Floating Microparticulate Oral Diltiazem Hydrochloride Delivery System for Improved Delivery to Heart

Purpose: To formulate and evaluate floating microparticulate oral diltiazem delivery system for possible delivery to the heart.Method: Floating microspheres were prepared using cellulose acetate and Eudragit RS100 polymers by emulsion solvent evaporation technique. The dried floating microspheres were evaluated for micromeritic properties (flow properties, density, particle size determination) scanning as well as by electron microscopy, and in vitro floatability and drug release studies.Results: The microspheres showed good buoyancy, good flow properties (angle of repose ranging from 24.29 to 29.02 º), particle size (262.09 to 409.60 μm) and good drug loading (74.29 to 92.09 %). The microspheres were porous, hollow and spherical. All the formulations showed good in vitro controlled drug release in the range of 77.62 ± 2.12 to 97.50 ± 1.04 % at the end of 12 h. Drug release was diffusion-controlled and followed zero order kinetics.Conclusion: Microparticulate floating (gastroretentive) oral drug delivery system of diltiazem prepared using cellulose acetate and Eudragit R5100 may be an effective alternative to conventional oral tablets for cardiac drug delivery.Keywords: Cardiac, Microparticulate, Drug release, Gastroretentive, Floating microspheres, Diltiazem hydrochlorid

p21-Activated Kinases 1, 2 and 4 in Endometrial Cancers: Effects on Clinical Outcomes and Cell Proliferation

p21-activated kinases (Paks) are serine/threonine protein kinases involved in biological events linked to malignant tumor progression. In this study, expression of Pak1, p-Pak2 Ser20, Pak4, pPak4 Ser474 in 21 normal endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial cancers was assessed by immunohistochemistry and correlated with clinicopathological parameters. We also accessed the proliferative role and downstream targets of Pak1 in endometrial cancer. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus of endometrial tissues. In normal endometrium, significantly higher Pak1 (P = 0.028) and cytoplasmic p-Pak2 (P = 0.048) expression was detected in proliferative endometrium than secretory endometrium. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 was significantly overexpressed in endometrial cancer when compared to atrophic endometrium (all P<0.05). Moreover, type I endometrioid carcinomas showed significantly higher Pak1 expression than type II non-endometrioid carcinomas (P<0.001). On the other hand, Pak1, Pak4 and p-Pak4 expression negatively correlated with histological grade (all P<0.05) while p-Pak2 and cytoplasmic Pak4 expression inversely correlated with myometrial invasion (all P<0.05). Furthermore, patients with endometrial cancers with lower cytoplasmic Pak4 expression showed poorer survival (P = 0.026). Multivariate analysis showed cytoplasmic Pak4 is an independent prognostic factor. Functionally, knockdown of Pak1, but not Pak4, in endometrial cancer cell line led to reduced cell proliferation along with reduced cyclin D1, estrogen receptor (ERα) and progestogen receptor (PR) expression. Significant correlation between Pak1 and PR expression was also detected in clinical samples. Our findings suggest that Pak1 and cytoplasmic p-Pak2 may promote cell proliferation in normal endometrium during menstral cycle. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 are involved in the pathogenesis of endometrial cancer especially in postmenopausal women. Pak1 promote endometrial cancer cell proliferation, particular in type I endometrioid carcinoma. Cytoplasmic Pak4 can be potential prognostic marker in endometrial cancer.published_or_final_versio

Overexpression of Forkhead Box Protein M1 (FOXM1) in Ovarian Cancer Correlates with Poor Patient Survival and Contributes to Paclitaxel Resistance

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Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease

The MDM2–p53–pyruvate carboxylase signalling axis couples mitochondrial metabolism to glucose-stimulated insulin secretion in pancreatic β-cells

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Metal-insulator transition in vanadium dioxide nanobeams: probing sub-domain properties of strongly correlated materials

Many strongly correlated electronic materials, including high-temperature superconductors, colossal magnetoresistance and metal-insulator-transition (MIT) materials, are inhomogeneous on a microscopic scale as a result of domain structure or compositional variations. An important potential advantage of nanoscale samples is that they exhibit the homogeneous properties, which can differ greatly from those of the bulk. We demonstrate this principle using vanadium dioxide, which has domain structure associated with its dramatic MIT at 68 degrees C. Our studies of single-domain vanadium dioxide nanobeams reveal new aspects of this famous MIT, including supercooling of the metallic phase by 50 degrees C; an activation energy in the insulating phase consistent with the optical gap; and a connection between the transition and the equilibrium carrier density in the insulating phase. Our devices also provide a nanomechanical method of determining the transition temperature, enable measurements on individual metal-insulator interphase walls, and allow general investigations of a phase transition in quasi-one-dimensional geometry.Comment: 9 pages, 3 figures, original submitted in June 200

No evidence for a superior platform to develop therapeutic antibodies rapidly in response to MERS-CoV and other emerging viruses

Pascal et al. (1) generated mAbs using a platform called VelocImmune and evaluated their potency against the Middle East respiratory syndrome coronavirus (MERS-CoV) in vitro side by side with mAbs previously reported and in a mouse model developed by using VelociGene technology. The authors concluded that “Traditional approaches for development of antibodies are poorly suited to combating the emergence of novel pathogens…and that this study forms the basis for a rapid response to address the public threat resulting from emerging coronaviruses or other pathogens that pose a serious threat to human health in the future.” To support the superiority of their approach, as implied by this statement, the authors cited human mAbs previously published by three groups (2–4) and compared some of them with their own REGN3051 and REGN3048, which they found to be “more effective neutralizers than previously isolated MERS-CoV monoclonal antibodies.” They also report that their antibodies “are >1 log better inhibitors compared with other published antibodies developed with conventional approaches.” However, they did not evaluate the exceptionally potent (picomolar IC50) mAbs from one group (2) and used only published sequences, but not mAbs, provided by the investigators from the other groups (3, 4). Thus, effects that could affect potency, including those resulting from posttranslational modifications, are excluded. They also claim that the VelocImmune platform can rapidly (“within several weeks”) identify potent mAbs. However, using phage display for panning of a very large human antibody library, Ying et al. (2) identified the exceptionally potent mAb m336 in a week. According to the authors, their mouse model of MERS-CoV infection was established by replacing the mouse gene encoding a receptor targeted by the virus (DPP4) with its human counterpart, such that “this humanized DPP4 in vivo model of MERS-CoV infection recapitulates pathological sequelae that are seen in MERS-CoV infection of humans.” To our knowledge, currently, there is no animal model that can recapitulate pathology of human MERS-CoV infections in humans; therefore, it follows from this statement that their model is superior to others, which is not based on evidence. Because a full understanding of MERS pathogenesis and pathology in humans is uncertain, claiming that their model recapitulates pathological sequelae in humans, especially in the absence of morbidity and mortality, seems premature and unjustifiable. Moreover, a marmoset model (5) may be the most relevant model of MERS-CoV infection and disease. It is not cited in the text, although the reference for it is given in the bibliography. Finally, in the title of the article, the authors claim that their antibodies are fully human. However, only the germ-line antibodies inserted in the mouse genome are fully human. Because the maturation of those antibodies is in mice and the tolerance checkpoints are by mouse proteins in a mouse environment, the somatic mutations could lead to cross-reactivity of their antibodies with human tissues and immunogenicity, and therefore to undesirable adverse events and safety concerns. Taken together, the data do not provide evidence that their platform of developing mAbs, as well as models of infection and disease, is superior.published_or_final_versio

SMART: Unique splitting-while-merging framework for gene clustering

Copyright @ 2014 Fa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Successful clustering algorithms are highly dependent on parameter settings. The clustering performance degrades significantly unless parameters are properly set, and yet, it is difficult to set these parameters a priori. To address this issue, in this paper, we propose a unique splitting-while-merging clustering framework, named “splitting merging awareness tactics” (SMART), which does not require any a priori knowledge of either the number of clusters or even the possible range of this number. Unlike existing self-splitting algorithms, which over-cluster the dataset to a large number of clusters and then merge some similar clusters, our framework has the ability to split and merge clusters automatically during the process and produces the the most reliable clustering results, by intrinsically integrating many clustering techniques and tasks. The SMART framework is implemented with two distinct clustering paradigms in two algorithms: competitive learning and finite mixture model. Nevertheless, within the proposed SMART framework, many other algorithms can be derived for different clustering paradigms. The minimum message length algorithm is integrated into the framework as the clustering selection criterion. The usefulness of the SMART framework and its algorithms is tested in demonstration datasets and simulated gene expression datasets. Moreover, two real microarray gene expression datasets are studied using this approach. Based on the performance of many metrics, all numerical results show that SMART is superior to compared existing self-splitting algorithms and traditional algorithms. Three main properties of the proposed SMART framework are summarized as: (1) needing no parameters dependent on the respective dataset or a priori knowledge about the datasets, (2) extendible to many different applications, (3) offering superior performance compared with counterpart algorithms.National Institute for Health Researc

Overexpression of proto-oncogene FBI-1 activates membrane type 1-matrix metalloproteinase in association with adverse outcome in ovarian cancers

<p>Abstract</p> <p>Background</p> <p>FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) is a member of the POK (POZ and Kruppel) family of transcription factors and play important roles in cellular differentiation and oncogenesis. Recent evidence suggests that FBI-1 is expressed at high levels in a subset of human lymphomas and some epithelial solid tumors. However, the function of FBI-1 in human ovarian cancers remains elusive.</p> <p>Results</p> <p>In this study, we investigated the role of FBI-1 in human ovarian cancers, in particularly, its function in cancer cell invasion via modulating membrane type 1-matrix metalloproteinase (MT1-MMP). Significantly higher FBI-1 protein and mRNA expression levels were demonstrated in ovarian cancers samples and cell lines compared with borderline tumors and benign cystadenomas. Increased FBI-1 mRNA expression was correlated significantly with gene amplification (P = 0.037). Moreover, higher FBI-1 expression was found in metastatic foci (P = 0.036) and malignant ascites (P = 0.021), and was significantly associated with advanced stage (P = 0.012), shorter overall survival (P = 0.032) and disease-free survival (P = 0.016). <it>In vitro</it>, overexpressed FBI-1 significantly enhanced cell migration and invasion both in OVCA 420 and SKOV-3 ovarian carcinoma cells, irrespective of <it>p53 </it>status, accompanied with elevated expression of MT1-MMP, but not MMP-2 or TIMP-2. Moreover, knockdown of MT1-MMP abolished FBI-1-mediated cell migration and invasion. Conversely, stable knockdown of FBI-1 remarkably reduced the motility of these cells with decreased expression of MT1-MMP. Promoter assay and chromatin immunoprecipitation study indicated that FBI-1 could directly interact with the promoter spanning ~600bp of the 5'-flanking sequence of MT1-MMP and enhanced its expression in a dose-dependent manner. Furthermore, stable knockdown and ectopic expression of FBI-1 decreased and increased cell proliferation respectively in OVCA 420, but not in the p53 null SKOV-3 cells.</p> <p>Conclusions</p> <p>Our results suggested an important role of FBI-1 in ovarian cancer cell proliferation, cell mobility, and invasiveness, and that FBI-1 can be a potential target of chemotherapy.</p