Connexin 43 confers chemoresistance through activating PI3K.

Circumventing chemoresistance is crucial for effectively treating cancer including glioblastoma, a lethal brain cancer. The gap junction protein connexin 43 (Cx43) renders glioblastoma resistant to chemotherapy; however, targeting Cx43 is difficult because mechanisms underlying Cx43-mediated chemoresistance remain elusive. Here we report that Cx43, but not other connexins, is highly expressed in a subpopulation of glioblastoma and Cx43 mRNA levels strongly correlate with poor prognosis and chemoresistance in this population, making Cx43 the prime therapeutic target among all connexins. Depleting Cx43 or treating cells with αCT1-a Cx43 peptide inhibitor that sensitizes glioblastoma to the chemotherapy temozolomide-inactivates phosphatidylinositol-3 kinase (PI3K), whereas overexpression of Cx43 activates this signaling. Moreover, αCT1-induced chemo-sensitization is counteracted by a PI3K active mutant. Further research reveals that αCT1 inactivates PI3K without blocking the release of PI3K-activating molecules from membrane channels and that Cx43 selectively binds to the PI3K catalytic subunit ß (PIK3CB, also called PI3Kß or p110ß), suggesting that Cx43 activates PIK3CB/p110ß independent of its channel functions. To explore the therapeutic potential of simultaneously targeting Cx43 and PIK3CB/p110ß, αCT1 is combined with TGX-221 or GSK2636771, two PIK3CB/p110ß-selective inhibitors. These two different treatments synergistically inactivate PI3K and sensitize glioblastoma cells to temozolomide in vitro and in vivo. Our study has revealed novel mechanistic insights into Cx43/PI3K-mediated temozolomide resistance in glioblastoma and demonstrated that targeting Cx43 and PIK3CB/p110ß together is an effective therapeutic approach for overcoming chemoresistance.

Management of mammalian bites to the external genitalia: a scoping review.

OBJECTIVE: To review existing publications to determine the approaches for the medical and operative management of mammalian bites to the external genitalia. MATERIALS AND METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Review guidelines were followed. Four databases were searched. Articles were independently screened and analysed by two reviewers. Publications were included if detailed summaries of genitalia bites and management were documented. Discrepancies were resolved by a third reviewer. Data were extracted from the final article cohort. RESULTS: A total of 42 articles were included in this scoping review with 67 cases of mammalian bites to the genitalia reported in the cohort. The most common injury site was the penis (44.9%). Dog and human bites were the most common type of mammalian bites (61.2% and 26.9%, respectively). In all, 13.4% of cases were managed with medical therapy while 86.6% of cases required surgical intervention. The most common intervention was wound irrigation, debridement, and primary closure (32.8%). Although uncommon, other operative approaches included skin flaps (7.5%) and grafts (4.5%), re-implantation (4.5%), urethroplasty/repair (7.5%), penectomy (3.0%), scrotoplasty (3.0%), and perineal urethrostomy (1.5%). The reported complication rate was 19.4%. The mean follow-up time was 39.9 months. CONCLUSION: Trauma related to mammalian bites is associated with high utilisation of healthcare resources and cost. Although management of such bites to the genitalia is controversial, surgical intervention is often warranted ranging from simple debridement of devitalised tissue to complex reconstructive surgery. This review underscores the need for further investigation of mammalian bites to the genitalia to improve surgical options and monitor for long-term complication rates.

Clinical Guidelines in Pediatric Hearing Loss: Systemic Review Using the Appraisal of Guidelines for Research and Evaluation II Instrument.

OBJECTIVES: Despite the importance, impact, and prevalence of pediatric hearing loss (HL), there are very few published clinical practice guidelines (CPG) supporting the evaluation and management of pediatric patients with HL. Our objective was to appraise existing CPGs to ensure safe and effective practices. METHODS: A literature search was conducted in PubMed, Google Scholar, EBSCO, as well as a manual Google search. Three independent assessors using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument evaluated CPGs related to HL in children. Standardized domain scores were calculated for each guideline. RESULTS: A total of four guidelines met the inclusion criteria and were appraised. Scope and purpose achieved a high median score of 83%. Stakeholder involvement, clarity of presentation, and editorial independence achieved intermediate scores of 67%, 54%, and 50%, respectively. The areas that required most improvement and achieved low scores were rigor of development and applicability, with scores of 22% and 38%, respectively. Based on the AGREE II measures, the four guidelines had domain scores less than 60% for each domain, and without modification no guideline could be recommended. CONCLUSIONS: Based on the AGREE II, the qualities of CPGs for pediatric HL have several shortcomings, and the need for a comprehensive CPG remains. Rigor of development and applicability present the greatest opportunities for improvement of these CPGs. Laryngoscope, 130:212-216, 2020.

Nail and Locking Plate for Periprosthetic Fractures.

The incidence of periprosthetic fractures have been increasing, and in patients with osteopenic bone, high body mass index, or a combination both, they are difficult to treat and pose a high risk for malunion. Previous studies have compared the use of locking plates and intramedullary nails, and have found that each has its own strengthens and drawbacks, but neither is superior in terms of treating periprosthetic fractures. Here, we present the technique and series of patients treated with a combination of a retrograde intramedullary nail and flare-to-flare lateral locking plate without the use of allograft or autograft supplementation.

Re-examining Prostate-specific Antigen (PSA) Density: Defining the Optimal PSA Range and Patients for Using PSA Density to Predict Prostate Cancer Using Extended Template Biopsy.

OBJECTIVE: To compare the predictive accuracy of prostate-specific antigen (PSA) density vs PSA across different PSA ranges and by prior biopsy status in a prospective cohort undergoing prostate biopsy. MATERIALS AND METHODS: Men from a prospective trial underwent an extended template biopsy to evaluate for prostate cancer at 26 sites throughout the United States. The area under the receiver operating curve assessed the predictive accuracy of PSA density vs PSA across 3 PSA ranges (<4 ng/mL, 4-10 ng/mL, >10 ng/mL). We also investigated the effect of varying the PSA density cutoffs on the detection of cancer and assessed the performance of PSA density vs PSA in men with or without a prior negative biopsy. RESULTS: Among 1290 patients, 585 (45%) and 284 (22%) men had prostate cancer and significant prostate cancer, respectively. PSA density performed better than PSA in detecting any prostate cancer within a PSA of 4-10 ng/mL (area under the receiver operating characteristic curve [AUC]: 0.70 vs 0.53, P < .0001) and within a PSA >10 mg/mL (AUC: 0.84 vs 0.65, P < .0001). PSA density was significantly more predictive than PSA in detecting any prostate cancer in men without (AUC: 0.73 vs 0.67, P < .0001) and with (AUC: 0.69 vs 0.55, P < .0001) a previous biopsy; however, the incremental difference in AUC was higher among men with a previous negative biopsy. Similar inferences were seen for significant cancer across all analyses. CONCLUSION: As PSA increases, PSA density becomes a better marker for predicting prostate cancer compared with PSA alone. Additionally, PSA density performed better than PSA in men with a prior negative biopsy.

Symptomatic sacrococcygeal joint dislocation treated using closed manual reduction: A case report with 36-month follow-up and review of literature.

Dislocation of the sacrococcygeal joint is a rare injury from trauma to the buttocks, most often from falling backwards. Standard of care for this injury has not been determined because it is rare. Left untreated this can cause coccydynia in the long-term. Here we present a case report to describe the treatment of an anterior sacrococcygeal dislocation with closed manual reduction. A 13-year-old female presented to the emergency department with buttock pain after slipping backwards down the stairs. On X-ray the coccyx was in bayonette apposition to the anterior distal sacrum and shortened by 6 mm. To manage the injury, closed manual reduction of the sacrococcygeal joint was performed. To our knowledge, this is the first successful case of sacrococcygeal dislocation treated with closed manual reduction, resulting in complete relief of symptoms at 36 months follow-up. Sacrococcygeal dislocations can be treated with closed manual reduction, resulting in lower morbidity and faster recovery compared to surgical treatment.

Patient-derived glioblastoma stem cells respond differentially to targeted therapies.

The dismal prognosis of glioblastoma is, at least in part, attributable to the difficulty in eradicating glioblastoma stem cells (GSCs). However, whether this difficulty is caused by the differential responses of GSCs to drugs remains to be determined. To address this, we isolated and characterized ten GSC lines from established cell lines, xenografts, or patient specimens. Six lines formed spheres in a regular culture condition, whereas the remaining four lines grew as monolayer. These adherent lines formed spheres only in plates coated with poly-2-hydroxyethyl methacrylate. The self-renewal capabilities of GSCs varied, with the cell density needed for sphere formation ranging from 4 to 23.8 cells/well. Moreover, a single non-adherent GSC either remained quiescent or divided into two cells in four-seven days. The stem cell identity of GSCs was further verified by the expression of nestin or glial fibrillary acidic protein. Of the two GSC lines that were injected in immunodeficient mice, only one line formed a tumor in two months. The protein levels of NOTCH1 and platelet derived growth factor receptor alpha positively correlated with the responsiveness of GSCs to γ-secretase inhibitor IX or imatinib, two compounds that inhibit these two proteins, respectively. Furthermore, a combination of temozolomide and a connexin 43 inhibitor robustly inhibited the growth of GSCs. Collectively, our results demonstrate that patient-derived GSCs exhibit different growth rates in culture, possess differential capabilities to form a tumor, and have varied responses to targeted therapies. Our findings underscore the importance of patient-derived GSCs in glioblastoma research and therapeutic development.

WITHDRAWN: Re: Vasectomy and Prostate Cancer Incidence and Mortality in a Large US Cohort.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.eururo.2016.11.008. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Connexin 43 Inhibition Sensitizes Chemoresistant Glioblastoma Cells to Temozolomide.

Resistance of glioblastoma (GBM) to the front-line chemotherapeutic agent temozolomide (TMZ) continues to challenge GBM treatment efforts. The repair of TMZ-induced DNA damage by O-6-methylguanine-DNA methyltransferase (MGMT) confers one mechanism of TMZ resistance. Paradoxically, MGMT-deficient GBM patients survive longer despite still developing resistance to TMZ. Recent studies indicate that the gap junction protein connexin 43 (Cx43) renders GBM cells resistant to TMZ through its carboxyl terminus (CT). In this study, we report insights into how Cx43 promotes TMZ resistance. Cx43 levels were inversely correlated with TMZ sensitivity of GBM cells, including GBM stem cells. Moreover, Cx43 levels inversely correlated with patient survival, including as observed in MGMT-deficient GBM patients. Addition of the C-terminal peptide mimetic αCT1, a selective inhibitor of Cx43 channels, sensitized human MGMT-deficient and TMZ-resistant GBM cells to TMZ treatment. Moreover, combining αCT1 with TMZ-blocked AKT/mTOR signaling, induced autophagy and apoptosis in TMZ-resistant GBM cells. Our findings suggest that Cx43 may offer a biomarker to predict the survival of patients with MGMT-independent TMZ resistance and that combining a Cx43 inhibitor with TMZ could enhance therapeutic responses in GBM, and perhaps other TMZ-resistant cancers.