Mannosylated linear and cyclic single amino acid mutant peptides using a small 10 amino acid linker constitute promising candidates against Multiple Sclerosis

Multiple sclerosis (MS) is a serious autoimmune demyelinating disease leading to loss of neurological function. The design and synthesis of various altered peptide ligands (APLs) of immunodominant epitopes of myelin proteins to alter the autoimmune response, is a promising therapeutic approach for MS. In this study, linear and cyclic peptide analogues based on the myelin basic protein 83-99 (MBP83-99) immunodominant epitope conjugated to reduced mannan via the (KG)5 and KLH bridge respectively, were evaluated for their biological/immunological profiles in SJL/J mice. Of all the peptide analogues tested, linear MBP83-99(F91) and linear MBP83-99(Y91) conjugated to reduced mannan via a (KG)5 linker and cyclic MBP83-99(F91) conjugated to reduce mannan via KLH linker, yielded the best immunological profile and constitute novel candidates for further immunotherapeutic studies against MS in animal models and in human clinical trials

Central gene expression changes associated with enhanced neuroendocrine and autonomic response habituation to repeated noise stress after voluntary wheel running in rats

Accumulating evidence indicates that regular physical exercise benefits health in part by counteracting some of the negative physiological impacts of stress. While some studies identified reductions in some measures of acute stress responses with prior exercise, limited data were available concerning effects on cardiovascular function, and reported effects on HPA axis responses were largely inconsistent. Given that exposure to repeated or prolonged stress is strongly implicated in the precipitation and exacerbation of illness, we proposed the novel hypothesis that physical exercise might facilitate adaptation to repeated stress, and subsequently demonstrated significant enhancement of both HPA axis (glucocorticoid) and cardiovascular (tachycardia) response habituation to repeated noise stress in rats with long-term access to running wheels compared to sedentary controls. Stress habituation has been attributed to modifications of brain circuits, but the specific sites of adaptation and the molecular changes driving its expression remain unclear. Here, in situ hybridization histochemistry was used to examine regulation of select stress-associated signaling systems in brain regions representing likely candidates to underlie exercise-enhanced stress habituation. Analyzed brains were collected from active (6 weeks of wheel running) and sedentary rats following control, acute, or repeated noise exposures that induced a significantly faster rate of glucocorticoid response habituation in active animals but preserved acute noise responsiveness. Nearly identical experimental manipulations also induce a faster rate of cardiovascular response habituation in exercised, repeatedly stressed rats. The observed regulation of the corticotropin-releasing factor and brain-derived neurotrophic factor systems across several brain regions suggests widespread effects of voluntary exercise on central functions and related adaptations to stress across multiple response modalities

Episensitization: Defying Time’s Arrow

The development of cancer is driven by complex genetic and epigenetic changes that result in aberrant and uncontrolled cellular growth. Epigenetic changes, in particular, are implicated in the silencing or activation of key genes that control cellular growth and apoptosis and contribute to transformative potential. The purpose of this review is to define and assess the treatment strategy of episensitization, or the ability to sensitize cancer cells to subsequent therapy by resetting the epigenetic infrastructure of the tumor. One important facet is resensitization by epigenetic mechanisms, which goes against the norm, i.e., challenges the long-held doctrine in oncology that the reuse of previously tried and failed therapies is a clinically pointless endeavor. Thus, episensitization is a hybrid term, which covers recent clinically relevant observations and refers to the epigenomic mechanism of resensitization. Among the many formidable challenges in the treatment of cancer, the most inevitable is the development of acquired therapeutic resistance. Here, we present the basic principles behind episensitization and highlight the evidence suggesting that epigenetically mediated histone hypoacetylation and DNA hypermethylation events may reverse clinical drug resistance. The potential reversibility of epigenetic changes and the microenvironmental impact of epigenetic control on gene expression may mediate a return to a baseline state of treatment susceptibility. Episensitization is a novel and highly practical management strategy both to prevent the practice of permanent treatment discontinuation with the occurrence of resistance, which rapidly exhausts remaining options in the pharmaceutical armamentarium and to significantly extend patient survival. Accordingly, this review highlights several epigenetic agents including decitabine, vorinostat, entinostat, 5-azacitidine, oncolytic viruses and RRx-001

Optogenetic stimulation of VTA dopamine neurons reveals that tonic but not phasic patterns of dopamine transmission reduce ethanol self-administration

There is compelling evidence that acute ethanol exposure stimulates ventral tegmental area (VTA) dopamine cell activity and that VTA-dependent dopamine release in terminal fields within the nucleus accumbens plays an integral role in the regulation of ethanol drinking behaviors. Unfortunately, due to technical limitations, the specific temporal dynamics linking VTA dopamine cell activation and ethanol self-administration are not known. In fact, establishing a causal link between specific patterns of dopamine transmission and ethanol drinking behaviors has proven elusive. Here, we sought to address these gaps in our knowledge using a newly developed viral-mediated gene delivery strategy to selectively express Channelrhodopsin-2 (ChR2) on dopamine cells in the VTA of wild-type rats. We then used this approach to precisely control VTA dopamine transmission during voluntary ethanol drinking sessions. The results confirmed that ChR2 was selectively expressed on VTA dopamine cells and delivery of blue light pulses to the VTA induced dopamine release in accumbal terminal fields with very high temporal and spatial precision. Brief high frequency VTA stimulation induced phasic patterns of dopamine release in the nucleus accumbens. Lower frequency stimulation, applied for longer periods mimicked tonic increases in accumbal dopamine. Notably, using this optogenetic approach in rats engaged in an intermittent ethanol drinking procedure, we found that tonic, but not phasic, stimulation of VTA dopamine cells selectively attenuated ethanol drinking behaviors. Collectively, these data demonstrate the effectiveness of a novel viral targeting strategy that can be used to restrict opsin expression to dopamine cells in standard outbred animals and provide the first causal evidence demonstrating that tonic activation of VTA dopamine neurons selectively decreases ethanol self-administration behaviors

Estimation of cell-type composition including T and B cell subtypes for whole blood methylation microarray data

DNA methylation levels vary markedly by cell-type makeup of a sample. Understanding these differences and estimating the cell-type makeup of a sample is an important aspect of studying DNA methylation. DNA from leukocytes in whole blood is simple to obtain and pervasive in research. However, leukocytes contain many distinct cell types and subtypes. We propose a two-stage model that estimates the proportions of 6 main cell types in whole blood (CD4+ T cells, CD8+ T cells, monocytes, B cells, granulocytes, and natural killer cells) as well as subtypes of T and B cells. Unlike previous methods that only estimate overall proportions of CD4+ T cell, CD8+ T cells, and B cells, our model is able to estimate proportions of naïve, memory, and regulatory CD4+ T cells as well as naïve and memory CD8+ T cells and naïve and memory B cells. Using real and simulated data, we are able to demonstrate that our model is able to reliably estimate proportions of these cell types and subtypes. In studies with DNA methylation data from Illumina’s HumanMethylation450k arrays, our estimates will be useful both for testing for associations of cell type and subtype composition with phenotypes of interest as well as for adjustment purposes to prevent confounding in epigenetic association studies. Additionally, our method can be easily adapted for use with whole genome bisulfite sequencing data or any other genome-wide methylation data platform

Volume Modulated Arc Therapy (VMAT) for pulmonary Stereotactic Body Radiotherapy (SBRT) in patients with lesions in close approximation to the chest wall

Chest wall pain and discomfort has been recognized as a significant late effect of radiation therapy in historical and modern treatment models. Stereotactic Body Radiotherapy (SBRT) is becoming an important treatment tool in oncology care for patients with intrathoracic lesions. For lesions in close approximation to the chest wall including lesions requiring motion management, SBRT techniques can deliver high dose to the chest wall. As an unintended target of consequence, there is possibility of generating significant chest wall pain and discomfort as a late effect of therapy. The purpose of this paper is to evaluate the potential role of Volume Modulated Arc Therapy (VMAT) technologies in decreasing chest wall dose in SBRT treatment of pulmonary lesions in close approximation to the chest wall.Ten patients with pulmonary lesions of various sizes and topography in close approximation to the chest wall were selected for retrospective review. All volumes including target, chest wall, ribs, and lung were contoured with maximal intensity projection maps and four-dimensional computer tomography planning. Radiation therapy planning consisted of static techniques including Intensity Modulated Radiation Therapy compared to VMAT therapy to a dose of 60Gy in 12Gy fractions. Dose volume histogram to rib, chest wall, and lung were compared between plans with statistical analysis.In all patients dose and volume were improved to ribs and chest wall using VMAT technologies compared to static field techniques. On average, volume receiving 30Gy to the chest wall was improved by 72%;the ribs by 60%. In only one patient did the VMAT treatment technique increase pulmonary volume receiving 20Gy (V20).VMAT technology has potential of limiting radiation dose to sensitive chest wall regions in patients with lesions in close approximation to this structure. This would also have potential value to lesions treated with SBRT in other body regions where targets abut critical structures