Oncolytic virotherapy induced CSDE1 neo-antigenesis restricts VSV replication but can be targeted by immunotherapy

In our clinical trials of oncolytic vesicular stomatitis virus expressing interferon beta (VSV-IFNβ), several patients achieved initial responses followed by aggressive relapse. We show here that VSV-IFNβ-escape tumors predictably express a point-mutated CSDE1P5S form of the RNA-binding Cold Shock Domain-containing E1 protein, which promotes escape as an inhibitor of VSV replication by disrupting viral transcription. Given time, VSV-IFNβ evolves a compensatory mutation in the P/M Inter-Genic Region which rescues replication in CSDE1P5S cells. These data show that CSDE1 is a major cellular co-factor for VSV replication. However, CSDE1P5S also generates a neo-epitope recognized by non-tolerized T cells. We exploit this predictable neo-antigenesis to drive, and trap, tumors into an escape phenotype, which can be ambushed by vaccination against CSDE1P5S, preventing tumor escape. Combining frontline therapy with escape-targeting immunotherapy will be applicable across multiple therapies which drive tumor mutation/evolution and simultaneously generate novel, targetable immunopeptidomes associated with acquired treatment resistance

Cardiovascular health and particulate vehicular emissions: a critical evaluation of the evidence

A major public health goal is to determine linkages between specific pollution sources and adverse health outcomes. This paper provides an integrative evaluation of the database examining effects of vehicular emissions, such as black carbon (BC), carbonaceous gasses, and ultrafine PM, on cardiovascular (CV) morbidity and mortality. Less than a decade ago, few epidemiological studies had examined effects of traffic emissions specifically on these health endpoints. In 2002, the first of many studies emerged finding significantly higher risks of CV morbidity and mortality for people living in close proximity to major roadways, vs. those living further away. Abundant epidemiological studies now link exposure to vehicular emissions, characterized in many different ways, with CV health endpoints such as cardiopulmonary and ischemic heart disease and circulatory-disease-associated mortality; incidence of coronary artery disease; acute myocardial infarction; survival after heart failure; emergency CV hospital admissions; and markers of atherosclerosis. We identify numerous in vitro, in vivo, and human panel studies elucidating mechanisms which could explain many of these cardiovascular morbidity and mortality associations. These include: oxidative stress, inflammation, lipoperoxidation and atherosclerosis, change in heart rate variability (HRV), arrhythmias, ST-segment depression, and changes in vascular function (such as brachial arterial caliber and blood pressure). Panel studies with accurate exposure information, examining effects of ambient components of vehicular emissions on susceptible human subjects, appear to confirm these mechanisms. Together, this body of evidence supports biological mechanisms which can explain the various CV epidemiological findings. Based upon these studies, the research base suggests that vehicular emissions are a major environmental cause of cardiovascular mortality and morbidity in the United States. As a means to reduce the public health consequences of such emissions, it may be desirable to promulgate a black carbon (BC) PM2.5 standard under the National Ambient Air Quality Standards, which would apply to both on and off-road diesels. Two specific critical research needs are identified. One is to continue research on health effects of vehicular emissions, gaseous as well as particulate. The second is to utilize identical or nearly identical research designs in studies using accurate exposure metrics to determine whether other major PM pollutant sources and types may also underlie the specific health effects found in this evaluation for vehicular emissions

State of the art of immunoassay methods for B-type natriuretic peptides: An update

The aim of this review article is to give an update on the state of the art of the immunoassay methods for the measurement of B-type natriuretic peptide (BNP) and its related peptides. Using chromatographic procedures, several studies reported an increasing number of circulating peptides related to BNP in human plasma of patients with heart failure. These peptides may have reduced or even no biological activity. Furthermore, other studies have suggested that, using immunoassays that are considered specific for BNP, the precursor of the peptide hormone, proBNP, constitutes a major portion of the peptide measured in plasma of patients with heart failure. Because BNP immunoassay methods show large (up to 50%) systematic differences in values, the use of identical decision values for all immunoassay methods, as suggested by the most recent international guidelines, seems unreasonable. Since proBNP significantly cross-reacts with all commercial immunoassay methods considered specific for BNP, manufacturers should test and clearly declare the degree of cross-reactivity of glycosylated and non-glycosylated proBNP in their BNP immunoassay methods. Clinicians should take into account that there are large systematic differences between methods when they compare results from different laboratories that use different BNP immunoassays. On the other hand, clinical laboratories should take part in external quality assessment (EQA) programs to evaluate the bias of their method in comparison to other BNP methods. Finally, the authors believe that the development of more specific methods for the active peptide, BNP1–32, should reduce the systematic differences between methods and result in better harmonization of results