Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer.

BACKGROUND: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. METHODS: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry. RESULTS: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, median progression-free and overall survival was 5 and 7 months, respectively. Bimiralisib was well tolerated, with expected hyperglycemia. Pharmacokinetic values were consistent with published studies. NOTCH1 mutations were detected in 83.3% of ctDNA. Staining for tumor cl-NOTCH1 was negative. The trial closed early due to sponsor insolvency. CONCLUSION: Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100).

Novel Systemic Treatment Modalities Including Immunotherapy and Molecular Targeted Therapy for Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common cancers worldwide. More than half of patients with HNSCC eventually experience disease recurrence and/or metastasis, which can threaten their long-term survival. HNSCCs located in the oral cavity and larynx are usually associated with tobacco and/or alcohol use, whereas human papillomavirus (HPV) infection, particularly HPV16 infection, is increasingly recognized as a cause of oropharyngeal HNSCC. Despite clinical, histologic, and molecular differences between HPV-positive and HPV-negative HNSCCs, current treatment approaches are the same. For recurrent disease, these strategies include chemotherapy, immunotherapy with PD-1-inhibitors, or a monoclonal antibody, cetuximab, that targets epidermal growth factor; these therapies can be administered either as single agents or in combination. However, these treatment strategies carry a high risk of toxic side effects; therefore, more effective and less toxic treatments are needed. The landscape of HNSCC therapy is changing significantly; numerous clinical trials are underway to test novel therapeutic options like adaptive cellular therapy, antibody-drug conjugates, new targeted therapy agents, novel immunotherapy combinations, and therapeutic vaccines. This review helps in understanding the various developments in HNSCC therapy and sheds light on the path ahead in terms of further research in this field.

Financial Risk Protection and Hospital Admission for Trauma in Cameroon: An Analysis of the Cameroon National Trauma Registry.

BACKGROUND: Half of the global population is at risk for catastrophic health expenditure (CHE) in the event that they require surgery. Universal health coverage fundamentally requires protection from CHE, particularly in low- and middle-income countries (LMICs). Financial risk protection reports in LMICs covering surgical care are limited. We explored the relationship between financial risk protection and hospital admission among injured patients in Cameroon to understand the role of health insurance in addressing unmet need for surgery in LMICs. METHODS: The Cameroon National Trauma Registry, a database of all injured patients presenting to the emergency departments (ED) of three Cameroonian hospitals, was retrospectively reviewed between 2015 and 2017. Multivariate regression analysis identified predictors of hospital admission after injury and of patient report of cost inhibiting their care. RESULTS: Of the 7603 injured patients, 95.7% paid out-of-pocket to finance ED care. Less than two percent (1.42%) utilized private insurance, and more than half (54.7%) reported that cost inhibited their care. In multivariate analysis, private insurance coverage was a predictor of hospital admission (OR 2.17, 95% CI: 1.26, 3.74) and decreased likelihood of cost inhibiting care (OR 0.34, 95% CI: 0.20, 0.60) when compared to individuals paying out-of-pocket. CONCLUSION: The prevalence of out-of-pocket spending among injured patients in Cameroon highlights the need for financial risk protection that encompasses surgical care. Patients with private insurance were more likely to be admitted to the hospital, and less likely to report that cost inhibited care, supporting private health insurance as a potential financing strategy.

A NOVEL SEARCH BUILDER TO EXPEDITE SEARCH STRATEGIES FOR SYSTEMATIC REVIEWS.

OBJECTIVES: Developing a search strategy for use in a systematic review is a time-consuming process requiring construction of detailed search strings using complicated syntax, followed by iterative fine-tuning and trial-and-error testing of these strings in online biomedical search engines. METHODS: Building upon limitations of existing online-only search builders, a user-friendly computer-based tool was created to expedite search strategy development as part of production of a systematic review. RESULTS: Search Builder 1.0 is a Microsoft Excel®-based tool that automatically assembles search strategy text strings for PubMed (www.pubmed.com) and Embase (www.embase.com), based on a list of user-defined search terms and preferences. With the click of a button, Search Builder 1.0 automatically populates the syntax needed for functional search strings, and copies the string to the clipboard for pasting into Pubmed or Embase. The offline file-based interface of Search Builder 1.0 also allows for searches to be easily shared and saved for future reference. CONCLUSIONS: This novel, user-friendly tool can save considerable time and streamline a cumbersome step in the systematic review process.

I heard about it from a friend: assessing interest in buprenorphine treatment.

BACKGROUND: In the United States, opioid abuse and dependence continue to be a growing problem, whereas treatment for opioid abuse and dependence remains fairly static. Buprenorphine treatment for opioid dependence is safe and effective but underutilized. Prior research has demonstrated low awareness and use of buprenorphine among marginalized groups. This study investigates syringe exchange participants' awareness of, exposure to, and interest in buprenorphine treatment. METHODS: Syringe exchange participants were recruited from a mobile unit performing outreach to 9 street-side sites in New York City. Computer-based interviews were conducted to determine (1) opioid users' awareness of, exposure to, and interest in buprenorphine treatment; and (2) the association between awareness or exposure and interest in buprenorphine treatment. Logistic regression models were used to examine the associations between awareness of, direct exposure (i.e., having taken buprenorphine) or indirect exposure (i.e., knowing someone who had taken buprenorphine)S to, and interest in buprenorphine treatment. RESULTS: Of 158 opioid users, 70% were aware of, 32% had direct exposure to, and 31% had indirect exposure to buprenorphine; 12% had been prescribed buprenorphine. Of 138 opioid users who had never been prescribed buprenorphine, 57% were interested in buprenorphine treatment. In multivariate models, indirect exposure was associated with interest in buprenorphine treatment (adjusted odds ratio [AOR] = 2.65, 95% confidence interval [CI]: 1.22-5.77), but awareness and direct exposure were not. CONCLUSIONS: Syringe exchange participants were mostly aware of buprenorphine and interested in treatment, but few had actually been prescribed buprenorphine. Because indirect exposure to buprenorphine was associated with interest in treatment, future interventions could capitalize on indirect exposure, such as through peer mentorship, to address underutilization of buprenorphine treatment.

Neonatal Serum Gentamicin Concentrations and Outcomes Following Maternal Once-Daily Gentamicin Dosing.

OBJECTIVE: This study evaluated newborn gentamicin serum concentrations after birth and the effects on the newborn after extended interval gentamicin dosing in peripartum mothers. METHODS: This was a single-center, retrospective chart review of neonates born to mothers that received peripartum once-daily gentamicin dosing of approximately 5 mg/kg within 12 hours of delivery. A gentamicin serum concentration was obtained immediately after birth in the newborn. The primary outcome was initial neonatal gentamicin serum concentration after birth. Several secondary outcomes were evaluated including nephrotoxicity and ototoxicity. A subgroup analysis comparing baseline demographics of mother-newborn dyads with birth neonatal serum concentrations of less than 2 mcg/mL versus 2 mcg/mL or greater was performed. RESULTS: A total of 32 mother-newborn dyads were included. Newborns had a median gestational age of 39.4 weeks and median birth weight of 3.4 kg. The mean initial gentamicin serum concentration was elevated at 3.1 ± 1.9 mcg/mL among all newborns. The median maternal dose based on actual body weight in newborns with gentamicin serum concentrations less than 2 mcg/mL was 3.5 (IQR, 3.3-4.8) mg/kg versus 4.8 (IQR, 4.3-5.2) mg/kg in those that had serum concentrations of 2 mcg/mL or greater (p = 0.025). All newborn gentamicin serum concentrations were less than 2 mcg/mL for maternal doses given less than 1 hour prior to delivery (n = 8). There were no significant differences in nephrotoxicity or ototoxicity. CONCLUSIONS: Peripartum once daily dosing of gentamicin administered between 1 to 12 hours of birth may lead to clinically significant serum concentrations in newborns.

Use of Calcitonin for Hypercalcemia in a Premature Neonate With Congenital Mesoblastic Nephroma.

We report on a premature neonate (31 4/7 weeks' gestation) who presented with hypercalcemia secondary to congenital mesoblastic nephroma (CMN), the most common type of renal tumor in neonates. Typical presentation includes a palpable abdominal mass or swelling and may include abdominal pain, hematuria, fever, or hypertension. A less common complication of CMN is hypercalcemia of malignancy. Although the primary management strategy for hypercalcemia of malignancy is to treat the underlying disease, there are several agents that can be used as well for acute hypercalcemia including fluids, loop diuretics, corticosteroids, bisphosphonates, and calcitonin. However, there is minimal evidence to guide efficacious and safe treatment selection and dosing as hypercalcemia is a rare complication of this tumor type. This case adds to the current body of literature as only the second case of parathyroid hormone-related peptide-mediated hypercalcemia in a preterm neonate treated with calcitonin and is the first to specify a successful dose escalation strategy of calcitonin for this indication.

Dexmedetomidine Versus Fentanyl for Neonates With Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia.

OBJECTIVE: Therapeutic hypothermia reduces the risk of death and major disability in neonates with moderate-to-severe hypoxic ischemic encephalopathy (HIE). Opioids and benzodiazepines are used to manage agitation but contribute to hemodynamic and respiratory instability. The objective of this study was to evaluate the safety and efficacy of dexmedetomidine (DEX) compared with fentanyl (FENT) in neonates with HIE undergoing therapeutic hypothermia. METHODS: This was a retrospective, single-center study comparing outcomes in neonates with HIE undergoing therapeutic hypothermia who received FENT to those who received DEX. RESULTS: A total of 45 neonates were included (FENT, n = 19; DEX, n = 26). The DEX group had a decreased need for sedative bolus doses during therapeutic hypothermia compared with the FENT group; however, there was no difference in number of uncontrolled agitation scores or need for additional scheduled sedatives. The DEX group had a shorter time to discontinuation of sedatives after rewarming compared with the FENT group (0.52 versus 5 days, respectively; p = 0.001), shorter time to extubation after birth (3.1 versus 11.3 days, respectively; p = 0.004), and earlier time to resumption of feeds (8.5 versus 13 days, respectively; p = 0.03). A non-statistically significant reduction in seizures was noted (3 versus 7 subjects, respectively; p = 0.07). There was no difference in baseline characteristics, mortality, or adverse effects. CONCLUSIONS: The use of DEX during therapeutic hypothermia for HIE appears to provide comparable control of agitation to FENT with a reduced need for additional sedatives and may lead to an earlier time to extubation and discontinuation of sedatives.

Comparison of Extracorporeal Life Support Anticoagulation Using Activated Clotting Time Only to a Multimodal Approach in Pediatric Patients.

OBJECTIVE: To evaluate an institutional practice change from an extracorporeal life support (ECLS) anticoagulation monitoring strategy of activated clotting time (ACT) alone to a multimodal strategy including ACT, activated partial thrombin time, heparin anti-factor-Xa, and thromboelastography. METHODS: This was a retrospective review of patients younger than 18 years on ECLS and heparin between January 2014 and June 2020 at a single institution. RESULTS: Twenty-seven patients used an ACT-directed strategy and 25 used a multimodal strategy. The ACT-directed group was on ECLS for a shorter median duration than the multimodal group (136 versus 164 hours; p = 0.046). There was a non-significant increase in major hemorrhage (85.1% versus 60%; p = 0.061) and a significantly higher incidence of central nervous system (CNS) hemorrhage in the ACT-directed group (29.6% versus 0%; p = 0.004). Rates of thrombosis were similar, with a median of 3 circuit changes per group (p = 0.921). The ACT-directed group had larger median heparin doses (55 versus 34 units/kg/hr; p < 0.001), required more dose adjustments per day (3.8 versus 1.7; p < 0.001), and had higher rates of heparin doses >50 units/kg/hr (62.9% versus 16%; p = 0.001). More anticoagulation parameters were supratherapeutic (p = 0.015) and fewer were therapeutic (p < 0.001) in the ACT-directed group. CONCLUSIONS: Patients with a multimodal strategy for monitoring anticoagulation during ECLS had lower rates of CNS hemorrhage and decreased need for large heparin doses of >50 units/kg/hr without an increase in clotting complications, compared with ACT-directed anticoagulation. Multimodal anticoagulation monitoring appears superior to ACT-only strategies and may reduce heparin exposure and risk of hemorrhagic complications for pediatric patients on ECLS.

Combined TRIP13 and Aurora Kinase Inhibition Induces Apoptosis in Human Papillomavirus-Driven Cancers.

PURPOSE: Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers. EXPERIMENTAL DESIGN: We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression. RESULTS: Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that the mechanism of sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition-induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells' sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reduced Aurora kinase inhibition-induced apoptosis, whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells. CONCLUSIONS: Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.

Sustained Aurora Kinase B Expression Confers Resistance to PI3K Inhibition in Head and Neck Squamous Cell Carcinoma.

Tumor suppressor mutations in head and neck squamous cell carcinoma (HNSCC) dominate the genomic landscape, hindering the development of effective targeted therapies. Truncating and missense mutations in NOTCH1 are frequent in HNSCC, and inhibition of PI3K can selectively target NOTCH1 mutant (NOTCH1MUT) HNSCC cells. In this study, we identify several proteins that are differentially regulated in HNSCC cells after PI3K inhibition based on NOTCH1MUT status. Expression of Aurora kinase B (Aurora B), AKT, and PDK1 following PI3K inhibition was significantly lower in NOTCH1MUT cell lines than in wild-type NOTCH1 (NOTCH1WT) cells or NOTCH1MUT cells with acquired resistance to PI3K inhibition. Combined inhibition of PI3K and Aurora B was synergistic, enhancing apoptosis in vitro and leading to durable tumor regression in vivo. Overexpression of Aurora B in NOTCH1MUT HNSCC cells led to resistance to PI3K inhibition, while Aurora B knockdown increased sensitivity of NOTCH1WT cells. In addition, overexpression of Aurora B in NOTCH1MUT HNSCC cells increased total protein levels of AKT and PDK1. AKT depletion in NOTCH1WT cells and overexpression in NOTCH1MUT cells similarly altered sensitivity to PI3K inhibition, and manipulation of AKT levels affected PDK1 but not Aurora B levels. These data define a novel pathway in which Aurora B upregulates AKT that subsequently increases PDK1 selectively in NOTCH1MUT cells to mediate HNSCC survival in response to PI3K inhibition. These findings may lead to an effective therapeutic approach for HNSCC with NOTCH1MUT while sparing normal cells. SIGNIFICANCE: Aurora B signaling facilitates resistance to PI3K inhibition in head and neck squamous cell carcinoma, suggesting that combined inhibition of PI3K and Aurora kinase is a rational therapeutic strategy to overcome resistance.

Comparison of Neonatal Outcomes With and Without Prophylaxis With Indomethacin in Premature Neonates.

OBJECTIVE: Historically, prophylactic indomethacin (pINDO) has been used in some institutions for patent ductus arteriosus (PDA) in extremely low birthweight neonates while other institutions have used it as prophylaxis for intraventricular hemorrhage (IVH). The objective of this study was to evaluate the incidence of IVH and PDA with or without pINDO in premature neonates. METHODS: This was a retrospective, single-center study comparing neonatal outcomes in neonates weighing 1250 grams or less who received pINDO (pINDO group) to those who did not (No pINDO group) after our institution discontinued its routine use. RESULTS: A total of 399 infants were included for analysis (pINDO, n = 141; No pINDO, n = 258). No difference was found between pINDO and No pINDO groups in incidence of any IVH (18% vs 14%, respectively) or severe IVH (7% vs 3%, respectively) when adjusting for gestational age and antenatal corticosteroids. Although the incidence of moderate-to-large PDA was lower in the pINDO group (13% vs 23%, respectively, adjusted p = 0.002), there was no significant difference for PDA requiring surgery (4% vs 3%, respectively). Results demonstrated a higher incidence of bronchopulmonary dysplasia (BPD) in the pINDO group (55% vs 41%, respectively, adjusted p = 0.014). CONCLUSION: No difference in the incidence of IVH, severe IVH, or PDA requiring surgery was observed between groups, whereas an increase in BPD was seen with use of pINDO. These data support our institutional practice change to discontinue routine use of pINDO in premature neonates. Further research is needed to guide clinical practice.

Serotonin as a Mitogen in the Gastrointestinal Tract: Revisiting a Familiar Molecule in a New Role.

Serotonin signaling is ubiquitous in the gastrointestinal (GI) system, where it acts as a neurotransmitter in the enteric nervous system (ENS) and influences intestinal motility and inflammation. Since its discovery, serotonin has been linked to cellular proliferation in several types of tissues, including vascular smooth muscle, neurons, and hepatocytes. Activation of serotonin receptors on distinct cell types has been shown to induce well-known intracellular proliferation pathways. In the GI tract, potentiation of serotonin signaling results in enhanced intestinal epithelial proliferation, and decreased injury from intestinal inflammation. Furthermore, activation of the type 4 serotonin receptor on enteric neurons leads to neurogenesis and neuroprotection in the setting of intestinal injury. It is not surprising that the mitogenic properties of serotonin are pronounced within the GI tract, where enterochromaffin cells in the intestinal epithelium produce 90% of the body's serotonin; however, these proliferative effects are attributed to increased serotonin signaling within the ENS compartment as opposed to the intestinal mucosa, which are functionally and chemically separate by virtue of the distinct tryptophan hydroxylase enzyme isoforms involved in serotonin synthesis. The exact mechanism by which serotonergic neurons in the ENS lead to intestinal proliferation are not known, but the activation of muscarinic receptors on intestinal crypt cells indicate that cholinergic signaling is essential to this signaling pathway. Further understanding of serotonin's role in mucosal and enteric nervous system mitogenesis may aid in harnessing serotonin signaling for therapeutic benefit in many GI diseases, including inflammatory bowel disease, malabsorptive conditions, and cancer.

Evaluation of Appropriateness and Cost Savings of Pharmacist-Driven Palivizumab Ordering.

OBJECTIVES: Guidelines by the AAP for the use of palivizumab prophylaxis for respiratory syncytial virus (RSV) recommend administration within 72 hours prior to discharge for selected high-risk patient populations. Our institution historically administered palivizumab on a fixed-day schedule of Mondays and Thursdays, but adjusted the practice in fall 2017 to a pharmacist-driven flex-schedule based on anticipated discharge date. This review evaluated the effect of pharmacist-driven palivizumab ordering on the appropriateness of palivizumab administrations, based on AAP and institutional recommendations. Additionally, this review evaluated for effects on institutional cost. METHODS: This was a retrospective single-center evaluation including patients for whom palivizumab was ordered between July 1, 2016, and June 30, 2018. Patients in the 2016-2017 RSV season were in the fixed-day group, while patients in the 2017-2018 RSV season were in the flex-schedule group. RESULTS: A total of 142 palivizumab doses were evaluated. Overall, 97% of administrations were for an appropriate indication. All doses administered inappropriately (n = 4) occurred in the fixed-day group. In the fixed-day group, 48.6% of doses were given within 72 hours prior to discharge, which increased to 70.1% in the flex-schedule group (p = 0.01). The amount of drug saved by batching was 1 vial for every 4.9 patients in the fixed-day group, and 1 vial for every 4.8 patients in the flex-schedule group. CONCLUSIONS: There was a statistically significant improvement in compliance with AAP recommendations following the implementation of pharmacist-driven flex-schedule for palivizumab, compared to a fixed-day batching schedule. There was no significant difference in cost.

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma.

Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1's role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer's genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.

Use of Smoking Cessation Methods Among Patients Receiving Office-based Buprenorphine Maintenance Treatment.

OBJECTIVES: Provision of smoking-cessation treatment is limited in office-based buprenorphine maintenance treatment (BMT) settings. This study describes smoking and smoking-cessation behaviors among patients receiving office-based BMT. METHODS: Cross-sectional study of patients receiving office-based BMT at a community health center in the Bronx, NY. We interviewed patients assessing sociodemographic, and substance use and tobacco use characteristics, including methods used for smoking cessation. We reported simple frequencies and explored associations of BMT characteristics with smoking behaviors. RESULTS: Of 68 patients, 87.7% were current cigarette smokers, 7.9% were former smokers, and 4.4% had never smoked. Of lifetime smokers, 83.1% reported at least 1 prior quit attempt, and 78.5% had used medication (75.4% used nicotine replacement therapy, 29.2% varenicline, and 9.2% bupropion). Ten patients (15.4%) reported using electronic cigarettes to try to quit smoking. Stopping "cold turkey" (40.0%) and gradually decreasing the number of cigarettes smoked (32.3%) were nonpharmacological methods of quitting tried most often. Use of behavioral support, including stop-smoking programs and counseling, was low. Higher dose and longer duration of BMT was associated with greater smoking frequency. CONCLUSIONS: Patients receiving BMT have a high prevalence of cigarette smoking, though most have tried to quit, and have prior experience with pharmacotherapy for smoking cessation. Efforts to optimize smoking-cessation treatments among BMT patients are needed.

Smurf2-Mediated Stabilization of DNA Topoisomerase IIα Controls Genomic Integrity.

DNA topoisomerase IIα (Topo IIα) ensures genomic integrity and unaltered chromosome inheritance and serves as a major target of several anticancer drugs. Topo IIα function is well understood, but how its expression is regulated remains unclear. Here, we identify the E3 ubiquitin ligase Smurf2 as a physiologic regulator of Topo IIα levels. Smurf2 physically interacted with Topo IIα and modified its ubiquitination status to protect Topo IIα from the proteasomal degradation in dose- and catalytically dependent manners. Smurf2-depleted cells exhibited a reduced ability to resolve DNA catenanes and pathological chromatin bridges formed during mitosis, a trait of Topo IIα-deficient cells and a hallmark of chromosome instability. Introducing Topo IIα into Smurf2-depleted cells rescued this phenomenon. Smurf2 was a determinant of Topo IIα protein levels in normal and cancer cells and tissues, and its levels affected cell sensitivity to the Topo II-targeting drug etoposide. Our results identified Smurf2 as an essential regulator of Topo IIα, providing novel insights into its control and into the suggested tumor-suppressor functions of Smurf2. Cancer Res; 77(16); 4217-27. ©2017 AACR.

HIV-infected Women's Perspectives on the Use of the Internet for Social Support: A Potential Role for Online Group-based Interventions.

While the development and implementation of HIV-related online interventions has expanded, few have been tailored for women or have leveraged Web 2.0's capabilities to provide social support. We conducted semi-structured interviews with 27 women with HIV at an urban community health center to understand their perspectives on the potential role of the Internet and the use of an online group format to provide social support. Data were analyzed using the constant comparative method. We identified six themes: a need for groups and increased sense of connectedness, convenience and accessibility, trust as a precondition for participating, online groups as a potential facilitator or barrier to expression, limited digital access and literacy, and privacy concerns. Overall, women were highly supportive of online group-based interventions but acknowledged the need for increased digital access and Internet navigation training. Hybrid (in-person and online) interventions may be most useful for women with HIV.