Microtubule-Targeting Agents: Disruption of the Cellular Cytoskeleton as a Backbone of Ovarian Cancer Therapy.

Microtubules are dynamic polymers composed of α- and ß-tubulin heterodimers. Microtubules are universally conserved among eukaryotes and participate in nearly every cellular process, including intracellular trafficking, replication, polarity, cytoskeletal shape, and motility. Due to their fundamental role in mitosis, they represent a classic target of anti-cancer therapy. Microtubule-stabilizing agents currently constitute a component of the most effective regimens for ovarian cancer therapy in both primary and recurrent settings. Unfortunately, the development of resistance continues to present a therapeutic challenge. An understanding of the underlying mechanisms of resistance to microtubule-active agents may facilitate the development of novel and improved approaches to this disease.

Selective targeting of metastatic ovarian cancer using an engineered anthrax prodrug activated by membrane-anchored serine proteases.

Treatments for advanced and recurrent ovarian cancer remain a challenge due to a lack of potent, selective, and effective therapeutics. Here, we developed the basis for a transformative anticancer strategy based on anthrax toxin that has been engineered to be selectively activated by the catalytic power of zymogen-activating proteases on the surface of malignant tumor cells to induce cell death. Exposure to the engineered toxin is cytotoxic to ovarian tumor cell lines and ovarian tumor spheroids derived from patient ascites. Preclinical studies demonstrate that toxin treatment induces tumor regression in several in vivo ovarian cancer models, including patient-derived xenografts, without adverse side effects, supportive of progression toward clinical evaluation. These data lay the groundwork for developing therapeutics for treating women with late-stage and recurrent ovarian cancers, utilizing a mechanism distinct from current anticancer therapies.

The advent of membrane-less zinc-anode aqueous batteries with lithium battery-like voltage.

Zinc (Zn)-anode batteries, although safe and non-flammable, are precluded from promising applications because of their low voltage (<2 V) and poor rechargeability. Here, we report the fabrication of rechargeable membrane-less Zn-anode batteries with high voltage properties (2.5 to 3.4 V) achieved through coupling cathodes and Zn-anodes in gelled concentrated acid and alkaline solutions separated by a gelled buffer interlayer containing the working ions. The concentrated gelled buffer interlayers perform dual functions of regulating the pH of the system and acting as the source and sink of the working ions. With this strategy we show low-cost membrane-less 2.5 to 3.4 V Zn-manganese dioxide (MnO2) batteries capable of cycling 10-100% of 617 mA h g-1-MnO2 and 20-30% of 820 mA h g-1-Zn and demonstrate their application in electric vehicles. This strategy is then applied to other oxide-based cathode systems like Cu2O and V2O5, where voltages of 2 to 3 V are obtained in membrane-less batteries.

Microtentacle Formation in Ovarian Carcinoma.

BACKGROUND: The development of chemoresistance to paclitaxel and carboplatin represents a major therapeutic challenge in ovarian cancer, a disease frequently characterized by malignant ascites and extrapelvic metastasis. Microtentacles (McTNs) are tubulin-based projections observed in detached breast cancer cells. In this study, we investigated whether ovarian cancers exhibit McTNs and characterized McTN biology. METHODS: We used an established lipid-tethering mechanism to suspend and image individual cancer cells. We queried a panel of immortalized serous (OSC) and clear cell (OCCC) cell lines as well as freshly procured ascites and human ovarian surface epithelium (HOSE). We assessed by Western blot ß-tubulin isotype, α-tubulin post-translational modifications and actin regulatory proteins in attached/detached states. We studied clustering in suspended conditions. Effects of treatment with microtubule depolymerizing and stabilizing drugs were described. RESULTS: Among cell lines, up to 30% of cells expressed McTNs. Four McTN morphologies (absent, symmetric-short, symmetric-long, tufted) were observed in immortalized cultures as well as ascites. McTN number/length varied with histology according to metastatic potential. Most OCCC overexpressed class III ß-tubulin. OCCC/OSC cell lines exhibited a trend towards more microtubule-stabilizing post-translational modifications of α-tubulin relative to HOSE. Microtubule depolymerizing drugs decreased the number/length of McTNs, confirming that McTNs are composed of tubulin. Cells that failed to form McTNs demonstrated differential expression of α-tubulin- and actin-regulating proteins relative to cells that form McTNs. Cluster formation is more susceptible to microtubule targeting agents in cells that form McTNs, suggesting a role for McTNs in aggregation. CONCLUSIONS: McTNs likely participate in key aspects of ovarian cancer metastasis. McTNs represent a new therapeutic target for this disease that could refine therapies, including intraperitoneal drug delivery.

Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer.

BACKGROUND: This multi-center RP2 study assessed activity/safety of ixabepilone + bevacizumab compared to ixabepilone in platinum-resistant/refractory ovarian/fallopian tube/primary peritoneal cancer. Additional objectives were to examine the role of prior bevacizumab and taxanes, and explore class III-ß-tubulin (TUBB3) as a predictive biomarker. METHODS: Participants were randomised to receive ixabepilone 20 mg/m2 days 1, 8, 15 with (IXA + BEV) or without (IXA) bevacizumab 10 mg/kg days 1, 15 every 28 days. Patients were stratified by prior BEV. The primary endpoint was PFS. OS, safety, and ORR served as secondary endpoints. RESULTS: Among 76 evaluable patients who received IXA + BEV (n = 39) compared to IXA (n = 37), the ORR was 33% (n = 13) versus 8% (n = 3)(P = 0.004), durable at 6 months in 37% (n = 14) and 3% (n = 1) (P < 0.001). BEV significantly improved PFS (median:5.5 vs 2.2 months, HR = 0.33, 95%CI 0.19-0.55, P < 0.001) and OS (median:10.0 vs 6.0 months, HR = 0.52, 95%CI 0.31-0.87, P = 0.006). Both regimens were well-tolerated. TUBB3 expression did not predict response. Subgroup analyses revealed minimal effect of prior BEV or taxane resistant/refractory status on response to IXA + BEV. CONCLUSIONS: IXA + BEV is a well-tolerated, effective combination for platinum/taxane-resistant ovarian cancer that extends PFS and likely OS relative to IXA monotherapy. Prior receipt of BEV should not preclude the use of IXA + BEV. TUBB3 is not a predictive biomarker. CLINICAL TRIAL REGISTRATION: NCT3093155.

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.

Ultra-early synostectomy and cranial remodeling orthoses in the management of craniosynostoses.

OBJECTIVE: The advent of endoscopic synostectomy has enabled early surgery for infants with craniosynostosis. Even though diagnosis is often made at birth, endoscopic synostectomy has traditionally been delayed until the infant is 3 months of age. There have been very few published reports of this procedure being performed in the early neonatal period. The authors discuss their experience with ultra-early endoscopic synostectomy, defined as an operation for infants aged 8 weeks or younger. METHODS: A retrospective analysis of infants who underwent operations at or before 8 weeks of age between 2011 and 2020 was done. RESULTS: Twenty-five infants underwent operations: 11 were 2 weeks of age or younger, 8 were between 3 and 4 weeks of age, and 6 were between 5 and 8 weeks of age. The infants weighed between 2.25 and 4.8 kg. Eighteen had single-suture synostosis, and 7 had multiple sutures involved. Of these 7, 4 had syndromic craniosynostosis. The average operative time was 35 minutes, and it was less than 40 minutes in 19 cases. The estimated operative blood loss was 25 ml or less in 19 cases; 5 infants required an intraoperative blood transfusion. In 1 child with syndromic multisuture craniosynostosis, the surgery was staged due to blood loss. Two children experienced complications related to the procedure: one had an incidental durotomy with skin infection, and the other had postoperative kernicterus. All infants were fitted for cranial remodeling orthoses following surgery. Three of the 25 infants required reoperations, with 2 patients with syndromic craniosynostosis needing repeat surgery for cranial volume expansion and cosmetic appearance. Another child with syndromic craniosynostosis is awaiting cranial expansion surgery. Follow-up varied between 6 months and 8 years. CONCLUSIONS: The data show that ultra-early synostectomy is safe and not associated with increased complications compared with surgery performed between 3 and 6 months of age. Infants with multisuture synostosis had increased operative time, required blood transfusion, and were more likely to require a second operation.

Zincate-Blocking-Functionalized Polysulfone Separators for Secondary Zn-MnO2 Batteries.

Alkaline zinc-manganese dioxide (Zn-MnO2) batteries are well suited for grid storage applications because of their inherently safe, aqueous electrolyte and established materials supply chain, resulting in low production costs. With recent advances in the development of Cu/Bi-stabilized birnessite cathodes capable of the full 2-electron capacity equivalent of MnO2 (617 mA h/g), there is a need for selective separators that prevent zincate (Zn(OH)4)2- transport from the anode to the cathode during cycling, as this electrode system fails in the presence of dissolved zinc. Herein, we present the synthesis of N-butylimidazolium-functionalized polysulfone (NBI-PSU)-based separators and evaluate their ability to selectively transport hydroxide over zincate. We then examine their impact on the cycling of high depth of discharge Zn/(Cu/Bi-MnO2) batteries when inserted in between the cathode and anode. Initially, we establish our membranes' selectivity by performing zincate and hydroxide diffusion tests, showing a marked improvement in zincate-blocking (DZn (cm2/min): 0.17 ± 0.04 × 10-6 for 50-PSU, our most selective separator vs 2.0 ± 0.8 × 10-6 for Cellophane 350P00 and 5.7 ± 0.8 × 10-6 for Celgard 3501), while maintaining similar crossover rates for hydroxide (DOH (cm2/min): 9.4 ± 0.1 × 10-6 for 50-PSU vs 17 ± 0.5 × 10-6 for Cellophane 350P00 and 6.7 ± 0.6 × 10-6 for Celgard 3501). We then implement our membranes into cells and observe an improvement in cycle life over control cells containing only the commercial separators (cell lifetime extended from 21 to 79 cycles).

EP4 and Class III ß-Tubulin Expression in Uterine Smooth Muscle Tumors: Implications for Prognosis and Treatment.

The microtubule-stabilizing agent docetaxel in combination with gemcitabine represents one of the most effective regimens against the aggressive gynecologic tumor leiomyosarcoma (LMS). Upregulation of class III ß-tubulin has previously been shown to confer taxane resistance in a variety of human cancers. Prostaglandin E2 receptor EP4 is linked to progression of a variety of human cancers and may represent a novel target for tumor inhibition in LMS. We evaluated the hypotheses that EP4 and class III ß-tubulin have increased expression in LMS in comparison to normal myometrium or benign tumors and that expression of class III ß-tubulin correlates with resistance to taxanes and poor clinical outcome. Gene expression was examined using TCGA data and correlated with clinicopathologic outcome which demonstrated that class III ß-tubulin is more highly expressed in more aggressive sarcomas with EP4 being widely expressed in all subtypes of sarcoma. Immunohistochemistry for EP4 and class III ß-tubulin was performed on patients with LMS, leiomyomatosis/STUMP, leiomyoma, and normal myometrium. Expression of EP4 and class III ß-tubulin were characterized for cell lines SK-UT-1, SK-UT-1B, and PHM-41 and these cell lines were treated with docetaxel alone and in combination with EP4 inhibitors. In taxane-resistant cell lines that overexpress class III ß-tubulin and EP4, treatment with EP4 inhibitor resulted in at least 2-fold sensitization to docetaxel. Expression of class III ß-tubulin and EP4 in LMS may identify patients at risk of resistance to standard chemotherapies and candidates for augmentation of therapy through EP4 inhibition.

Unusual case of anti-N-methyl-D-aspartic acid-receptor (NMDA-R) encephalitis and autoimmune polyglandular syndrome (APS).

Anti-N-methyl-D-aspartic acid-receptor (NMDA-R) encephalitis is a novel disease discovered within the past 10 years. It is an autoimmune disease (AD) that has been associated with other ADs, such as Graves' disease. However, association with autoimmune polyglandular syndromes (APS) has not been previously described. A 58-year-old woman presented with altered mental status and an 8-month history of weight loss, apathy and somnolence. Laboratory evaluation confirmed Graves' disease with thyrotoxicosis and type 1 diabetes mellitus. Despite treatment, she continued to have a fluctuating mental status. Further diagnostic evaluation included an abdominal MRI that showed a cystic lobular left adnexal mass. Serum anti-NMDA-R antibodies were positive, raising concern for NMDA-R encephalitis. Bilateral salpingo-oophorectomy was performed, with pathology consistent with cystadenofibroma. She had a favourable recovery with marked clinical improvement. Anti-NMDA-R antibodies were negative 2 months following surgery. The concomitant occurrence of APS and anti-NMDA-R encephalitis suggests a shared mechanism of autoimmune pathophysiology.

Novel approach to temozolomide resistance in malignant glioma: connexin43-directed therapeutics.

Resistance of malignant glioma, including glioblastoma (GBM), to the chemotherapeutic temozolomide (TMZ) remains a key obstacle in treatment strategies. The gap junction protein connexin43 (Cx43) has complex roles in the establishment, progression, and persistence of malignant glioma. Recent findings demonstrate that connexins play an important role in the microenvironment of malignant glioma and that Cx43 is capable of conferring chemotherapeutic resistance to GBM cells. Carboxyl-terminal Cx43 peptidomimetics show therapeutic promise in overcoming TMZ resistance via mechanisms that may include modulating junctional activity between tumor cells and peritumoral cells and/or downstream molecular signaling events mediated by Cx43 protein binding. High levels of intra-tumor and inter-tumor heterogeneity make it difficult to clearly define specific populations for Cx43-targeted therapy; hence, development of in vitro models that better mimic the microenvironment of malignant glioma, and the incorporation of patient-derived stem cells, could provide opportunities for patient-specific drug screening. This review summarizes recent advances in understanding the roles of Cx43 in malignant glioma, with a special focus on tumor microenvironment, TMZ resistance, and therapeutic opportunity offered by Cx43 peptidomimetics.

Gender-transformative Bandebereho couples' intervention to promote male engagement in reproductive and maternal health and violence prevention in Rwanda: Findings from a randomized controlled trial.

BACKGROUND: Rigorous evidence of the effectiveness of male engagement interventions, particularly on how these interventions impact relationship power dynamics and women's decision-making, remains limited. This study assessed the impact of the Bandebereho gender-transformative couples' intervention on impact on multiple behavioral and health-related outcomes influenced by gender norms and power relations. METHODS: We conducted a multi-site randomised controlled trial in four Rwandan districts with expectant/current fathers and their partners, who were randomised to the intervention (n = 575 couples) or control group (n = 624 couples). Primary outcomes include women's experience of physical and sexual IPV, women's attendance and men's accompaniment at ANC, modern contraceptive use, and partner support during pregnancy. At 21-months post-baseline, 1123 men and 1162 partners were included in intention to treat analysis. Generalized estimating equations with robust standard errors were used to fit the models. FINDINGS: The Bandebereho intervention led to substantial improvements in multiple reported outcomes. Compared to the control group, women in the intervention group reported: less past-year physical (OR 0.37, p<0.001) and sexual IPV (OR 0.34, p<0.001); and greater attendance (IRR 1.09, p<0.001) and male accompaniment at antenatal care (IRR 1.50, p<0.001); and women and men in the intervention group reported: less child physical punishment (women: OR 0.56, p = 0.001; men: OR 0.66, p = 0.005); greater modern contraceptive use (women: OR 1.53, p = 0.004; men: OR 1.65, p = 0.001); higher levels of men's participation in childcare and household tasks (women: beta 0.39, p<0.001; men: beta 0.33, p<0.001); and less dominance of men in decision-making. CONCLUSIONS: Our study strengthens the existing evidence on male engagement approaches; together with earlier studies our findings suggest that culturally adapted gender-transformative interventions with men and couples can be effective at changing deeply entrenched gender inequalities and a range of health-related behavioral outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02694627.

Barriers to Timely Completion of Radiation Therapy in Patients with Cervical Cancer in an Urban Tertiary Care Center.

Background In 2017, there will be an estimated 12,820 women diagnosed with cervical cancer in the United States, causing an estimation of 4,210 deaths. Among U.S. women, there is a 33% greater incidence and 71% higher cervical cancer mortality in high-poverty counties when compared to low-income counties [1]. In those dispositioned to chemoradiation, treatment time of less than eight weeks is associated with compromised pelvic control. We sought to identify patient or disease characteristics and socioeconomic or psychosocial barriers that contribute to delays in treatment completion in order to formulate new policies to address these needs. ​​​​​​Methods Cervical cancer patients treated with primary chemoradiation through the University of Maryland from 2011-2016 were identified retrospectively. Patients were placed in one of two groups: those who completed radiation treatment within 56 days, and those who failed to complete treatment within 56 days. Time to completion of radiation therapy was evaluated in relation to patient and disease variables. ​​​​Results Forty-three patients with sufficient information for inclusion were identified. The median age was 51 years. Ten patients were stage I at diagnosis (23.3%), 16 were stage II (37.2%), 11 were stage III (25.5%) and six were stage IV (14%). Histopathology revealed squamous cell carcinoma in 37 patients (86%), adenocarcinoma in three patients (7%), mixed histology in two patients (4.7%), and neuroendocrine histology in one patient (2.3%). Twenty patients (46.5%) completed treatment within the recommended timeframe of 56 days while 23 patients (53.5%) did not. The most common reasons for a protracted treatment, or failure to complete the prescribed treatment were non-compliance/psychosocial factors (10 patients, 43.5%). Age, race, primary language, marital status, insurance, employment status, HIV status, mental health, substance abuse, tobacco use, stage at diagnosis, performance status at diagnosis, BMI (body mass index, kg/m2) at diagnosis, and income by zip code were not significantly associated with protracted treatment. The distance to treatment center was a significant factor (p=0.07); patients who lived closest to the treatment center were least likely to complete RT in the designated time frame. This is most likely due to the location of the treatment center, which is in the heart of an urban, low socioeconomic area. Conclusions More than half of all cervical cancer patients presenting to an urban tertiary care center do not complete chemoradiation therapy in the recommended timeframe. Underlying psychosocial factors are prominent. The role for patient navigation in this vulnerable population must be investigated.

Regenerable Cu-intercalated MnO2 layered cathode for highly cyclable energy dense batteries.

Manganese dioxide cathodes are inexpensive and have high theoretical capacity (based on two electrons) of 617 mAh g-1, making them attractive for low-cost, energy-dense batteries. They are used in non-rechargeable batteries with anodes like zinc. Only ∼10% of the theoretical capacity is currently accessible in rechargeable alkaline systems. Attempts to access the full capacity using additives have been unsuccessful. We report a class of Bi-birnessite (a layered manganese oxide polymorph mixed with bismuth oxide (Bi2O3)) cathodes intercalated with Cu2+ that deliver near-full two-electron capacity reversibly for >6,000 cycles. The key to rechargeability lies in exploiting the redox potentials of Cu to reversibly intercalate into the Bi-birnessite-layered structure during its dissolution and precipitation process for stabilizing and enhancing its charge transfer characteristics. This process holds promise for other applications like catalysis and intercalation of metal ions into layered structures. A large prismatic rechargeable Zn-birnessite cell delivering ∼140 Wh l-1 is shown.

ACR Appropriateness Criteria® Adjuvant Management of Early-Stage Endometrial Cancer.

These consensus guidelines on adjuvant radiotherapy for early-stage endometrial cancer were developed from an expert panel convened by the American College of Radiology. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method; and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. After a review of the published literature, the panel voted on three variants to establish best practices for the utilization of imaging, radiotherapy, and chemotherapy after primary surgery for early-stage endometrial cancer.

Compatibility of Radiofrequency Surgical Sponge Detection Technology with Cardiac Implantable Electronic Devices and Temporary Pacemakers.

BACKGROUND: Radiofrequency (RF) technology has improved detection of retained surgical sponges with a reported 100% sensitivity and specificity. However, the potential for interactions of the RF signals emitted by the detection system with cardiac implantable electronic devices (CIEDs) or temporary pacemakers may limit its use in those patients with these devices. This study investigated whether RF detection technology causes interference or clinically significant changes in the programmed settings of implanted pacemakers and defibrillators or temporary epicardial pacemakers. METHODS: Fifty patients who were scheduled either for CIED removal or placement of a temporary epicardial pacemaker (at the time of open heart surgery) were recruited for this study. Device settings and measurements from separate interrogations before and after scanning with the RF detection system were compared. For the temporary pacemakers, we observed for any changes in hemodynamics or signs of pacing interference. RESULTS: Twenty (40%) pacemakers, 20 (40%) implantable cardioverter defibrillators, and 10 (20%) temporary pacemakers were analyzed in this study. During scanning, no signal interference was detected in any permanent device, and there were no significant changes in programmed settings after scanning with the RF detection system. However, pacing inhibition was detected with temporary pacing systems when programmed to a synchronous mode (DDD). CONCLUSIONS: RF detection technology can be safely used to scan for retained surgical sponges in patients with permanent CIEDs and temporary pacemakers set to asynchronous mode.

ACR Appropriateness Criteria® Management of Recurrent Endometrial Cancer.

OBJECTIVES: In women with endometrial carcinoma (EC), tumor recurrences tend to occur in the 2- to 3-year period following surgical staging. Management of disease recurrence in EC poses significant challenges. These patients represent a heterogenous group where histologic subtypes, previous adjuvant management, interval since completion of adjuvant therapy, and size and site(s) of disease recurrence all have important implications on salvage therapies and prognosis. No randomized controlled trials have been published to determine optimal management in this group of patients. An expert panel was convened to reach consensus on the most appropriate management options in this group of patients. METHODS: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. RESULTS: Five clinical variants were developed to address common scenarios in the management of women with recurrent EC. Group members reached consensus on the appropriateness of specific evaluation and treatment approaches with numerical ratings. CONCLUSIONS: In combining available medical literature and expert opinions, this manuscript may serve as an aid for other practitioners in the appropriate management of women with recurrent EC.