Effect of HIV-1 envelope cytoplasmic tail on adenovirus primed virus encoded virus-like particle immunizations

Publication date: Available online 12 September 2016
Source:Vaccine
Author(s): Anne-Marie C. Andersson, Emeline Ragonnaud, Kelly E. Seaton, Sheetal Sawant, Antonella Folgori, Stefano Colloca, Celia Labranche, David C. Montefiori, Georgia D. Tomaras, Peter J. Holst
The low number of envelope (Env) spikes presented on native HIV-1 particles is a major impediment for HIV-1 prophylactic vaccine development. We designed virus-like particle encoding adenoviral vectors utilizing SIVmac239 Gag as an anchor for full length and truncated HIV-1 M consensus Env. Truncated Env overexpressed VRC01 and 17b binding antigen on the surface of transduced cells while the full length Env vaccine presented more and similar amounts of antigen binding to the trimer conformation sensitive antibodies PGT151 and PGT145, respectively. The adenoviral vectors were used to prime Balb/c mice followed by sequential boosting with chimpanzee type 63, and chimpanzee type 3 adenoviral vectors encoding SIVmac239 Gag and full length consensus Env. Both vaccine regimens induced increasing titers of binding antibody responses after each immunization, and significant differences in immune responses between the two groups were observed after the final immunization. Full length Env priming skewed antibody responses towards gp41, while truncated Env priming induced responses primarily targeting gp120 containing and derived antigens. Importantly, no differences in neutralizing antibody responses were found between the different priming regimens as both induced high titered tier 1 neutralizing antibodies, but no tier 2 antibodies, possibly reflecting the similar presentation of trimer specific antibody epitopes. The described vaccine regimens provide insight into the effects of the HIV-1 Env cytoplasmic tail on epitope presentation and subsequent immune responses, which is relevant for the interpretation of current clinical trials that are using truncated Env as an immunogen. The regimens described here provide similar neutralization titers, and thus are useful for investigating the importance of specificity in non-neutralizing antibody mediated protection against viral challenge.



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IJMS, Vol. 17, Pages 1538: Extraordinary Adaptive Plasticity of Colorado Potato Beetle: “Ten-Striped Spearman” in the Era of Biotechnological Warfare

Expanding from remote areas of Mexico to a worldwide scale, the ten-striped insect, the Colorado potato beetle (CPB, Leptinotarsa decemlineata Say), has risen from being an innocuous beetle to a prominent global pest. A diverse life cycle, phenotypic plasticity, adaptation to adverse conditions, and capability to detoxify or tolerate toxins make this insect appear to be virtually "indestructible". With increasing advances in molecular biology, tools of biotechnological warfare were deployed to combat CPB. In the last three decades, genetically modified potato has created a new challenge for the beetle. After reviewing hundreds of scientific papers dealing with CPB control, it became clear that even biotechnological means of control, if used alone, would not defeat the Colorado potato beetle. This control measure once again appears to be provoking the potato beetle to exhibit its remarkable adaptability. Nonetheless, the potential for adaptation to these techniques has increased our knowledge of this pest and thus opened possibilities for devising more sustainable CPB management programs.

http://ift.tt/2c5S8XR

IJMS, Vol. 17, Pages 1542: Convergent Effects of Resveratrol and PYK2 on Prostate Cells

Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans.

http://ift.tt/2c5SKNj

IJMS, Vol. 17, Pages 1537: Comprehensive Proteomic Analysis of Spider Dragline Silk from Black Widows: A Recipe to Build Synthetic Silk Fibers

The outstanding material properties of spider dragline silk fibers have been attributed to two spidroins, major ampullate spidroins 1 and 2 (MaSp1 and MaSp2). Although dragline silk fibers have been treated with different chemical solvents to elucidate the relationship between protein structure and fiber mechanics, there has not been a comprehensive proteomic analysis of the major ampullate (MA) gland, its spinning dope, and dragline silk using a wide range of chaotropic agents, inorganic salts, and fluorinated alcohols to elucidate their complete molecular constituents. In these studies, we perform in-solution tryptic digestions of solubilized MA glands, spinning dope and dragline silk fibers using five different solvents, followed by nano liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) analysis with an Orbitrap Fusion™ Tribrid™. To improve protein identification, we employed three different tryptic peptide fragmentation modes, which included collision-induced dissociation (CID), electron transfer dissociation (ETD), and high energy collision dissociation (HCD) to discover proteins involved in the silk assembly pathway and silk fiber. In addition to MaSp1 and MaSp2, we confirmed the presence of a third spidroin, aciniform spidroin 1 (AcSp1), widely recognized as the major constituent of wrapping silk, as a product of dragline silk. Our findings also reveal that MA glands, spinning dope, and dragline silk contain at least seven common proteins: three members of the Cysteine-Rich Protein Family (CRP1, CRP2 and CRP4), cysteine-rich secretory protein 3 (CRISP3), fasciclin and two uncharacterized proteins. In summary, this study provides a proteomic blueprint to construct synthetic silk fibers that most closely mimic natural fibers.

http://ift.tt/2cnQWBn

IJMS, Vol. 17, Pages 1539: Characterization of Post-Translational Modifications to Calsequestrins of Cardiac and Skeletal Muscle

Calsequestrin is glycosylated and phosphorylated during its transit to its final destination in the junctional sarcoplasmic reticulum. To determine the significance and universal profile of these post-translational modifications to mammalian calsequestrin, we characterized, via mass spectrometry, the glycosylation and phosphorylation of skeletal muscle calsequestrin from cattle (B. taurus), lab mice (M. musculus) and lab rats (R. norvegicus) and cardiac muscle calsequestrin from cattle, lab rats and humans. On average, glycosylation of skeletal calsequestrin consisted of two N-acetylglucosamines and one mannose (GlcNAc2Man1), while cardiac calsequestrin had five additional mannoses (GlcNAc2Man6). Skeletal calsequestrin was not phosphorylated, while the C-terminal tails of cardiac calsequestrin contained between zero to two phosphoryls, indicating that phosphorylation of cardiac calsequestrin may be heterogeneous in vivo. Static light scattering experiments showed that the Ca2+-dependent polymerization capabilities of native bovine skeletal calsequestrin are enhanced, relative to the non-glycosylated, recombinant isoform, which our crystallographic studies suggest may be due to glycosylation providing a dynamic "guiderail"-like scaffold for calsequestrin polymerization. Glycosylation likely increases a polymerization/depolymerization response to changing Ca2+ concentrations, and proper glycosylation, in turn, guarantees both effective Ca2+ storage/buffering of the sarcoplasmic reticulum and localization of calsequestrin (Casq) at its target site.

http://ift.tt/2c5Ridy

Generation of an in vitro 3D PDAC stroma rich spheroid model

Publication date: November 2016
Source:Biomaterials, Volume 108
Author(s): Matthew J. Ware, Vazrik Keshishian, Justin J. Law, Jason C. Ho, Carlos A. Favela, Paul Rees, Billie Smith, Sayeeduddin Mohammad, Rosa F. Hwang, Kimal Rajapakshe, Cristian Coarfa, Shixia Huang, Dean P. Edwards, Stuart J. Corr, Biana Godin, Steven A. Curley
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cells (PSC) are myofibroblast-like cells located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracellular matrix components and producing the dense PDAC stroma. Currently, only a few orthotopic or ectopic animal tumor models, where PDAC cells are injected into the pancreas or subcutaneous tissue layer, or genetically engineered animals offer tumors that encompass some stromal component. Herein, we report generation of a simple 3D PDAC in vitro micro-tumor model without an addition of external extracellular matrix, which encompasses a rich, dense and active stromal compartment. We have achieved this in vitro model by incorporating PSCs into 3D PDAC cell culture using a modified hanging drop method. It is now known that PSCs are the principal source of fibrosis in the stroma and interact closely with cancer cells to create a tumor facilitatory environment that stimulates local and distant tumor growth. The 3D micro-stroma models are highly reproducible with excellent uniformity, which can be used for PDAC-stroma interaction analysis and high throughput automated drug-screening assays. Additionally, the increased expression of collagenous regions means that molecular based perfusion and cytostaticity of gemcitabine is decreased in our Pancreatic adenocarcinoma stroma spheroids (PDAC-SS) model when compared to spheroids grown without PSCs. We believe this model will allow an improved knowledge of PDAC biology and has the potential to provide an insight into pathways that may be therapeutically targeted to inhibit PSC activation, thereby inhibiting the development of fibrosis in PDAC and interrupting PSC-PDAC cell interactions so as to inhibit cancer progression.



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Utilizing clathrin triskelions as carriers for spatially controlled multi-protein display

Publication date: November 2016
Source:Biomaterials, Volume 108
Author(s): Michael B. Deci, Scott W. Ferguson, Maixian Liu, Damian C. Peterson, Sujatha P. Koduvayur, Juliane Nguyen
The simultaneous and spatially controlled display of different proteins on nanocarriers is a desirable property not often achieved in practice. Here, we report the use of clathrin triskelions as a versatile platform for functional protein display. We hypothesized that site-specific molecular epitope recognition would allow for effective and ordered protein attachment to clathrin triskelions. Clathrin binding peptides (CBPs) were genetically fused to mCherry and green fluorescent protein (GFP), expressed, and loaded onto clathrin triskelions by site-specific binding. Attachment was confirmed by surface plasmon resonance. mCherry fusion proteins modified with various CBPs displayed binding affinities between 470 nM and 287 μM for the clathrin triskelions. Simultaneous attachment of GFP-Wbox and mCherry-Cbox fusion constructs to the clathrin terminal domain was verified by Förster resonance energy transfer. The circulating half-lives, area under the curve, and the terminal half-lives of GFP and mCherry were significantly increased when attached to clathrin triskelions. Clathrin triskelion technology is useful for the development of versatile and multifunctional carriers for spatially controlled protein or peptide display with tremendous potential in nanotechnology, drug delivery, vaccine development, and targeted therapeutic applications.

Graphical abstract

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Head and neck cancer: Gemcitabine improves patient survival

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.149

Author: Peter Sidaway

http://ift.tt/2cbGIVF

Breast cancer: Genetic signature might spare 100,000 women annually from chemotherapy

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.150

Author: David Killock

http://ift.tt/2cspf8U

Breast cancer: CTC heterogeneity is dynamic

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.152

Author: Diana Romero

http://ift.tt/2cbFDxm

Lung cancer: First-line immunotherapy in lung cancer — taking the first step

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.148

Authors: Stephen V. Liu & Giuseppe Giaccone

The use of programmed cell-death protein 1 (PD-1) inhibitors has become the standard-of-care approach for patients with advanced-stage, previously treated non-small-cell lung cancer. The inevitable adoption of these agents in the first-line setting is rapidly approaching, but the optimal strategy remains unclear. Two published clinical trial reports, examining different approaches, help to frame this question.

http://ift.tt/2cso1dA

Immunotherapy: CAR T cells pursue CLL cells and avoid innocent bystanders

Nature Reviews Clinical Oncology. doi:10.1038/nrclinonc.2016.153

Author: David Killock

http://ift.tt/2cbFUjM

Intratumoral Heterogeneity of Frameshift Mutations in MECOM Gene is Frequent in Colorectal Cancers with High Microsatellite Instability

Abstract

MECOM gene, also known as EVI, encodes a transcriptional regulator involved in hematopoiesis, apoptosis, development and proliferation. In blood system, MECOM is considered an oncogene, but in solid tumors it has both oncogenic and tumor suppressor activities. Low frequent somatic mutations of MECOM have been detected in many cancers including colorectal cancers (CRC), but the mutation status with respect to the microsatellite instability (MSI) has not been studied. There is an A7 mononucleotide repeat in MECOM coding sequences that could be a mutation target in the cancers with MSI. We analyzed the A7 of MECOM in 79 CRCs with high MSI (MSI-H) and 65 microsatellite stable/low MSI (MSS/MSI-L) CRCs by single-strand conformation polymorphism analysis and DNA sequencing. Overall, we found MECOM frameshift mutations in 6 (7.6 %) CRCs with MSI-H, but not in MSS/MSI-L cancers (0/65) (p < 0.025). We also analyzed intratumoral heterogeneity (ITH) of the MECOM frameshift mutation in 16 CRCs and found that four CRCs (25.0 %) harbored regional ITH of the frameshift mutations. Our data indicate that MECOM gene harbors both somatic frameshift mutations and mutational ITH, which together may be features of CRC with MSI-H.

http://ift.tt/2csxiWm

Glycated albumin: from biochemistry and laboratory medicine to clinical practice

Abstract

This review summarizes current knowledge about glycated albumin. We review the changes induced by glycation on the properties of albumin, the pathological implications of high glycated albumin levels, glycated albumin quantification methods, and the use of glycated albumin as a complementary biomarker for diabetes mellitus diagnosis and monitoring and for dealing with long-term complications. The advantages and limits of this biomarker in different clinical settings are also discussed.

http://ift.tt/2c5Fqsa

Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease

Abstract

The long-term effect of therapeutic diets in obesity treatment is a challenge at present. The current study aimed to evaluate the long-term effect of a very low-calorie-ketogenic (VLCK) diet on excess adiposity. Especial focus was set on visceral fat mass, and the impact on the individual burden of disease. A group of obese patients (n = 45) were randomly allocated in two groups: either the very low-calorie-ketogenic diet group (n = 22), or a standard low-calorie diet group; (n = 23). Both groups received external support. Adiposity parameters and the cumulative number of months of successful weight loss (5 or 10 %) over a 24-month period were quantified. The very low-calorie-ketogenic diet induced less than 2 months of mild ketosis and significant effects on body weight at 6, 12, and 24 months. At 24 months, a trend to regress to baseline levels was observed; however, the very low-calorie-ketogenic diet induced a greater reduction in body weight (−12.5 kg), waist circumference (−11.6 cm), and body fat mass (−8.8 kg) than the low-calorie diet (−4.4 kg, −4.1 cm, and −3.8 kg, respectively; p < 0.001). Interestingly, a selective reduction in visceral fat measured by a specific software of dual-energy x-ray absorptiometry (DEXA)-scan (−600 g vs. −202 g; p < 0.001) was observed. Moreover, the very low-calorie-ketogenic diet group experienced a reduction in the individual burden of obesity because reduction in disease duration. Very low-calorie-ketogenic diet patients were 500 months with 5 % weight lost vs. the low-calorie diet group (350 months; p < 0.001). In conclusion, a very low-calorie-ketogenic diet was effective 24 months later, with a decrease in visceral adipose tissue and a reduction in the individual burden of disease.

http://ift.tt/2cbBOIb

Multiaxial Polarity Determines Individual Cellular and Nuclear Chirality

Abstract

Intrinsic cell chirality has been implicated in the left–right (LR) asymmetry of embryonic development. Impaired cell chirality could lead to severe birth defects in laterality. Previously, we detected cell chirality with an in vitro micropatterning system. Here, we demonstrate for the first time that chirality can be quantified as the coordination of multiaxial polarization of individual cells and nuclei. Using an object labeling, connected component based method, we characterized cell chirality based on cell and nuclear shape polarization and nuclear positioning of each cell in multicellular patterns of epithelial cells. We found that the cells adopted a LR bias the boundaries by positioning the sharp end towards the leading edge and leaving the nucleus at the rear. This behavior is consistent with the directional migration observed previously on the boundary of micropatterns. Although the nucleus is chirally aligned, it is not strongly biased towards or away from the boundary. As the result of the rear positioning of nuclei, the nuclear positioning has an opposite chirality to that of cell alignment. Overall, our results have revealed deep insights of chiral morphogenesis as the coordination of multiaxial polarization at the cellular and subcellular levels.

http://ift.tt/2csnrMX

Co-targeting of Adenosine Signaling Pathways for Immunotherapy: Potentiation by Fc Receptor Engagement

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Rony Dahan, Jeffrey V. Ravetch
Targeting the signaling pathway of the immunosuppressive metabolite adenosine is an emerging approach for cancer immunotherapy. In this issue of Cancer Cell, Young et al. describe that co-inhibition of the adenosingenic pathway through blockade of both CD73 and A2AR enhances antitumor efficacy through distinct mechanisms.

Teaser

Targeting the signaling pathway of the immunosuppressive metabolite adenosine is an emerging approach for cancer immunotherapy. In this issue of Cancer Cell, Young et al. describe that co-inhibition of the adenosingenic pathway through blockade of both CD73 and A2AR enhances antitumor efficacy through distinct mechanisms.


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Modeling SF3B1 Mutations in Cancer: Advances, Challenges, and Opportunities

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Daichi Inoue, Omar Abdel-Wahab
In this issue of Cancer Cell, Obeng et al. identify the consequences of expressing the most common mutation in the spliceosomal gene SF3B1 on hematopoiesis. The knockin mouse model described represents a valuable tool to dissect the effects of SF3B1 mutations on transformation, splicing, and less well-characterized functions of SF3B1.

Teaser

In this issue of Cancer Cell, Obeng et al. identify the consequences of expressing the most common mutation in the spliceosomal gene SF3B1 on hematopoiesis. The knockin mouse model described represents a valuable tool to dissect the effects of SF3B1 mutations on transformation, splicing, and less well-characterized functions of SF3B1.


http://ift.tt/2chRixl

Powering Tumor Metastasis with Recycled Fuel

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Mien-Chie Hung, Riyao Yang, Yutong Sun
Receptor tyrosine kinase (RTK) recycling is of critical importance for RTK signaling and cancer, yet the process is poorly understood. In this issue, Ye et al. identify GOLM1 as a cargo adaptor that drives hepatocellular carcinoma metastasis by promoting EGFR recycling and provide insights into how this process is regulated.

Teaser

Receptor tyrosine kinase (RTK) recycling is of critical importance for RTK signaling and cancer, yet the process is poorly understood. In this issue, Ye et al. identify GOLM1 as a cargo adaptor that drives hepatocellular carcinoma metastasis by promoting EGFR recycling and provide insights into how this process is regulated.


http://ift.tt/2co0fC4

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Ilaria Marigo, Serena Zilio, Giacomo Desantis, Bernhard Mlecnik, Andrielly H.R. Agnellini, Stefano Ugel, Maria Stella Sasso, Joseph E. Qualls, Franz Kratochvill, Paola Zanovello, Barbara Molon, Carola H. Ries, Valeria Runza, Sabine Hoves, Amélie M. Bilocq, Gabriela Bindea, Emilia M.C. Mazza, Silvio Bicciato, Jérôme Galon, Peter J. Murray, Vincenzo Bronte
Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8⁺ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1⁺ myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies.

Graphical abstract

Teaser

Marigo et al. show that nitric oxide produced by Tip-DCs, a subset of tumor-infiltrating myeloid cells, is important for tumor control by adoptive cell therapy (ACT). Tip-DCs require the CD40-CD40L pathway but not CSF-1R; CSF-1R blockade reduces immunosuppressive macrophages and improves tumor control by ACT.


http://ift.tt/2chRk8j

Co-inhibition of CD73 and A2AR Adenosine Signaling Improves Anti-tumor Immune Responses

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Arabella Young, Shin Foong Ngiow, Deborah S. Barkauskas, Erin Sult, Carl Hay, Stephen J. Blake, Qihui Huang, Jing Liu, Kazuyoshi Takeda, Michele W.L. Teng, Kris Sachsenmeier, Mark J. Smyth
Preclinical studies targeting the adenosinergic pathway have gained much attention for their clinical potential in overcoming tumor-induced immunosuppression. Here, we have identified that co-blockade of the ectonucleotidase that generates adenosine CD73 and the A2A adenosine receptor (A2AR) that mediates adenosine signaling in leuokocytes, by using compound gene-targeted mice or therapeutics that target these molecules, limits tumor initiation, growth, and metastasis. This tumor control requires effector lymphocytes and interferon-γ, while antibodies targeting CD73 promote an optimal therapeutic response in vivo when engaging activating Fc receptors. In a two-way mixed leukocyte reaction using a fully human anti-CD73, we demonstrated that Fc receptor binding augmented the production of proinflammatory cytokines.

Graphical abstract

Teaser

Young et al. show that blockade of CD73 and A2AR, two components of the adenosinergic pathway, has more potent anti-tumor activity than blockade of either, partly due to increased CD73 expression in the absence of A2AR. Moreover, anti-CD73 antibodies require the FcR binding domain for optimal anti-tumor activity.


http://ift.tt/2chSIb7

Tipping the Balancing ACT

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Shari Pilon-Thomas, Brian Ruffell
Adoptive cell transfer therapy has emerged as a powerful treatment for metastatic melanoma, but efficacy is limited by an inhospitable tumor microenvironment. In this issue of Cancer Cell, Marigo et al. demonstrate that therapy requires induced expression of nitric oxide synthase 2 in monocyte-derived dendritic cells.

Teaser

Adoptive cell transfer therapy has emerged as a powerful treatment for metastatic melanoma, but efficacy is limited by an inhospitable tumor microenvironment. In this issue of Cancer Cell, Marigo et al. demonstrate that therapy requires induced expression of nitric oxide synthase 2 in monocyte-derived dendritic cells.


http://ift.tt/2cJr7ea

Physiologic Expression of Sf3b1K700E Causes Impaired Erythropoiesis, Aberrant Splicing, and Sensitivity to Therapeutic Spliceosome Modulation

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Esther A. Obeng, Ryan J. Chappell, Michael Seiler, Michelle C. Chen, Dean R. Campagna, Paul J. Schmidt, Rebekka K. Schneider, Allegra M. Lord, Lili Wang, Rutendo G. Gambe, Marie E. McConkey, Abdullah M. Ali, Azra Raza, Lihua Yu, Silvia Buonamici, Peter G. Smith, Ann Mullally, Catherine J. Wu, Mark D. Fleming, Benjamin L. Ebert
More than 80% of patients with the refractory anemia with ring sideroblasts subtype of myelodysplastic syndrome (MDS) have mutations in Splicing Factor 3B, Subunit 1 (SF3B1). We generated a conditional knockin mouse model of the most common SF3B1 mutation, Sf3b1^K700E. Sf3b1^K700E mice develop macrocytic anemia due to a terminal erythroid maturation defect, erythroid dysplasia, and long-term hematopoietic stem cell (LT-HSC) expansion. Sf3b1^K700E myeloid progenitors and SF3B1-mutant MDS patient samples demonstrate aberrant 3′ splice-site selection associated with increased nonsense-mediated decay. Tet2 loss cooperates with Sf3b1^K700E to cause a more severe erythroid and LT-HSC phenotype. Furthermore, the spliceosome modulator, E7017, selectively kills SF3B1^K700E-expressing cells. Thus, SF3B1^K700E expression reflects the phenotype of the mutation in MDS and may be a therapeutic target in MDS.

Graphical abstract

Teaser

Obeng et al. generate knockin mice with Sf3b1^K700E, a prevalent mutation in myelodysplastic syndrome (MDS). Sf3b1^+/K700E mice display characteristics of MDS. Mouse and human MDS cells expressing SF3B1^K700E exhibit aberrant 3′ splice-site selection, and SF3B1^K700E sensitizes cells to a spliceosome modulator.


http://ift.tt/2ckunw0

Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Lucie Brisson, Piotr Bański, Martina Sboarina, Coralie Dethier, Pierre Danhier, Marie-Joséphine Fontenille, Vincent F. Van Hée, Thibaut Vazeille, Morgane Tardy, Jorge Falces, Caroline Bouzin, Paolo E. Porporato, Raphaël Frédérick, Carine Michiels, Tamara Copetti, Pierre Sonveaux
Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy. We report that lactate sustains autophagy in cancer. In cancer cells preferentially to normal cells, lactate dehydrogenase B (LDHB), catalyzing the conversion of lactate and NAD⁺ to pyruvate, NADH and H⁺, controls lysosomal acidification, vesicle maturation, and intracellular proteolysis. LDHB activity is necessary for basal autophagy and cancer cell proliferation not only in oxidative cancer cells but also in glycolytic cancer cells.

Graphical abstract

Teaser

Brisson et al. show that lactate dehydrogenase B (LDHB) is critical for lysosomal activity and autophagy in cancer cells. Silencing LDHB selectively inhibits the proliferation of both oxidative and glycolytic cancer cells over normal cells, suggesting inhibition of LDHB as a promising anticancer approach.


http://ift.tt/2ckulo5

Feedback Activation of Leukemia Inhibitory Factor Receptor Limits Response to Histone Deacetylase Inhibitors in Breast Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Hanlin Zeng, Jia Qu, Nan Jin, Jun Xu, Chenchu Lin, Yi Chen, Xinying Yang, Xiang He, Shuai Tang, Xiaojing Lan, Xiaotong Yang, Ziqi Chen, Min Huang, Jian Ding, Meiyu Geng
Histone deacetylase (HDAC) inhibitors have demonstrated clinical benefits in subtypes of hematological malignancies. However, the efficacy of HDAC inhibitors in solid tumors remains uncertain. This study takes breast cancer as a model to understand mechanisms accounting for limited response of HDAC inhibitors in solid tumors and to seek combination solutions. We discover that feedback activation of leukemia inhibitory factor receptor (LIFR) signaling in breast cancer limits the response to HDAC inhibition. Mechanistically, HDAC inhibition increases histone acetylation at the LIFR gene promoter, which recruits bromodomain protein BRD4, upregulates LIFR expression, and activates JAK1-STAT3 signaling. Importantly, JAK1 or BRD4 inhibition sensitizes breast cancer to HDAC inhibitors, implicating combination inhibition of HDAC with JAK1 or BRD4 as potential therapies for breast cancer.

Graphical abstract

Teaser

Zeng et al. show that HDAC inhibitors (HDACi) promote BRD4-mediated activation of LIFR, which in turn activates JAK1-STAT3 signaling and restrains the efficacy of HDACi in breast cancer. Concurrent inhibition of BRD4 or JAK sensitizes breast cancer, in particular the triple-negative subset, to HDACi.


http://ift.tt/2ckujfW

Small-Molecule Targeting of E3 Ligase Adaptor SPOP in Kidney Cancer

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Zhong-Qiang Guo, Tong Zheng, Baoen Chen, Cheng Luo, Sisheng Ouyang, Shouzhe Gong, Jiafei Li, Liu-Liang Mao, Fulin Lian, Yong Yang, Yue Huang, Li Li, Jing Lu, Bidong Zhang, Luming Zhou, Hong Ding, Zhiwei Gao, Liqun Zhou, Guoqiang Li, Ran Zhou, Ke Chen, Jingqiu Liu, Yi Wen, Likun Gong, Yuwen Ke, Shang-Dong Yang, Xiao-Bo Qiu, Naixia Zhang, Jin Ren, Dafang Zhong, Cai-Guang Yang, Jiang Liu, Hualiang Jiang
In the cytoplasm of virtually all clear-cell renal cell carcinoma (ccRCC), speckle-type POZ protein (SPOP) is overexpressed and misallocated, which may induce proliferation and promote kidney tumorigenesis. In normal cells, however, SPOP is located in the nucleus and induces apoptosis. Here we show that a structure-based design and subsequent hit optimization yield small molecules that can inhibit the SPOP-substrate protein interaction and can suppress oncogenic SPOP-signaling pathways. These inhibitors kill human ccRCC cells that are dependent on oncogenic cytoplasmic SPOP. Notably, these inhibitors minimally affect the viability of other cells in which SPOP is not accumulated in the cytoplasm. Our findings validate the SPOP-substrate protein interaction as an attractive target specific to ccRCC that may yield novel drug discovery efforts.

Graphical abstract

Teaser

Using a structure-based design followed by hit optimization, Guo et al. report small-molecule inhibitors that disrupt oncogenic SPOP-mediated pathways by blocking SPOP-substrate interactions and suppress human clear-cell renal cell carcinoma in vitro and in vivo, suggesting the potential of SPOP-targeted therapy.


http://ift.tt/2cFuKTE

Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Najoua Lalaoui, Kay Hänggi, Gabriela Brumatti, Diep Chau, Nhu-Y.N. Nguyen, Lazaros Vasilikos, Lisanne M. Spilgies, Denise A. Heckmann, Chunyan Ma, Margherita Ghisi, Jessica M. Salmon, Geoffrey M. Matthews, Elisha de Valle, Donia M. Moujalled, Manoj B. Menon, Sukhdeep Kaur Spall, Stefan P. Glaser, Jennifer Richmond, Richard B. Lock, Stephen M. Condon, Raffi Gugasyan, Matthias Gaestel, Mark Guthridge, Ricky W. Johnstone, Lenka Munoz, Andrew Wei, Paul G. Ekert, David L. Vaux, W. Wei-Lynn Wong, John Silke




http://ift.tt/2cFtXSU

Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Haidong Tang, Yang Wang, Lukasz K. Chlewicki, Yuan Zhang, Jingya Guo, Wei Liang, Jieyi Wang, Xiaoxiao Wang, Yang-Xin Fu




http://ift.tt/2cVYL3X

IDH1, Histone Methylation, and So Forth

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Virginie Penard-Lacronique, Olivier A. Bernard




http://ift.tt/2cFtKiv

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Publication date: 12 September 2016
Source:Cancer Cell, Volume 30, Issue 3
Author(s): Zoi Karoulia, Yang Wu, Tamer A. Ahmed, Qisheng Xin, Julien Bollard, Clemens Krepler, Xuewei Wu, Chao Zhang, Gideon Bollag, Meenhard Herlyn, James A. Fagin, Amaia Lujambio, Evripidis Gavathiotis, Poulikos I. Poulikakos




http://ift.tt/2cswwJ8

Clustered double-strand breaks in heterochromatin perturb DNA repair after high linear energy transfer irradiation

Publication date: Available online 13 September 2016
Source:Radiotherapy and Oncology
Author(s): Yvonne Lorat, Sara Timm, Burkhard Jakob, Gisela Taucher-Scholz, Claudia E. Rübe
Background and purposeHigh linear energy transfer (LET) radiotherapy offers superior dose conformity and biological effectiveness compared with low-LET radiotherapy, representing a promising alternative for radioresistant tumours. A prevailing hypothesis is that energy deposition along the high-LET particle trajectories induces DNA lesions that are more complex and clustered and therefore more challenging to repair. The precise molecular mechanisms underlying the differences in radiobiological effects between high-LET and low-LET radiotherapies remain unclear.Material and MethodsHuman fibroblasts were irradiated with high-LET carbon ions or low-LET photons. At 0.5h and 5h post exposure, the DNA-damage pattern in the chromatin ultrastructure was visualised using gold-labelled DNA-repair factors. The induction and repair of single-strand breaks, double-strand breaks (DSBs), and clustered lesions were analysed in combination with terminal dUTP nick-end labelling of DNA breaks.ResultsHigh-LET irradiation induced clustered lesions with multiple DSBs along ion trajectories predominantly in heterochromatic regions. The cluster size increased over time, suggesting inefficient DSB repair. Low-LET irradiation induced many isolated DSBs throughout the nucleus, most of which were efficiently rejoined.ConclusionsThe clustering of DSBs in heterochromatin following high-LET irradiation perturbs efficient DNA repair, leading to greater biological effectiveness of high-LET irradiation versus that of low-LET irradiation.



http://ift.tt/2csgFae

Prospective swallowing outcomes after IMRT for oropharyngeal cancer: Dosimetric correlations in a population-based cohort

Publication date: October 2016
Source:Oral Oncology, Volume 61
Author(s): Gordon Z. Guo, Keith R. Sutherland, Candace Myers, Pascal Lambert, Shaun K. Loewen, Harvey C. Quon
ObjectivesTo identify dose constraints to preserve swallowing after head and neck (H&N) radiotherapy using prospectively collected functional outcomes.Materials and methodsStage III–IV oropharyngeal cancer patients were prospectively evaluated using the Royal Brisbane Hospital Outcome Measure for Swallowing and Performance Status Scale for H&N Cancer Patients at pre-treatment and 3, 6, 12, and 24months after intensity-modulated radiotherapy. Dosimetric parameters were correlated with swallowing function.ResultsNinety-six patients were evaluated with median follow-up of 14.1months (interquartile range 9.9–26.3). Six patients (8.3%) remained feeding tube (FT) dependent at 12months. At 2years, 32.6% tolerated a normal diet without restrictions. Mean doses of 55Gy to supraglottic larynx, 44Gy to glottic larynx, 48Gy to cricopharyngeus, and 44Gy to esophageal inlet were associated with >25% risk of FT dependence at 6months.ConclusionHigher mean doses to the larynx and pharyngo-esophageal junction were associated with longer duration of FT dependence and dietary restrictions.



http://ift.tt/2csupEX

Construct validity and responsiveness of Movakic: An instrument for the evaluation of motor abilities in children with severe multiple disabilities

Publication date: December 2016
Source:Research in Developmental Disabilities, Volume 59
Author(s): Sonja M. Mensch, Michael A. Echteld, Heleen M. Evenhuis, Eugène A.A. Rameckers
Movakic is a newly developed instrument for measurement of motor abilities in children with severe multiple disabilities, with a satisfactory feasibility and content validity and good inter-observer and test-retest reliability.The objective of this study was to investigate its construct validity and responsiveness to change.Sixty children with severe multiple disabilities (mean age 7.7 years, range 2–16) were measured using Movakic six times during 18 months. Construct validity was assessed by correlating Movakic scores with expert judgment. In order to assess responsiveness, scores during 3-months intervals were compared (mean score-changes and intraclass correlations) during which some children experienced meaningful events influencing motor abilities and during which others experienced no such event.Forty-five percent of children had a lower cognitive development level than 6-month, 52% had Gross Motor Function Classification System level V and 37% had level IV. For 27 children all measurements were completed, six children dropped out. Construct validity was good (r=0.50–0.71). Responsiveness was demonstrated by significantly larger score changes after events than when such events did not occur.Movakic is a valid instrument for measuring motor abilities in children with severe multiple disabilities. Results suggest responsiveness to change in motor abilities after meaningful events.



http://ift.tt/2cTIwBu

Serum Procalcitonin: An Independent Predictor of Clinical Outcome in Health Care-Associated Pneumonia

Background: Early prediction of the clinical outcomes for health care-associated pneumonia (HCAP) patients is challenging. Objectives: This is the first study to evaluate procalcitonin (PCT) as a predictor of outcomes in HCAP patients. Methods: We conducted an observational study based on data for HCAP patients prospectively collected between 2011 and 2014. Outcome variables were intensive care unit (ICU) admission and 30-day mortality. PCT was categorized into three groups: 2.0 ng/ml. We analysed multiple variables including age, sex, comorbidities, clinical findings, and PCT group to assess their association with outcomes. Results: Of 245 HCAP patients, 99 (40.4%) were admitted to an ICU and 44 (18.0%) died within 30 days. The median PCT level was significantly higher in the ICU admission (1.19 vs. 0.4 ng/ml; p 2.0 ng/ml) was strongly associated with ICU admission [odds ratio 3.734, 95% confidence interval (CI) 1.753-7.951; p = 0.001] and 30-day mortality (hazard ratio 2.254, 95% CI 1.250-5.340; p = 0.035). In receiver operating characteristic analysis, PCT had a poor discrimination power regarding ICU admission [0.695 of the area under the curve (AUC)] and a fair discrimination power regarding 30-day mortality in HCAP patients (0.768 of the AUC). Conclusions: High PCT on admission was strongly associated with ICU admission and 30-day mortality in HCAP patients. However, application of PCT alone seems to be limited to predicting outcomes.
Respiration

http://ift.tt/2cksIq9

Im Gedenken an Professor Dr. Dr. Michael Wannenmacher

http://ift.tt/2cA0Baa

Glycated albumin: from biochemistry and laboratory medicine to clinical practice

Abstract

This review summarizes current knowledge about glycated albumin. We review the changes induced by glycation on the properties of albumin, the pathological implications of high glycated albumin levels, glycated albumin quantification methods, and the use of glycated albumin as a complementary biomarker for diabetes mellitus diagnosis and monitoring and for dealing with long-term complications. The advantages and limits of this biomarker in different clinical settings are also discussed.

http://ift.tt/2c5Fqsa

Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease

Abstract

The long-term effect of therapeutic diets in obesity treatment is a challenge at present. The current study aimed to evaluate the long-term effect of a very low-calorie-ketogenic (VLCK) diet on excess adiposity. Especial focus was set on visceral fat mass, and the impact on the individual burden of disease. A group of obese patients (n = 45) were randomly allocated in two groups: either the very low-calorie-ketogenic diet group (n = 22), or a standard low-calorie diet group; (n = 23). Both groups received external support. Adiposity parameters and the cumulative number of months of successful weight loss (5 or 10 %) over a 24-month period were quantified. The very low-calorie-ketogenic diet induced less than 2 months of mild ketosis and significant effects on body weight at 6, 12, and 24 months. At 24 months, a trend to regress to baseline levels was observed; however, the very low-calorie-ketogenic diet induced a greater reduction in body weight (−12.5 kg), waist circumference (−11.6 cm), and body fat mass (−8.8 kg) than the low-calorie diet (−4.4 kg, −4.1 cm, and −3.8 kg, respectively; p < 0.001). Interestingly, a selective reduction in visceral fat measured by a specific software of dual-energy x-ray absorptiometry (DEXA)-scan (−600 g vs. −202 g; p < 0.001) was observed. Moreover, the very low-calorie-ketogenic diet group experienced a reduction in the individual burden of obesity because reduction in disease duration. Very low-calorie-ketogenic diet patients were 500 months with 5 % weight lost vs. the low-calorie diet group (350 months; p < 0.001). In conclusion, a very low-calorie-ketogenic diet was effective 24 months later, with a decrease in visceral adipose tissue and a reduction in the individual burden of disease.

http://ift.tt/2cbBOIb

Evaluation of a New Brain Tissue Probe for Cerebral Blood Flow Monitoring in an Experimental Pig Model.

BACKGROUND: Bedside monitoring of cerebral blood flow (CBF) may provide new insights into the pathophysiology of brain injury, allow early detection of secondary ischemia, and help guide therapy. OBJECTIVE: To evaluate a new brain tissue probe for serial CBF monitoring using near-infrared spectroscopy and indocyanine green dye dilution (NeMo Probe) compared with the existing thermal diffusion probe (QFlow 500 Probe). METHODS: In 7 pigs, the NeMo Probe and QFlow 500 Probe were inserted into the subcortical white matter. Parallel measurements were recorded during (1) baseline, (2) hypotension, (3) hypertension, and (4) hyperventilation. Thereafter, protocol points 1 through 4 were repeated once. The Spearman correlation (rs), Bland-Altman plot, concordance rate, and coefficient of variation were used for statistical analysis. RESULTS: There was poor agreement between 56 pairs of absolute CBF values (rs = 0.52, P

http://ift.tt/2c5EP9H

Analysis of semen parameters in a young cohort of cancer patients

Abstract

Background

Infertility can be the result of some common cancer treatments and can significantly impact quality of life. Semen cryopreservation allows for fertility preservation. We analyzed the semen parameters of specimens collected from pubertal males from the Children's Hospital of Philadelphia (CHOP) in order to expand current knowledge on the quality of these specimens and inform a standard clinical practice.

Procedure

Males who were at least Tanner stage III and newly diagnosed with cancer at CHOP were approached regarding sperm banking. The success and quality of the samples collected were analyzed and compared in relation to prior treatment, age, and diagnosis.

Results

From 399 patients approached for semen collection, 339 (85%) attempted to bank sperm, of which 265 (78%) were successful and 60 (15%) refused to participate. Therapy prior to sperm banking significantly impacted a successful collection (P < 0.01). Only 16.9% of the untreated patients were azoospermic, whereas 84.0% of the treated subjects were azoospermic. Older patients were less likely to be azoospermic and have a greater quality collection when compared with younger patients (P < 0.01). However, 65% of our youngest patients still were able to cryopreserve semen. There was no difference in azoospermia across diagnostic groups (P = 0.35), though there were differences in quality of semen parameters across diagnoses.

Conclusion

Our data support that sperm banking pubertal males prior to the initiation of therapy is feasible. While there were differences in quality of semen parameters across age and diagnostic groups, most males, regardless of age or diagnosis, had adequate specimens for cryopreservation.

http://ift.tt/2cVOvZu

Cranial epidural hematomas: A case series and literature review of this rare complication associated with sickle cell disease

Abstract

Background

Patients with sickle cell disease (SCD) may experience many complications of the central nervous system (CNS) including stroke, silent cerebral infarcts, and neuropsychological deficits. Cranial epidural hematoma is a rare but potentially serious complication.

Procedure

Case series of cranial epidural hematomas in children with SCD from three different institutions is considered, along with a literature review of cranial epidural hematomas in this population.

Results

Seven children with SCD with cranial epidural hematomas were identified from three different institutions. All patients were male and the age at presentation ranged from 10 to 18 years. Two patients presented with headache (28.6%), while the rest had no neurologic symptoms at presentation. Four patients required urgent neurosurgical intervention (57.1%) and one patient died (14.3%). A literature review identified 18 additional cases of cranial epidural hematomas in children with SCD. Of these, treatment ranged from supportive care to neurosurgical intervention. Twelve patients completely recovered (66.7%), one patient had long-term cognitive impairment (5.6%), and four patients died (22.2%). Combined with our data, cranial epidural hematomas have a mortality rate of 20.0%.

Conclusions

Although rare, cranial epidural hematoma can be fatal and should be considered in patients with acute neurological symptoms.

http://ift.tt/2cFiBya

Transcriptome and digital gene expression analysis of herbaceous peony ( Paeonia lactiflora Pall.) to screen thermo-tolerant related differently expressed genes

Abstract

Herbaceous peony (Paeonia lactiflora Pall.) is easily injured by heat stress (HS), which greatly restricts its application and promotion. In this study, the thermo-tolerance of three representative P. lactiflora cultivars had been firstly assessed. 'Zifengyu' was identified as the thermo-tolerant cultivar with relatively lower values and smaller variations in malondialdehyde, hydrogen peroxide (H₂O₂) and proline contents under HS. Subsequently, their transcriptomes were sequenced by RNA sequencing (RNA-seq) technology to construct a complete database. 81,599 unigenes were obtained, and 34,940 unigenes had been annotated. Moreover, through digital gene expression analysis of thermo-tolerant 'Zifengyu' and moderately thermo-tolerant 'Hongyanzhenghui', 161 heat stress response genes had been screened involving heat shock protein genes, plant hormone signal transduction related genes, fatty acid synthesis genes, reactive oxygen species-scavenging genes and secondary metabolites related genes. And the effectively and timely response of these genes to HS could endow thermo-tolerance to 'Zifengyu'. Among these genes, 11 key thermo-tolerant related genes whose expressions were all significantly up-regulated in 'Zifengyu' and 'Hongyanzhenghui' during development and the former possessed higher levels could be regarded as the candidate genes, including isoprene synthase gene, 2 peroxidase genes, 3-oxoacyl-acyl carrier protein reductase gene (FabG), 3 transcription factor genes (bHLH, NAC and WRKY), HSP20 and 3 HSP70. These results could provide a better understanding of heat stress response in P. lactiflora, and pave for the breeding of thermo-tolerant cultivars.

http://ift.tt/2cAwSh4

Bacteriological profile and antibiotic sensitivity patterns of blood cultures

2016-09-13T00-32-58Z
Source: International Journal of Contemporary Pediatrics
K. Ashwin Reddy, S. Uday Kanth.
ABSTRACT Background: Neonatal septicemia is a significant cause of morbidity and mortality worldwide especially so in developing countries. To reduce the mortality caused by neonatal septicemia, it became vital to diagnose it as soon as possible and treat with administration of appropriate antibiotics. The objective of the study was bacteriological spectrum in blood culture of neonates admitted in a hospital, and antibiotic susceptibility pattern of blood culture positive isolates. Methods: A total of 593 blood culture sample were received from NICU admissions for a period of 15 months were included for this study. Under aseptic precautions, 1 ml of blood was collected from a peripheral vein and inoculated into a bottle of Brain Heart Infusion broth and was incubated for 7 days. Repeated sub-culturing was done as per standard procedures. Inoculation on blood agar and Mac-Conkeys agar plates were made. Any growth was subjected for identification by appropriate biochemical tests. Antibiotic susceptibility testing was done by disc diffusion method. Results: Of the 593 cases studied 12.14 % were blood culture positive. Among the blood culture positive neonates 67% were male neonates. Late onset septicemia (87.5%) was more common than early onset septicemia (12.5%). Gram negative organisms 46 (63.88%) were predominant than Gram positive organisms 18 (25%). Klebsiella pneumonia 18 (25%), Citrobacter 10 (13.88%), and Pseudomonas auroginosa was found in 7 (9.72%). The other organisms isolated were Escherichia coli 06 (8.33%), Enterobacter 04 (5.55%), Gram positive organisms were obtained in 18 (25.00%) out of 72 cases. MSSA 06 (8.33%), Enterococci 06 (8.33%) was the commonest organisms isolated. Most of the isolates were more susceptible imipenem, meropenem, and ciprofloxacin to amikacin antibiotics. Conclusions: Blood culture remains the gold standard for the diagnosis of neonatal septicemia. Periodic surveillance of organisms and their antibiotic sensitivity patterns are essential to understand and to prevent emergence of resistant organisms. Effective/Correct selection of antibiotic is essential to decrease mortality and morbidity in the vulnerable group of neonatal population.


http://ift.tt/2cJi2Cf

Effect of porous layer engineered with acid vapor etching on optical properties of solid silicon nanowire arrays

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Chohdi Amri, Rachid Ouertani, Abderrahmean Hamdi, Radhouane Chtourou, Hatem Ezzaouia
In this paper, we report, for the first time, an investigative study involving the engineering of lightly doped porous silicon nanowire arrays (pSiNWs) by exposing solid silicon nanowire arrays (SiNWs) to an acid vapor emanating from HF/HNO3 hot solution. SEM and TEM images exhibit vertically distributed SiNW arrays on the whole silicon (Si) surface with relatively smooth surface sidewalls. By submitting the SiNW arrays to Acid Vapor Etching (AVE), they become porous with a substantial decrease in their densities and lengths. Increasing etching duration leads to a higher porosity without affecting the wire diameter which remains almost constant nearly 100nm. Exceeding a critical etching duration, a porous structure is observed superseding the SiNW structure. The morphological characterizations have been correlated to the optical properties. We note a blue shift of the strong visible photoluminescence (PL) bands after AVE treatment due to the decrease of the silicon quantum dots diameter (Si-QDs). UV–Visible measurement shows a decrease of the total reflectivity by 5% after AVE treatment.

Graphical abstract

http://ift.tt/2cs8Otl

Bienzymatic nanoreactors composed of chloroperoxidase–glucose oxidase on Au@Fe3O4 nanoparticles: Dependence of catalytic performance on the bioarchitecture

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Fengqin Gao, Yucheng Jiang, Mancheng Hu, Shuni Li, Quanguo Zhai
The operational stability of chloroperoxidase (CPO) was considerably enhanced by coupling with glucose oxidase (GOx) because H2O2 could be generated in situ from glucose and oxygen. In this paper, a CPO–GOx nanoreactor was fabricated on the surface of Au@Fe3O4 nanoparticles through layer-by-layer assembly using the specific avidin–biotin interaction. The X-ray diffraction data indicated the presence of both Fe and Au in the Au@Fe3O4 carrier. The Au@Fe3O4 displayed a uniform core/shell nanostructure, whereas the nanoparticles of the bienzymatic reactor were larger than the carrier. The catalytic activity of CPO was highly dependent on the structure of the enzymatic nanoreactor. The activity of Au@Fe3O4–GOx (inner)–CPO (outer) was 15.5% higher than that of Au@Fe3O4–CPO (inner)–GOx (outer). Moreover, Au@Fe3O4–GOx–CPO exhibited better thermostability. Au@Fe3O4–GOx–CPO retained 53.2% of its initial activity after incubation for 1.0h at 60°C and 30.4% of its initial activity after 18h at 50°C. Au@Fe3O4–GOx–CPO had good reusability. It retained more than 62.4% of its activity after the 12th cycle. This was attributed to the cage-like structure in Au@Fe3O4–GOx–CPO, which could effectively prevent the removal of the enzyme molecules from the carrier.

Graphical abstract

http://ift.tt/2cs94bK

LaPO4 as a toughening agent for rare earth zirconate ceramics

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Caimei Wang, Lei Guo, Fuxing Ye
Gd2Zr2O7−x mol% LaPO4 (x=0, 10, 20, 30, 40, 50, 60, 100) composites were produced, and their phase constitution and toughness were investigated. XRD and Raman spectra results revealed that Gd2Zr2O7 pyrochlore and LaPO4 monazite phases were compatible in Gd2Zr2O7-LaPO4 composite, and no chemical reaction occurred. TEM analysis demonstrated the coexistence of Gd2Zr2O7 and LaPO4 phases. The toughness of Gd2Zr2O7-LaPO4 composite first increased with the increase of the LaPO4 content, followed by a downward trend. The layer-structure of LaPO4 phase and its weak bond with Gd2Zr2O7 matrix could cause the initial increase in the toughness, and the growth of LaPO4 grains might contribute to the reduced toughness. Considering the fact that rare earth zirconates have similar structure and properties, it could be expected that LaPO4 can be designed as a toughening agent for all the compounds, but there exists an optimal LaPO4 addition content for desirable toughness.

Graphical abstract

http://ift.tt/2cs84V0

Influence of intrinsic strain on irradiation induced damage: the role of threshold displacement and surface binding energies

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): J. Guénolé, A. Prakash, E. Bitzek
Focused ion beam (FIB) machining has become a standard tool for sample preparation and in combination with digital image correlation (DIC) for the evaluation of local intrinsic stresses by measuring strain relaxation. However, FIB milling always leads to irradiation damage of the material. Current models for the formation of irradiation damage and the sputter yield are based on two key parameters, the threshold displacement energy (TDE) and surface binding energy (SBE), which are usually determined from unstrained systems with idealized surfaces. Here we use atomistic simulations to determine the TDE and SBE for strained silicon and aluminum and compare the results to full cascade simulations. A clear, material class dependent influence of the strain state on the TDE is observed, and surface amorphisation is shown to significantly increase the SBE of {001} surfaces.

Graphical abstract

http://ift.tt/2cs8rPl

Influence of ω phase precipitation on mechanical performance and corrosion resistance of Ti–Nb–Zr alloy

Publication date: 5 December 2016
Source:Materials & Design, Volume 111
Author(s): Qiang Li, Junjie Li, Guanghao Ma, Xuyan Liu, Deng Pan
A recently investigated Ti–24at.% Nb–2at.% Zr alloy was cold-rolled with reductions of 75% and 95%, and the resulting materials were heat-treated under the same conditions. The two types of specimens obtained through this procedure show the same phase composition. Precipitation of an isothermal ω phase leads to some improvement in the properties of the 75%-rolled specimens. The 95%-rolled and subsequently heated specimens exhibit different performances compared to the 75%-rolled samples heated under the same processing conditions. The stress-induced martensitic transformation is inhibited in the 95%-rolled specimens, owing to the combined effects of the isothermal ω phase and texture. The Ti–24at.% Nb–2at.% Zr alloy shows open circuit potential and corrosion behavior similar to commercially pure Ti. The corrosion resistance of the alloy is reduced upon precipitation of the ω phase, owing to an unstable passive film.

Graphical abstract

http://ift.tt/2cs8j28

Functional Foods : Did you know that certain foods or food components may provide health and wellness benefits? These foods, also known as “functional foods,” are thought to provide benefits beyond basic nutrition and may play a role in reducing or minimizing the risk of certain diseases and other health conditions. Examples of these foods include fruits and vegetables, whole grains, fortified foods and beverages and some dietary supplements. Functional characteristics of many traditional foods are being discovered and studied, while new food products are being developed to include beneficial components. By knowing which foods can provide specific health benefits,you can make food and beverage choices that allow you to take greater control of your health. http://www.foodinsight.org/Content/3842/Final%20Functional%20Foods%20Backgrounder.pdf

https://plus.google.com/109691449614437014953/posts/H5g5mRaKegs

​

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

EmboTrap II Clot Retriever for Acute Ischemic Stroke Cleared in Europe

Neuravi, a company out of Galway, Ireland, won the European CE Mark for its EmboTrap II Revascularization Device to treat acute ischemic stroke. The device is made to trap clots, deliver TICI 2b-3 reperfusion, and consistently grab onto the clot as it's removed from the patient.

Based on the original EmboTrap that came to market in Europe last year, the new device is intended to treat a greater range of clot lengths via a .021″ microcatheter.

"The EmboTrap platform has been a great addition to my clinical practice. In my first nine cases using the device, I was able to get TICI 2b-3 reperfusion in one pass. Now with the EmboTrap II, I've had comparably good results when treating longer occlusions," said Christian Taschner, M.D., professor of Radiology, University of Freiburg, Germany, in a press release. "In fact, in early evaluations of the EmboTrap II 5×33 at six centers, 16 of 17 cases resulted in TICI 2b-3 flow. The open design of the device helps trap clot inside and also makes it quite flexible, which is important when removing clot from the arteries of the brain."

Product page: emboTrap II…

Press release: Neuravi…

This post EmboTrap II Clot Retriever for Acute Ischemic Stroke Cleared in Europe appeared first on Medgadget.

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Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: A comparison across three assays

Abstract

Context

The short ACTH stimulation test (250μg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds.

Objective

To propose a morning baseline cortisol criterion of three of the most commonly-used modern cortisol immunoassays - Advia Centaur (Siemens), Architect (Abbott) and the Roche Modular System (Roche) - that could predict adrenal sufficiency.

Design

Observational, retrospective cross-sectional study at two centres.

Patients and Measurements

Retrospective analysis of the results of 1019 SSTs with the Advia Centaur, 449 SSTs with the Architect, and 2050 SSTs with the Roche Modular System assay. Serum cortisol levels were measured prior to injection of 250μg Synacthen and after 30 minutes. Overall, we were able to collate data from a total of 3518 SSTs in 3571 patients.

Results

Using receiver-operator curve analysis, baseline cortisol levels for predicting passing the SST with 100% specificity were 358 nmol/l for Siemens, 336 nmol/l for Abbott and 506 nmol/l for Roche. Utilising these criteria: 589, 158 and 578 SSTs respectively for Siemens, Abbott and Roche immunoassays could have been avoided.

Conclusions

We have defined assay-specific morning cortisol levels that are able to predict the integrity of the hypothalamo-pituitary-adrenal axis. We propose that this represents a valid tool for the initial assessment of adrenal function and has the potential to obviate the need for dynamic testing in a significant number of patients.

This article is protected by copyright. All rights reserved.

http://ift.tt/2c3oAdr

Reversal of congenital hypogonadotropic hypogonadism in a man with Kallmann syndrome due to SOX10 mutation

Abstract

Congenital hypogonadotropic hypogonadism (CHH) with either normal olfaction or anosmia (Kallmann syndrome (KS)) is a cause of pubertal failure secondary to pituitary gonadotropin deficiency. It appears during fetal life and persists throughout the postnatal, pre- and post-pubertal periods (1). For many years KS was considered to be a genetic disorder in which CHH persists throughout life, but case series of KS/CHH reported over the past 15 years show that gonadotropin and testicular functions can recover spontaneously, partially or completely (2,3).

This article is protected by copyright. All rights reserved.

http://ift.tt/2c550m1

Botulinum toxin injection for contouring shoulder

http://ift.tt/2ck9bYf

Herpesviral-bacterial co-infection in mandibular third molar pericoronitis

Abstract

Objective

The aim of this study was to assess the presence of herpesviruses and periodontopathic bacteria and to establish their potential association with pericoronitis.

Materials and methods

Fifty samples obtained with paper points (30 from pericoronitis and 20 controls) were subjected to polymerase chain reaction (PCR) analysis. A single-stage and nested PCR assays were used to detect herpesviruses: human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) and six periodontopathic anaerobic bacteria: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Parvimonas micra, Treponema denticola, and Tannarella forsythia.

Results

Pericoronitis samples harbored HCMV and EBV at significantly higher rates than the control group (70 vs. 40 % and 46.7 vs. 15 %, P = 0.035, P = 0.021, respectively). P. micra and T. forsythia (66.7 vs. 0 %, and 40 vs. 10 %, P = 0.001, P = 0.021, respectively) were significantly more common in pericoronitis compared to the control group. Multivariate logistic regression analysis showed that the presence of T. forsythia was associated with pericoronitis development (OR 7.3, 95 % CI, 1.2–43.2, P = 0.028).

Conclusion

The occurrence of HCVM and EBV extends our previous knowledge on microbiota in pericoronitis. These PCR-based findings demonstrated that bacterial and viral DNA occurred concomitantly in pericoronitis samples. T. forsythia appeared to be significantly associated with pericoronitis development in the examined sample.

Clinical relevance

Herpesviral-bacterial co-infections might exacerbate the progression of pericoronitis.

http://ift.tt/2cijMld

Herpesviral-bacterial co-infection in mandibular third molar pericoronitis

Abstract

Objective

The aim of this study was to assess the presence of herpesviruses and periodontopathic bacteria and to establish their potential association with pericoronitis.

Materials and methods

Fifty samples obtained with paper points (30 from pericoronitis and 20 controls) were subjected to polymerase chain reaction (PCR) analysis. A single-stage and nested PCR assays were used to detect herpesviruses: human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) and six periodontopathic anaerobic bacteria: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Parvimonas micra, Treponema denticola, and Tannarella forsythia.

Results

Pericoronitis samples harbored HCMV and EBV at significantly higher rates than the control group (70 vs. 40 % and 46.7 vs. 15 %, P = 0.035, P = 0.021, respectively). P. micra and T. forsythia (66.7 vs. 0 %, and 40 vs. 10 %, P = 0.001, P = 0.021, respectively) were significantly more common in pericoronitis compared to the control group. Multivariate logistic regression analysis showed that the presence of T. forsythia was associated with pericoronitis development (OR 7.3, 95 % CI, 1.2–43.2, P = 0.028).

Conclusion

The occurrence of HCVM and EBV extends our previous knowledge on microbiota in pericoronitis. These PCR-based findings demonstrated that bacterial and viral DNA occurred concomitantly in pericoronitis samples. T. forsythia appeared to be significantly associated with pericoronitis development in the examined sample.

Clinical relevance

Herpesviral-bacterial co-infections might exacerbate the progression of pericoronitis.

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Improving and accelerating the differentiation and functional maturation of human stem cell-derived neurons: role of extracellular calcium and GABA

Abstract

Neurons differentiated from pluripotent stem cells using established neural culture conditions often exhibit functional deficits. Recently, we have developed enhanced media which both synchronise the neurogenesis of pluripotent stem cell-derived neural progenitors and accelerate their functional maturation; together these media are termed SynaptoJuice. This pair of media are pro-synaptogenic and generate authentic, mature synaptic networks of connected forebrain neurons from a variety of induced pluripotent and embryonic stem cell lines. Such enhanced rate and extent of synchronised maturation of pluripotent stem cell-derived neural progenitor cells generates neurons which are characterised by a relatively hyperpolarized resting membrane potential, higher spontaneous and induced action potential activity, enhanced synaptic activity, more complete development of a mature inhibitory GABA_A receptor phenotype and faster production of electrical network activity when compared to standard differentiation media. This entire process - from pre-patterned neural progenitor to active neuron - takes 3 weeks or less, making it an ideal platform for drug discovery and disease modelling in the fields of human neurodegenerative and neuropsychiatric disorders, such as Huntington's disease, Parkinson's disease, Alzheimer's disease or Schizophrenia.

This article is protected by copyright. All rights reserved

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Regenerative potential of human airway stem cells in lung epithelial engineering

Publication date: November 2016
Source:Biomaterials, Volume 108
Author(s): Sarah E. Gilpin, Jonathan M. Charest, Xi Ren, Luis F. Tapias, Tong Wu, Daniele Evangelista-Leite, Douglas J. Mathisen, Harald C. Ott
Bio-engineered organs for transplantation may ultimately provide a personalized solution for end-stage organ failure, without the risk of rejection. Building upon the process of whole organ perfusion decellularization, we aimed to develop novel, translational methods for the recellularization and regeneration of transplantable lung constructs.We first isolated a proliferative KRT5⁺TP63⁺ basal epithelial stem cell population from human lung tissue and demonstrated expansion capacity in conventional 2D culture. We then repopulated acellular rat scaffolds in ex vivo whole organ culture and observed continued cell proliferation, in combination with primary pulmonary endothelial cells. To show clinical scalability, and to test the regenerative capacity of the basal cell population in a human context, we then recellularized and cultured isolated human lung scaffolds under biomimetic conditions. Analysis of the regenerated tissue constructs confirmed cell viability and sustained metabolic activity over 7 days of culture. Tissue analysis revealed extensive recellularization with organized tissue architecture and morphology, and preserved basal epithelial cell phenotype. The recellularized lung constructs displayed dynamic compliance and rudimentary gas exchange capacity. Our results underline the regenerative potential of patient-derived human airway stem cells in lung tissue engineering. We anticipate these advances to have clinically relevant implications for whole lung bioengineering and ex vivo organ repair.

Graphical abstract

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Bamboo (Acidosasa edulis) shoot shell biochar: Its potential isolation and mechanism to perrhenate as a chemical surrogate for pertechnetate

Publication date: December 2016
Source:Journal of Environmental Radioactivity, Volume 165
Author(s): Hui Hu, Bangqiang Jiang, Huixiong Wu, Jubin Zhang, Xiaohui Chen
In this work, a biochar was prepared from bamboo (Acidosasa edulis) shoot shell through slow pyrolysis (under 300–700 °C). Characterization with various tools showed that the biochar surface was highly hydrophobic and also had more basic functional groups. Batch sorption experiments showed that the biochar had strong sorption ability to perrhenate (a chemical surrogate for pertechnetate) with maximum sorption capacity of 46.46 mg/g, which was significantly higher than commercial coconut shell activated carbon and some adsorbents reported previously. Desorption experiments showed that more than 94% of total perrhenate adsorbed could be recovered using 0.1 mol/L KOH as a desorption medium. Pearson correlation analysis showed that the recovery of perrhenate by the biochars was mainly through surface adsorption mechanisms involving both high hydrophobicity and high basic sites of biochar surface.

Graphical abstract

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Chemical fractionation of radium-226 in NORM contaminated soil from oilfields

Publication date: December 2016
Source:Journal of Environmental Radioactivity, Volume 165
Author(s): Jamal Al Abdullah, Mohammad Said Al-Masri, Yusr Amin, Ibrahim Awad, Zuhair Sheaib
Contamination of soil with ²²⁶Ra is a common problem in the oilfields, leading to costly remediation and disposal programmes. The present study focuses on the chemical fractionation and mobility of ²²⁶Ra in contaminated soils collected from an oilfield using a three-step sequential extraction procedure (BCR). The total activity concentrations of ²²⁶Ra in contaminated soils were measured and found to be in the range from 1030 ± 90 to 7780 ± 530 Bq kg⁻¹, with a mean activity concentration of 2840 ± 1840 Bq kg⁻¹. The correlation between the total concentration of ²²⁶Ra and soil properties, mainly pH, LOI, Corg, clay and Ca, was investigated using the principal component analysis method (PCA). The chemical fractionation of ²²⁶Ra was studied using the sequential extraction method (BCR). The highest fraction of ²²⁶Ra (27–65%) was found to be in the acid-reducible fraction, which suggests that ²²⁶Ra is mainly bound to FeMn oxides. The BCR method showed that high percentages of ²²⁶Ra were found to be in mobile soil phases (between 45 and 99%). Consequently, groundwater contamination could occur due to the remobilization of ²²⁶Ra from soils under normal environmental conditions. However, the obtained results could be useful to reduce the volume of NORM wastes generated from the oilfields and decision-making process for final treatment and disposal of NORM-contaminated soil.



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Studying factors affecting the indoor gamma radiation dose using the MCNP5 simulation software

Publication date: December 2016
Source:Journal of Environmental Radioactivity, Volume 165
Author(s): M. Orabi
Different factors and parameters affecting the indoor gamma radiation dose are considered and investigated. The change of the dose with different positions inside the room is discussed. The relative doses are also calculated for different changes; with different room dimensions, different wall thicknesses, and different building material densities. Some other factors are also discussed. The study is carried out by executing some models designed by the MCNP version 5 simulation software. The calculations of the dose rates are performed by adopting a simple and convenient calculation model which is based on the obtained relative changes of the dose rates with the different factors.



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Toxins, Vol. 8, Pages 267: Bioactivation and Regioselectivity of Pig Cytochrome P450 3A29 towards Aflatoxin B1

Due to unavoidable contaminations in feedstuff, pigs are easily exposed to aflatoxin B1 (AFB1) and suffer from poisoning, thus the poisoned products potentially affect human health. Heretofore, the metabolic process of AFB1 in pigs remains to be clarified, especially the principal cytochrome P450 oxidases responsible for its activation. In this study, we cloned CYP3A29 from pig liver and expressed it in Escherichia coli, and its activity has been confirmed with the typical P450 CO-reduced spectral characteristic and nifedipine-oxidizing activity. The reconstituted membrane incubation proved that the recombinant CYP3A29 was able to oxidize AFB1 to form AFB1-exo-8,9-epoxide in vitro. The structural basis for the regioselective epoxidation of AFB1 by CYP3A29 was further addressed. The T309A mutation significantly decreased the production of AFBO, whereas F304A exhibited an enhanced activation towards AFB1. In agreement with the mutagenesis study, the molecular docking simulation suggested that Thr309 played a significant role in stabilization of AFB1 binding in the active center through a hydrogen bond. In addition, the bulk phenyl group of Phe304 potentially imposed steric hindrance on the binding of AFB1. Our study demonstrates the bioactivation of pig CYP3A29 towards AFB1 in vitro, and provides the insight for understanding regioselectivity of CYP3A29 to AFB1.

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Are some agents less likely to deposit gadolinium in the brain?

Publication date: Available online 11 September 2016
Source:Magnetic Resonance Imaging
Author(s): Alexander Radbruch
In December 2013, a groundbreaking study by Kanda et al. was published showing that the serial injection of gadolinium based contrast agents (GBCAs) is correlated with a signal intensity increase in the dentate nucleus (DN) and the globus pallidus (GP) on unenhanced T1 weighted MR images. Subsequent studies by Kanda et al. and McDonald et al. on brain tissue from deceased patients provided evidence that the reported signal intensity increase in the brain correlates with gadolinium deposits in the brain tissue. In the following, multiple retrospective patient studies and animal studies assessed the potential of the marketed GBCAs to cause hyperintensities or gadolinium deposits in the brain, respectively. This review summarizes the evidence provided by these studies and additionally takes into account data from in vitro studies on the stability of GBCAs. The author concludes that there is a body of evidence suggesting that the potential of a GBCA to cause hyperintensities or gadolinium deposition in the brain corresponds with its stability and is particularly depending on the group of the specific GBCA as either linear or macrocyclic.



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The American Association for the Surgery of Trauma grading scale for 16 emergency general surgery conditions: Disease-specific criteria characterizing anatomic severity grading

No abstract available

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What is the effectiveness of the negative pressure wound therapy (NPWT) in patients treated with open abdomen technique? A systematic review and meta-analysis

BACKGROUND: The open abdomen technique may be used in critically ill patients to manage abdominal injury, reduce the septic complications, and prevent the abdominal compartment syndrome. Many different techniques have been proposed and multiple studies have been conducted, but the best method of temporary abdominal closure has not been determined yet. Recently, new randomized and nonrandomized controlled trials have been published on this topic. We aimed to perform an up-to-date systematic review on the management of open abdomen, including the most recent published randomized and nonrandomized controlled trials, to compare negative pressure wound therapy (NPWT) with no NPWT and define if one technique has better outcomes than the other with regard to primary fascial closure, postoperative 30-day mortality and morbidity, enteroatmospheric fistulae, abdominal abscess, bleeding, and length of stay. METHODS: According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions, an online literature research (until July 1, 2015) was performed on MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, and Cochrane Library databases. The MeSH terms and free words used "vacuum assisted closure" "vac;", "open abdomen", "damage control surgery", and "temporary abdominal closure". No language restriction was made. RESULTS: The initial systematic literature search yielded 452 studies. After a careful assessment of the titles and of the full text was obtained, eight articles fulfilled inclusion criteria. We analyzed 1,225 patients, of whom 723 (59%) underwent NPWT and 502 (41%) did not undergo NPWT, and performed four subgroups: VAC versus Bogota bag technique (two studies, 106 participants), VAC versus mesh-foil laparostomy (two studies, 159 participants), VAC versus laparostomy (adhesive impermeable with midline zip) (one study, 106 participants), and NPWT versus no NPWT techniques (three studies, 854 participants) in which it is not possible to perform an analysis of the different types of treatment. Comparing the NPWT group and the group without NPWT, there was no statistically significant difference in fascial closure (63.5% vs 69.5%; odds ratio [OR], 0.74; 95% confidence interval [CI], 0.27–2.06; p = 0.57), postoperative 30-day overall morbidity (p = 0.19), postoperative enteroatmospheric fistulae rate (2.1% vs 5.8%; OR, 0.63; 95% CIs, 0.12–3.15; p = 0.57), in the postoperative bleeding rate (5.7% vs 14.9%; OR, 0.58; 95% CIs, 0.05–6.84; p = 0.87), and postoperative abdominal abscess rate (2.4% vs 5.6%; OR, 0.42; 95% CI, 0.13–1.34; p = 0.14). On the other hand, statistical significance was found between the NPWT group and the group without NPWT in the postoperative mortality rate (28.5% vs 41.4%; OR, 0.46; 95% CI, 0.23–0.91; p = 0.03) and in the length of stay in the intensive care unit (mean difference, −4.53; 95% CI, −5.46 to 3.60; p

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DESIGN AND DOCKING STUDY OF SOME (E)-N'-(SUBSTITUTED-BENZYLIDENE)-2-(2-CHLORO-4-FLUOROPHENYL) ACETOHYDRAZIDE COMPOUNDS FOR ANTI-MICROBIAL ACTIVITY

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Ajit Kumar Mishra*, Neha Singh, Manju Kumari, Binita Kumari, Birendra Kumar, Divya Mishra.
In this work, we collected the three dimensional structure of Enterotoxin B which plays an important role in staphylococcus pathway. The protein structures were collected from PDB data bank. From the 3D structures of the proteins, the targeted derivatives were designed. Docking studies was performed with designed ligands from the drug. The drug derivatives docked to the protein by hydrogen boding interactions and these interactions play an important role in the binding studies. Docking results showed the best compounds among the derivatives.


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FORMULATION AND EVALUATION OF FAST MOUTH DISSOLVING CHEWABLE TABLET OF ALBENDAZOLE

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Dr. O. G. Bhusnure*, Shaikh Faisal Ekbal, Mane Jyoti, Sayyed Sarfaraz Ali, Hucche Bhimashankar, Surkute Ganesh.
Fast dissolving tablet format is designed to allow administration of an oral solid dose form in the absence of water or fluid intake. Such tablets readily dissolve or disintegrate in the saliva. Albendazole is anthalmentic agent which is used in disease like worms. As a vermicidal,albendazole causes degenerative alterations in the intestinal cells of the worm by binding to the colchicine-sensitive site of tubulin, thus inhibiting its polymerization or assembly into microtubules. It is a BCS class II drug. It exhibits poor bioavailability of about

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DEVELOPMENT OF VALIDATED SPECTROFLUORIMETRIC METHOD FOR THE ESTIMATION OF BUCLIZINE HYDROCHLORIDE FROM THE TABLET DOSAGE FORM

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
A. Suganthi*, A. Fathimunnisa, S. Sumithra and T.K. Ravi.
Buclizine hydrochloride from its tablet dosage form was estimated by developing a novel validated indirect spectrofluorimetric method. Here the Buclizine hydrochloride was derivatized into nitro compound using nitrating mixture with an aid of heat which showed good fluorescence in water at 446 nm after excited at 350 nm. The calibration graph showed linear over the range 200-1000 ng/ml. The assay of buclizine hydrochloride in marketed formulations was found to be 98.96 ± 0.1586. Recovery values were close to 100% with the % RSD values of 0.432% and 0.673% at 50% and 100% level respectively. From the results of validation it was observed that the method was found to be simple, accurate, sensitive and reproducible. Hence the proposed method can be used for routine quality control analysis.


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FATTY ACID BINDING PROTEIN-1 (FABP-1) OF ECHINOCOCCUS GRANULOSUS- A PROMISING VACCINE CANDIDATE- AN IN SILICO ANALYSIS

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Varun Chauhan, Gurjeet Kaur, Naveen, Kapil Goyal, Rakesh Sehgal.
E. granulosus responsible for causing Cystic echinococcosis (CE), a highly pathogenic infection, is causing considerable morbidity and mortality in humans. Fatty Acid Binding Proteins have been suggested to be promising vaccine candidates against several parasitic Platyhelminthes. The present study was thus aimed to identify HLA class I (HLA*A-02:01) restricted T cell epitopes, one of the most common occurring HLA Class I allele in human population, and B cell epitopes by screening of FABP-1 protein of E. granulosus using in-silico approach. The most promising predicted T cell epitopes were docked with HLA-*A 02:01 allele in order to ascertain the binding pattern of the identified peptides and HLA allele. The identified B and T cell epitopes were confirmed by visualizing there locations on the 3D model of FABP-1 protein. We believe that the present study will further help the researchers in better understanding the immune responses generated in an intermediate host in response to FABP protein of the parasite and may provide a platform to facilitate subunit vaccine design.


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NOVEL RP-HPLC-PDA METHOD FOR THE ESTIMATION OF CHLORPHENIRAMINE MALEATE IN BULK AND DOSAGE FORMS

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Ramya.V, Vijaya Lakshmi .M*, Pravallika .M, Buchi N. Nalluri.
A simple, precise and accurate RP-HPLC-PDA method has been developed and validated for the estimation of Chlorpheniramine Maleate, an antihistaminic in bulk and pharmaceutical dosage forms. It is a synthetic first generation alkylamine developed for the treatment of allergic conditions. Chromatography was carried out on an Inertsil C18 (250 x4.6mm, 5μm) column with a mobile phase combination of 10mM Ammonium Acetate and Acetonitrile in the ratio of 40:60v/v. The detection wavelength was carried out at 220 nm. The flow rate is 1.2 ml/min. The retention time is 5.122 minutes. The linearity was found in the range of 5-25μg/ml (r=0.999) and percent RSD is less than 2. The mean recoveries obtained for Chlorpheniramine Maleate were in the range of 98.77-99.42%. The LOD and LOQ values were found to be 0.315μg/ml and 0.949μg/ml. The method was validated as per ICH guidelines and can be applied for quality control analysis of Chlorpheniramine Maleate in bulk and pharmaceutical dosage forms.


http://ift.tt/2cCL9Z4

IDENTIFICATION OF NATURAL LEAD MOLECULES OF CENTELLA ASIATICA AND AZADIRACHTA INDICA TARGETING CHOLERA TOXIN THROUGH STRUCTURE BASED DRUG DESIGN

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Kishore Sarma, Biswajyoti Borkakoty*, Pratap Parida, Sudipta Sankar Bora, P. K. Mohapatra, Dipanakar Biswas, Jagadish Mahanta.
Vibrio cholerae, the causative organism of cholera, infects the small intestine causing severe diarrhea that can lead to death if untreated. Cholera toxin (CT) is primarily responsible for exhibiting the cholera symptoms. Although in numerous study, anticholera activity of Centella asiatica and Azadirachta indica has been evaluated and proved, the active principles and their modes of action are still elusive. In order to unveil the active principles of Centella asiatica and Azadirachta indica as potential inhibitor of CT, a ligand library of the reported compounds from these two plants was prepared and was used for molecular docking against three putative drug targets of CT. Progressive knowledge of computer aided drug designing approach was employed to screen out novel lead candidates. Comparative molecular docking analysis inferred that kaempferol 7-O-glucoside, a flavonol glucoside of Centella asiatica had the highest binding affinity with two of the selected drug targets and third best binding affinity with the third drug target of CT. In silico ADME/Tox profiling showed least toxicity with low bioavailibility. This study suggested that kaempferol 7-O-glucoside has the highest binding affinity with the identified ligandable sites of active CT and may be considered as a candidate inhibitor of CT in the lumen of gastrointestinal tract. Further clinical trials of kaempferol 7-O-glucoside may lead to a candidate drug molecule to fight against cholera infection.


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FORMULATION AND EVALUATION OF HERBAL EMULGEL OF LANTANA CAMARA LEAVES EXTRACT FOR WOUND HEALING ACTIVITY IN DIABETIC RATS

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Sk. Shaheda Sultana*, G.Swapna, G. Sai Sri Lakshmi, S. Swathi, G. Nirmala Jyothi, A. Seetha Devi.
The main aim of this work was to formulate the leaf extract of Lantana camara in to an emulgel and investigate their excision wound healing activity in Diabetic rats. Ethanolic extract of dried leaves of Lantana camara were subjected to preliminary phytochemical evaluation. Emulgel formulations were prepared using different types of gelling agents: Carbopol 934, Na CMC, HPMC, HPMC K15M, and HEC. The influence of the type of the gelling agent on the drug release from the prepared emulgel was investigated. The prepared emulgel were evaluated for their physical appearance, pH, Viscosity, Spreadability, in-vitro drug release, pharmacological activity and stability. From the results it was found that the formulation EGF2 with 1%w/w Sodium CMC shows better drug release (92.8% at 8 h) and higher pharmacological activity compared to other formulations. Herbal emulgel of ethanolic extract of Lantana camara shows significant improvement in excision wound contraction and hence this is a promising candidate for wound healing in diabetic rats.


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MONITORING OF ADVERSE DRUG REACTIONS (ADR) IN CHRONIC MYELOID LEUKEMIA (CML) PATIENTS TREATED WITH IMATINIB AT A TERTIARY CARE HOSPITAL

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Thanmaya S., Geetha K.M*.
Imatinib is a tyrosine kinase inhibitor and potently inhibits protein tyrosine kinases which include BCR-ABL which is constitutively active in CML. It targets the ATP binding site of receptors. The present investigation was carried out to monitor the adverse reactions of the drug Imatinib mesylate prescribed for chronic myeloid leukemia (CML) patients of different phases. All subjects defined as per the inclusion criteria were included in the study after obtaining the written informed consent. Detailed histories of the patients were gathered by discussions held with the doctors, nurses and the patient attendees. Disease responses were assessed with respect to BCR-ABL. Patients were then checked for the preexisting adverse reactions and were first treated for that before they were included in the study. Later these patients were treated with Tab Imatinib 400 mg once daily. With regular visit and interaction with the patients and by studying the reports, adverse reactions were recorded with the guidance of doctors. Adverse drug reactions (ADR s) of Imatinib were classified based on various criteria viz. gender, phases of CML, age, hematological and non- hematological adverse events and it was observed that there were no significant correlation with age and phases of CML. Out of 83 patients who were included in the study, it was found that CML is more common in males and between the age group of 30-39 yrs. Most of the patients were diagnosed when they were in chronic phase. The common non- hematological adverse effects that were observed was abdominal pain, head ache, GI disturbances etc. and few patients experienced hematological adverse effects such as thrombocytopenia, anemia etc.


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EVALUATION OF MEDICATION ADHERENCE AND IMPACT OF PATIENT COUNSELING ON QUALITY OF LIFE IN PATIENTS SUFFRING FROM TYPE 2 DIABETES MELLITUS IN A TERTIARY CARE TEACHING HOSPITAL

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Nally Suman Raj, A.J. Rocky, A. Chandrakanth, C. Praneeth, Dr. B.V.S. Lakshmi, Mr. T. Praveen Kumar.
India is the diabetes capital of the world. Diabetes is growing alarmingly in India, home to more than 65.1 million people with the disease, compared to 50.8 million in 2010. Adherence to medication is a crucial part of patient care and indispensable for reaching clinical goals. The WHO, in its 2003 report on medication adherence, states that increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in specific medical treatment. The main aim of the present study was to evaluate medication adherence of patients suffering from type 2 diabetes mellitus and counsel them towards improving of quality of life. This was a prospective observational study, conducted over 6 months period from December 2015 to June 2016, in a tertiary care hospital. A total 300 patients were studies for the evaluation of their medication adherence and were counselled accordingly. Moriskys 8 item medication adherence scale was used to measure the adherence of the subjects. After counselling them KAP questionnaire was used to assess the outcome of the counselling. We found that patient counselling played an important role in the patients adherence towards medication which resulted in better therapeutic outcome which was noticed from their laboratory parameters. Thus, patient counselling plays a major role in medication adherence and therefore in improvement of quality of life.


http://ift.tt/2cSyT8U

MYCOSYNTHESIS OF SILVER NANOPARTICLES BY ALTERNARIA SP ISOLATED FROM BARK PART OF CALOPHYLLUM APETALUM

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
C P Chandrappa, M Govindappa, N Chandrasekar, Sonia Sarkar, Sepuri Ooha, R Channabasava, C P Ramesh.
The present study described the formation of silver nanoparticles by the extract of Alternaria sp. obtained from bark part of Calophyllum apetalum Willd. Alternaria extract have mixed with silver nitrate to synthesize silver nanoparticles. Synthesized silver nanoparticles were characterized by UV-vis spectroscopy, Scaning electron microscopy and X-Ray diffraction studies. Silver nanoparticles have acquired Surface plasmon reverberation spectra at 425nm and round shapes of the silver nanoparticles have determined by SEM analysis. X-ray diffraction studies confirm that the synthesized nanoparticles by Altenaria extract were crystalline silver. This approach is one of the primary, efficient and rapid strategies to synthesize silver nanoparticles at ambient temperature without application of hazardous agents.


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TRANSDERMAL UNANI FEMALE CONTRACEPTIVE FORMULATION: DESIGNING AND IN-VITRO TRANSDERMAL ACTIVITY EVALUATION

2016-09-12T01-57-19Z
Source: Indo American Journal of Pharmaceutical Research
Tarannum*, Mohammad Idris.
The transdermal drug delivery system has an important place in the medical field. This delivery system has several advantages over the oral and parental route of drug administration. The concept of transdermal drug delivery system was already exists in the Unani system of medicine. Several dosage forms for transdermal drug delivery system in single as well as in compound formulation were mentioned in the classical literature of Unani system. Unani medicine is enriched with several drugs honored to possess antifertility property. Unani antifertility agents are recommended for both- male and female as oral and/or local application. Several single drugs as well as compound formulations are mentioned in Unani classical literature to control the fertility. With this background an effort was made with two objectives. First was to design a transdermal Unani female contraceptive formulation (TUFCF) based on four ingredients i.e. Leaves of Henna (Lawsonia inermis), rhizome of Pakhanbed (Bergenia ciliata), Sibr (Latex of Aloe barbadensis) and Khar-e-Chirchita (Achyranthes aspera). Secondly to evaluate in-vitro transdermal penetration potential of the TUFCF by Franz diffusion cell method, qualitatively and quantitatively. Qualitatively the test formulation reveals significant presence of phytochemicals by chemical test method. Quantitatively it showed 35.07% release across the membrane. Hence, it was concluded that the test formulation possessed the transdermal activity.


http://ift.tt/2cSzxDj