Clustered structural and functional plasticity of dendritic spines

Publication date: Available online 13 September 2016
Source:Brain Research Bulletin
Author(s): Ju Lu, Yi Zuo
The configuration of synaptic circuits underlies their ability to process and store information. Research on dendritic spines has revealed that their structural and functional alterations are clustered along the parent dendrite. Here we review the evidence supporting such notion of clustered synaptic plasticity, discuss its functional implications and possible contributing factors, and suggest potential strategies to deal with open challenges.



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Natriuretic peptide receptor A inhibition suppresses gastric cancer development through reactive oxygen species-mediated G2/M cell cycle arrest and cell death

Publication date: Available online 12 September 2016
Source:Free Radical Biology and Medicine
Author(s): Zheng Li, Ji-Wei Wang, Wei-Zhi Wang, Xiao-Fei Zhi, Qun Zhang, Bo-Wen Li, Lin-Jun Wang, Kun-Ling Xie, Jin-Qiu Tao, Jie Tang, Song Wei, Yi Zhu, Hao Xu, Dian-Cai Zhang, Li Yang, Ze-Kuan Xu
Natriuretic peptide receptor A (NPRA), the major receptor for atrial natriuretic peptide (ANP), has been implicated in tumorigenesis; however, the role of ANP-NPRA signaling in the development of gastric cancer remains unclear. Immunohistochemical analyses indicated that NPRA expression was positively associated with gastric tumor size and cancer stage. NPRA inhibition by shRNA induced G2/M cell cycle arrest, cell death, and autophagy in gastric cancer cells, due to accumulation of reactive oxygen species (ROS). Either genetic or pharmacologic inhibition of autophagy led to caspase-dependent cell death. Therefore, autophagy induced by NPRA silencing may represent a cytoprotective mechanism. ROS accumulation activated c-Jun N-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). ROS-mediated activation of JNK inhibited cell proliferation by disturbing cell cycle and decreased cell viability. In addition, AMPK activation promoted autophagy in NPRA-downregulated cancer cells. Overall, our results indicate that the inhibition of NPRA suppresses gastric cancer development and targeting NPRA may represent a promising strategy for the treatment of gastric cancer.

Graphical abstract

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Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis

Publication date: Available online 12 September 2016
Source:Free Radical Biology and Medicine
Author(s): Da Hyun Lee, Dai Hoon Han, Ki Taek Nam, Jeong Su Park, Soo Hyun Kim, Milim Lee, Gyuri Kim, Byung Soh Min, Bong-Soo Cha, Yu Seol Lee, Su Haeng Sung, Haengdueng Jeong, Hye Won Ji, Moon Joo Lee, Jae Sung Lee, Hui-Young Lee, Yoomi Chun, Joungmok Kim, Masaaki Komatsu, Yong-ho Lee, Soo Han Bae
Oxidative stress is important for the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a chronic disease that ranges from hepatic steatosis to nonalcoholic steatohepatitis (NASH). The nuclear factor erythroid 2-related factor 2–Kelch-like ECH associated protein 1 (Nrf2-Keap1) pathway is essential for cytoprotection against oxidative stress. In this study, we found that oxidative stress or inflammatory biomarkers and TUNEL positive cells were markedly increased in NASH patients compared to normal or simple steatosis. In addition, we identified that the hepatic mRNA levels of Nrf2 target genes such as Nqo-1 and GSTA-1 were significantly increased in NASH patients. Ezetimibe, a drug approved by the Food and Drug Administration for the treatment of hypercholesterolemia, improves NAFLD and alleviates oxidative stress. However, the precise mechanism of its antioxidant function remains largely unknown. We now demonstrate that ezetimibe activates Nrf2-Keap1 pathway which was dependent of autophagy adaptor protein p62, without causing cytotoxicity. Ezetimibe activates AMP-activated protein kinase (AMPK), which in turn phosphorylates p62 (p-S351) via their direct interaction. Correspondingly, Ezetimibe protected liver cells from saturated fatty acid-induced apoptotic cell death through p62-dependent Nrf2 activation. Furthermore, its role as an Nrf2 activator was supported by methione- and choline- deficient (MCD) diet-induced NASH mouse model, showing that ezetimibe decreased the susceptibility of the liver to oxidative injury. These data demonstrate that the molecular mechanisms underlying ezetimibe's antioxidant role in the pathogenesis of NASH.

Graphical abstract

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An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy

Publication date: Available online 12 September 2016
Source:Free Radical Biology and Medicine
Author(s): Jiayu Zhu, Huihui Wang, Feng Chen, Jingqi Fu, Yuanyuan Xu, Yongyong Hou, Henry H. Kou, Cheng Zhai, M. Bud Nelson, Qiang Zhang, Melvin E. Andersen, Jingbo Pi
The nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor regulating a wide array of genes for antioxidant and detoxification enzymes in response to oxidative and xenobiotic stress. A large number of Nrf2-antioxidant response element (ARE) activators have been screened for use as chemopreventive agents in oxidative stress-related diseases and even cancer. However, constitutive activation of Nrf2 occurs in a variety of cancers. Aberrant activation of Nrf2 is correlated with cancer progression, chemoresistance, and radioresistance. In this review, we examine recent studies of Nrf2-ARE inhibitors in the context of cancer therapy. We enumerate the possible Nrf2-inhibiting mechanisms of these compounds, their effects sensitizing cancer cells to chemotherapeutic agents, and the prospect of applying them in clinical cancer therapy.

Graphical abstract

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Copeptin in obese children and adolescents: Relationships to body mass index, cortisol and gender

Abstract

Objective

Copeptin has been reported to be associated with stress, obesity and the Metabolic Syndrome (MetS) in adults. However, data in childhood are scarce. Therefore, we studied the relationships between copeptin, cortisol, puberty, and parameters of the MetS in children.

Design

Cross-sectional study.

Patients

51 obese children (10.8±3.2years, 39% male, 45% prepubertal, body mass index standard deviation score (BMI-SDS) 2.77±0.56) and 24 lean children of similar age, gender, and pubertal stage.

Measurements

Copeptin, serum cortisol, 24h urinary free cortisol, BMI-SDS and, as parameters of the MetS, insulin resistance index (HOMA), HbA1c, uric acids, blood pressure and lipids.

Results

Copeptin levels were significantly (p=0.047) higher in obese children (5.8±2.8pmol/l) compared to lean children (4.6±2.2pmol/l). BMI-SDS (coefficient 0.38 ±0.35, p=0.033), but not any parameter of the MetS, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender and pubertal stage. 24h urinary free cortisol (coefficient 0.13±0.06,p<0.001), but not serum cortisol, was significantly related to copeptin in multiple linear regression analyses adjusted for age, gender, pubertal stage and BMI-SDS. Pubertal boys (6.6±2.8pmol/l) demonstrated significantly (p=0.042) higher copeptin levels compared to pubertal girls (4.8±2.6pmol/l), while coeptin concentrations did not differ between prepubertal girls and boys.

Conclusions

Copeptin levels are related to 24h urinary free cortisol in obese children. Pubertal boys, but not prepubertal boys demonstrated higher copeptin levels than girls, suggesting that sex hormones are involved in the regulation of copeptin levels. Further studies are necessary to understand the relationship between obesity, cortisol, gender, pubertal stage and copeptin levels.

This article is protected by copyright. All rights reserved.

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Constitutively active Stat5b signaling confers tolerogenic functions to dendritic cells of NOD mice and halts diabetes progression

Publication date: Available online 12 September 2016
Source:Journal of Autoimmunity
Author(s): Echarki Zerif, Aida Maalem, Simon Gaudreau, Chantal Guindi, Muhammad Ramzan, Steeve Véroneau, Denis Gris, Jana Stankova, Marek Rola-Pleszczynski, Walid Mourad, Gilles Dupuis, Abdelaziz Amrani
Defects in dendritic cells (DCs) development and function lead to autoimmune disorders. Autoimmune diabetes in humans and NOD mice results from a breakdown of self-tolerance, ending in T cell-mediated β-cell destruction. DCs dysfunction in NOD mice results in part from a defect in the JAK-STAT5 signaling pathway associated with the idd4 susceptibility locus. The involvement of Stat5b in DCs tolerogenic functions remains unknown. We have generated transgenic mice (NOD.CD11c^Stat5b−CA) expressing a constitutively active form of the Stat5b gene (Stat5b-CA) under control of CD11c promoter. All NOD.CD11c^Stat5b−CA mice were protected against diabetes. Protection was associated with an increased in the pool and suppressive function of Tregs, a promotion of Th2 and Tc2 immune response and a decreased percentage of CD8⁺ T cells. Splenic DCs of NOD.CD11c^Stat5b−CA mice acquired a mature phenotype, promoted and induced better conversion of CD4⁺CD25^-Foxp3^- T cells into Tregs (CD4⁺CD25⁺Foxp3⁺ T cells) than DCs of NOD mice. Stat5b-CA.DC-educated CD4⁺CD25⁻ T cells delayed diabetes onset whereas Stat5b-CA.DC-educated Tregs blocked ongoing diabetes in 8–10 weeks old NOD recipient mice. Importantly, injection of Stat5b.CA.DC to 8–10-week old NOD mice halted diabetes progression and educated their splenocytes to loose their diabetogenic potential when transferred to NOD.SCID mice. Our work is the first to report that an active form of Stat5b restored DCs tolerogenic functions that re-educated Tregs to re-establish and to sustain long-term protective immune response against diabetes in NOD mice.



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First Successful Eye Surgeries Performed on the Preceyes System

Preceyes, a Dutch spinout company from Eindhoven University of Technology that was incorporated in 2011, has announced the successful use of the company's surgical robotic system in the first of 12 patients undergoing treatment, led by professor Robert MacLaren at the University of Oxford.

The robotic technology is intended to improve clinical outcomes in the 1.3 million surgical procedures performed annually worldwide to treat vitreoretinal disease. Utilizing the Preceyes platform the system's creators also hope to open-up innovative drug and gene therapy treatment options for the estimated 50-75 million people suffering with retinal disease induced visual impairment.

Conventional vitreoretinal surgical procedures require ultra-precise manual movements of surgical equipment within the eye at the sub-millimeter scale, often risking hemorrhage or retinal damage. The Preceyes system integrates robotic control of these surgical instruments at the operating table, while keeping the surgeon in constant contact with the patient throughout the procedure.

The surgical system improves performance by downscaling hand movements and filtering-out any operator unsteadiness or tremor. This gives the surgeon a unique level of precision, down to the scale of a human hair, and allows for the possibility of performing procedures that were previously impossible.

The Preceyes system also allows for an instrument's position to be fixed while the interventionist alters their grip or prepares the patient for targeted drug delivery. This position "freezing" function is particularly important for the emerging field of retinal gene therapy, which has hopes of reversing blindness, as stem cells may be precisely injected over a number of minutes.

The Preceyes team plans to launch the surgical system with a targeted market entrance in late 2018.

Here's a company video explaining the workings of the Preceyes surgical system:

Link: Preceyes homepage…

This post First Successful Eye Surgeries Performed on the Preceyes System appeared first on Medgadget.

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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.

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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.

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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.

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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.

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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

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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

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Breast cancer: CTC heterogeneity is dynamic

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

Author: Diana Romero

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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.

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

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

Author: David Killock

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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.

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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.

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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.

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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.

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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.


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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.


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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




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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.


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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

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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