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Bovine viral diarrhea virus (BVDV) plays a key role in bovine respiratory disease complex, which can lead to pneumonia, diarrhea and death of calves. Current vaccines are not very effective due, in part, to immunosuppressive traits and failure to induce broad protection. There are diverse BVDV strains and thus, current vaccines contain representative genotype 1 and 2 viruses (BVDV-1 & 2) to broaden coverage. BVDV modified live virus (MLV) vaccines are superior to killed virus vaccines, but they are susceptible to neutralization and complement-mediated destruction triggered by passively acquired antibodies, thus limiting their efficacy. We generated three novel mosaic polypeptide chimeras, designated NproE2123; NS231; and NS232, which incorporate protective determinants that are highly conserved among BVDV-1a, 1b, and BVDV-2 genotypes. In addition, strain-specific protective antigens from disparate BVDV strains were included to broaden coverage. We confirmed that adenovirus constructs expressing these antigens were strongly recognized by monoclonal antibodies, polyclonal sera, and IFN-γ-secreting T cells generated against diverse BVDV strains. In a proof-of-concept efficacy study, the multi-antigen proto-type vaccine induced higher, but not significantly different, IFN-γ spot forming cells and T-cell proliferation compared to a commercial MLV vaccine. In regards to the humoral response, the prototype vaccine induced higher BVDV-1 specific neutralizing antibody titers, whereas the MLV vaccine induced higher BVDV-2 specific neutralizing antibody titers. Following BVDV type 2a (1373) challenge, calves immunized with the proto-type or the MLV vaccine had lower clinical scores compared to naïve controls. These results support the hypothesis that a broadly protective subunit vaccine can be generated using mosaic polypeptides that incorporate rationally selected and validated protective determinants from diverse BVDV strains. Furthermore, regarding biosafety of using a live vector in cattle, we showed that recombinant human adenovirus-5 was cleared within one week following intradermal inoculation.

Breast cancer is a common health problem affecting 20% of population. One of the risk factors affecting the causation of development of breast cancer is the environmental pollution by chemical and radiation . The presumptive theory lying behind is that ionizing radiation has genotoxic affect causing damage to DNA and mutation with gene alteration that increase the risk in both male and female The breast cancer risk includes being female ,getting older ,and DNA mutation .the study was carried out in Al-wasity secondary school to detect the existence of chemical and radiological remnants of stored weapons during the Iraqi war [2003] using inspector [1000] that detect harmful radiation as gamma rays ,neutron ,and radon ,it was clear that no radiation was detected above the normally and internationally allowed levels in the field of the study .so it is wise to look for other relevant risk factors that may be related to the causation of the ca.breast.

Abstract Synthetized by the liver and metabolized by the gut microbiota, BA are involved in metabolic liver diseases that are associated with cardiovascular disorders. Animal models of atheroma documented a powerful anti-atherosclerotic effect of bile acids (BA). This prospective study examined whether variations in circulating BA are predictive of coronary artery disease (CAD) in human. Consecutive patients undergoing coronary angiography were enrolled. Circulating and fecal BA were measured by high pressure liquid chromatography and tandem mass spectrometry. Of 406 screened patients, 80 were prospectively included and divided in two groups with (n = 45) and without (n = 35) CAD. The mean serum concentration of total BA was twice lower in patients with, versus without CAD (P = 0.005). Adjusted for gender and age, this decrease was an independent predictor of CAD. In a subgroup of 17 patients, statin therapy doubled the serum BA concentration. Decreased serum concentrations of BA were predictors of CAD in humans. A subgroup analysis showed a possible correction by statins. With respect to the anti-atherosclerotic effect of BA in animal models, and their role in human lipid metabolism, this study describe a new metabolic disturbance associated to CAD in human.

Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.

Patients with myotonic dystrophy (MD) suffer from severe cardiac issues of unknown aetiology. Freyermuth et al. show that fatal changes in cardiac electrophysiological properties in humans and mice with MD may arise from misregulation of the alternative splicing of the cardiac Na+ channel SCN5Atranscript, resulting in expression of its fetal form.

Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. We designed this study to determine the prevalence of left bundle branch block (LBBB), whether there is a relationship between LBBB and genetic pattern, and to assess predictive factors for acute cardiac events and mortality in adult DMD patients.We reviewed the charts of DMD followed at the Home Mechanical Ventilation Unit of the Raymond Poincare University Hospital.A total of 121 patients, aged from 18 to 41 years have been included in our study. Median vital capacity (VC) was 12% [7; 19.5] of predicted. Almost all patients were on home mechanical ventilation (95%). LBBB was present in 15 patients (13%); among them, 10 disclosed exonic deletions. After a median follow up of 6 years, 21 patients (17%) experienced acute heart failure (AHF), 7 patients (6%) supraventricular arrhythmia, 3 patients (2.4%) ventricular tachycardia, 4 patients (3%) significant electrical disturbances. LBBB was significantly associated with cardiac events (OR = 12.7; 95%CI [3.78-42.7]; p

[This corrects the article DOI: 10.1371/journal.pone.0116388.].

BACKGROUND:Type 2C and 2D limb girdle muscular dystrophies (LGMD) are a group of autosomal recessive limb girdle muscular dystrophies manifested by proximal myopathy, impaired respiratory muscle function and cardiomyopathy. The correlation and the prognostic impact of respiratory and heart impairment are poorly described. We aimed to describe the long-term cardiac and respiratory follow-up of these patients and to determine predictive factors of cardio-respiratory events and mortality in LGMD 2C and 2D. METHODS:We reviewed the charts of 34 LGMD patients, followed from 2005 to 2015, to obtain echocardiographic, respiratory function and sleep recording data. We considered respiratory events (acute respiratory failure, pulmonary sepsis, atelectasis or pneumothorax), cardiac events (acute heart failure, significant cardiac arrhythmia or conduction block, ischemic stroke) and mortality as outcomes of interest for the present analysis. RESULTS:A total of 21 patients had type 2C LGMD and 13 patients had type 2D. Median age was 30 years [IQR 24-38]. At baseline, median pulmonary vital capacity (VC) was 31% of predicted value [20-40]. Median maximal inspiratory pressure (MIP) was 31 cmH2O [IQR 20.25-39.75]. Median maximal expiratory pressure (MEP) was 30 cm H2O [20-36]. Median left ventricular ejection fraction (LVEF) was 55% [45-64] with 38% of patients with LVEF

Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM's and MAPKAPK's in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.

Researchers are currently seeking relevant lung cancer biomarkers in order to make informed decisions regarding therapeutic selection for patients in so-called "precision medicine." However, there are challenges to obtaining adequate lung cancer tissue for molecular analyses. Furthermore, current molecular testing of tumors at the genomic or transcriptomic level are very indirect measures of biological response to a drug, particularly for small molecule inhibitors that target kinases. Kinase activity profiling is therefore theorized to be more reflective of in vivo biology than many current molecular analysis techniques. As a result, this study seeks to prove the feasibility of combining a novel minimally invasive biopsy technique that expands the number of lesions amenable for biopsy with subsequent ex vivo kinase activity analysis.Eight patients with lung lesions of varying location and size were biopsied using the novel electromagnetic navigational bronchoscopy (ENB) technique. Basal kinase activity (kinomic) profiles and ex vivo interrogation of samples in combination with tyrosine kinase inhibitors erlotinib, crizotinib, and lapatinib were performed by PamStation 12 microarray analysis.Kinomic profiling qualitatively identified patient specific kinase activity profiles as well as patient and drug specific changes in kinase activity profiles following exposure to inhibitor. Thus, the study has verified the feasibility of ENB as a method for obtaining tissue in adequate quantities for kinomic analysis and has demonstrated the possible use of this tissue acquisition and analysis technique as a method for future study of lung cancer biomarkers.We demonstrate the feasibility of using ENB-derived biopsies to perform kinase activity assessment in lung cancer patients.

We have recently cloned a novel splice variant of cyclin D2 termed as cycD2SV. CycD2SV overexpression in several immortalized cell lines led to formation of ubiquitinated protein aggregates accompanied by a significant decrease in cell proliferation. Based on immuno co-localization and ultrastructural analysis experiments, cycD2SV protein aggregates were frequently found in various subcellular compartments such as endosomes, autophagosomes, lysosomes and the microtubule organizing centre. Secondary structure analysis revealed that the amino terminal α-helix in cycD2SV is not tightly packed with the cyclin box suggesting a misfolded conformation compared to other cyclins. Deletion analysis suggests that 1-53 amino acid region of cycD2SV may be required for protein aggregation and 54-136 amino acid region may mediate cell cycle inhibition. Based on co-immunoprecipitation experiments, we have shown that cycD2SV binds to cycD2 as well as CDK4. In addition, gene expression analysis demonstrated an upregulation in GADD45α and dynamin 2 mRNA levels in cycD2SV overexpressing cells. These two proteins are known to play critical roles in the DNA damage response and apoptosis pathways. TUNEL experiments were negative for apoptosis, however, cycD2SV expressing cells were more sensitive to cell death induced by external stressors such as trypsinization. Collectively our results suggest that cycD2SV mediates cell cycle inhibition by sequestering endogenous cell cycle proteins, such as cycD2 and CDK4, and possibly targeting them for ubiquitin mediated protein degradation.