Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups

Functional Dichotomy between NKG2D and CD28-Mediated Co-Stimulation in Human CD8+ T Cells

Both CD28 and NKG2D can function as co-stimulatory receptors in human CD8+ T cells. However, their independent functional contributions in distinct CD8+ T cell subsets are not well understood. In this study, CD8+ T cells in human peripheral blood- and lung-derived lymphocytes were analyzed for CD28 and NKG2D expression and function. We found a higher level of CD28 expression in PBMC-derived naïve (CD45RA+CD27+) and memory (CD45RA−CD27+) CD8+ T cells (CD28Hi), while its expression was significantly lower in effector (CD45RA+CD27−) CD8+ T cells (CD28Lo). Irrespective of the differences in the CD28 levels, NKG2D expression was comparable in all three CD8+ T cell subsets. CD28 and NKG2D expressions followed similar patterns in human lung-resident GILGFVFTL/HLA-A2-pentamer positive CD8+ T cells. Co-stimulation of CD28Lo effector T cells via NKG2D significantly increased IFN-γ and TNF-α levels. On the contrary, irrespective of its comparable levels, NKG2D-mediated co-stimulation failed to augment IFN-γ and TNF-α production in CD28Hi naïve/memory T cells. Additionally, CD28-mediated co-stimulation was obligatory for IL-2 generation and thereby its production was limited only to the CD28Hi naïve/memory subsets. MICA, a ligand for NKG2D was abundantly expressed in the tracheal epithelial cells, validating the use of NKG2D as the major co-stimulatory receptor by tissue-resident CD8+ effector T cells. Based on these findings, we conclude that NKG2D may provide an expanded level of co-stimulation to tissue-residing effector CD8+ T cells. Thus, incorporation of co-stimulation via NKG2D in addition to CD28 is essential to activate tumor or tissue-infiltrating effector CD8+ T cells. However, boosting a recall immune response via memory CD8+ T cells or vaccination to stimulate naïve CD8+ T cells would require CD28-mediated co-stimulation

Red blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb.

Myocardial ischemia is one of the leading health problems worldwide. Therapy consists of the restitution of coronary perfusion which is followed by myocardial inflammation. Platelet-neutrophil interaction is a crucial process during inflammation, yet its consequences are not fully understood. Here, we show that platelet-neutrophil complexes (PNCs) are increased in patients with acute myocardial infarction and that this is associated with increased levels of neuronal guidance protein semaphorin 7A (SEMA7A). To investigate this further, we injected WT animals with Sema7a and found increased infarct size with increased numbers of PNCs. Experiments in genetically modified animals identify Sema7a on red blood cells to be crucial for this condition. Further studies revealed that Sema7a interacts with the platelet receptor glycoprotein Ib (GPIb). Treatment with anti-Sema7a antibody protected from myocardial tissue injury. In summary, we show that Sema7a binds to platelet GPIb and enhances platelet thrombo-inflammatory activity, aggravating post-ischemic myocardial tissue injury

Quantitative copy number analysis by Multiplex Ligation-dependent Probe Amplification (MLPA) of BRCA1-associated breast cancer regions identifies BRCAness

Our group has previously employed array Comparative Genomic Hybridization (aCGH) to assess the genomic patterns of BRCA1-mutated breast cancers. We have shown that the so-called BRCA1-like(aCGH) profile is also present in about half of all triple-negative sporadic breast cancers and is predictive for benefit from intensified alkylating chemotherapy. As aCGH is a rather complex method, we translated the BRCA1(aCGH) profile to a Multiplex Ligation-dependent Probe Amplification (MLPA) assay, to identify both BRCA1-mutated breast cancers and sporadic cases with a BRCA1-like(aCGH) profile. The most important genomic regions of the original aCGH based classifier (3q22-27, 5q12-14, 6p23-22, 12p13, 12q21-23, 13q31-34) were mapped to a set of 34 MLPA probes. The training set consisted of 39 BRCA1-like(aCGH) breast cancers and 45 non-BRCA1-like(aCGH) breast cancers, which had previously been analyzed by aCGH. The BRCA1-like(aCGH) group consisted of germline BRCA1-mutated cases and sporadic tumours with low BRCA1 gene expression and/or BRCA1 promoter methylation. We trained a shrunken centroids classifier on the training set and validation was performed on an independent test set of 40 BRCA1-like(aCGH) breast cancers and 32 non-BRCA1-like(aCGH) breast cancer tumours. In addition, we validated the set prospectively on 69 new triple-negative tumours. BRCAness in the training set of 84 tumours could accurately be predicted by prediction analysis of microarrays (PAM) (accuracy 94%). Application of this classifier on the independent validation set correctly predicted BRCA-like status of 62 out of 72 breast tumours (86%). Sensitivity and specificity were 85% and 87%, respectively. When the MLPA-test was subsequently applied to 46 breast tumour samples from a randomized clinical trial, the same survival benefit for BRCA1-like tumours associated with intensified alkylating chemotherapy was shown as was previously reported using the aCGH assay. Since the MLPA assay can identify BRCA1-deficient breast cancer patients, this method could be applied both for clinical genetic testing and as a predictor of treatment benefit. BRCA1-like tumours are highly sensitive to chemotherapy with DNA damaging agents, and most likely to poly ADP ribose polymerase (PARP)-inhibitors. The MLPA assay is rapid and robust, can easily be multiplexed, and works well with DNA derived from paraffin-embedded tissue

The kinome of Phytophthora infestans reveals oomycete-specific innovations and links to other taxonomic groups

<p>Abstract</p> <p>Background</p> <p>Oomycetes are a large group of economically and ecologically important species. Its most notorious member is <it>Phytophthora infestans</it>, the cause of the devastating potato late blight disease. The life cycle of <it>P. infestans </it>involves hyphae which differentiate into spores used for dispersal and host infection. Protein phosphorylation likely plays crucial roles in these stages, and to help understand this we present here a genome-wide analysis of the protein kinases of <it>P. infestans </it>and several relatives. The study also provides new insight into kinase evolution since oomycetes are taxonomically distant from organisms with well-characterized kinomes.</p> <p>Results</p> <p>Bioinformatic searches of the genomes of <it>P. infestans</it>, <it>P. ramorum</it>, and <it>P. sojae </it>reveal they have similar kinomes, which for <it>P. infestans </it>contains 354 eukaryotic protein kinases (ePKs) and 18 atypical kinases (aPKs), equaling 2% of total genes. After refining gene models, most were classifiable into families seen in other eukaryotes. Some ePK families are nevertheless unusual, especially the tyrosine kinase-like (TKL) group which includes large oomycete-specific subfamilies. Also identified were two tyrosine kinases, which are rare in non-metazoans. Several ePKs bear accessory domains not identified previously on kinases, such as cyclin-dependent kinases with integral cyclin domains. Most ePKs lack accessory domains, implying that many are regulated transcriptionally. This was confirmed by mRNA expression-profiling studies that showed that two-thirds vary significantly between hyphae, sporangia, and zoospores. Comparisons to neighboring taxa (apicomplexans, ciliates, diatoms) revealed both clade-specific and conserved features, and multiple connections to plant kinases were observed. The kinome of <it>Hyaloperonospora arabidopsidis</it>, an oomycete with a simpler life cycle than <it>P. infestans</it>, was found to be one-third smaller. Some differences may be attributable to gene clustering, which facilitates subfamily expansion (or loss) through unequal crossing-over.</p> <p>Conclusion</p> <p>The large sizes of the <it>Phytophthora </it>kinomes imply that phosphorylation plays major roles in their life cycles. Their kinomes also include many novel ePKs, some specific to oomycetes or shared with neighboring groups. Little experimentation to date has addressed the biological functions of oomycete kinases, but this should be stimulated by the structural, evolutionary, and expression data presented here. This may lead to targets for disease control.</p

The Angio-Fibrotic Switch of VEGF and CTGF in Proliferative Diabetic Retinopathy

BACKGROUND: In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) cause blindness by neovascularization and subsequent fibrosis, but their relative contribution to both processes is unknown. We hypothesize that the balance between levels of pro-angiogenic VEGF and pro-fibrotic CTGF regulates angiogenesis, the angio-fibrotic switch, and the resulting fibrosis and scarring. METHODS/PRINCIPAL FINDINGS: VEGF and CTGF were measured by ELISA in 68 vitreous samples of patients with proliferative DR (PDR, N = 32), macular hole (N = 13) or macular pucker (N = 23) and were related to clinical data, including degree of intra-ocular neovascularization and fibrosis. In addition, clinical cases of PDR (n = 4) were studied before and after pan-retinal photocoagulation and intra-vitreal injections with bevacizumab, an antibody against VEGF. Neovascularization and fibrosis in various degrees occurred almost exclusively in PDR patients. In PDR patients, vitreous CTGF levels were significantly associated with degree of fibrosis and with VEGF levels, but not with neovascularization, whereas VEGF levels were associated only with neovascularization. The ratio of CTGF and VEGF was the strongest predictor of degree of fibrosis. As predicted by these findings, patients with PDR demonstrated a temporary increase in intra-ocular fibrosis after anti-VEGF treatment or laser treatment. CONCLUSIONS/SIGNIFICANCE: CTGF is primarily a pro-fibrotic factor in the eye, and a shift in the balance between CTGF and VEGF is associated with the switch from angiogenesis to fibrosis in proliferative retinopathy

Steroids Up-Regulate p66Shc Longevity Protein in Growth Regulation by Inhibiting Its Ubiquitination

p66Shc, an isoform of Shc adaptor proteins, mediates diverse signals, including cellular stress and mouse longevity. p66Shc protein level is elevated in several carcinomas and steroid-treated human cancer cells. Several lines of evidence indicate that p66Shc plays a critical role in steroid-related carcinogenesis, and steroids play a role in its elevated levels in those cells without known mechanism.In this study, we investigated the molecular mechanism by which steroid hormones up-regulate p66Shc protein level. In steroid-treated human prostate and ovarian cancer cells, p66Shc protein levels were elevated, correlating with increased cell proliferation. These steroid effects on p66Shc protein and cell growth were competed out by the respective antagonist. Further, actinomycin D and cyclohexamide could only partially block the elevated p66Shc protein level by steroids. Treatment with proteasomal inhibitors, but not lysosomal protease inhibitor, resulted in elevated p66Shc protein levels, even higher than that by steroids. Using prostate cancer cells as a model, immunoprecipitation revealed that androgens and proteasomal inhibitors reduce the ubiquitinated p66Shc proteins.The data collectively indicate that functional steroid receptors are required in steroid up-regulation of p66Shc protein levels in prostate and ovarian cancer cells, correlating with cell proliferation. In these steroid-treated cells, elevated p66Shc protein level is apparently in part due to inhibiting its ubiquitination. The results may lead to an impact on advanced cancer therapy via the regulation of p66Shc protein by up-regulating its ubiquitination pathway

Modelling the covariance structure in marginal multivariate count models: Hunting in Bioko Island.

The main goal of this article is to present a flexible statistical modelling framework to deal with multivariate count data along with longitudinal and repeated measures structures. The covariance structure for each response variable is defined in terms of a covariance link function combined with a matrix linear predictor involving known matrices. In order to specify the joint covariance matrix for the multivariate response vector, the generalized Kronecker product is employed. We take into account the count nature of the data by means of the power dispersion function associated with the Poisson–Tweedie distribution. Furthermore, the score information criterion is extended for selecting the components of the matrix linear predictor. We analyse a data set consisting of prey animals (the main hunted species, the blue duiker Philantomba monticola and other taxa) shot or snared for bushmeat by 52 commercial hunters over a 33-month period in Pico Basilé, Bioko Island, Equatorial Guinea. By taking into account the severely unbalanced repeated measures and longitudinal structures induced by the hunters and a set of potential covariates (which in turn affect the mean and covariance structures), our method can be used to indicate whether there was statistical evidence of a decline in blue duikers and other species hunted during the study period. Determining whether observed drops in the number of animals hunted are indeed true is crucial to assess whether species depletion effects are taking place in exploited areas anywhere in the world. We suggest that our method can be used to more accurately understand the trajectories of animals hunted for commercial or subsistence purposes and establish clear policies to ensure sustainable hunting practices

Lupus nephritis in Chinese children--a territory-wide cohort study in Hong Kong

We report a multicenter study of Chinese children in Hong Kong with systemic lupus erythematosus (SLE) nephritis. Children were included if: they fulfilled the ACR criteria, had significant proteinuria or casturia, were Chinese and younger than 19 years and had been diagnosed with SLE between January 1990 and December 2003. Investigators in each center retrieved data on clinical features, biopsy reports, treatment and outcome of these patients. There were 128 patients (eight boys, 120 girls; mean age: 11.9+/-2.8 years). About 50% presented with multisystem illness and 40% with nephritic/nephrotic symptoms. Negative anti-dsDNA antibodies were found in 6% of the patients. Renal biopsy revealed WHO Class II, III, IV and V nephritis in 13 (10%), 22 (17%), 69 (54%) and 13 (10%) patients, respectively. The clinical severity of the nephritis did not accurately predict renal biopsy findings. The follow-up period ranged from 1 to 16.5 years (mean+/-SD: 5.76+/-3.61 years). During the study five patients died (two from lupus flare, one from cardiomyopathy, two from infections). Four patients had endstage renal failure (ESRF) (one died during a lupus flare). All deaths and end-stage renal failure occurred in the Class IV nephritis group. Chronic organ damage was infrequent in the survivors. The actuarial patient survival rates at 5, 10 and 15 years of age were 95.3, 91.8, and 91.8%, respectively. For Class IV nephritis patients, the survival rates without ESRF at 5, 10, and 15 years were 91.5, 82.3 and 76%, respectively. The survival and chronic morbidity rates of the Chinese SLE children in the present study are comparable to those of other published studies.postprin