Exploring the feasibility of indocyanine green fluorescence for intraoperative ureteral visualisation in robotic transvaginal natural orifice transluminal endoscopy surgery during endometriosis resection.

BACKGROUND: To assess the feasibility of use of indocyanine green (ICG) in identifying and minimising urinary tract injury during surgical resection of endometriosis through robotic transvaginal natural orifice transluminal endoscopy surgery (RvNOTES). METHODS: We conducted a retrospective case series in two academic tertiary care hospitals. We examined 53 patients who underwent RvNOTES hysterectomy with planned endometriosis resection. RESULTS: The study involved 53 patients undergoing RvNOTES with ICG fluorescence for endometriosis resection. Mean patient age was 37.98 ± 6.65 years. Operative time averaged 181.32 ± 53.94 min, with estimated blood loss at 45.57 ± 33.62 mL. Postoperative stay averaged 0.23 ± 0.47 days. No ICG-related complications occurred. CONCLUSION: No complications occurred with ICG fluorescence in RvNOTES. It appears to be a safe option for ureteral localisation and preservation. ICG fluorescence is widely used in diverse medical specialities for identifying ureters during complex surgeries. Larger studies are needed to firmly establish its advantages in intraoperative ureteral visualisation during RvNOTES for deep infiltrative endometriosis.

Retraction Notice to: Circular RNA Cdr1as Upregulates SCAI to Suppress Cisplatin Resistance in Ovarian Cancer via miR-1270 Suppression.

[This retracts the article DOI: 10.1016/j.omtn.2019.07.012.].

Nifuroxazide suppresses PD-L1 expression and enhances the efficacy of radiotherapy in hepatocellular carcinoma.

Radiation therapy is a primary treatment for hepatocellular carcinoma (HCC), but its effectiveness can be diminished by various factors. The over-expression of PD-L1 has been identified as a critical reason for radiotherapy resistance. Previous studies have demonstrated that nifuroxazide exerts antitumor activity by damaging the Stat3 pathway, but its efficacy against PD-L1 has remained unclear. In this study, we investigated whether nifuroxazide could enhance the efficacy of radiotherapy in HCC by reducing PD-L1 expression. Our results showed that nifuroxazide significantly increased the sensitivity of tumor cells to radiation therapy by inhibiting cell proliferation and migration while increasing apoptosis in vitro. Additionally, nifuroxazide attenuated the up-regulation of PD-L1 expression induced by irradiation, which may be associated with increased degradation of PD-L1 through the ubiquitination-proteasome pathway. Furthermore, nifuroxazide greatly enhanced the efficacy of radiation therapy in H22-bearing mice by inhibiting tumor growth, improving survival, boosting the activation of T lymphocytes, and decelerating the ratios of Treg cells in spleens. Importantly, nifuroxazide limited the increased expression of PD-L1 in tumor tissues induced by radiation therapy. This study confirms, for the first time, that nifuroxazide can augment PD-L1 degradation to improve the efficacy of radiation therapy in HCC-bearing mice.

Polypyrimidine tract-binding protein 3/insulin-like growth factor 2 mRNA-binding proteins 3/high-mobility group A1 axis promotes renal cancer growth and metastasis.

Polypyrimidine tract-binding protein 3 (PTBP3) plays an important role in the post-transcriptional regulation of gene expression, including mRNA splicing, translation, and stability. Increasing evidence has shown that PTBP3 promotes cancer progression in several tumor types. However, the molecular mechanisms of PTBP3 in renal cell carcinoma (RCC) remain unknown. Here, tissue microarrays (TMAs) suggested that PTBP3 expression was increased in human RCC and that high PTBP3 expression was correlated with poor five-year overall survival and disease-free survival. We also showed that PTBP3 binds with HMGA1 mRNA in the 3'UTR region and let-7 miRNAs. PTBP3 interacted with IGF2BP3, and the PTBP3/IGF2BP3 axis prevented let-7 mediated HMGA1 mRNA silencing. PTBP3 promotes renal cancer cell growth and metastasis in vitro and in vivo. Taken together, our findings indicate PTBP3 serves as a regulator of HMGA1 and suggest its potential as a therapeutic agent for RCC.

Attenuated Salmonella-delivered PD-1 siRNA enhances the antitumor effects of EZH2 inhibitors in colorectal cancer.

Immunotherapy has made significant progress in the treatment of malignant tumors. However, strategies to combine immunotherapy with anticancer drugs have attracted great attention due to the low response rate and unique toxicity profile of immunotherapies and the subsequent development of acquired resistance in some initial responders. EZH2, a histone methyl transferase subunit of a Polycomb repressor complex,is highly expressed in a variety of tumors, and targeting EZH2 has become a new strategy for tumor therapy and drug combination. Here，we studied the effect of EZH2 inhibitors on colorectal cancer cells and their combination with immunotherapy. Our results demonstrated that EZH2 inhibitors can not only significantly inhibit the survival of colorectal cancer (CRC) cells and induce apoptosis, effectively inhibit cell invasion and migration, but also cause an increase in the expression of PD-L1 receptors on the cell surface. To determine the effect of EZH2 in combination with immunotherapy, we combine EZH2 inhibitors with PD-1 siRNA delivered by attenuated Salmonella. The vivo experiments have shown that the combination of EZH2 inhibitors and Salmonella-delivered PD-1 siRNA can further inhibit the development of CRC, trigger effective anti-tumor immunity, and improve therapeutic efficacy. Its underlying mechanisms mainly involve synergistic immunomodulation and apoptosis. This study suggests an emerging strategy based on a combination of EZH2 inhibitor and immunotherapy based on PD-1 inhibition.

lncRNA DARS-AS1 Modulates TSPAN1-Mediated ITGA2 Hypomethylation by Interaction with miR-194-5p Thus Promoting Ovarian Cancer Progression.

Objective: Ovarian cancer (OC) is usually called the "silent killer" due to its asymptomatic characteristics until advanced stages, thus being a significant threat to female health worldwide. In this work, we characterized an oncogenic DARS-AS1 role in OC. Methods: The aggressiveness behaviors of the OC cell model were examined by CCK-8 assay, transwell invasion assay, flow cytometry, and immunoblotting analysis of apoptosis-related proteins. Interactions of miR-194-5p with lncRNA DARS-AS1 or TSPAN1 and of TSPAN1 with ITGA2 were validated by using a luciferase activity assay and chromatin immunoprecipitation (ChIP) assay. Results: The OC cell model exhibited overexpressed lncRNA DARS-AS1 compared to normal cells. lncRNA DARS-AS1 knockdown led to reduced OC cell growth and metastasis while inducing the apoptosis in the OC cell model. lncRNA DARS-AS1 positively regulated TSPAN1 expression by binding with miR-194-5p and TSPAN1-mediated ITGA2 hypomethylation in OC cells. Further rescue function studies demonstrated that lncRNA DARS-AS1 affected OC cell viability, migration, invasion, and apoptosis ability by modulating miR-194-5p and TSPAN1 expressions. Conclusion: Our work demonstrates that lncRNA DARS-AS1 promotes OC progression by modulating TSPAN1 and ITGA2 hypomethylation by binding with miR-194-5p.

Comparison of survival outcomes between squamous cell carcinoma and adenocarcinoma/adenosquamous carcinoma of the cervix after radical radiotherapy and chemotherapy.

BACKGROUND: This study aimed to compare the survival outcomes between squamous cell carcinoma (SCC) and adenocarcinoma/adenosquamous carcinoma (AC/ASC) of the cervix after radical radiotherapy and chemotherapy. METHODS: Propensity score matching (1:4) was used to compare overall survival (OS) and disease-free survival (DFS) in cervical cancer patients with SCC and AC/ASC in China. RESULTS: Five thousand four hundred sixty-six patients were enrolled according to the criteria. The 5-year OS and DFS in the SCC group (n = 5251) were higher than those in the AC/ASC group (n = 215). After PSM (1:4), the 5-year OS and DFS in the SCC group were higher than those in the AC/ASC group (72.2% vs 56.9%, p < 0.001, HR = 1.895; 67.6% vs 47.8%, p < 0.001, HR = 2.056). In stage I-IIA2 patients, after PSM (1:4), there was no significant difference in 5-year OS between the SCC group (n = 143) and the AC/ASC group (n = 34) (68.5% vs 67.8%, P = 0.175). However, the 5-year DFS in the SCC group was higher than that in the AC/ASC group (71.0% vs 55.7%, P = 0.045; HR = 2.037, P = 0.033). In stage IIB-IV patients, after PSM (1:4), the 5-year OS and DFS in the SCC group (n = 690) were higher than those in the AC/ASC group (n = 173) (70.7% vs 54.3% P < 0.001 vs 1.940%, P < 0.001 vs 45.8%, p < 0.001). CONCLUSIONS: For stage I-IIA2, there was no significant difference in 5-year survival time, but patients with AC/ASC were more likely to relapse. In the more advanced IIB-IV stage, the oncological outcome of radical radiotherapy and chemotherapy of cervical AC/ASC was worse than that of SCC.

Role of endoplasmic reticulum stress in apoptosis induced by HK2 inhibitor and its potential as a new drug combination strategy.

Compared with normal cells, tumor cells mainly obtain energy through aerobic glycolysis. Hexokinase 2 (HK2) plays a key role in the regulation of tumor cell aerobic glycolysis, and targeting HK2 has become a new strategy for cancer treatment. However, little is known about the role of HK2 in colon cancer and the regulation of its targeted inhibitors. In this study, we found that the expression of HK2 in colorectal cancer tissues was significantly higher than that in adjacent tissues, and the expression level of HK2 in metastatic colorectal cancer was further increased. Meanwhile, the expression level of HK2 was closely related to clinical TNM stage and outcome of colorectal cancer patients. We provide here evidence that HK2 inhibitor 3-Bromopyruvate acid (3-BP) can significantly inhibit the survival and proliferation of colon cancer cells, and induce apoptosis through mitochondrial apoptosis signaling pathway. In addition, we found that 3-BP can also induce endoplasmic reticulum stress in colon cancer cells, the mechanism may be through the increase of intracellular calcium concentration. In vitro and in vivo experiments showed that inhibition of endoplasmic reticulum stress could further increase the proliferation inhibition and apoptosis induced by 3-BP. Collectively, our results show that HK2 is highly expressed in colorectal cancer. 3-BP, an inhibitor of HK2, can induce apoptosis and endoplasmic reticulum stress in colon cancer cells. Endoplasmic reticulum stress plays a protective role in cell death induced by 3-BP. This result suggested that targeting HK2 and endoplasmic reticulum stress may be a valuable strategy in targeted and combination therapy of colon cancer.

Evaluation of the learning curve and safety outcomes in robotic assisted vaginal natural orifice transluminal endoscopic hysterectomy: A case series of 84 patients.

BACKGROUND: To explore the learning curve and safety outcomes of robotic assisted transvaginal natural orifice transluminal endoscopic surgery (R-vNOTES) for hysterectomy in benign gynaecological diseases. METHODS: A retrospective chart review of all patients undergoing R-vNOTES hysterectomy for benign gynaecological disease from 2019 to 2021. SETTING: An academic tertiary care university hospital in Houston, TX, USA. RESULTS: 84 patients were identified that met the study requirements. The mean hysterectomy time was 77.27 ± 2.89 min. The median additional operation time was 63 (8-206) min. There were two conversions to robotic assisted single incision laparoscopy. Thirteen (15.48%) patients had an associated complication. Analysis of the learning curve suggests plateauing of hysterectomy time at approximately 10 cases and time for robot docking and port placement after 10-20 cases. CONCLUSION: R-vNOTES is a safe and effective route for hysterectomy. For a surgeon with experience in laparoscopic single site surgery and abdominal robotic surgery, they need to perform 10 cases of R-vNOTES hysterectomy and 10-20 cases in port placement and robotic docking to achieve proficiency.

Laparoscopic Single-site "In-bag" Ovarian Dermoid Cystectomy in a 16-week- pregnant Patient.

STUDY OBJECTIVE: To demonstrate a novel "in-bag" ovarian cystectomy technique for a large adnexal mass in pregnancy. DESIGN: Stepwise demonstration with narrated video. SETTING: An academic tertiary care hospital. The patient was a 26-year-old woman, gravida 1, para 0, at gestational age of 7 weeks and 3 days who presented to the emergency department with persistent left pelvic pain and was diagnosed with a 16 cm × 10 cm × 12 cm dermoid cyst. She re-presented at gestational age of 16 weeks and 3 days with worsening pelvic pain, and the decision was made to proceed with surgical intervention. INTERVENTIONS: Laparoscopic transumbilical single-site surgery for the surgical management of adnexal masses in pregnancy has been demonstrated to be feasible and safe [1-3]. However, single-site laparoscopic ovarian cystectomy can be very challenging in pregnancy, especially when the need for suturing arises. Exteriorizing the ovary and cyst after intraperitoneal drainage may allow for extracorporeal suturing that is faster and easier; however, it may increase the probability of spillage of cystic contents if it is not performed in a bag, which can then cause peritonitis in cases of dermoid cysts. A combination of in-bag and extracorporeal ovarian cystectomy is a novel alternative minimally invasive approach that is cosmetic, safe, and effective. Several helpful techniques in this novel combination technique include the following: • Creating an umbilical incision of at least 2 cm or one that is large enough for better manipulation of both the surgical bag and adnexal mass. • Tightening the bag appropriately around the infundibulopelvic ligament so that it is not too tight leading to compromised blood supply and tissue necrosis, yet not too loose resulting in leakage of cystic contents. • Ensuring that the infundibulopelvic ligament is stabilized within the surgical bag. • Inserting small-sized wound retractor into the bag for better exposure during cystectomy. • Having a double-suction irrigation setup for large adnexal masses, as demonstrated in this patient, to reduce the spillage of cystic contents. The procedure was successfully performed in approximately 110 minutes, and the fetal heart rate postprocedure was 128 bpm through bedside transabdominal ultrasound. Estimated blood loss was 5 mL, and the patient was discharged the same day with an uneventful 4-week postoperative follow-up. CONCLUSION: Laparoscopic single-site "in-bag" ovarian dermoid cystectomy is feasible, effective, and safe in pregnant patients with a large adnexal mass. This technique results in better stabilization of the ovarian cyst and reduction of cystic content spillage.

Exosomal lncRNA UCA1 modulates cervical cancer stem cell self-renewal and differentiation through microRNA-122-5p/SOX2 axis.

BACKGROUND: There is growing evidence discussing the role of long non-coding RNAs (lncRNAs) in cervical cancer (CC). We performed this study to explore the impact of exosomal lncRNA urothelial cancer-associated 1 (UCA1) in CC stem cells by sponging microRNA-122-5p (miR-122-5p) and regulating SOX2 expression. METHODS: CC stem cells (CD133+CaSki) and exosomes were extracted and identified. The synthesized UCA1- and miR-122-5p-related sequences were transfected into CaSki cells, CaSki cells-derived exosomes were extracted and then co-cultured with CD133+CaSki cells. The functional roles of UCA1 and miR-122-5p in self-renewal and differentiation ability of CC stem cells were determined using ectopic expression, knockdown/depletion and reporter assay experiments. An in vivo experiment was performed to verify the in vitro results. RESULTS: Up-regulated UCA1 and SOX2 and down-regulated miR-122-5p were found in CaSki-Exo. Exosomes promoted invasion, migration, proliferation and restrained apoptosis of CD133+CaSki cells. Silencing UCA1 or up-regulating miR-122-5p degraded SOX2 expression, and reduced invasion, migration and proliferation of CD133+CaSki cells while advanced apoptosis and suppressed the tumor volume and weight in nude mice. CONCLUSION: Our study provides evidence that CaSki-Exo can promote the self-renewal and differentiation ability of CC stem cells while silencing UCA1 or up-regulating miR-122-5p restrains self-renewal and differentiation of CC stem cells.

The role of miR-27b-3p/HOXA10 axis in the pathogenesis of endometriosis.

BACKGROUND: To explore the effects of microRNA (miR)-27b-3p-mediated homeobox A10 (HOXA10) on the proliferation, migration, and invasion of endometriosis cells (hEM15A). METHODS: First, quantitative polymerase chain reaction (qPCR) was performed for the measurement of miR-27b-3p and HOXA10 expression in hEM15A cells and human embryonic stem cells (hESC). Then, the targeted relationship of miR-27b-3p with HOXA10 was verified by conducting a dual-luciferase reporter experiment. Subsequently, qPCR and western blot were performed to determine the effect of miR-27b-3p on HOXA10 expression. Finally, Cell Counting Kit-8, Transwell, and scratch assays were employed to determine the effects of miR-27b-3p and HOXA10 on the proliferative, migratory, and invasive abilities of hEM15A cells. RESULTS: In hEM15A cells, miR-27b-3p expression was increased and showed a negative correlation with the expression of HOXA10 (P<0.05). The dual-luciferase reporter experiment confirmed that miR-27b-3p targeted the HOXA10 gene. Furthermore, qPCR and western blotting showed that miR-27b-3p regulated the expression of HOXA10. The proliferation, migration, and invasion abilities of hEM15A cells was significantly inhibited by suppressing miR-27b-3p expression or overexpressing HOXA10 (P<0.05). Meanwhile, concurrent overexpression of miR-27b-3p and HOXA10 did not affect hEM15A cell activity (P>0.05). CONCLUSIONS: Upregulation of miR-27b-3p can suppress HOXA10 expression, resulting in the enhancement of hEM15A cell proliferation, migration, and invasion.

Integration of a Robotic Platform for Sacrocolpopexy in Transvaginal Natural Orifice Transluminal Endoscopic Surgery: A Novel Surgical Technique.

OBJECTIVE: To demonstrate the feasibility and the simplified surgical techniques of intraabdominal suturing and knot-tying in robotic transvaginal natural orifice transluminal endoscopic surgery (RV-NOTES) sacrocolpopexy. MATERIALS AND METHODS: We report on two patients with symptomatic stage II apical pelvic organ prolapse who underwent a new technique of RV-NOTES sacrocolpopexy. Case one: A 69-year-old G2P2002 with a history of two prior vaginal deliveries presented with a vaginal bulge and pressure symptoms. She was initially fitted for a pessary but was unsatisfied and elected to proceed with surgical intervention. Case two: A 50-year-old G2P0011 female with a history of one prior vacuum-assisted vaginal delivery presented with symptoms of vaginal mass and bleeding due to an endometrial polyp. She was noted to have stage 2 apical prolapse and opted for transvaginal sacrocolpopexy. RESULTS: Both patients were observed overnight and discharged home twelve hours after surgery on postoperative day 1, after completing a voiding trial. For both patients, the postoperative course was unremarkable, and they only required one day of pain medications. At the three-week follow-up visit, they endorsed no postoperative pain or complications, and the POP-Q stage was noted to be 0. Patients had telemedicine visits at eight weeks postoperatively, at which time they had returned to their regular activities and denied symptoms of vaginal bulge or pressure. CONCLUSION: Robotic assisted transvaginal NOTES sacrocolpopexy is a feasible and an alternative to traditional laparoscopic NOTES sacrocolpopexy.

Stepwise Laparoendoscopic Single-site Pectopexy for Pelvic Organ Prolapse.

STUDY OBJECTIVE: To demonstrate stepwise techniques for the successful use of the laparoendoscopic single-site surgery (LESS) technique for safely performing pectopexy. DESIGN: Stepwise demonstration with narrated video footage (Canadian Task Force classification III). SETTING: An academic tertiary care hospital. INTERVENTIONS: Patient was a 48-year-old, gravida 2 para 2, having had 2 normal spontaneous vaginal deliveries, with stage III anterior vaginal prolapse and stage III uterine prolapse and posterior vaginal prolapse. The preoperative vaginal length was 6 cm. Laparoscopic sacrocolpopexy is the current gold standard for pelvic organ prolapse demonstrating a low recurrence rate; however, it can be technically challenging to perform, particularly in women with obesity or in the event of an anatomic variation. The pectineal ligament, also known as Cooper's ligament, is familiar to surgeons and can be used for a tension-free mesh suspension in patients with prolapse. Integration of LESS and pectopexy is a novel alternative, minimally invasive approach that is more cosmetic, simpler, and effective. The key steps in LESS pectopexy include the following: MEASUREMENTS AND MAIN RESULTS: The procedure was performed successfully in approximately 80 minutes with a postoperative vaginal length of 6 cm. Postoperative pelvic organ prolapse quantification was stage 0. CONCLUSION: LESS is a feasible technique for pectopexy in patients with pelvic organ prolapse. A LESS pectopexy results in better cosmesis and offers an alternative for patients with challenging pelvic organ prolapse, such as those with obesity.

Comparative study on the oncological prognosis of laparoscopy and laparotomy for stage IIA1 cervical squamous cell carcinoma.

OBJECTIVE: To compare the 5-year overall survival (OS) and disease-free survival (DFS) rate of laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) for stage IIA1 cervical squamous cell carcinoma. METHODS: Based on a large database containing information on the clinical diagnosis and treatment of cervical cancer in China, the oncological outcomes of the two surgical approaches for stage IIA1 cervical squamous cell carcinoma were compared after 1:2 propensity score matching (PSM). RESULTS: After 1:2 propensity score matching (PSM), 510 patients were included in the LRH group, and 999 patients were included in the ARH group. LRH showed a similar 5-year OS but a lower DFS rate (81.3% vs. 87.4%, P = 0.018) than ARH. In the multivariate analysis, LRH was identified as an independent risk factor for worse 5-year DFS (HR = 1.569, 95% CI: 1.131-2.176, P = 0.007). Among patients with a tumour size <2 cm, the LRH and ARH groups showed similar OS and DFS rates after 1:2 PSM, and multivariate analysis showed that the surgical approach was not an independent risk factor affecting the OS or DFS rate. Among patients with a tumour size ≥2 cm and <4 cm, there was no difference in OS between the LRH and ARH groups after matching, but the DFS in the LRH group was significantly lower than that in the ARH group (81.1% vs 86.2%, P = 0.034). In the multivariate analysis, the laparoscopic approach was not associated with OS but was independently associated with worse DFS (HR = 1.546, 95% CI: 1.094-2.185, P = 0.014). CONCLUSIONS: LRH was associated with poorer 5-year DFS than ARH in patients with stage IIA1 cervical squamous cell carcinoma. However, LRH showed 5-year OS and DFS rates similar to those of ARH among patients with a tumour size <2 cm. For patients with a tumour size ≥2 cm and <4 cm, LRH showed a lower DFS rate than ARH.

N6-methyladenosine METTL3 promotes cervical cancer tumorigenesis and Warburg effect through YTHDF1/HK2 modification.

N6-methyladenosine (m6A) serves as the most common and conserved internal transcriptional modification. However, the roles of m6A on cervical cancer (CC) tumorigenesis are still unclear. Here, results indicated that METTL3 was significantly upregulated in CC tissue and cells, which was closely correlated with the lymph node metastasis and poor prognosis of CC patients. MeRIP-Seq analysis revealed the m6A profiles in CC cells. Functionally, METTL3 promoted the proliferation and Warburg effect (aerobic glycolysis) of CC cells. Mechanistically, METTL3 targeted the 3'-Untranslated Region (3'-UTR) of hexokinase 2 (HK2) mRNA. Moreover, METTL3 recruited YTHDF1, a m6A reader, to enhance HK2 stability. These findings demonstrated that METTL3 enhanced the HK2 stability through YTHDF1-mediated m6A modification, thereby promoting the Warburg effect of CC, which might promote a novel insight for the CC treatment.

miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer.

Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, investigation about molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The molecular mechanisms responsible for the chemoresistance of cervical cancer were investigated by the use of doxorubicin (Dox)-resistant HeLa/Dox and SiHa/Dox cells. Our data showed that chemoresistant cells exhibited significantly higher glucose consumption, lactate production rate, and ATP levels than that of their parental cells. Among metabolic and glycolytic related genes, the expression of PDK4 was upregulated in Dox-resistant cells. Knockdown of PDK4 can decrease glucose consumption, lactate production rate, and ATP levels and further sensitize resistant cervical cancer cells to Dox treatment. By screening microRNAs (miRNAs), which can regulate expression of PDK4, we found that miR-16-5p was downregulated in chemoresistant cells. Overexpression of miR-16-5p can decrease the expression of PDK4 and sensitize the resistant cells to Dox treatment. Xenograft models confirmed that knockdown of PDK4 can increase chemotherapy efficiency for in vivo tumor growth. Collectively, our data suggested that miR-16-5p/PDK4-mediated metabolic reprogramming is involved in chemoresistance of cervical cancer.

Ca2+ signaling modulation using cancer cell membrane coated chitosan nanoparticles to combat multidrug resistance of cancer.

Off-target drug delivery, together with multidrug resistance (MDR), are two keys obstacles that account for the disappointing outcome in clinical chemotherapy of cancer. To solve these dilemmas, Herein, we constructed cancer cell membrane (CCM) modified silica (CS) nanoparticles (CCM/CS) to co-deliver Ca2+ channel siRNA with doxorubicin (DOX) to construct a platform (CCM/CS/R-D) for the efficient therapy of cervical cancer. It was demonstrated that the optimal CCM/CS/R-D was spherical nanoparticles with size at 122.39 ±â€¯4.69 nm and the surface charge of -27.76 ±â€¯3.12 mV. In addition, the CCM/CS/R-D showed acid responsive drug release while high stability under physiological conditions with negligible hemolysis. The CCM/CS/R-D showed CCM mediated cellular uptake and efficient endosomal escape as well as siRNA transfection potential (comparable to that of PEI 25 K) on MDR cervical cancer cells (HeLa/DOX). Most importantly, the MDR of cancer cells was conquered through modulation of T-type Ca2+ (Cav) channels. It was observed that the Cav channel siRNA could negatively regulate the level of cytosolic Ca2+ concentration which triggered G0/G1 phase cell cycle arrest and elevated intracellular drug retention in HeLa/DOX cells without significantly affect the expression of P-glycolprotein (P-gp). The in vitro and in vivo experiments revealed that CCM/CS/R-D exerted greatly enhanced tumor targetability and therapeutic effect on HeLa/DOX, which was superior than CS/R-D or mono delivery system (CCM/CS/R or CCM/CS/D).

Treatment with metformin and sorafenib alleviates endometrial hyperplasia in polycystic ovary syndrome by promoting apoptosis via synergically regulating autophagy.

This study aimed to investigate the molecular mechanisms underlying the roles of metformin (MET) and Sorafenib (SOR) in the treatment of endometrial hyperplasia (EH) in polycystic ovary syndrome (PCOS). Effects of MET and SOR on the area of endometrium and myometrium were detected. Western blot analysis and immunohistochemistry assays were carried out to detect the levels of mammalian target of rapamycin complex 1 (mTORC1), mTORC2, LC3-II, P62, and Caspase-3 in rats and cultured cells. Furthermore, cell counting kit-8 assay and flow cytometry analysis was carried out to determine the apoptotic profiles of treated cells. MET and SOR could apparently decrease the areas of endometrium and myometrium in PCOS. MET notably enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC1 and P62. Similarly, SOR also enhanced the expression of LC3-II and Caspase-3 in PCOS while substantially reducing the level of mTORC2 and P62. Treatment with MET and SOR significantly inhibited the proliferation of HCC-94 and HEC-1-A cells while promoting their apoptosis by upregulating the expression of Caspase-3. In cells treated with MET, the expression of mTORC1 and LC3-II was upregulated while the expression of P62 was downregulated. Similarly, in cells treated with SOR, the expression of mTORC2 and LC3-II was also upregulated while the expression of P62 was also downregulated. Furthermore, MET showed no effect on mTORC2 expression, while SOR showed no effect on mTORC1 expression. In this study, we suggested that MET and SOR alleviated the risk of EH in PCOS via the mTORC1/autophagy/apoptosis axis and mTORC2/autophagy/apoptosis axis, respectively.

Circular RNA Cdr1as Upregulates SCAI to Suppress Cisplatin Resistance in Ovarian Cancer via miR-1270 Suppression.

The aim of this study is to explore the roles of circular RNA (circRNA) Cdr1as on cisplatin resistance in ovarian cancer and explore the underlying mechanisms. We investigated the expression of circRNAs in five paired cisplatin-sensitive and cisplatin-resistant tissues of ovarian cancer by microarray analysis. The quantitative real-time PCR analysis was to investigate the expression pattern of Cdr1as in cisplatin-resistant ovarian cancer patient tissues and cell lines. Then, the effects of Cdr1as on cisplatin resistance, cell proliferation, and apoptosis were assessed in ovarian cancer cells. In this study, Cdr1as was observed to be downregulated in cisplatin-resistant patient tissues and cell lines. Overexpression of Cdr1as inhibited cell proliferation and promoted the cisplatin-induced cell apoptosis in ovarian cancer cells. Then we demonstrated that repressed Cdr1as promoted the miR-1270 expression, and miR-1270 could bind to the predicted binding site of Cdr1as. Furthermore, we found that miR-1270 displayed its role via modulating the Suppressor of Cancer Cell Invasion (SCAI) expression. Importantly, we demonstrated that Cdr1as was downregulated in serum exosomes from cisplatin-resistant patients. In summary, our study demonstrated that Cdr1as sensitizes ovarian cancer to cisplatin by regulating the miR-1270/SCAI signaling pathway.