Human papilloma virus (HPV) is an etiological agent of oropharyngeal squamous cell carcinoma (OPSCC). Patients with HPV+ OPSCC have high long-term survival rates: however, current radiation protocols are aggressive and can result in life-long morbidities, including difficulty swallowing, chronic dry-mouth, and altered speech. In this episode, Curtis Pickering and colleagues evaluated gene expression profiles, tumor presentation, and clinical response in a cohort of patients with HPV+ OPSCC and identified a signature associated with poor treatment response. This signature has potential to inform treatment of patients with HPV+ OPSCC, thereby reducing radiation for those with low-risk disease.
Polymyxin B (PMB) is a potent antibiotic that is used for treating life-threatening Gram-negative infections; however, PMB is considered a last line of defense due to dose-limiting nephrotoxicity. Analogs of PMB are being developed with the goal of retaining antibiotic activity while reducing drug toxicity, which is challenging to determine in preclinical animal models. In this episode, Edward Kelly and colleagues use a microphysiological system to model the human kidney proximal tubule to evaluate the toxicity of PMB and two structural polymyxin analogs. The results of this study indicate that organ on chip systems have high potential for drug toxicity screening and for elucidating mechanisms of toxicity.
Fibrosis is characterized by excess ECM deposition and occurs in a variety of organ systems, resulting in reduced function and possible failure. Therapeutic strategies for limiting and preventing fibrosis are lacking, and drivers of this pathogenic response are not fully understood. In this episode, Manuel Mayr and colleagues used a proteomic approach to evaluate the effect of targeting microRNA-21 (miR-21), which has been implicated in the fibrogenic response. While inhibition of miR-21 did not markedly alter ECM deposition, reduction of miR-21 limited the release of TGF-β1 and other profibrotic factors from platelets. These results provide a previously unrecognized mechanism for the known antifibrotic effects of miR-21 inhibition.
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by progressive demyelination and disability. Epstein-Barr (EBV) virus has been implicated in the pathogenesis of MS, as high anti-EBV titers have been reported in patients with MS. In this episode, Michael Pender and Rajiv Khanna discuss the results of an open-label, dose escalation trial designed to evaluate the safety and efficacy of adoptively transferred in vitro-expanded EBV-specific T cells for patients with progressive MS. Clinical improvement was seen 7 of the 10 patients, with the greatest benefit for patients that received T cells with strong EBV reactivity. The results from this initial trial indicate that the EBV-specific adoptive T cell therapy is well tolerated and support further investigation of this approach in efficacy trials.
Patients with J wave syndromes (JWS), such as Brugada syndrome and early repolarization syndrome are vulnerable to life-threatening ventricular arrhythmias. Factors that promote JWS are not fully understood and models of the disease are limited. In this episode, Mu Chen and Peng-Sheng Chen describe their work, which shows that activation small-conductance calcium-activated potassium (SK) current (IKAS) in conjunction with inhibition of the sodium current with CyPPA induces JWS-associated phenotypes in perfused rabbit hearts. Moreover, inhibition of IKAS in this model eliminated JWS-like manifestations. The results of this study provide important insight into the drivers of JWS and suggest that IKAS inhibition be further explored for JWS.