Evidence supported by Mendelian randomization: impact on inflammatory factors in knee osteoarthritis.

Background: Prior investigations have indicated associations between Knee Osteoarthritis (KOA) and certain inflammatory cytokines, such as the interleukin series and tumor necrosis factor-alpha (TNFα). To further elaborate on these findings, our investigation utilizes Mendelian randomization to explore the causal relationships between KOA and 91 inflammatory cytokines. Methods: This two-sample Mendelian randomization utilized genetic variations associated with KOA from a large, publicly accessible Genome-Wide Association Study (GWAS), comprising 2,227 cases and 454,121 controls of European descent. The genetic data for inflammatory cytokines were obtained from a GWAS summary involving 14,824 individuals of European ancestry. Causal relationships between exposures and outcomes were primarily investigated using the inverse variance weighted method. To enhance the robustness of the research results, other methods were combined to assist, such as weighted median, weighted model and so on. Multiple sensitivity analysis, including MR-Egger, MR-PRESSO and leave one out, was also carried out. These different analytical methods are used to enhance the validity and reliability of the final results. Results: The results of Mendelian randomization indicated that Adenosine Deaminase (ADA), Fibroblast Growth Factor 5(FGF5), and Hepatocyte growth factor (HFG) proteins are protective factors for KOA (IVWADA: OR = 0.862, 95% CI: 0.771-0.963, p = 0.008; IVWFGF5: OR = 0.850, 95% CI: 0.764-0.946, p = 0.003; IVWHFG: OR = 0.798, 95% CI: 0.642-0.991, p = 0.042), while Tumor necrosis factor (TNFα), Colony-stimulating factor 1(CSF1), and Tumor necrosis factor ligand superfamily member 12(TWEAK) proteins are risk factors for KOA. (IVWTNFα: OR = 1.319, 95% CI: 1.067-1.631, p = 0.011; IVWCSF1: OR = 1.389, 95% CI: 1.125-1.714, p = 0.002; IVWTWEAK: OR = 1.206, 95% CI: 1.016-1.431, p = 0.032). Conclusion: The six proteins identified in this study demonstrate a close association with the onset of KOA, offering valuable insights for future therapeutic interventions. These findings contribute to the growing understanding of KOA at the microscopic protein level, paving the way for potential targeted therapeutic approaches.

Tasquinimod enhances the sensitivity of ovarian cancer cells to cisplatin by regulating the Nur77-Bcl-2 apoptotic pathway.

BACKGROUND: Resistance to cisplatin (DDP) in ovarian cancer therapy has been a major clinical barrier. Drug-resistant cancers have been shown to downregulate the proapoptotic protein B-cell lymphoma-2 (Bcl-2) to inhibit apoptosis. Therefore, we explored whether tasquinimod could modulate resistance to DDP through apoptotic pathways. OBJECTIVES: We aimed to explore the relationship between tasquinimod, Nur77-Bcl-2 apoptosis pathway and sensitivity of the ovarian carcinoma cell line SKOV3 and the DDP-resistant strain SKOV3/DDP cells to DDP. MATERIAL AND METHODS: First, SKOV3 and SKOV3/DDP cells were treated with 2 µg/mL DDP or 40 µM tasquinimod. Western blot and quantitative real-time polymerase chain reaction (qPCR) were then used to analyze the expression of histone deacetylase 4 (HDAC4), Nur77, Bcl-2 (BH3 domain-specific), and caspase-3. Flow cytometry, scratch-wound assay and immunofluorescence were used to detect apoptosis, migration rate, and related expression of Nur77 and Bcl-2 (BH3 domain-specific). Subsequently, 5×107 SKOV3 or SKOV3/DDP cells cultured with 2 µg/mL DDP were injected into 4-week-old female BALB/c nude mice. Then, the mice were administered 4 mg/kg DDP and 50 mg/kg tasquinimod every 3 days. Finally, the changes in tumor diameter and weight were measured. RESULTS: After treatment of SKOV3 and SKOV3/DDP cells with tasquinimod, cell migration and HDAC4 expression levels were significantly reduced, while Nur77 expression was increased. Tasquinimod treatment enhanced the expression of Nur77 and caspase-3, and cells transfected with si-Nur77 showed the opposite result. Transfection of si-Nur77 reduced the expression of caspase-3 and Nur77 in the SKOV3/DDP cells that were treated with both DDP and tasquinimod. After injection of SKOV3/DDP cells into the mice, the tumor diameter, mass and in vivo HDAC4 level were significantly decreased by tasquinimod. Meanwhile, the levels of Nur77 and Bcl-2 (BH3 domain-specific) were increased. CONCLUSIONS: Tasquinimod upregulated the Nur77/Bcl-2 pathway to induce apoptosis in SKOV3/DDP cells and enhanced the anti-tumor effect of DDP in SKOV3/DDP xenografts. Therefore, tasquinimod can be expected to find clinical applications in enhancing DDP resistance.

A simple polarimetric measurement based on a computational algorithm.

A simple and compact polarimeter comprising two electrically controlled liquid-crystal variable retarders (LCVRs) and a linear polarizer is demonstrated, which is enabled by analyzing the intensity variation of the modulated output light based on a computational algorithm. A proof-of-concept prototype is presented, which is mounted onto a power meter or a CMOS camera for the intensity data collection. The polarimetric measurement for the spatial variant polarization states of light is also verified, indicating the possibility of achieving a resolution-lossless polarimeter. Thus, our proposed method shows a cost-effective way to realize a compact polarimeter in polarization optics.

Orientated construction of visible-light-assisted peroxymonosulfate activation system for antibiotic removal: Significant enhancing effect of Cl.

Antibiotic contaminants can migrate over long distances in the water, thus possibly causing severe detriment to the environment and even potential harm to human health. Heterogeneous activation of peroxymonosulfate (PMS) assisted by visible light is an emerging and promising technology for the purification of such wastewater. This study designed an ultra-efficient and stable PMS activator (FeCN) to restore the typical antibiotic-polluted water under harsh conditions. About 90.94% of sulfamethoxazole (SMX) was degraded in 35 min in the constructed FeCN+PMS/vis system, and the reaction rate constant was nearly 50-fold higher than direct photocatalysis. Electron spin resonance, quenching experiments, LC/MS technique, eco-toxicity assessment, and density functional theory validated that the SMX removal was dominated by the attack of h+, •O2- and 1O2 on the active atoms of SMX molecules with high Fukui index, presenting as a simultaneous degradation and detoxification process. Such a visible-light-assisted PMS activation system also had good resistance to the environmental water bodies and a broad spectrum in the degradation of various pollutants. In particular, Cl- (50 mM) could significantly accelerate the removal of SMX with a 32.6-fold increase in catalytic activity, and the mineralization efficiency could reach 56.6% under identical conditions. Moreover, this Cl- containing system excluded the degradation products of disinfection by-products, and such a system was also versatile for different contaminants. This work demonstrates the feasibility of the FeCN+PMS/vis system for the remediation of antibiotic-contaminated wastewater in the presence and absence of Cl-, and also highlights their great potential in WWTPs.

Oncogenic microRNA-181d binding to OGT contributes to resistance of ovarian cancer cells to cisplatin.

Ovarian cancer (OC), a common gynecological cancer, is characterized by a high malignant potential. MicroRNAs (miRNAs or miRs) have been associated with the chemo- or radiotherapeutic resistance of human malignancies. Herein, the current study set out to explore the regulatory mechanism of miR-181d involved in the cisplatin (DDP) resistance of OC cells. Firstly, in-situ hybridization method was performed to identify miR-181d expression in ovarian tissues of DDP-resistant or DDP-sensitive patients. In addition, miR-181d expression in A2780 cells and A2780/DDP cell lines was determined by RT-qPCR. Gain- and loss-of-function experiments were then performed to characterize the effect of miR-181d on OC cell behaviors. We probed the miR-181d affinity to OGT, as well as the downstream glycosylation of KEAP1 and ubiquitination of NRF2. Further, in vivo experiments were performed to define the role of miR-181d in tumor resistance to DDP. miR-181d was highly expressed in the ovarian tissues of DDP-resistant patients and the A2780/DDP cell line. Ectopic expression of miR-181d augmented DDP resistance in OC cells. In addition, miR-181d was found to target the 3'UTR of OGT mRNA, and negatively regulate the OGT expression. Mechanistic results indicated that OGT repressed NRF2 expression through glycosylation of KEAP1, thereby inhibiting the DDP resistance of OC cells. Furthermore, miR-181d negatively orchestrated the OGT/KEAP1/NRF2 axis to enhance the OC resistance to DDP in vivo. Overall, these findings suggest that miR-181d-mediated OGT inhibition restricts the glycosylation of KEAP1, and then reduces the ubiquitination and degradation of NRF2, leading to DDP resistance of OC. This study provides new insights for prevention and control of OC.

Metformin inhibits the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination.

Ovarian cancer is the most lethal diseases among women. The chemo-resistance has been a big challenge for the cancer treatment. It has been reported that metformin may inhibit ovarian cancer and is able to impede the development of drug resistance, but the molecular mechanisms remain elusive. In this study, we explored the molecular roles of metformin in Parkin expression and p53 ubiquitination in chemo-resistant ovarian cancer cells. Firstly, ovarian cancer and chemo-resistant ovarian cancer cells were selected for determining the expression of Parkin, p53, and p53 signaling pathway-related factors. Then the cell proliferation and viability after loss- and gain-of-function assays were measured. Besides, immunoprecipitation (IP) was used to determine the interactions between Parkin and p53, and the ubiquitination level of p53 was measured using in vitro ubiquitination assay. Finally, the degradation of p53 proteasome regulated by Parkin was monitored using the MG132 proteasome inhibitor. We found that metformin significantly inhibited the growth of ovarian cancer parental cells and chemo-resistant cells, and metformin promoted Parkin expression in chemo-resistant cells. Further, up-regulated Parkin expression promoted the ubiquitination and degradation of p53, and metformin inhibited the expression of p53 to suppress the proliferation of chemo-resistant ovarian cancer cells. Mechanistically, metformin could inhibit the growth of ovarian cancer cells by promoting the Parkin-induced p53 ubiquitination. Altogether, our study demonstrated an inhibitory role of metformin in the growth of chemo-resistant cancer cells through promoting the Parkin-induced p53 ubiquitination, which provides a novel mechanism of metformin for treating ovarian cancer.

Removal of Retained Adherent Placental Remnants Using the Hysteroscopy Endo-Operative System.

STUDY OBJECTIVE: Removal of retained adherent placental remnants (RAPRs) may be challenging using traditional 5Fr or 7Fr hysteroscopic grasping forceps because they are very small. This is particularly true when the retained placental remnant is large. This video demonstrates the advantages of using the Hysteroscopy Endo-Operative System (HEOS), a specially designed operative hysteroscope with a 13Fr working channel, to remove retained placental remnants. DESIGN: Step-by-step explanation of the technique using videos and pictures (educative video) (Canadian Task Force Classification III). SETTING: Third Xiangya Hospital of Central South University, Hunan, China. PATIENT: A 32-year-old woman was diagnosed with RAPRs 5 weeks after the evacuation of retained placenta after a spontaneous abortion at 16 weeks' gestation. Gynecologic examination revealed an anterior 8-week uterus and no tenderness. Serum ß-human chorionic gonadotropin was 150 mIU/L. Sonography revealed an irregular intrauterine mass, 3.5 cm × 3.5 cm × 3 cm in size. INTERVENTION: Removal of RAPRs using HEOS (Sopro-comeg Company, Bordeaux, France). MEASUREMENT AND MAIN RESULTS: The operation time was only 12 minutes. The RAPRs were removed completely and quickly in 1 procedure with no complications. The serum ß-human chorionic gonadotropin titer normalized 1 week after the procedure. This study was approved by the institutional review board of the Third Xiangya Hospital of Central South University. CONCLUSIONS: When indicated, removal of RAPRs using HEOS is safe and simple because of its large and strong cold forceps. Additionally, it avoids electrical and thermal injury to the endometrium, which is particularly important in a population that wants to preserve fertility.

Management of long-term and reversible hysteroscopic sterilization: a novel device with nickel-titanium shape memory alloy.

BACKGROUND: Female sterilization is the second most commonly used method of contraception in the United States. Female sterilization can now be performed through laparoscopic, abdominal, or hysteroscopic approaches. The hysteroscopic sterilization may be a safer option than sterilization through laparoscopy or laparotomy because it avoids invading the abdominal cavity and undergoing general anaesthesia. Hysteroscopic sterilization mainly includes chemical agents and mechanical devices. Common issues related to the toxicity of the chemical agents used have raised concerns regarding this kind of contraception. The difficulty of the transcervical insertion of such mechanical devices into the fallopian tubes has increased the high incidence of device displacement or dislodgment. At present, Essure® is the only commercially available hysteroscopic sterilization device being used clinically. The system is irreversible and is not effective immediately. PRESENTATION OF THE HYPOTHESIS: Our new hysteroscopic sterility system consists of nickel-titanium (NiTi) shape memory alloy and a waterproof membrane. The NiTi alloy is covered with two coatings to avoid toxic Ni release and to prevent stimulation of epithelial tissue growth around the oviducts. Because of the shape memory effect of the NiTi alloy, the device works like an umbrella: it stays collapsed at low temperature before placement and opens by the force of shape memory activated by the body temperature after it is inserted hysteroscopically into the interstitial tubal lumen. The rim of the open device will incise into interstitial myometrium during the process of unfolding. Once the device is fixed, it blocks the tube completely. When the patient no longer wishes for sterilization, the device can be closed by perfusing liquid with low temperature into the uterine cavity, followed by prospective hysteroscopic removal. After the device removal, the fallopian tube will revert to its physiological functions. TESTING THE HYPOTHESIS: Currently, experimental and clinical studies are needed to attest the safety, efficiency and reversibility of the novel sterilization device. IMPLICATIONS OF THE HYPOTHESIS: If our hypothesis is confirmed, appropriate and reversible contraceptive can be achieved with the device we have designed, which may have significant repercussions for numerous women worldwide.