Citations

Abstract Despite the tremendous success of the classical “isolate, inactivate, and inject” approach to vaccine development, new breakthroughs in vaccine research are increasingly reliant on novel approaches that incorporate cutting edge technology and advances in innate and adaptive immunology, microbiology, virology, pathogen biology, genetics, bioinformatics, and many other disciplines in order to: (1) deepen our understanding of the key biological processes that lead to protective immunity, (2) observe vaccine responses on a global, systems level, and (3) directly apply the new knowledge gained to the development of next-generation vaccines with improved safety profiles, enhanced efficacy, and even targeted utility in select populations. Here we highlight five key components foundational to vaccinomics efforts: applied immunogenomics, next generation sequencing and other cutting-edge “omics” technologies, advanced bioinformatics and analysis techniques, and finally, systems biology applied to immune profiling and vaccine responses. We believe these “game changers” will play a critical role in moving us toward the rational and directed development of new vaccines in the 21st century.

Abstract Purpose: Inherited variability in the prognosis of lung cancer patients treated with platinum-based chemotherapy has been widely investigated. However, the overall contribution of genetic variation to platinum response is not well established. To identify novel candidate single nucleotide polymorphisms (SNP)/genes, we carried out a genome-wide association study (GWAS) for cisplatin cytotoxicity by using lymphoblastoid cell lines (LCL), followed by an association study of selected SNPs from the GWAS with overall survival (OS) in lung cancer patients. Experimental Design: A GWAS for cisplatin was conducted with 283 ethnically diverse LCLs. A total of 168 top SNPs were genotyped in 222 small cell lung cancer (SCLC) and 961 non-SCLC (NSCLC) patients treated with platinum-based therapy. Association of the SNPs with OS was determined by using the Cox regression model. Selected candidate genes were functionally validated by siRNA knockdown in human lung cancer cells. Results: Among 157 successfully genotyped SNPs, 9 and 10 SNPs were top SNPs associated with OS for patients with NSCLC and SCLC, respectively, although they were not significant after adjusting for multiple testing. Fifteen genes, including 7 located within 200 kb up or downstream of the 4 top SNPs and 8 genes for which expression was correlated with 3 SNPs in LCLs were selected for siRNA screening. Knockdown of DAPK3 and METTL6, for which expression levels were correlated with the rs11169748 and rs2440915 SNPs, significantly decreased cisplatin sensitivity in lung cancer cells. Conclusions: This series of clinical and complementary laboratory-based functional studies identified several candidate genes/SNPs that might help predict treatment outcomes for platinum-based therapy of lung cancer. Clin Cancer Res; 17(17); 5801–11. ©2011 AACR.

Abstract In this article we define vaccinomics as the integration of immunogenetics and immunogenomics with systems biology and immune profiling. Vaccinomics is based on the use of cutting edge, high-dimensional (so called “omics”) assays and novel bioinformatics approaches to the development of next-generation vaccines and the expansion of our capabilities in individualized medicine. Vaccinomics will allow us to move beyond the empiric “isolate, inactivate, and inject” approach characterizing past vaccine development efforts, and toward a more detailed molecular and systemic understanding of the carefully choreographed series of biological processes involved in developing viral vaccine-induced “immunity.” This enhanced understanding will then be applied to overcome the obstacles to the creation of effective vaccines to protect against pathogens, particularly hypervariable viruses, with the greatest current impact on public health. Here we provide an overview of how vaccinomics will inform vaccine science, the development of new vaccines and/or clinically relevant biomarkers or surrogates of protection, vaccine response heterogeneity, and our understanding of immunosenescence.

ABSTRACT Introduction Priapism describes a persistent erection lasting longer than 4 hours. Ischemic priapism and stuttering priapism are phenotypic manifestations of sickle-cell disease (SCD). Aims To define the types of priapism associated with SCD, to address pathogenesis, and to recommend best practices. Sources Literature review and published clinical guidelines. Summary of Findings Priapism is a full or partial erection that persists more than 4 hours. There are three kinds of priapism: ischemic priapism (veno-occlusive, low flow), stuttering priapism (recurrent ischemic priapism), and nonischemic priapism (arterial, high flow). Ischemic priapism is a pathologic phenotype of SCD. Ischemic priapism is a urologic emergency when untreated priapism results in corporal fibrosis and erectile dysfunction. The recommended treatment for ischemic priapism is decompression of the penis by needle aspiration and if needed, injection (or irrigation) with dilute sympathomimetic drugs. Stuttering priapism describes a pattern of recurring unwanted painful erections in men with SCD. Patients typically awaken with an erection that persists for several hours and becomes painful. The goals of managing stuttering ischemic priapism are: prevention of future episodes, preservation of erectile function, and balancing the risks vs. benefits of various treatment options. The current molecular hypothesis for stuttering priapism in SCD proposes that insufficient basal levels of phosphodiesterase type-5 are available in the corpora to degrade cyclic guanosine monophosphate (cGMP). Nocturnal erections result from normal neuronal production and surges of cGMP. In the context of SCD stuttering priapism, these nocturnal surges in cGMP go unchecked, resulting in stuttering priapism. Conclusions Considering the embarrassing nature of the problem and the dire consequences to erectile function, it is important to inform patients, parents, and providers about the relationship of SCD to prolonged painful erections. Prompt diagnosis and appropriate medical management of priapism are necessary to spare patients surgical interventions and preserve erectile function.

Background: Cortical spreading depression (CSD) is a wave of depolarization followed by depression of bioelectrical activity that slowly propagates through the cortex. CSD is believed to be the underlying mechanism of aura in migraine; however, whether CSD can elicit pain associated with migraine headache is unclear. Methods: Awake, freely moving rats were monitored for both CSD events and behavioral responses resulting from dural-cortical pinprick and/or KCl injection to the occipital cortex. Results: We observed tactile allodynia of the face and hindpaws, as well as enhanced Fos expression within the trigeminal nucleus caudalis (TNC) following CSD induced by KCl injection into the cortex, but not by pinprick. Application of KCl onto the dura elicited cutaneous allodynia and increased Fos staining in the TNC but did not elicit CSD events. Conclusions: These data suggest that sustained activation of trigeminal afferents that may be required to establish cutaneous allodynia may not occur following CSD events in normal animals.

The study of hemodynamic alterations following the creation of an arteriovenous fistula (AVF) is relevant to vascular adaptive responses and hemodialysis access dysfunction. This study examined such alterations in a murine AVF created by anastomosing the carotid artery to the jugular vein. AVF blood flow was markedly increased due to reduced AVF vascular resistance. Despite such markedly increased basal blood flow, AVF blood flow further increased in response to acetylcholine. This AVF model exhibited increased cardiac output and decreased systemic vascular resistance; the kidney, in contrast, exhibited decreased blood flow and increased vascular resistance. Augmentation in AVF blood flow was attended by increased arterial heme oxygenase-1 (HO-1) mRNA and protein expression, the latter localized to smooth muscle cells of the AVF artery; AVF blood flow was substantially reduced in HO-1−/− mice compared with HO-1+/+ mice. Finally, in a murine model of a representative disease known to exhibit impaired hemodynamic responses (sickle cell disease), the creation of an AVF was attended by decreased AVF flow and impaired AVF function. We conclude that this AVF model exhibits markedly increased AVF blood flow, a vasodilatory reserve capacity, increased cardiac output, decreased renal blood flow, and a dependency on intact hemodynamic responses, in general, and HO-1 expression, in particular, in achieving and maintaining AVF blood flow. We suggest that these findings support the utility of this model in investigating the basis for and the consequences of hemodynamic stress, including shear stress, and the pathobiology of hemodialysis AVF dysfunction.