stress incontinence. One week before the operation, the patients underwent pelvic floor ultrasonography. We measured the vertical distance between the bladder neck and posterior margin of the pubic symphysis, the posterior vesicourethral angle, the urethral rotation angle, the formation of funnel shape, the hiatus area, and the length of the urethra and the funnel shape. Postoperatively, the patients were evaluated for symptoms of stress urinary incontinence and with the 20-minute pad test. RESULTS The posterior vesicourethral angle with Valsalva maneuver, the difference in the posterior vesicourethral angle between the resting state and with the Valsalva state, and the angle of the proximal urethra were larger in the incontinence-positive group than in the incontinence-negative group (P<0.05). Funnel shape urethra was longer in the incontinence-positive group than in the incontinence-negative group (P<0.05). The cutoff value was 137.5° for the posterior vesicourethral angle with Valsalva maneuver, 39.5° for the difference in the posterior vesicourethral angle, 44.5° for the angle of the proximal urethra, and 0.35 cm for the length of the funnel shape. Multivariate analysis revealed that the difference between the posterior vesicourethral angle in the resting state and with Valsalva, the angle of the proximal urethra, and the length of funnel shape were strongly correlated with occult stress urinary incontinence. CONCLUSIONS Ultrasonography is an effective method for identifying occult stress urinary incontinence.

Improving social skills in children with ASD using a long-term, in-home social robot.

Social robots can offer tremendous possibilities for autism spectrum disorder (ASD) interventions. To date, most studies with this population have used short, isolated encounters in controlled laboratory settings. Our study focused on a 1-month, home-based intervention for increasing social communication skills of 12 children with ASD between 6 and 12 years old using an autonomous social robot. The children engaged in a triadic interaction with a caregiver and the robot for 30 min every day to complete activities on emotional storytelling, perspective-taking, and sequencing. The robot encouraged engagement, adapted the difficulty of the activities to the child's past performance, and modeled positive social skills. The system maintained engagement over the 1-month deployment, and children showed improvement on joint attention skills with adults when not in the presence of the robot. These results were also consistent with caregiver questionnaires. Caregivers reported less prompting over time and overall increased communication.

Induction of social behavior in zebrafish: live versus computer animated fish as stimuli.

The zebrafish offers an excellent compromise between system complexity and practical simplicity and has been suggested as a translational research tool for the analysis of human brain disorders associated with abnormalities of social behavior. Unlike laboratory rodents zebrafish are diurnal, thus visual cues may be easily utilized in the analysis of their behavior and brain function. Visual cues, including the sight of conspecifics, have been employed to induce social behavior in zebrafish. However, the method of presentation of these cues and the question of whether computer animated images versus live stimulus fish have differential effects have not been systematically analyzed. Here, we compare the effects of five stimulus presentation types: live conspecifics in the experimental tank or outside the tank, playback of video-recorded live conspecifics, computer animated images of conspecifics presented by two software applications, the previously employed General Fish Animator, and a new application Zebrafish Presenter. We report that all stimuli were equally effective and induced a robust social response (shoaling) manifesting as reduced distance between stimulus and experimental fish. We conclude that presentation of live stimulus fish, or 3D images, is not required and 2D computer animated images are sufficient to induce robust and consistent social behavioral responses in zebrafish.