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Summary Coactivator-associated arginine methyltransferase 1 (CARM1), a coactivator for various cancer-relevant transcription factors, is overexpressed in breast cancer. To elucidate the functions of CARM1 in tumorigenesis, we knocked out CARM1 from several breast cancer cell lines using Zinc-Finger Nuclease technology, which resulted in drastic phenotypic and biochemical changes. The CARM1 KO cell lines enabled identification of CARM1 substrates, notably the SWI/SNF core subunit BAF155. Methylation of BAF155 at R1064 was found to be an independent prognostic biomarker for cancer recurrence and to regulate breast cancer cell migration and metastasis. Furthermore, CARM1-mediated BAF155 methylation affects gene expression by directing methylated BAF155 to unique chromatin regions (e.g., c-Myc pathway genes). Collectively, our studies uncover a mechanism by which BAF155 acquires tumorigenic functions via arginine methylation.

Background Cardiovascular and arrhythmic events have been reported in hospitalized COVID-19 patients. However, arrhythmia manifestations and treatment strategies used in these patients have not been well-described. We sought to better understand the cardiac arrhythmic manifestations and treatment strategies in hospitalized COVID-19 patients through a worldwide crosssectional survey. Methods The Heart Rhythm Society (HRS) sent an online survey (via SurveyMonkey) to electrophysiology (EP) professionals (physicians, scientists, and allied professionals) across the globe. The survey was active from March 27 to April 13, 2020. Results A total of 1197 respondents completed the survey with 50% of respondents from outside the USA, representing 76 countries and 6 continents. Of respondents, 905 (76%) reported having COVID-19-positive patients in their hospital. Atrial fibrillation was the most commonly reported tachyarrhythmia whereas severe sinus bradycardia and complete heart block were the most common bradyarrhythmias. Ventricular tachycardia/ventricular fibrillation arrest and pulseless electrical activity were reported by 4.8% and 5.6% of respondents, respectively. There were 140 of 631 (22.2%) respondents who reported using anticoagulation therapy in all COVID-19-positive patients who did not otherwise have an indication. One hundred fifty-five of 498 (31%) reported regular use of hydroxychloroquine/chloroquine (HCQ) + azithromycin (AZM); concomitant use of AZM was more common in the USA. Sixty of 489 respondents (12.3%) reported having to discontinue therapy with HCQ + AZM due to significant QTc prolongation and 20 (4.1%) reported cases of Torsade de Pointes in patients on HCQ/chloroquine and AZM. Amiodarone was the most common antiarrhythmic drug used for ventricular arrhythmia management. Conclusions In this global survey of > 1100 EP professionals regarding hospitalized COVID-19 patients, a variety of arrhythmic manifestations were observed, ranging from benign to potentially life-threatening. Observed adverse events related to use of HCQ + AZM included prolonged QTc requiring drug discontinuation as well as Torsade de Pointes. Large prospective studies to better define arrhythmic manifestations as well as the safety of treatment strategies in COVID-19 patients are warranted.

Purpose The global incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing, and it has been proposed that a rising rate of human papillomavirus (HPV) associated cancers is driving the observed changes in OPSCC incidence. We carried out this systematic review to further examine the prevalence of HPV in OPSCC over time worldwide. Methods A systematic literature search was performed to identify all articles through January 31, 2014 that reported on the prevalence of HPV in OPSCC. Articles that met inclusion criteria were divided into four time frames (pre-1995, 1995—1999, 2000—2004, and 2005—present) based on the median year of the study's sample collection period. Employing a weighted analysis of variance (ANOVA) model, we examined the trends of HPV-positivity over time worldwide, in North America, and in Europe. Results Our literature search identified 699 unique articles. 175 underwent review of the entire study and 105 met inclusion criteria. These 105 articles reported on the HPV prevalence in 9541 OPSCC specimens across 23 nations. We demonstrated significant increases in the percentage change of HPV-positive OPSCCs from pre-1995 to present: 20.6% worldwide (p-value for trend: p<0.001), 21.6% in North America (p=0.013) and 21.5% in Europe (p=0.033). Discussion Interestingly, while in Europe there was a steady increase in HPV prevalence across all time frames, reaching nearly 50% most recently, in North America HPV prevalence appears to have plateaued over the past decade at about 65%. These findings may have important implications regarding predictions for the future incidence of OPSCC.

Purpose Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard of care treatments for HNSCC patients include surgery, radiation and chemotherapy. Additionally, the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult to treat malignancy. Thus, identification of new molecular targets is critical. Experimental Design In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient derived xenografts (PDXs), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard of care treatment regimes used in HNSCC. Results AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases and shorter relapse free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. Additionally, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance. Conclusion Collectively, this study provides evidence for the role of AXL in HNSCC pathogenesis and supports further pre-clinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC.

Objective Surgical site infection (SSI) is one of the most common post-operative complications following vascular reconstruction, producing significant morbidity and hospital readmission. In contrast to SSI that develops while patients are still hospitalized, little is known about the cohort of patients that develop SSI following discharge. In this study, we explore the factors that lead to post-discharge SSI, investigate the differences between risk factors for in-hospital versus post-discharge SSI, and develop a scoring system to identify patients that might benefit from post-discharge monitoring of their wounds. Methods Patients who underwent major vascular surgery from 2005–2012 for aneurysm and lower extremity occlusive disease were identified from the American College of Surgeons National Surgical Quality Improvement Program Participant Use Files. Patients were categorized as having no SSI, in-hospital SSI, or SSI after hospital discharge. Predictors of post-discharge SSI were determined by multivariable logistic regression and internally validated by bootstrap resampling. Risk scores were assigned to all significant variables in the model. Summative risk scores were collapsed into quartile-based ordinal categories and defined as low-, low/moderate-, moderate/high-, and high-risk. Multivariable logistic regression was used to determine predictors of in-hospital SSI. Results Of the 49,817 patients who underwent major vascular surgery, 4,449 (8.9%) were diagnosed with SSI (2.1% in-hospital; 6.9% post-discharge). By multivariable analysis, factors significantly associated with increased odds of post-discharge SSI include female gender, obesity, diabetes, smoking, hypertension, coronary artery disease, critical limb ischemia, chronic obstructive pulmonary disease, dyspnea, neurological disease, prolonged operative time >4 hours, American Society of Anesthesiology classification IV or V, lower extremity revascularization or aortoiliac procedure, and groin anastomosis. The model exhibited moderate discrimination (bias-corrected c-statistic, 0.691) and excellent internal calibration. The post-discharge SSI rate was 2.1% for low-risk patients, 5.1% for low/moderate-risk patients, 7.8% for moderate/high risk patients, and 14% for high-risk patients. In a comparative analysis, comorbidities were the primary driver of post-discharge SSI whereas in-hospital factors (operative time, emergency case status) and complications predicted in-hospital SSI. Conclusions The majority of SSIs after major vascular surgery develop following hospital discharge. We have created a scoring system that can select a cohort of patients at high-risk for SSI following discharge. These patients can be targeted for transitional care efforts focused on early detection and treatment with the goal of reducing morbidity and preventing readmission secondary to SSI.

Studies of vortical interactions in boundary layers have often invoked the continuous spectrum of the Orr-Sommerfeld (O-S) equation. These vortical eigenmodes provide a link between free-stream disturbances and the boundary-layer shear -a link which is absent in the inviscid limit due to shear sheltering. In the presence of viscosity, however, a shift in the dominant balance in the operator determines the structure of these eigenfunctions inside the mean shear. In order to explain the mechanics of shear sheltering and the structure of the continuous modes, both numerical and asymptotic solutions of the linear perturbation equation are presented in single-and two-fluid boundary layers. The asymptotic analysis identifies three limits: a convective shear-sheltering regime, a convective-diffusive regime and a diffusive regime. In the shear-dominated limit, the vorticity eigenfunction possesses a three-layer structure, the topmost being a region of exponential decay. The role of viscosity is most pronounced in the diffusive regime, where the boundary layer becomes 'transparent' to the oscillatory eigenfunctions. Finally, the convective-diffusive regime demonstrates the interplay between the the accumulative effect of the shear and the role of viscosity. The analyses are complemented by a physical interpretation of shearsheltering mechanism. The influence of a wallfilm, in particular viscosity and density stratification, and surface tension are also evaluated. It is shown that a modified wavenumber emerges across the interface and influences the penetration of vortical disturbances into the two-fluid shear flow.

Human papillomaviruses (HPVs) are involved in approximately 5% of all human cancer. Although initially recognized for causing nearly all cases of cervical carcinoma, much data has now emerged implicating HPVs as a causal factor in other anogenital cancers as well as a subset of head and neck squamous cell carcinomas (HNSCCs), most commonly oropharyngeal cancers. Numerous clinical trials have demonstrated that patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) have improved survival compared to patients with HPV– cancers. Furthermore, epidemiological evidence shows the incidence of OPSCC has been steadily rising over time in the United States. It has been proposed that an increase in HPV-related OPSCCs is the driving force behind the increasing rate of OPSCC. Although some studies have revealed an increase in HPV+ head and neck malignancies over time in specific regions of the United States, there has not been a comprehensive study validating this trend across the entire country. Therefore, we undertook this meta-analysis to assess all literature through August 2013 that reported on the prevalence of HPV in OPSCC for patient populations within the United States. The results show an increase in the prevalence of HPV+ OPSCC from 20.9% in the pre-1990 time period to 51.4% in 1990–1999 and finally to 65.4% for 2000–present. In this manner, our study provides further evidence to support the hypothesis that HPV-associated OPSCCs are driving the increasing incidence of OPSCC over time in the United States.