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Showing 100 Latest Publications
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TRPCs/Orai1-dependent Store-Operated Ca2+ Channels, new targets of aldosterone in cardiomyocytes.Friday, April 29, 2016
Sabourin J, Bartoli F, Antigny F, Gomez AM, Benitah JP,
The Journal of biological chemistry. 22-Apr-2016
The Store-Operated Ca2+ Entry (SOCE) has emerged as an important mechanism in cardiac pathology. However, the signals that upregulate SOCE in the heart remain unexplored. Clinical trials have emphasized the beneficial role of mineralocorticoid receptor (MR) signaling blockade in heart failure and associated arrhythmias. Accumulated evidences suggest that the mineralocorticoid hormone, aldosterone, through activation of its receptor (MR), might be a key regulator of Ca2+ influx in cardiomyocytes. We thus assessed whether and how SOCE involving TRPCs (Transient Receptor Potential Canonical) and Orai1 channels are regulated by aldosterone/MR in ventricular cardiomyocytes. Molecular screening using qRT-PCR and western-blot demonstrated that aldosterone treatment for 24 h specifically increased the mRNA and/or protein levels of Orai1, TRPC1, TRPC4, TRPC5 and STIM1 through MR activation. These effects were correlated with a specific enhancement of SOCE activities sensitive to SOC inhibitors (SKF-96365 and BTP2), to the potent Orai1 blocker, S66 and were prevented by TRPC1, TRPC4 and Orai1 dominant negative-mutants, or TRPC5 siRNA. Mechanistic approach showed that upregulation of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) mRNA expression by aldosterone is involved in enhanced SOCE. Functionally, 24 h aldosterone-enhanced SOCE is associated with increased diastolic [Ca2+]i which is blunted by SOC inhibitors. Our study provides the first evidence that aldosterone promotes TRPC1, TRPC4, TRPC5 and Orai1-mediated SOCE in cardiomyocytes, through MR and SGK1 pathway.
Sorafenib-resistant hepatocellular carcinoma stratified by phosphorylated ERK activates PD-1 immune checkpoint.Friday, April 29, 2016
Chen J, Ji T, Zhao J, Li G, Zhang J, Jin R, Liu J, Liu X, Liang X, Huang D, Xie A, Lin H, Cang Y, Cai X,
Oncotarget. 25-Apr-2016
Sorafenib is a multikinase inhibitor approved as the first line treatment for late stage hepatocellular carcinoma (HCC). Due to its significant variation in clinical benefits among patients, defining prognostic biomarkers for sorafenib sensitivity in HCC would allow targeted treatment. Phosphorylated extracellular signaling-regulated kinase (pERK) was proposed to predict the response to sorafenib in HCC, but clinical supports are mixed or even contradictory. Here we found that pERK expression levels are variable in different nodules from individual patient liver. Xenografts derived from resected tumors are resistant to sorafenib inhibition when expressing low levels of pERK. This correlation of low pERK levels and sorafenib resistance is corroborated by histological characterization of chemical-induced and genetic mouse models for pERK-positive and pERK-negative HCC respectively, as well as computed tomography (CT) imaging of patient tumors with validated pERK expression. Mouse and human HCC samples expressing low pERK show strong inflammatory infiltrating cells and significant enrichment of intratumoral CD8+ cytotoxic T lymphocytes that express programmed death receptor-1 (PD-1). These pERK-PD-1+ patients have poorer overall and disease-free survival than pERK+PD-1- patients. In conclusion, our data suggest that anti-PD-1 immunotherapy might complement sorafenib in treating HCC patients by targeting sorafenib-resistant cancer cells, and the dual pERK and PD-1 biomarkers would help HCC patient selection to achieve optimal clinical benefits.
Ubiquitin specific protease 19 involved in transcriptional repression of retinoic acid receptor by stabilizing CORO2A.Friday, April 29, 2016
Lim KH, Choi JH, Park JH, Cho HJ, Park JJ, Lee EJ, Li L, Choi YK, Baek KH,
Oncotarget. 25-Apr-2016
Deubiquitination via deubiquitinating enzymes (DUBs) has been emerged as one of the important post-translational modifications, resulting in the regulation of numerous target proteins. In this study, we screened new protein biomarkers for adipogenesis, and related studies showed that ubiquitin specific protease 19 (USP19) as a DUB is gradually decreased during adipogenesis and it regulates coronin 2A (CORO2A) as one of the components for the nuclear receptor co-repressor (NCoR) complex in some studies. The regulation of CORO2A through the deubiquitinating activity of USP19 affected the transcriptional repression activity of the retinoic acid receptor (RAR), suggesting that USP19 may be involved in the regulation of RAR-mediated adipogenesis.
TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting.Friday, April 29, 2016
Fountzilas G, Giannoulatou E, Alexopoulou Z, Zagouri F, Timotheadou E, Papadopoulou K, Lakis S, Bobos M, Poulios C, Sotiropoulou M, Lyberopoulou A, Gogas H, Pentheroudakis G, Pectasides D, Koutras A, Christodoulou C, Papandreou C, Samantas E, Papakostas P, Kosmidis P, Bafaloukos D, Karanikiotis C, Dimopoulos MA, Kotoula V,
Oncotarget. 26-Apr-2016
TP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.
----Cyclic AMP efflux inhibitors as potential therapeutic agents for leukemia.Friday, April 29, 2016
Perez DR, Smagley Y, Garcia M, Carter MB, Evangelisti A, Matlawska-Wasowska K, Winter SS, Sklar LA, Chigaev A,
Oncotarget. 25-Apr-2016
Apoptotic evasion is a hallmark of cancer. We propose that some cancers may evade cell death by regulating 3'-5'-cyclic adenosine monophosphate (cAMP), which is associated with pro-apoptotic signaling. We hypothesize that leukemic cells possess mechanisms that efflux cAMP from the cytoplasm, thus protecting them from apoptosis. Accordingly, cAMP efflux inhibition should result in: cAMP accumulation, activation of cAMP-dependent downstream signaling, viability loss, and apoptosis. We developed a novel assay to assess cAMP efflux and performed screens to identify inhibitors. In an acute myeloid leukemia (AML) model, several identified compounds reduced cAMP efflux, appropriately modulated pathways that are responsive to cAMP elevation (cAMP-responsive element-binding protein phosphorylation, and deactivation of Very Late Antigen-4 integrin), and induced mitochondrial depolarization and caspase activation. Blocking adenylyl cyclase activity was sufficient to reduce effects of the most potent compounds. These compounds also decreased cAMP efflux and viability of B-lineage acute lymphoblastic leukemia (B-ALL) cell lines and primary patient samples, but not of normal primary peripheral blood mononuclear cells. Our data suggest that cAMP efflux is a functional feature that could be therapeutically targeted in leukemia. Furthermore, because some of the identified drugs are currently used for treating other illnesses, this work creates an opportunity for repurposing.
Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation.Friday, April 29, 2016
Severson TM, Nevedomskaya E, Peeters J, Kuilman T, Krijgsman O, van Rossum A, Droog M, Kim Y, Koornstra R, Beumer I, Glas AM, Peeper D, Wesseling J, Simon IM, Wessels L, Linn SC, Zwart W,
Oncotarget. 25-Apr-2016
Estrogen receptor alpha (ERα)-positive breast cancers are frequently treated with tamoxifen, but resistance is common. It remains elusive how tamoxifen resistance occurs and predictive biomarkers for treatment outcome are needed. Because most biomarker discovery studies are performed using pre-treatment surgical resections, the effects of tamoxifen therapy directly on the tumor cell in vivo remain unexamined. In this study, we assessed DNA copy number, gene expression profiles and ERα/chromatin binding landscapes on breast tumor specimens, both before and after neoadjuvant tamoxifen treatment. We observed neoadjuvant tamoxifen treatment synchronized ERα/chromatin interactions and downstream gene expression, indicating that hormonal therapy reduces inter-tumor molecular variability. ERα-synchronized sites are associated with dynamic FOXA1 action at these sites, which is under control of growth factor signaling. Genes associated with tamoxifen-synchronized sites are capable of differentiating patients for tamoxifen benefit. Due to the direct effects of therapeutics on ERα behavior and transcriptional output, our study highlights the added value of biomarker discovery studies after neoadjuvant drug exposure.
How relevant is panallergen sensitisation in the development of allergies?Friday, April 29, 2016
McKenna OE, Asam C, R Araujo G, Roulias A, Goulart LR, Ferreira F,
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 29-Apr-2016
Panallergens comprise various protein families of plant as well as animal origin and are responsible for wide IgE cross-reactivity between related and unrelated allergenic sources. Such cross-reactivities include reactions between various pollen sources, pollen and plant-derived foods as well as invertebrate-derived inhalants and foodstuff. Here we provide an overview on the most clinically relevant panallergens from plants (profilins, polcalcins, non-specific lipid transfer proteins, pathogenesis-related protein family 10 members) and on the prominent animal-derived panallergen family, topomyosins. In addition, we explore the role of panallergens in the sensitisation process and progress of the allergic disease. Emphasis is given on epidemiological aspects of panallergen sensitisation and clinical manifestations. Finally, the issues related to diagnosis and therapy of patients sensitised to panallergens is outlined and the use of panallergens as predictors for cross-reactive allergy and as biomarkers for disease severity is discussed. This article is protected by copyright. All rights reserved.
Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia.Friday, April 29, 2016
Chiang S, Kovacevic Z, Sahni S, Lane DJ, Merlot AM, Kalinowski DS, Huang ML, Richardson DR,
Clinical science (London, England : 1979). 1-Jun-2016
The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron-sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.
Ethyl-2-amino-pyrrole-3-carboxylates are novel potent anticancer agents that affect tubulin polymerization, induce G2/M cell-cycle arrest, and effectively inhibit soft tissue cancer cell growth in vitro.Friday, April 29, 2016
Boichuk S, Galembikova A, Zykova S, Ramazanov B, Khusnutdinov R, Dunaev P, Khaibullina S, Lombardi V,
Anti-cancer drugs. 28-Apr-2016
Microtubules are known to be one of the most attractive and validated targets in cancer therapy. However, the clinical use of drugs that affect the dynamic state of microtubules has been hindered by chemoresistance and toxicity issues. Accordingly, the development of novel agents that target microtubules is needed. Here, we report the identification of novel compounds with pirrole and carboxylate structures: ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) that provide potent cytotoxic activities against multiple soft tissue cancer cell lines in vitro. Using the MTS cell proliferation assay, we assessed the activity of EAPCs on various cancer cell lines including leiomyosarcoma SK-LMS-1, rhabdomyosarcoma RD, gastrointestinal stromal tumor GIST-T1, A-673 Ewing's sarcoma, and U-2 OS osteosarcoma. We found that in the majority of cases, two EAPC compounds (EAPC-20 and EAPC-24) considerably inhibited cancer cell proliferation in vitro. The growth-inhibitory effects of EAPC-20 and EAPC-24 were time and dose dependent. The molecular mechanisms of action of these compounds were because of the inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to considerable accumulation of tumor cells in the M-phase. Finally, EAPCs induced tumor cell death by apoptotic pathways. The above-mentioned effects were also observed in most soft tissue tumor cell lines and the gastrointestinal stromal tumor cell line investigated. Taken together, our data identify potent antitumor activity of EAPCs in vitro, thus providing a novel scaffold with which to develop potent chemotherapeutic agents for cancer therapy.
Inhibitor Discovery for the Human GLUT1 from Homology Modeling and Virtual Screening.Friday, April 29, 2016
Ung PM, Song W, Cheng L, Zhao X, Hu H, Chen L, Schlessinger A,
ACS chemical biology. 29-Apr-2016
The human Glucose Transporter 1 (hGLUT1 or SLC2A1) is a facilitative membrane transporter found in the liver, intestines, kidney, and brain, where it transports sugars such as D-glucose and D-galactose. Genetic variations in hGLUT1 are associated with a broad range of diseases and metabolic disorders. For example, hGLUT1 is upregulated in various cancer types (e.g., breast carcinoma) to support the increased anaerobic glycolysis and the Warburg Effect. Thus, hGLUT1 is an emerging therapeutic target, which also transports commonly used cancer biomarkers (e.g., (18)F-DG). In this study, we use computational prediction followed by experimental testing, to characterize hGLUT1. We construct homology models of hGLUT1 in a partially occluded outward open ('occluded') conformation based on the X-ray structure of the E. coli xylose transporter, XylE. Comparison of the binding site of the occluded models to experimentally determined hGLUT structures revealed a hydrophobic pocket adjacent to the sugar-binding site, which was tested experimentally via site-directed mutagenesis. Virtual screening of various libraries of purchasable compounds against the occluded models, followed by experimental testing with cellular assays revealed seven previously unknown hGLUT1 ligands with IC50 values ranging from 0.45 μM to 59 μM. These ligands represent three unique chemotypes that are chemically different from any other known hGLUT1 ligands. The newly characterized hydrophobic pocket can potentially be utilized by the new ligands for increased affinity. Furthermore, the previously unknown hGLUT1 ligands can serve as chemical tools to further characterize hGLUT1 function or lead molecules for future drug development.
The Effect of Optokinetic Stimulation on Perceptual and Postural Symptoms in Visual Vestibular Mismatch Patients.Friday, April 29, 2016
Van Ombergen A, Lubeck AJ, Van Rompaey V, Maes LK, Stins JF, Van de Heyning PH, Wuyts FL, Bos JE,
PloS one. 29-4-2016
VVM patients differ from healthy controls in postural and subjective symptoms and motion is a crucial factor in provoking these symptoms. A possible explanation could be a central visual-vestibular integration deficit, which has implications for diagnostics and clinical rehabilitation purposes. Future research should focus on the underlying central mechanism of VVM and the effectiveness of optokinetic stimulation in resolving it.
Amyloid Imaging, Cerebrospinal Fluid Biomarkers Predict Driving Performance Among Cognitively Normal Individuals.Friday, April 29, 2016
Roe CM, Barco PP, Head DM, Ghoshal N, Selsor N, Babulal GM, Fierberg R, Vernon EK, Shulman N, Johnson A, Fague S, Xiong C, Grant EA, Campbell A, Ott BR, Holtzman DM, Benzinger TL, Fagan AM, Carr DB, Morris JC,
Alzheimer disease and associated disorders. 28-Apr-2016
Postmortem brain studies of older drivers killed in car accidents indicate that many had Alzheimer disease (AD) neuropathologic changes. We examined whether AD biomarkers are related to driving performance among cognitively normal older adults. Individuals with normal cognition, aged 65+ years, and driving at least once per week, were recruited. Participants (N=129) took part in clinical assessments, a driving test, and positron emission tomography imaging with Pittsburgh compound B (PIB) and/or cerebrospinal fluid (CSF) collection. General linear models tested whether the number of driving errors differed as a function of each of the biomarker variables (mean cortical binding potential for PIB, and CSF Aβ42, tau, ptau181, tau/Aβ42, ptau181/Aβ42). Higher ratios of CSF tau/Aβ42, ptau181/Aβ42, and PIB mean cortical binding potential, were associated with more driving errors (P<0.05). Preclinical AD may have subtle cognitive and functional effects, which alone may go unnoticed. However, when combined, these changes may impact complex behaviors such as driving.
Benefits of Selenium Supplementation on Leukocyte DNA Integrity Interact with Dietary Micronutrients: A Short Communication.Friday, April 29, 2016
Karunasinghe N, Zhu S, Ferguson LR,
Nutrients. 28-4-2016
A male cohort from New Zealand has previously shown variability in Selenium (Se) supplementation effects on measured biomarkers. The current analysis is to understand the reasons for variability of the H₂O₂-induced DNA damage recorded after Se supplementation. We have looked at the variation of demographic, lifestyle, medication, genetic and dietary factors and biomarkers measured at baseline and post-supplementation in these two extreme subgroups A and B. Group A showed increased H₂O₂-induced DNA damage and group B showed decreased damage after Se supplementation. We have also considered correlations of biomarkers and dietary factors in the complete dataset. The glutathione peroxidase (GPx) activity and DNA damage were significantly lower at post-supplementation in Group B compared to Group A. Post-supplementation, Group B showed a significant reduction in the GPx activity, while Group A showed a significant increase in DNA damage compared to baseline levels. Dietary methionine intake was significantly higher and folate intake was significantly lower in Group B compared to Group A. Se supplementation significantly increased the caspase-cleaved keratin 18 levels in both groups, indicating increased apoptotic potential of this supplement. Parameter correlation with the complete dataset showed dietary methionine to have a significant negative correlation with H₂O₂-induced DNA damage post-supplementation. The data suggest that Se supplementation is beneficial for the leukocyte DNA integrity only in interaction with the dietary methionine and folate intake.
New Concepts in Cancer Biomarkers: Circulating miRNAs in Liquid Biopsies.Friday, April 29, 2016
Larrea E, Sole C, Manterola L, Goicoechea I, Armesto M, Arestin M, Caffarel MM, Araujo AM, Araiz M, Fernandez-Mercado M, Lawrie CH,
International journal of molecular sciences. 27-4-2016
The effective and efficient management of cancer patients relies upon early diagnosis and/or the monitoring of treatment, something that is often difficult to achieve using standard tissue biopsy techniques. Biological fluids such as blood hold great possibilities as a source of non-invasive cancer biomarkers that can act as surrogate markers to biopsy-based sampling. The non-invasive nature of these "liquid biopsies" ultimately means that cancer detection may be earlier and that the ability to monitor disease progression and/or treatment response represents a paradigm shift in the treatment of cancer patients. Below, we review one of the most promising classes of circulating cancer biomarkers: microRNAs (miRNAs). In particular, we will consider their history, the controversy surrounding their origin and biology, and, most importantly, the hurdles that remain to be overcome if they are really to become part of future clinical practice.
Protective Effect of Tyrosol and S-Adenosylmethionine against Ethanol-Induced Oxidative Stress of Hepg2 Cells Involves Sirtuin 1, P53 and Erk1/2 Signaling.Friday, April 29, 2016
Stiuso P, Bagarolo ML, Ilisso CP, Vanacore D, Martino E, Caraglia M, Porcelli M, Cacciapuoti G,
International journal of molecular sciences. 27-4-2016
Oxidative stress plays a major role in ethanol-induced liver damage, and agents with antioxidant properties are promising as therapeutic opportunities in alcoholic liver disease. In the present work, we investigated the effect of S-adenosylmethionine (AdoMet), Tyrosol (Tyr), and their combination on HepG2 cells exposed to ethanol exploring the potential molecular mechanisms. We exposed HepG2 cells to 1 M ethanol for 4 and 48 h; thereafter, we recorded a decreased cell viability, increase of intracellular reactive oxygen species (ROS) and lipid accumulation, and the release into culture medium of markers of liver disease such as triacylglycerol, cholesterol, transaminases, albumin, ferritin, and homocysteine. On the other hand, AdoMet and Tyrosol were able to attenuate or antagonize these adverse changes induced by acute exposure to ethanol. The protective effects were paralleled by increased Sirtuin 1 protein expression and nuclear translocation and increased ERK1/2 phosphorylation that were both responsible for the protection of cells from apoptosis. Moreover, AdoMet increased p53 and p21 expression, while Tyrosol reduced p21 expression and enhanced the expression of uncleaved caspase 3 and 9, suggesting that its protective effect may be related to the inhibition of the apoptotic machinery. Altogether, our data show that AdoMet and Tyrosol exert beneficial effects in ethanol-induced oxidative stress in HepG2 cells and provide a rationale for their potential use in combination in the prevention of ethanol-induced liver damage.
KRAS/BRAF Analysis in Ovarian Low-Grade Serous Carcinoma Having Synchronous All Pathological Precursor Regions.Friday, April 29, 2016
Nakamura K, Nakayama K, Ishibashi T, Ishikawa N, Ishikawa M, Katagiri H, Minamoto T, Sato E, Sanuki K, Yamashita H, Iida K, Sultana R, Kyo S,
International journal of molecular sciences. 26-4-2016
Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains unclear as to how these mutations contribute to tumor progression. This is the first report to track the histopathological progression of serous adenofibroma to low-grade serous carcinoma. Each stage was individually analyzed by pathological and molecular genetic methods to determine what differences occur between the distinct stages of progression.
Salusins and adropin: New peptides potentially involved in lipid metabolism and atherosclerosis.Friday, April 29, 2016
Niepolski L, Grzegorzewska AE,
Advances in medical sciences. 3-Apr-2016
Dyslipidemia is one of the most potent risk factors for the development of atherosclerosis. The high atherosclerotic risk in dyslipidemic patients is associated with endothelial dysfunction. During the last two decades, novel bioactive peptides have emerged as potential biomarkers of endothelial dysfunction and dyslipidemia-salusins and adropin. Salusin-alpha is likely to prevent atherosclerosis, while salusin-beta may act as a potential proatherogenic factor. Adropin was recently identified as important for energy homeostasis and lipid metabolism. Adropin is closely related to the inhibition of atherosclerosis by up-regulation of the endothelial nitric oxide synthase expression through the vascular endothelial growth factor receptor-2. These peptides represent a novel target to limit diseases characterized by endothelial dysfunction and may form the basis for the development of new therapeutic agents for treating metabolic disorders associated with atherosclerosis.
Osteoprotegerin and osteoprotegerin/TRAIL ratio are associated with cardiovascular dysfunction and mortality among patients with renal failure.Friday, April 29, 2016
Kuźniewski M, Fedak D, Dumnicka P, Stępień E, Kuśnierz-Cabala B, Cwynar M, Sułowicz W,
Advances in medical sciences. 21-Mar-2016
Our study confirmed the role of OPG as a biomarker of cardiovascular dysfunction and a predictor of mortality in stage 5 CKD. OPG/TRAIL ratio can be proposed as a predictor of cardiovascular dysfunction and mortality.
Distinct Roles of Type I and Type III Interferons in Intestinal Immunity to Homologous and Heterologous Rotavirus Infections.Friday, April 29, 2016
Lin JD, Feng N, Sen A, Balan M, Tseng HC, McElrath C, Smirnov SV, Peng J, Yasukawa LL, Durbin RK, Durbin JE, Greenberg HB, Kotenko SV,
PLoS pathogens. Apr-2016
Type I (IFN-α/β) and type III (IFN-λ) interferons (IFNs) exert shared antiviral activities through distinct receptors. However, their relative importance for antiviral protection of different organ systems against specific viruses remains to be fully explored. We used mouse strains deficient in type-specific IFN signaling, STAT1 and Rag2 to dissect distinct and overlapping contributions of type I and type III IFNs to protection against homologous murine (EW-RV strain) and heterologous (non-murine) simian (RRV strain) rotavirus infections in suckling mice. Experiments demonstrated that murine EW-RV is insensitive to the action of both types of IFNs, and that timely viral clearance depends upon adaptive immune responses. In contrast, both type I and type III IFNs can control replication of the heterologous simian RRV in the gastrointestinal (GI) tract, and they cooperate to limit extra-intestinal simian RRV replication. Surprisingly, intestinal epithelial cells were sensitive to both IFN types in neonatal mice, although their responsiveness to type I, but not type III IFNs, diminished in adult mice, revealing an unexpected age-dependent change in specific contribution of type I versus type III IFNs to antiviral defenses in the GI tract. Transcriptional analysis revealed that intestinal antiviral responses to RV are triggered through either type of IFN receptor, and are greatly diminished when receptors for both IFN types are lacking. These results also demonstrate a murine host-specific resistance to IFN-mediated antiviral effects by murine EW-RV, but the retention of host efficacy through the cooperative action by type I and type III IFNs in restricting heterologous simian RRV growth and systemic replication in suckling mice. Collectively, our findings revealed a well-orchestrated spatial and temporal tuning of innate antiviral responses in the intestinal tract where two types of IFNs through distinct patterns of their expression and distinct but overlapping sets of target cells coordinately regulate antiviral defenses against heterologous or homologous rotaviruses with substantially different effectiveness.
Overall and class-specific scores of pesticide residues from fruits and vegetables as a tool to rank intake of pesticide residues in United States: A validation study.Friday, April 29, 2016
Hu Y, Chiu YH, Hauser R, Chavarro J, Sun Q,
Environment international. 25-Apr-2016
Pesticide residues in fruits and vegetables are among the primary sources of pesticide exposure through diet, but the lack of adequate measurements hinder the research on health effects of pesticide residues. Pesticide Residue Burden Score (PRBS) for estimating overall dietary pesticide intake, organochlorine pesticide score (OC-PRBS) and organophosphate pesticide score (OP-PRBS) for estimating organochlorine and organophosphate pesticides-specific intake, respectively, were derived using U.S. Department of Agriculture Pesticide Data Program data and National Health and Nutrition Examination Survey (NHANES) food frequency questionnaire data. We evaluated the performance of these scores by validating the scores against pesticide metabolites measured in urine or serum among 3,679 participants in NHANES using generalized linear regression. The PRBS was positively associated with a score summarizing the ranks of all pesticide metabolites in a linear fashion (p for linear trend <0.001). Furthermore, individuals in the top quintile of this score had urinary pesticide metabolite levels 13.0% (95% CI 8.3%-17.7%) higher than individuals in the lowest quintile. Similarly, we observed significant associations of the OC-PRBS and OP-PRBS with the levels of lipid-adjusted total serum organochlorine pesticides and urinary creatinine-adjusted organophosphate pesticides, respectively. The relative difference (RD) in average pesticide metabolite rank between extreme quintiles was 17.8% (95% CI: 11.1%-24.4%, p for trend <0.001) for the OP-PRBS, whereas the RD was marginally significant at 7.0% (95% CI: -0.5%-14.4%, p for trend 0.07) for the OC-PRBS. The PRBS and OP-PRBS had similar performance when they were derived from fruits and vegetables with high vs. low pesticide residues, respectively (p for trend <0.001 for all associations). The OP-PRBS was associated with all measured organophosphate pesticides, whereas the positive association between OC-PRBS and averaged measured organochlorine pesticide residue rank was primarily driven by hexachlorobenzene. OC-PRBS had better performance when derived from more contaminated fruits and vegetables (p for trend 0.07) than from less contaminated Fruits and vegetables (p for trend 0.63), although neither of the associations achieved statistical significance. The PRBS and the class-specific scores for two major types of pesticides were significantly associated with pesticide biomarkers. These scores can reasonably rank study participants by their pesticide residue exposures from fruits and vegetables in large-scale environmental epidemiological studies.
Eosinophils as Biomarkers of Chronic Obstructive Pulmonary Disease Exacerbation Risk. Maybe Just for Some?Friday, April 29, 2016
Wedzicha JA,
American journal of respiratory and critical care medicine. 1-May-2016
The Combined Deficiency of Immunoproteasome Subunits Affects Both the Magnitude and Quality of Pathogen- and Genetic Vaccination-Induced CD8+ T Cell Responses to the Human Protozoan Parasite Trypanosoma cruzi.Friday, April 29, 2016
Ersching J, Vasconcelos JR, Ferreira CP, Caetano BC, Machado AV, Bruna-Romero O, Baron MA, Ferreira LR, Cunha-Neto E, Rock KL, Gazzinelli RT, Rodrigues MM,
PLoS pathogens. Apr-2016
The β1i, β2i and β5i immunoproteasome subunits have an important role in defining the repertoire of MHC class I-restricted epitopes. However, the impact of combined deficiency of the three immunoproteasome subunits in the development of protective immunity to intracellular pathogens has not been investigated. Here, we demonstrate that immunoproteasomes play a key role in host resistance and genetic vaccination-induced protection against the human pathogen Trypanosoma cruzi (the causative agent of Chagas disease), immunity to which is dependent on CD8+ T cells and IFN-γ (the classical immunoproteasome inducer). We observed that infection with T. cruzi triggers the transcription of immunoproteasome genes, both in mice and humans. Importantly, genetically vaccinated or T. cruzi-infected β1i, β2i and β5i triple knockout (TKO) mice presented significantly lower frequencies and numbers of splenic CD8+ effector T cells (CD8+CD44highCD62Llow) specific for the previously characterized immunodominant (VNHRFTLV) H-2Kb-restricted T. cruzi epitope. Not only the quantity, but also the quality of parasite-specific CD8+ T cell responses was altered in TKO mice. Hence, the frequency of double-positive (IFN-γ+/TNF+) or single-positive (IFN-γ+) cells specific for the H-2Kb-restricted immunodominant as well as subdominant T. cruzi epitopes were higher in WT mice, whereas TNF single-positive cells prevailed among CD8+ T cells from TKO mice. Contrasting with their WT counterparts, TKO animals were also lethally susceptible to T. cruzi challenge, even after an otherwise protective vaccination with DNA and adenoviral vectors. We conclude that the immunoproteasome subunits are key determinants in host resistance to T. cruzi infection by influencing both the magnitude and quality of CD8+ T cell responses.
COPD biomarkers as tools for decision making in early clinical drug development.Friday, April 29, 2016
Taib Z, Jauhiainen A,
Biomarkers in medicine. 29-Apr-2016
In this perspective article, we discuss, from a statistician's perspective, how biomarkers can be useful in decision making in drug development with emphasis on early clinical development (Phase I and II) in chronic obstructive pulmonary disease. We illustrate with examples of how biomarkers can affect the very choice of treatment strategy: for example, targeting patients in early versus late phases of the disease or patients with particular extrapulmonary manifestations of chronic obstructive pulmonary disease. We also illustrate the use of biomarkers for establishing proof of mechanism in Phase I trials and how surrogate biomarkers can be used as end points in Phase II leading to shorter and more efficient proof-of-principle and dose-finding trials.
miRNA expression profiling of cerebrospinal fluid in patients with aneurysmal subarachnoid hemorrhage.Friday, April 29, 2016
Stylli SS, Adamides AA, Koldej RM, Luwor RB, Ritchie DS, Ziogas J, Kaye AH,
Journal of neurosurgery. 29-Apr-2016
OBJECTIVE MicroRNAs (miRNAs) regulate gene expression and therefore play important roles in many physiological and pathological processes. The aim of this pilot study was to determine the feasibility of extraction and subsequent profiling of miRNA from CSF samples in a pilot population of aneurysmal subarachnoid hemorrhage patients and establish if there is a distinct CSF miRNA signature between patients who develop cerebral vasospasm and those who do not. METHODS CSF samples were taken at various time points during the clinical management of a subset of SAH patients (SAH patient samples without vasospasm, n = 10; SAH patient samples with vasospasm, n = 10). CSF obtained from 4 patients without SAH was also included in the analysis. The miRNA was subsequently isolated and purified and then analyzed on an nCounter instrument using the Human V2 and V3 miRNA assay kits. The data were imported into the nSolver software package for differential miRNA expression analysis. RESULTS From a total of 800 miRNAs that could be detected with each version of the miRNA assay kit, a total of 691 miRNAs were communal to both kits. There were 36 individual miRNAs that were differentially expressed (p < 0.01) based on group analyses, with a number of miRNAs showing significant changes in more than one group analysis. The changes largely reflected differences between non-SAH and SAH groups. These included miR-204-5p, miR-223-3p, miR-337-5p, miR-451a, miR-489, miR-508-3p, miR-514-3p, miR-516-5p, miR-548 m, miR-599, miR-937, miR-1224-3p, and miR-1301. However, a number of miRNAs did exclusively differ between the vasospasm and nonvasospasm SAH groups including miR-27a-3p, miR-516a-5p, miR-566, and miR-1197. CONCLUSIONS The findings indicate that temporal miRNA profiling can detect differences between CSF from aneurysmal SAH and non-SAH patients. Moreover, the miRNA profile of CSF samples from patients who develop cerebral vasopasm may be distinguishable from those who do not. These results provide a foundation for future research at identifying novel CSF biomarkers that might predispose to the development of cerebral vasospasm after SAH and therefore influence subsequent clinical management.
Prognostic significance of mechanical biomarkers derived from pulse wave analysis for predicting long-term cardiovascular mortality in two population-based cohorts.Friday, April 29, 2016
Cheng HM, Chuang SY, Wang JJ, Shih YT, Wang HN, Huang CJ, Huang JT, Sung SH, Lakatta EG, Yin FC, Chou P, Yeh CJ, Bai CH, Pan WH, Chen CH,
International journal of cardiology. 17-Apr-2016
Of all PWA-derived biomarkers, SC and DC were consistently identified as valuable parameters for incremental cardiovascular risk prediction in two large prospective cohorts.
Coronary Artery-Bypass-Graft Surgery Increases the Plasma Concentration of Exosomes Carrying a Cargo of Cardiac MicroRNAs: An Example of Exosome Trafficking Out of the Human Heart with Potential for Cardiac Biomarker Discovery.Friday, April 29, 2016
Emanueli C, Shearn AI, Laftah A, Fiorentino F, Reeves BC, Beltrami C, Mumford A, Clayton A, Gurney M, Shantikumar S, Angelini GD,
PloS one. 17-4-2016
The plasma concentrations of exosomes and their cargo of cardiac miRs increased in patients undergoing CABG and were positively correlated with hs-cTnI. These data provide evidence that CABG induces the trafficking of exosomes from the heart to the peripheral circulation. Future studies are necessary to investigate the potential of circulating exosomes as clinical biomarkers in cardiac patients.
Assessment of Glioma Response to Radiotherapy Using Multiple MRI Biomarkers with Manual and Semiautomated Segmentation Algorithms.Friday, April 29, 2016
Yu Y, Lee DH, Peng SL, Zhang K, Zhang Y, Jiang S, Zhao X, Heo HY, Wang X, Chen M, Lu H, Li H, Zhou J,
Journal of neuroimaging : official journal of the American Society of Neuroimaging. 29-Apr-2016
The semiautomated method of tumor extraction showed greater efficiency and stability than the manual method. Apparent diffusion coefficient, blood flow, and APTw are all useful biomarkers in assessing glioma response to radiotherapy.
PDGFRβ Is a Novel Marker of Stromal Activation in Oral Squamous Cell Carcinomas.Friday, April 29, 2016
Kartha VK, Stawski L, Han R, Haines P, Gallagher G, Noonan V, Kukuruzinska M, Monti S, Trojanowska M,
PloS one. 29-4-2016
Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC), we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA). Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migration, including platelet-derived growth factor receptor beta (PDGFRβ), which was found to be the highest-ranking receptor protein genome-wide. Similar analyses performed on ten additional TCGA cancer datasets revealed that other tumor types shared CAF markers with OSCC, including PDGFRβ, which was found to significantly correlate with the reference collagen expression in ten of the 11 cancer types tested. Subsequent immunostaining of OSCC specimens demonstrated that PDGFRβ was abundantly expressed in stromal fibroblasts of all tested cases (12/12), while it was absent in tumor cells, with greater specificity than other known markers such as alpha smooth muscle actin or podoplanin (3/11). Overall, this study identified PDGFRβ as a novel marker of stromal activation in OSCC, and further characterized a list of promising candidate CAF markers that may be relevant to other carcinomas. Our novel approach provides for a fast and accurate method to identify CAF markers without the need for large-scale immunostaining experiments.
[Evidence and Evidence Gaps - an Introduction].Friday, April 29, 2016
Dreier G, Löhler J,
Laryngo- rhino- otologie. Apr-2016
Background: Treating patients requires the inclusion of existing evidence in any health care decision, to be able to choose the best diagnosis or treatment measure or to make valid prognosis statements for a particular patient in consideration of the physician's own expertise.The basis are clinical trials, the results of which are ideally gathered in systematic reviews, rated, summarized and published. In addition to the GCP (Good Clinical Practice)-compliant planning, conducting and analysis of clinical studies it is essential, that all study results are made publicly available, in order to avoid publication bias. This includes the public registration of planned and discontinued trials. History: In the last 25 years, the evidence-based medicine (EbM) has increasingly found its way into clinical practice and research. Here EbM is closely associated with the names Archibald Cochrane and David Sackett. In Germany, both the German Cochrane Centre (DCZ) and the network of evidence-based medicine (DNEbM) were established approximately 15 years ago. In the international Cochrane Collaboration clinicians and other scientists like statisticians interdisciplinary work side by side to develop the methods of evidence-based medicine and to address the topics of evidence generation and processing as well as the transfer of knowledge. Challenge: Existing evidence primarily serves doctors to support their decision-making, but is also the basis for providing scientific proof for a health care intervention's benefit to patients and ultimately payers/health insurances. The closure of existing evidence gaps requires substantial human and financial resources, a complex organizational structure and can only succeed with the involvement of clinical and methodological expertise and specific knowledge in the field of clinical research. In addition, the knowledge must be transferred into practice, using journals, guidelines, conferences, databases, information portals with processed evidence and not least the medical education of students.One problem is the wealth of information, so that in clinical practice there may be gaps in knowledge of actual evidence. Usually it still takes several years until new knowledge is fully implemented in daily practice. Objectives: The German Society of Otolaryngology, Head and Neck Surgery (DGHNOKHC) and the German professional association of otolaryngologists (BVHNO) have a vested interest in supporting their members in the generation, processing and dissemination of evidence, and to foster the transfer of knowledge into practice. This includes the areas of diagnosis, treatment, prognosis and prevention as well as drug therapies or the application of medical devices or surgical procedures. Crucial is the regular determination of existing evidence gaps, including in the area of already established procedures, which must be followed by a prioritization of research questions and subsequent conduct of clinical research. Only with combined efforts even large trials can be performed, to test therapies and diagnostics for example, also after approval under everyday conditions. Methods, Results and Vision: The executive committees of DGHNOKHC and BVHNO have together founded the German Clinical Trials Unit for Ear, Nose and Throat medicine, Head and Neck Surgery (DSZ-HNO) to assist their members in the identification of evidence gaps and the planning and conduct of systematic reviews and clinical trials. The first projects have been started, including a BMBF(German Ministry for education and research)-funded clinical trial for the treatment of sudden hearing loss and a survey to detect evidence gaps in Otolaryngology. It seems both reasonable and feasible to provide a structure such as a jointly-run study center for doctors in hospitals and medical practices to assist in clinical research and to anchor the principles of evidence-based medicine in daily life.
Alzheimer's Disease Risk Genes and Lipid Regulators.Friday, April 29, 2016
El Gaamouch F, Jing P, Xia J, Cai D,
Journal of Alzheimer's disease : JAD. 23-Apr-2016
Brain lipid homeostasis plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis.
Structural basis for the dimerization and substrate recognition specificity of porcine epidemic diarrhea virus 3C-like protease.Friday, April 29, 2016
Ye G, Deng F, Shen Z, Luo R, Zhao L, Xiao S, Fu ZF, Peng G,
Virology. 26-Apr-2016
Porcine epidemic diarrhea virus (PEDV), a member of the genus Alphacoronavirus, has caused significant damage to the Asian and American pork industries. Coronavirus 3C-like protease (3CL(pro)), which is involved in the processing of viral polyproteins for viral replication, is an appealing antiviral drug target. Here, we present the crystal structures of PEDV 3CL(pro) and a molecular complex between an inactive PEDV 3CL(pro) variant C144A bound to a peptide substrate. Structural characterization, mutagenesis and biochemical analysis reveal the substrate-binding pockets and the residues that comprise the active site of PEDV 3CL(pro). The dimerization of PEDV 3CL(pro) is similar to that of other Alphacoronavirus 3CL(pro)s but has several differences from that of SARS-CoV 3CL(pro) from the genus Betacoronavirus. Furthermore, the non-conserved motifs in the pockets cause different cleavage of substrate between PEDV and SARS-CoV 3CL(pro)s, which may provide new insights into the recognition of substrates by 3CL(pro)s in various coronavirus genera.
Traceability Assessment and Performance Evaluation of Results for Measurement of Abbott Clinical Chemistry Assays on 4 Chemistry Analyzers.Friday, April 29, 2016
Lim J, Song KE, Song SH, Choi HJ, Koo SH, Kwon GC,
Archives of pathology & laboratory medicine. May-2016
-Abbott clinical chemistry assays met the performance criteria based on desirable biological variation for precision, bias, and total error. They also showed excellent linearity and carryover. Therefore, these clinical chemistry assays were found to be accurate and reliable and are readily applicable on the various platforms used in this study.
Precision Medicine in Gastrointestinal Pathology.Friday, April 29, 2016
Wang DH, Park JY,
Archives of pathology & laboratory medicine. May-2016
-Translating our ability to sequence thousands of genes into meaningful improvements in patient survival will be the challenge for the next decade.
Molecular Subtypes of Colorectal Cancer and Their Clinicopathologic Features, With an Emphasis on the Serrated Neoplasia Pathway.Friday, April 29, 2016
Bae JM, Kim JH, Kang GH,
Archives of pathology & laboratory medicine. May-2016
-Because colorectal cancers arise from 2 different morphologic multistep carcinogenesis pathways with varying contributions from 3 different molecular carcinogenesis pathways, colorectal cancer is a heterogeneous and complex disease. Thus, molecular subtyping of colorectal cancers is an important approach to characterizing their heterogeneity with respect to not only prognosis and therapeutic response but also biology and natural history.
Identification of Serum miR-146a and miR-155 as Novel Noninvasive Complementary Biomarkers for Ankylosing Spondylitis.Friday, April 29, 2016
Qian BP, Ji ML, Qiu Y, Wang B, Yu Y, Shi W, Luo YF,
Spine. May-2016
NA.
Design, synthesis and biological evaluation of PSMA/hepsin-targeted heterobivalent ligands.Friday, April 29, 2016
Subedi M, Minn I, Chen J, Kim Y, Ok K, Jung YW, Pomper MG, Byun Y,
European journal of medicinal chemistry. 14-Apr-2016
Cell surface biomarkers such as prostate-specific membrane antigen (PSMA) and hepsin have received considerable attention as targets for imaging prostate cancer (PCa) due to their high cell surface expression in such tumors and easy access for imaging probes. Novel amidine-containing indole analogs (13-21) as hepsin inhibitors were designed and synthesized. These compounds showed in vitro inhibitory activity against hepsin with IC50 values from 5.9 to 70 μM. Based on the SAR of amidine-derived analogs, the novel heterobivalent compound 30, targeting both hepsin and PSMA, was synthesized by linking compound 18 with Lys-urea-Glu, the key scaffold for the specific binding to PSMA, followed by the conjugation of the optical dye SulfoCy7. Compound 30 exhibited inhibitory activities against PSMA and hepsin, with IC50 values of 28 nM and 2.8 μM, respectively. In vitro cell uptake and preliminary in vivo optical imaging studies of 30 showed selective binding and retention in both PSMA and hepsin high-expressing PC3/ML-PSMA-HPN cells as compared with low-expressing PC3/ML cells.
GCGene: a gene resource for gastric cancer with literature evidence.Friday, April 29, 2016
Zhao M, Chen L, Liu Y, Qu H,
Oncotarget. 26-Apr-2016
Gastric cancer (GC) is the fifth most common cancer and third leading cause of cancer-related deaths worldwide. Its lethality primarily stems from a lack of detection strategies for early stages of GC and a lack of noninvasive detection strategies for advanced stages. The development of early diagnostic biomarkers largely depends on understanding the biological pathways and regulatory mechanisms associated with putative GC genes. Unfortunately, the GC-implicated genes that have been identified thus far are scattered among thousands of published studies, and no systematic summary is available, which hinders the development of a large-scale genetic screen. To provide a publically accessible resource tool to meet this need, we constructed a literature-based database GCGene (Gastric Cancer Gene database) with comprehensive annotations supported by a user-friendly website. In the current release, we have collected 1,815 unique human genes including 1,678 protein-coding and 137 non-coding genes curated from extensive examination of 3,142 PubMed abstracts. The resulting database has a convenient web-based interface to facilitate both textual and sequence-based searches. All curated genes in GCGene are downloadable for advanced bioinformatics data mining. Gene prioritization was performed to rank the relative relevance of these genes in GC development. The 100 top-ranked genes are highly mutated according to the cohort of published studies we reviewed. By conducting a network analysis of these top-ranked GC-associated genes in the human interactome, we were able to identify strong links between 8 highly connected genes with low expression and patient survival time. GCGene is freely available to academic users at http://gcgene.bioinfo-minzhao.org/.
Copy number variations in urine cell free DNA as biomarkers in advanced prostate cancer.Friday, April 29, 2016
Xia Y, Huang CC, Dittmar R, Du M, Wang Y, Liu H, Shenoy N, Wang L, Kohli M,
Oncotarget. 26-Apr-2016
Genetic profiling of urine cell free DNA (cfDNA) has not been evaluated in advanced prostate cancer. We performed whole genome sequencing of urine cfDNAs to identify tumor-associated copy number variations in urine before and after initiating androgen deprivation therapy in HSPC stage and docetaxel chemotherapy in CRPC stage. A log2 ratio-based copy number analysis detected common genomic abnormalities in prostate cancer including AR amplification in 5/10 CRPC patients. Other abnormalities identified included TMPRSS2-ERG fusion, PTEN gene deletion, NOTCH1 locus amplification along with genomic amplifications at 8q24.3, 9q34.3, 11p15.5 and 14q11.2, and deletions at 4q35.2, 5q31.3, 7q36.3, 12q24.33, and 16p11.2. By comparing copy number between pre- and post-treatment, we found significant copy number changes in 34 genomic loci. To estimate the somatic tumor DNA fraction in urine cfDNAs, we developed a Urine Genomic Abnormality (UGA) score algorithm that summed the top ten most significant segments with copy number changes. The UGA scores correlated with tumor burden and the change in UGA score after stage-specific therapies reflected disease progression status and overall survival. The study demonstrates the potential clinical utility of urine cfDNAs in predicting treatment response and monitoring disease progression.
S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide.Friday, April 29, 2016
Stewart RL, Carpenter BL, West DS, Knifley T, Liu L, Wang C, Weiss HL, Gal TS, Durbin EB, Arnold SM, O'Connor KL, Chen M,
Oncotarget. 25-Apr-2016
S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.
The International Committee of Medical Journal Editors proposal for sharing clinical trial data and the possible implications for the peer review process.Friday, April 29, 2016
Kavsak PA,
Annals of translational medicine. Mar-2016
Toward precision medicine in neurological diseases.Friday, April 29, 2016
Tan L, Jiang T, Tan L, Yu JT,
Annals of translational medicine. Mar-2016
Technological development has paved the way for accelerated genomic discovery and is bringing precision medicine into view. The goal of precision medicine is to deliver optimally targeted and timed interventions tailored to an individual's molecular drivers of disease. Neurological diseases are promisingly suited models for precision medicine because of the rapidly expanding genetic knowledge base, phenotypic classification, the development of biomarkers and the potential modifying treatments. Moving forward, it is crucial that through these integrated research platforms to provide analysis both for accurate personal genome analysis and gene and drug discovery. Here we describe our vision of how precision medicine can bring greater clarity to the clinical and biological complexity of neurological diseases.
Correlation of thyroid dysfunction and cognitive impairments induced by subcortical ischemic vascular disease.Friday, April 29, 2016
Chen Z, Liang X, Zhang C, Wang J, Chen G, Zhang H, Sun Z,
Brain and behavior. Apr-2016
These findings might contribute to a more accurate clinical diagnosis and differentiation among normal controls, SIVDND, SVMCI, and VD patients, in order to develop appropriate intervention approaches for SIVD therapeutic treatment.
Molecular Characterization of Streptococcus agalactiae Isolates From Pregnant and Non-Pregnant Women at Yazd University Hospital, Iran.Friday, April 29, 2016
Sadeh M, Firouzi R, Derakhshandeh A, Bagher Khalili M, Kong F, Kudinha T,
Jundishapur journal of microbiology. Feb-2016
The determination of serotype and surface proteins of GBS strains distribution would ‎be ‎relevant ‎for the future possible formulation of a GBS vaccine.
Pathotypic and Phylogenetic Study of Diarrheagenic Escherichia coli and Uropathogenic E. coli Using Multiplex Polymerase Chain Reaction.Friday, April 29, 2016
Salmani H, Azarnezhad A, Fayazi MR, Hosseini A,
Jundishapur journal of microbiology. Feb-2016
ETEC and EAggEC were the most detected E. coli among stool and UTI samples, emphasizing the need to dedicate more health care attention to this group. In addition, our phylogenetic study may be helpful in figuring out the infection origin and for epidemiological studies. Nonetheless, more research studies with larger sample sizes are suggested for confirming our results.
Antioxidant Effects of Sheep Whey Protein on Endothelial Cells.Friday, April 29, 2016
Kerasioti E, Stagos D, Georgatzi V, Bregou E, Priftis A, Kafantaris I, Kouretas D,
Oxidative medicine and cellular longevity. 2016
Excessive production of reactive oxygen species (ROS) may cause endothelial dysfunction and consequently vascular disease. In the present study, the possible protective effects of sheep whey protein (SWP) from tert-butyl hydroperoxide- (tBHP-) induced oxidative stress in endothelial cells (EA.hy926) were assessed using oxidative stress biomarkers. These oxidative stress biomarkers were glutathione (GSH) and ROS levels determined by flow cytometry. Moreover, thiobarbituric acid-reactive substances (TBARS), protein carbonyls (CARB), and oxidized glutathione (GSSG) were determined spectrophotometrically. The results showed that SWP at 0.78, 1.56, 3.12, and 6.24 mg of protein mL(-1) increased GSH up to 141%, while it decreased GSSG to 46.7%, ROS to 58.5%, TBARS to 52.5%, and CARB to 49.0%. In conclusion, the present study demonstrated for the first time that SWP protected endothelial cells from oxidative stress. Thus, SWP may be used for developing food supplements or biofunctional foods to attenuate vascular disturbances associated with oxidative stress.
Establishing an analytic pipeline for genome-wide DNA methylation.Friday, April 29, 2016
Wright ML, Dozmorov MG, Wolen AR, Jackson-Cook C, Starkweather AR, Lyon DE, York TP,
Clinical epigenetics. 2016
The need for research investigating DNA methylation (DNAm) in clinical studies has increased, leading to the evolution of new analytic methods to improve accuracy and reproducibility of the interpretation of results from these studies. The purpose of this article is to provide clinical researchers with a summary of the major data processing steps routinely applied in clinical studies investigating genome-wide DNAm using the Illumina HumanMethylation 450K BeadChip. In most studies, the primary goal of employing DNAm analysis is to identify differential methylation at CpG sites among phenotypic groups. Experimental design considerations are crucial at the onset to minimize bias from factors related to sample processing and avoid confounding experimental variables with non-biological batch effects. Although there are currently no de facto standard methods for analyzing these data, we review the major steps in processing DNAm data recommended by several research studies. We describe several variations available for clinical researchers to process, analyze, and interpret DNAm data. These insights are applicable to most types of genome-wide DNAm array platforms and will be applicable for the next generation of DNAm array technologies (e.g., the 850K array). Selection of the DNAm analytic pipeline followed by investigators should be guided by the research question and supported by recently published methods.
Genetic Abnormalities in Biliary Brush Samples for Distinguishing Cholangiocarcinoma from Benign Strictures in Primary Sclerosing Cholangitis.Friday, April 29, 2016
Timmer MR, Lau CT, Meijer SL, Fockens P, Rauws EA, Ponsioen CY, Calpe S, Krishnadath KK,
Gastroenterology research and practice. 2016
Background. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and is strongly associated with cholangiocarcinoma (CCA). The lack of efficient diagnostic methods for CCA is a major problem. Testing for genetic abnormalities may increase the diagnostic value of cytology. Methods. We assessed genetic abnormalities for CDKN2A, TP53, ERBB2, 20q, MYC, and chromosomes 7 and 17 and measures of genetic clonal diversity in brush samples from 29 PSC patients with benign biliary strictures and 12 patients with sporadic CCA or PSC-associated CCA. Diagnostic performance of cytology alone and in combination with genetic markers was evaluated by sensitivity, specificity, and area under the curve analysis. Results. The presence of MYC gain and CDKN2A loss as well as a higher clonal diversity was significantly associated with malignancy. MYC gain increased the sensitivity of cytology from 50% to 83%. However, the specificity decreased from 97% to 76%. The diagnostic accuracy of the best performing measures of clonal diversity was similar to the combination of cytology and MYC. Adding CDKN2A loss to the panel had no additional benefit. Conclusion. Evaluation of MYC abnormalities and measures of clonal diversity in brush cytology specimens may be of clinical value in distinguishing CCA from benign biliary strictures in PSC.
Effectiveness of Magnifying Narrow-Band Imaging Endoscopy for Differential Diagnosis between the High-Risk Mixed-Type and Low-Risk Simple-Type of Low-Grade, Well-Differentiated Gastric Tubular Adenocarcinoma.Friday, April 29, 2016
Saitoh T, Takamura A, Watanabe G, Sugitani S, Ajioka Y,
Gastroenterology research and practice. 2016
Backgrounds. Magnifying endoscopy with narrow-band imaging (NBI-ME) is useful for diagnosing differentiated early gastric cancer (D-EGC). D-EGC is classified as high- or low-grade based on its glandular architectural and cytological atypia. Low-grade, well-differentiated tubular adenocarcinoma (LG-tub1) mixed with high-grade tub1 (HG-tub1) and/or other histological types (M-LG-tub1) may indicate a primitive high-risk malignant lesion compared to histologically simple-type LG-tub1 (S-LG-tub1). Because LG-tub1 is occasionally difficult to diagnose due to its unclear demarcation under conventional white light endoscopy, early precise diagnoses are important. Methods. We compared NBI-ME and postendoscopic submucosal dissection histological findings for 30 S-LG-tub1 and 15 M-LG-tub1 lesions. We classified the NBI-ME findings of S-LG-tub1 (and not D-EGC) into four patterns. The differential diagnosis between M-LG-tub1 and S-LG-tub1 depended on the presence of more than one of these patterns without or with other patterns (referred to as "limited-to-four-pattern [LFP] sign-positive" and "sign-negative", resp.). Result. The sensitivity, specificity, accuracy, positive and negative predictive values, and intraobserver and interobserver agreement, using the "LFP sign" for the differential diagnosis between M-LG-tub1 and S-LG-tub1, were 87.9%, 91.7%, 88.9%, 96.7%, 73.3%, and k = 0.842 and k = 0.737, respectively. Conclusion. NBI-ME may be useful in differentiating between high-risk M-LG-tub1 and low-risk S-LG-tub1.
Macular thickness as a predictor of loss of visual sensitivity in ethambutol-induced optic neuropathy.Friday, April 29, 2016
Peng CX, Zhang AD, Chen B, Yang BJ, Wang QH, Yang M, Wei SH,
Neural regeneration research. Mar-2016
Ethambutol is a common cause of drug-related optic neuropathy. Prediction of the onset of ethambutol-induced optic neuropathy and consequent drug withdrawal may be an effective method to stop visual loss. Previous studies have shown that structural injury to the optic nerve occurred earlier than the damage to visual function. Therefore, we decided to detect structural biomarkers marking visual field loss in early stage ethambutol-induced optic neuropathy. The thickness of peripapillary retinal nerve fiber layer, macular thickness and visual sensitivity loss would be observed in 11 ethambutol-induced optic neuropathy patients (22 eyes) using optical coherence tomography. Twenty-four healthy age- and sex-matched participants (48 eyes) were used as controls. Results demonstrated that the temporal peripapillary retinal nerve fiber layer thickness and average macular thickness were thinner in patients with ethambutol-induced optic neuropathy compared with healthy controls. The average macular thickness was strongly positively correlated with central visual sensitivity loss (r (2) =0.878, P=0.000). These findings suggest that optical coherence tomography can be used to efficiently screen patients. Macular thickness loss could be a potential factor for predicting the onset of ethambutol-induced optic neuropathy.
BACE1 in the retina: a sensitive biomarker for monitoring early pathological changes in Alzheimer's disease.Friday, April 29, 2016
Li L, Luo J, Chen D, Tong JB, Zeng LP, Cao YQ, Xiang J, Luo XG, Shi JM, Wang H, Huang JF,
Neural regeneration research. Mar-2016
Because of a lack of sensitive biomarkers, the diagnosis of Alzheimer's disease (AD) cannot be made prior to symptom manifestation. Therefore, it is crucial to identify novel biomarkers for the presymptomatic diagnosis of AD. While brain lesions are a major feature of AD, retinal pathological changes also occur in patients. In this study, we investigated the temporal changes in β-site APP-cleaving enzyme 1 (BACE1) expression in the retina and brain to determine whether it could serve as a suitable biomarker for early monitoring of AD. APP/PS-1 transgenic mice, 3, 6 and 8 months of age, were used as an experimental group, and age-matched C57/BL6 wild-type mice served as the control group. In the Morris water maze test, there were no significant differences in escape latency or in the number of crossings in the target area among mice of different ages. Compared with wild-type mice, no changes in learning or memory abilities were detected in transgenic mice at 3 months of age. However, compared with wild-type mice, the escape latency was significantly increased in transgenic mice at 6 months, starting on day 3, and at 8 months, starting on day 2, during Morris water maze training. In addition, the number of crossings of the target area was significantly decreased in transgenic mice. The learning and memory abilities of transgenic mice were further worsened at 8 months of age. Immunohistochemical staining revealed no BACE1 plaques in wild-type mice at 3, 6 or 8 months or in transgenic mice at 3 months, but they were clearly found in the entorhinal cortex, hippocampus and prefrontal cortex of transgenic mice at 6 and 8 months. BACE1 expression was not detected in the retina of wild-type mice at 3 months, but weak BACE1 expression was detected in the ganglion cell layer, inner plexiform layer and outer plexiform layer at 6 and 8 months. In transgenic mice, BACE1 expression in the ganglion cell layer was increased at 3 months, and BACE1 expression in the ganglion cell layer, inner plexiform layer and outer plexiform layer was significantly increased at 6 and 8 months, compared with age-matched wild-type mice. Taken together, these results indicate that changes in BACE1 expression appear earlier in the retina than in the brain and precede behavioral deficits. Our findings suggest that abnormal expression of BACE1 in the retina is an early pathological change in APP/PS-1 transgenic mice, and that BACE1 might have potential as a biomarker for the early diagnosis of AD in humans.
Enzymatic remodeling of heparan sulfate: a therapeutic strategy for systemic and localized amyloidoses?Friday, April 29, 2016
Nishitsuji K, Saito H, Uchimura K,
Neural regeneration research. Mar-2016
Longitudinal Changes in Vascular Risk Markers and Mortality Rates among a Latino Population with Hypertension.Friday, April 29, 2016
Pflederer MC, Long CS, Beaty B, Havranek EP, Mehler PS, Keniston A, Krantz MJ,
Texas Heart Institute journal / from the Texas Heart Institute of St. Luke's Episcopal Hospital, Texas Children's Hospital. Apr-2016
Vascular markers such as pulse-wave velocity and carotid intima-media thickness (CIMT) might improve the prediction of incident cardiovascular disease beyond traditional risk factors. These vascular markers have not been well characterized in minority populations and might be more useful than inflammatory biomarkers. We conducted a prospective, longitudinal cohort study among hypertensive patients in an urban safety-net hospital. We evaluated inflammatory biomarkers, arterial pulse-wave velocity, and carotid intima-media thickness at baseline, 1 year, and 2 years. The primary outcome variable was CIMT. Generalized linear mixed-effects models were used to evaluate associations between CIMT and predictive variables accounting for the correlation of multiple measurements within subjects over time. For our secondary outcome, we used administrative and National Death Index data to determine all-cause death, and univariate relationships were evaluated. Among 175 subjects, 117 were Latino (67%) and 117 were female (67%). Pulse-wave velocity and CIMT regressed over time (both P <0.001) and were highly correlated (P <0.001). Only pulse-wave velocity (P=0.002) and total cholesterol (P=0.03) were associated with CIMT in time-varying covariate analysis. At a median follow-up period of 80 months, 17 of 175 subjects had died (10%). Higher baseline CIMT and pulse-wave velocity were associated with increased mortality rates (both P <0.01). No serum inflammatory marker was significantly correlated with longitudinal changes in CIMT or death. In conclusion, both arterial stiffness and preclinical carotid atherosclerosis were associated with increased mortality rates and might be useful risk-stratification markers among this minority population.
Breed- and age-related differences in canine mammary tumors.Friday, April 29, 2016
Kim HW, Lim HY, Shin JI, Seung BJ, Ju JH, Sur JH,
Canadian journal of veterinary research = Revue canadienne de recherche vétérinaire. Apr-2016
Triple-negative breast cancer is a type of breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2). It is an important and clinically relevant condition as it has a poor prognosis and is difficult to treat. Basal-like triple-negative cancer is highly prevalent in both African-Americans and adolescents. We therefore examined whether such a cancer likewise occurs in specific breeds and age groups in dogs, focusing on basal-like triple-negative cancer in particular. In this study, 181 samples from dogs with malignant mammary carcinoma from the 5 most common breeds and 2 age groups in Korea were analyzed. Histological classification and molecular subtyping, including assessment of immunohistochemical findings, were carried out. Twenty-five of 28 (89.3%) triple-negative carcinomas were identified as basal-like triple-negative carcinomas. Analysis of associations of classified factors revealed that the shih tzu breed (9/25, 36.0%) and advanced-age (19/25, 76.0%) groups were characterized by higher prevalence of basal-like triple-negative tumors with diverse histological types and of a higher grade. These results suggest that breed- and age-related differences can be identified in canine mammary carcinoma and, notably, in the shih tzu breed and at older ages. Further investigation of these distinguishing characteristics of the shih tzu breed is warranted.
Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation.Friday, April 29, 2016
Rialdi A, Campisi L, Zhao N, Lagda AC, Pietzsch C, Ho JS, Martinez-Gil L, Fenouil R, Chen X, Edwards M, Metreveli G, Jordan S, Peralta Z, Munoz-Fontela C, Bouvier N, Merad M, Jin J, Weirauch M, Heinz S, Benner C, van Bakel H, Basler C, García-Sastre A, Bukreyev A, Marazzi I,
Science (New York, N.Y.). 28-Apr-2016
The host innate immune response is the first line of defense against pathogens and is orchestrated by the concerted expression of genes induced by microbial stimuli. Deregulated expression of these genes is linked to the initiation and progression of diseases associated with exacerbated inflammation. Here, we identify Topoisomerase 1 (Top1) as a positive regulator of RNA polymerase II (RNAPII) transcriptional activity at pathogen-induced genes. Depletion or chemical inhibition of Top1 suppresses the host response against Influenza and Ebola viruses as well as bacterial products. As a result, therapeutic pharmacological inhibition of Top1 protects mice from death in experimental models of lethal inflammation. Our results indicate that Top1 inhibition could be used as therapy against life threatening infections characterized by an acutely exacerbated immune response.
Approaches to improve the pharmacokinetics of radiolabeled GLP-1 receptor ligands using antagonistic tracers.Friday, April 29, 2016
Rylova SN, Waser B, Del Pozzo L, Tönnesmann R, Mansi R, Meyer PT, Reubi JC, Maecke HR,
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 28-Apr-2016
Our results suggest that iodinated Ex(9-39)NH2 may be a very promising tracer for imaging GLP-1 receptor expression in vivo. Due to 20-fold improved tumor-to-kidney ratio it may offer higher sensitivity in detection of insulinomas and imaging of beta cell mass in diabetic patients. Further studies with (124)I-BH-Ex(9-39)NH2 are warranted.
Bone marrow fibrosis in myelodysplastic syndromes: a prospective evaluation including mutational analysis.Friday, April 29, 2016
Ramos F, Robledo C, Izquierdo-García FM, Suárez-Vilela D, Benito R, Fuertes M, Insunza A, Barragán E, Del Rey M, de Morales JM, Tormo M, Salido E, Zamora L, Pedro C, Sánchez-Del-Real J, Díez-Campelo M, Del Cañizo C, Sanz GF, Hernández-Rivas JM,
Oncotarget. 26-Apr-2016
The biological and molecular events that underlie bone marrow fibrosis in patients with myelodysplastic syndromes are poorly understood, and its prognostic role in the era of the Revised International Prognostic Scoring System (IPSS-R) is not yet fully determined. We have evaluated the clinical and biological events that underlie bone marrow fibrotic changes, as well as its prognostic role, in a well-characterized prospective patient cohort (n=77) of primary MDS patients. The degree of marrow fibrosis was linked to parameters of erythropoietic failure, marrow cellularity, p53 protein accumulation, WT1 gene expression, and serum levels of CXCL9 and CXCL10, but not to other covariates including the IPSS-R score. The presence of bone marrow fibrosis grade 2 or higher was associated with the presence of mutations in cohesin complex genes (31.5% vs. 5.4%, p=0.006). By contrast, mutations in CALR, JAK2, PDGFRA, PDGFRB,and TP53 were very rare. Survival analysis showed that marrow fibrosis grade 2 or higher was a relevant significant predictor for of overall survival, and independent of age, performance status, and IPSS-R score in multivariate analysis.
Cytoplasmic, full length and novel cleaved variant, TBLR1 reduces apoptosis in prostate cancer under androgen deprivation.Friday, April 29, 2016
Daniels G, Zhang X, Zhong X, Santiago L, Wang LH, Wu X, Zhang JY, Liang F, Li X, Neubert TA, Steinke L, Shen Y, Basch R, Schneider R, Levy DE, Lee P,
Oncotarget. 26-Apr-2016
TBLR1/TBL1XR1, a core component of the nuclear receptor corepressor (NCoR) complex critical for the regulation of multiple nuclear receptors, is a transcriptional coactivator of androgen receptor (AR) and functions as a tumor suppressor when expressed in the nucleus in prostate. Subcellular localization of a protein is critical for its function, and although TBLR1, as a transcriptional cofactor, has been primarily viewed as a nuclear protein, many cells also express variable levels of cytoplasmic TBLR1 and its cytoplasmic specific functions have not been studied. Prostate cancer (PCa) cells express moderately higher level of cytoplasmic TBLR1 compared to benign prostate cells. When comparing androgen-dependent (AD) to androgen-independent (AI) PCa, AI cells contain very high levels of TBLR1 cytoplasmic expression and low levels of nuclear expression. Overexpression of cytoplasmic TBLR1 in AD cells inhibits apoptosis induced by androgen deprivation therapy, either in an androgen free condition or in the presence of bicalutamide. Additionally, we identified a cytoplasmic specific isoform of TBLR1 (cvTBLR1) approximately 5 kDa lower in molecular weight, that is expressed at higher levels in AI PCa cells. By immunoprecipitation, we purified cvTBLR1 and using mass spectrometry analysis combined with N-terminal TMPP labeling and Edman degradation, we identified the cleavage site of cvTBLR1 at amino acid 89, truncating the first 88 amino acids of the N-terminus of the full length protein. Functionally, cvTBLR1 expressed in the cytoplasm reduced apoptosis in PCa cells and promoted growth, migration, and invasion. Finally, we identified a nuclear export signal sequence for TBLR1 cellular localization by deletion and site-directed mutagenesis. The roles of TBLR1 and cvTBLR1 provide novel insights into the mechanism of castration resistance and new strategies for PCa therapy.
Integrin signaling via FAK-Src controls cytokinetic abscission by decelerating PLK1 degradation and subsequent recruitment of CEP55 at the midbody.Friday, April 29, 2016
Kamranvar SA, Gupta DK, Huang Y, Gupta RK, Johansson S,
Oncotarget. 26-Apr-2016
Adhesion to extracellular matrix is required for cell cycle progression through the G1 phase and for the completion of cytokinesis in normal adherent cells. Cancer cells acquire the ability to proliferate anchorage-independently, a characteristic feature of malignantly transformed cells. However, the molecular mechanisms underlying this escape of the normal control mechanisms remain unclear. The current study aimed to identify adhesion-induced reactions regulating the cytokinesis of non-transformed human fibroblasts.The adhesion-dependent control of cytokinesis was found to occur at a late stage close to the abscission, during which the endosomal sorting complex required for transport (ESCRT) severs the thin intercellular bridge connecting two nascent daughter cells. CEP55, a key protein involved in the abscission process, was localized at the midbody in both adherent and non-adherent fibroblasts, but it was unable to efficiently recruit ALIX, TSG101, and consequently the ESCRT-III subunit CHMP4B was missing in the non-adherent cells. PLK1, a kinase that prevents premature recruitment of CEP55 to the midbody, disappeared from this site more rapidly in the non-adherent cells. A FAK-Src signaling pathway downstream of integrin-mediated cell adhesion was found to decelerate both PLK1 degradation and CEP55 accumulation at the midbody. These data identify the regulation of PLK1 and CEP55 as steps where integrins exert control over the cytokinetic abscission.
Urinary 5-Aminolevulinic Acid Concentrations as a Potential Tumor Marker for Colorectal Cancer Screening and Recurrence.Friday, April 29, 2016
Kamada Y, Murayama Y, Ota U, Takahashi K, Arita T, Kosuga T, Konishi H, Morimura R, Komatsu S, Shiozaki A, Kuriu Y, Ikoma H, Nakanishi M, Ichikawa D, Fujiwara H, Okamoto K, Tanaka T, Otsuji E,
Anticancer research. May-2016
These results suggest that the measurement of porphyrin metabolites in urine may potentially serve as a new screening and recurrence marker for CRC.
Increase in Gene Expression of TYMP, DPYD and HIF1A Are Associated with Response to Preoperative Chemoradiotherapy Including S-1 or UFT for Rectal Cancer.Friday, April 29, 2016
Sadahiro S, Suzuki T, Tanaka A, Okada K, Saito G, Kamijo A, Nagase H,
Anticancer research. May-2016
Increases in gene expression levels of TYMP, DPYD, and HIF1A in tumor tissues at 7 days after the start of CRT may be useful for predicting the efficacy of CRT including S-1 or UFT.
Interaction Between Beta-Catenin and EGFR Expression by Immunohistochemistry Identifies Prognostic Subgroups in Early High-risk Triple-negative Breast Cancer.Friday, April 29, 2016
Lakis S, Dimoudis S, Kotoula V, Alexopoulou Z, Kostopoulos I, Koletsa T, Bobos M, Timotheadou E, Papaspirou I, Efstratiou I, Aravantinos G, Karavasilis V, Zagouri F, Gogas H, Razis E, Pentheroudakis G, Christodoulou C, Pectasides D, Fountzilas G,
Anticancer research. May-2016
Wnt and epidermal growth factor receptor (EGFR) pathway abnormalities and de-stabilization of cell adhesion are all important aspects of the pathogenesis of triple-negative breast cancer (TNBC). Herein we investigated how the expression of related protein markers may affect the outcome of patients bearing TNBC treated in the adjuvant setting. Immunohistochemistry for beta-catenin, Myc (Wnt pathway), E-cadherin, P-cadherin (cell-adhesion), EGFR and cytokeratin 5 (CK5) (identification of basal-like tumors) was carried out in 364 centrally confirmed TNBCs. Survival analysis was performed with Cox-regression models according to dichotomized continuous protein expression data and marker interactions. In 352 evaluable tumors, 81.5% were basal-like TNBC. E-cadherin and P-cadherin were positively associated, with co-expression being present in 68% of tumors. Individual markers did not affect patient outcome. However, a statistically significant interaction was shown such that low expression of beta-catenin in the cell membrane, defined as expression below the median of the H-score distribution, was associated with unfavourable disease-free survival among tumors that expressed EGFR, but not in the absence of EGFR expression (interaction p=0.0085). The interaction persisted after correcting for clinicopathological variables. A considerable number of TNBC co-expresses E-cadherin and P-cadherin, while membranous localization of beta-catenin may predict patient outcome in an EGFR-dependent manner. This novel interaction seems worthy for validating with regards to its biological and clinical relevance.
Nuclear Accumulation of Heat-shock Protein 90 Is Associated with Poor Survival and Metastasis in Patients with Non-small Cell Lung Cancer.Friday, April 29, 2016
Su JM, Hsu YY, Lin P, Chang H,
Anticancer research. May-2016
Nuclear accumulation of HSP90 might be a predictor of metastasis and survival in patients with NSCLC.
Survival After Surgical Treatment of Lung Cancer Arising in the Population Exposed to Illegal Dumping of Toxic Waste in the Land of Fires ('Terra dei Fuochi') of Southern Italy.Friday, April 29, 2016
Rocco G, Petitti T, Martucci N, Piccirillo MC, LA Rocca A, LA Manna C, DE Luca G, Morabito A, Chirico A, Franco R, Accardo R, Normanno N, Botti G, Lodato S, Ciliberto G, Pedicini T, Giordano A,
Anticancer research. May-2016
Following surgery for lung cancer, TdF and non-TdF surgical candidates had similar long-term survival. Originating from the TdF does not seem to be associated with worse outcomes after surgical treatment of patients with lung cancer.
Lymphoid Hyperplasia of the Orbit and Ocular Adnexa: A Clinico-Pathological Review.Friday, April 29, 2016
Andrew NH, Coupland SE, Pirbhai A, Selva D,
Survey of ophthalmology. 25-Apr-2016
Lymphoid hyperplasia (LH) is a benign lymphoproliferative disorder that, in a minority of cases, may be associated with concurrent or metachronous non-Hodgkin lymphoma (NHL) . LH cases are further subdivided into 'reactive' and 'atypical' categories based upon the presence or absence of unequivocal malignant features. With improving molecular diagnostic technologies, 'reactive' LH is by far the most common category of LH, with atypical LH accounting for only a small minority of specimens. Similarly, lesions previously diagnosed as LH are now being revised as low-grade B-cell NHL or diagnosed as newly described benign conditions such as IgG4-related disease. Additional differential diagnoses include specific and non-specific orbital inflammations, infiltrative processes, and depositions. Hence, there are emerging changes in the patterns and proportions of entities that fall within the spectrum of lymphoproliferative disorders of the orbit and ocular adnexa. Reactive LH and low-grade malignant lymphoproliferative disorders in the orbit and ocular adnexa are clinically and radiologically indistinguishable from each other, requiring tissue biopsy in all cases. The prognosis of ocular adnexal LH is generally favorable, but the small risk of NHL mandates follow-up for at least five years. We summarize the current state of knowledge on LH occurring in the orbit and ocular adnexa.
Fabrication and characterization of novel nano-biocomposite scaffold of chitosan-gelatin-alginate-hydroxyapatite for bone tissue engineering.Friday, April 29, 2016
Sharma C, Dinda AK, Potdar PD, Chou CF, Mishra NC,
Materials science & engineering. C, Materials for biological applications. 1-Jul-2016
A novel nano-biocomposite scaffold was fabricated in bead form by applying simple foaming method, using a combination of natural polymers-chitosan, gelatin, alginate and a bioceramic-nano-hydroxyapatite (nHAp). This approach of combining nHAp with natural polymers to fabricate the composite scaffold, can provide good mechanical strength and biological property mimicking natural bone. Environmental scanning electron microscopy (ESEM) images of the nano-biocomposite scaffold revealed the presence of interconnected pores, mostly spread over the whole surface of the scaffold. The nHAp particulates have covered the surface of the composite matrix and made the surface of the scaffold rougher. The scaffold has a porosity of 82% with a mean pore size of 112±19.0μm. Swelling and degradation studies of the scaffold showed that the scaffold possesses excellent properties of hydrophilicity and biodegradability. Short term mechanical testing of the scaffold does not reveal any rupturing after agitation under physiological conditions, which is an indicative of good mechanical stability of the scaffold. In vitro cell culture studies by seeding osteoblast cells over the composite scaffold showed good cell viability, proliferation rate, adhesion and maintenance of osteoblastic phenotype as indicated by MTT assay, ESEM of cell-scaffold construct, histological staining and gene expression studies, respectively. Thus, it could be stated that the nano-biocomposite scaffold of chitosan-gelatin-alginate-nHAp has the paramount importance for applications in bone tissue-engineering in future regenerative therapies.
Novel meloxicam releasing electrospun polymer/ceramic reinforced biodegradable membranes for periodontal regeneration applications.Friday, April 29, 2016
Yar M, Farooq A, Shahzadi L, Khan AS, Mahmood N, Rauf A, Chaudhry AA, Rehman IU,
Materials science & engineering. C, Materials for biological applications. 1-Jul-2016
Periodontal disease is associated with the destruction of periodontal tissues, along with other disorders/problems including inflammation of tissues and severe pain. This paper reports the synthesis of meloxicam (MX) immobilized biodegradable chitosan (CS)/poly(vinyl alcohol) (PVA)/hydroxyapatite (HA) based electrospun (e-spun) fibers and films. Electrospinning was employed to produce drug loaded fibrous mats, whereas films were generated by solvent casting method. In-vitro drug release from materials containing varying concentrations of MX revealed that the scaffolds containing higher amount of drug showed comparatively faster release. During initial first few hours fast release was noted from membranes and films; however after around 5h sustained release was achieved. The hydrogels showed good swelling property, which is highly desired for soft tissue engineered implants. To investigate the biocompatibility of our synthesized materials, VERO cells (epithelial cells) were selected and cell culture results showed that these all materials were non-cytotoxic and also these cells were very well proliferated on these synthesized scaffolds. These properties along with the anti-inflammatory potential of our fabricated materials suggest their effective utilization in periodontital treatments.
Overexpression of trophoblast cell surface antigen 2 as an independent marker for a poor prognosis and as a potential therapeutic target in epithelial ovarian carcinoma.Friday, April 29, 2016
Xu N, Zhang Z, Zhu J, Xu L, Li Y, Duan L, Mao Y, Li H,
International journal of experimental pathology. 29-Apr-2016
Most patients with epithelial ovarian cancer (EOC) are diagnosed at an advanced stage, and therapeutic options for these patients are limited. The identification of suitable biomarkers could be helpful for patients with EOC, who might benefit from targeted therapies even in advanced stages of the disease. Trophoblast cell surface antigen 2 (TROP2) is highly expressed in various human malignant tumours; however, this has not been demonstrated clearly in EOC. In this study, we further evaluated whether TROP2 is a promising marker for EOC, and thus also a potential target for EOC immunotherapy. Quantitative real-time polymerase chain reaction (qPCR) and fluorescence-activated cell sorting (FACS) analysis were employed to determine TROP2 mRNA and protein expression in both human EOC and normal ovarian cell lines. Additionally, TROP2 protein expression was measured by immunohistochemistry in 128 EOC tissue samples, 21 normal ovarian tissues and 18 normal fallopian tubes. The correlations between TROP2 protein expression and patients' clinicopathological features were investigated, and survival outcomes were analysed. TROP2 mRNA and protein levels were upregulated significantly in EOC cell lines compared with normal cell lines. The protein of TROP2 was expressed in the majority of EOC tissue samples (90.6%) and overexpressed in 75 (58.6%) of the 128 tumour samples. TROP2 overexpression was correlated with relevant clinicopathological characteristics and was associated with significantly shortened overall survival and disease-free survival. Furthermore, TROP2 was an independent prognostic marker for EOCs as analysed by Cox regression. TROP2 was a potential biomarker for targeted therapy in patients with TROP2-overexpressing EOC.
A synthetic cell-penetrating dominant-negative ATF5 peptide exerts anti-cancer activity against a broad spectrum of treatment resistant cancers.Friday, April 29, 2016
Karpel-Massler G, Horst BA, Shu C, Chau L, Tsujiuchi T, Bruce JN, Canoll P, Greene LA, Angelastro JM, Siegelin MD,
Clinical cancer research : an official journal of the American Association for Cancer Research. 28-Apr-2016
Our data support the idea that CP-d/n-ATF5-S1, administered as a single reagent or in combination with other drugs, holds promise as an innovative, safe and efficient anti-neoplastic agent against treatment-resistant cancers.
Transforming Growth Factor-β Limits Secretion of Lumican by Activated Stellate Cells within Primary Pancreatic Adenocarcinoma Tumors.Friday, April 29, 2016
Fleming JB, Kang Y, Roife D, Lee Y, Lv H, Suzuki R, Ling J, Rios Perez MV, Li X, Dai B, Pratt M, Truty MJ, Chatterjee D, Wang H, Thomas RM, Wang Y, Koay EJ, Chiao PJ, Katz MH,
Clinical cancer research : an official journal of the American Association for Cancer Research. 28-Apr-2016
Our results demonstrate that activated pancreatic stellate cells within PDAC secrete lumican under the negative control of TGF-β; once secreted, the extracellular lumican enhances stellate cell adhesion and mobility in a collagen rich environment.
Development and clinical validation of a blood test based on 29-gene expression for early detection of colorectal cancer.Friday, April 29, 2016
Ciarloni L, Hosseinian Ehrensberger S, Imaizumi N, Monnier-Benoit S, Nichita C, Myung SJ, Kim JS, Song SY, Kim TI, van der Weg B, Meier R, Borovicka J, Beglinger C, Vallet C, Maerten P, Ruegg C, Dorta G,
Clinical cancer research : an official journal of the American Association for Cancer Research. 28-Apr-2016
We report the validation of a novel blood test, Colox®, for the detection of CRC and LAP based on a 29-gene panel and the CEA and CYFRA21-1 plasma biomarkers. The performance and convenience of this routine blood test provides physicians a useful tool to test average risk individuals unwilling to undergo upfront colonoscopy.
Genome-wide association analysis of actigraphic sleep phenotypes in the LIFE Adult Study.Friday, April 29, 2016
Spada J, Scholz M, Kirsten H, Hensch T, Horn K, Jawinski P, Ulke C, Burkhardt R, Wirkner K, Loeffler M, Hegerl U, Sander C,
Journal of sleep research. 29-Apr-2016
The genetic basis of sleep is still poorly understood. Despite the moderate to high heritability of sleep-related phenotypes, known genetic variants explain only a small proportion of the phenotypical variance. However, most previous studies were based solely upon self-report measures. The present study aimed to conduct the first genome-wide association (GWA) of actigraphic sleep phenotypes. The analyses included 956 middle- to older-aged subjects (40-79 years) from the LIFE Adult Study. The SenseWear Pro 3 Armband was used to collect 11 actigraphic parameters of night- and daytime sleep and three parameters of rest (lying down). The parameters comprised measures of sleep timing, quantity and quality. A total of 7 141 204 single nucleotide polymorphisms (SNPs) were analysed after imputation and quality control. We identified several variants below the significance threshold of P ≤ 5× 10(-8) (not corrected for analysis of multiple traits). The most significant was a hit near UFL1 associated with sleep efficiency on weekdays (P = 1.39 × 10(-8) ). Further SNPs were close to significance, including an association between sleep latency and a variant in CSNK2A1 (P = 8.20 × 10(-8) ), a gene known to be involved in the regulation of circadian rhythm. In summary, our GWAS identified novel candidate genes with biological plausibility being promising candidates for replication and further follow-up studies.
Leaf-based physiological, metabolic, and ultrastructural changes in cultivated cotton cultivars under cadmium stress mediated by glutathione.Friday, April 29, 2016
Daud MK, Mei L, Azizullah A, Dawood M, Ali I, Mahmood Q, Ullah W, Jamil M, Zhu SJ,
Environmental science and pollution research international. 29-Apr-2016
Cadmium (Cd) pollution is present in the world over especially in the industrialized parts of the world. To reduce Cd accumulation in various crops especially food crops, alleviating agents such as reduced glutathione (GSH) can be applied, which are capable either to exclude or to sequester Cd contamination. This study investigated the leaf-based spatial distribution of physiological, metabolic, and microstructural changes in two cotton cultivars (Coker 312 and TM-1) under GSH-mediated Cd stress using single levels of Cd (50 μM) and GSH (50 μM) both separately and in mix along with control. Results showed that GSH revived the morphology and physiology of both cotton cultivars alone or in mix with Cd. Cd uptake was enhanced in all segments of leaf and whole leaf upon the addition of GSH. GSH alleviated Cd-induced reduction in the photosynthetic pigment compositions and chlorophyll a fluorescence parameters. Mean data of biomarkers (2,3,5-triphenyltetrazolium (TTC), total soluble protein (TSP), malondialdehyde (MDA), hydrogen peroxide (H2O2)) revealed the adverse effects of Cd stress on leaf segments of both cultivars, which were revived by GSH. The oxidative metabolism induced by Cd stress was profoundly influenced by exogenous GSH application. The microstructural alterations were mainly confined to chloroplastic regions of leaves under Cd-stressed conditions, which were greatly revived upon the GSH addition. As a whole, Cd stress greatly affected TM-1 as compared to Coker 312. These results suggest a positive role of GSH in alleviating Cd-mediated changes in different leaf sections of cotton cultivars.
A Proteoglycan-Like Molecule Offers Insights Into Ground Substance Changes During Holothurian Intestinal Regeneration.Friday, April 29, 2016
Vázquez-Vélez GE, Rodríguez-Molina JF, Quiñones-Frías MC, Pagán M, García-Arrarás JE,
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 28-Apr-2016
SummaryExtracellular matrix remodeling is an essential component of regenerative processes in metazoans. Among these animals, holothurians (sea cucumbers) are distinguished by their great regenerative capacities. We have previously shown that fibrous collagen as well as other fibrous components disappear from the connective tissue (CT) early during intestinal regeneration, and later return as the organ primordia form. We now report on changes of the nonfibrous component of the CT. We have used Alcian Blue staining and an antibody, Proteoglycan Like-1 (PGL-1), that recognizes a proteoglycan-like antigen to identify the presence of proteoglycans in normal and regenerating intestines. Our results show that early in regeneration, the ground substance resembles that of the mesentery, the structure from where the new intestine originates. As regeneration proceeds, Alcian Blue staining and PGL-1 labeling reorganize, so that by 4 weeks the normal intestinal CT pattern is achieved. Together with our previous findings, the data suggest that CT components that might be detrimental to regeneration disappear early on, while those that might be beneficial to regeneration, such as proteoglycans, are present throughout the regenerative process.
Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association.Friday, April 29, 2016
Murphy E, Ardehali H, Balaban RS, DiLisa F, Dorn GW, Kitsis RN, Otsu K, Ping P, Rizzuto R, Sack MN, Wallace D, Youle RJ,
Circulation research. 28-Apr-2016
Cardiovascular disease is a major leading cause of morbidity and mortality in the United States and elsewhere. Alterations in mitochondrial function are increasingly being recognized as a contributing factor in myocardial infarction and in patients presenting with cardiomyopathy. Recent understanding of the complex interaction of the mitochondria in regulating metabolism and cell death can provide novel insight and therapeutic targets. The purpose of this statement is to better define the potential role of mitochondria in the genesis of cardiovascular disease such as ischemia and heart failure. To accomplish this, we will define the key mitochondrial processes that play a role in cardiovascular disease that are potential targets for novel therapeutic interventions. This is an exciting time in mitochondrial research. The past decade has provided novel insight into the role of mitochondria function and their importance in complex diseases. This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.
Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants.Friday, April 29, 2016
Spratley SJ, Hill CH, Viuff AH, Edgar JR, Skjødt K, Deane JE,
Traffic (Copenhagen, Denmark). 29-Apr-2016
Krabbe disease is a severe, fatal neurodegenerative disorder caused by defects in the lysosomal enzyme galactocerebrosidase (GALC). The correct targeting of GALC to the lysosome is essential for the degradation of glycosphingolipids including the primary lipid component of myelin. Over 100 different mutations have been identified in GALC that cause Krabbe disease but the mechanisms by which they cause disease remain unclear. We have generated monoclonal antibodies against full-length human GALC and used these to monitor the trafficking and processing of GALC variants in cell-based assays and by immunofluorescence microscopy. Striking differences in the secretion, processing and endosomal targeting of GALC variants allows the classification of these into distinct categories. A subset of GALC variants are not secreted by cells, not proteolytically processed, and remain trapped in the ER; these are likely to cause disease due to protein misfolding and should be targeted for pharmacological chaperone therapies. Other GALC variants can be correctly secreted by cells and cause disease due to catalytic defects in the enzyme active site, inappropriate post-translational modification or a potential inability to bind essential co-factors. The classification of disease pathogenesis presented here provides a molecular framework for appropriate targeting of future Krabbe disease therapies.
A Double-Blind, Randomized, Crossover Study to Compare the Effectiveness of Montelukast on Atopic Dermatitis in Korean Children.Friday, April 29, 2016
Jeon YH, Min TK, Yang HJ, Pyun BY,
Allergy, asthma & immunology research. Jul-2016
There was no statistically significant difference in clinical improvement or biomarkers between montelukast and placebo treatment. Therefore, conventional treatments with skin care and infection control might be more important strategies in the treatment of atopic dermatitis.
Somatic DICER1 mutations in adult-onset pulmonary blastoma.Friday, April 29, 2016
de Kock L, Bah I, Brunet J, Druker H, Astigarraga I, Bosch-Barrera J, Soglio DB, Nguyen VH, Malkin D, Priest JR, Foulkes WD,
The European respiratory journal. 28-Apr-2016
Detection of SYT-SSX mutant transcripts in formalin-fixed paraffin-embedded sarcoma tissues using one-step reverse transcriptase real-time PCR.Friday, April 29, 2016
Norlelawati AT, Mohd Danial G, Nora H, Nadia O, Zatur Rawihah K, Nor Zamzila A, Naznin M,
The Malaysian journal of pathology. Apr-2016
This study has shown that the application of One-Step reverse transcriptase real time PCR for the detection SYT-SSX transcript is feasible as an aid in confirming the diagnosis of synovial sarcoma.
Gene Therapy for Coagulation Disorders.Friday, April 29, 2016
Swystun LL, Lillicrap D,
Circulation research. 29-Apr-2016
Molecular genetic details of the human coagulation system were among the first successes of the genetic revolution in the 1980s. This information led to new molecular diagnostic strategies for inherited disorders of hemostasis and the development of recombinant clotting factors for the treatment of the common inherited bleeding disorders. A longer term goal of this knowledge has been the establishment of gene transfer to provide continuing access to missing or defective hemostatic proteins. Because of the relative infrequency of inherited coagulation factor disorders and the availability of safe and effective alternative means of management, the application of gene therapy for these conditions has been slow to realize clinical application. Nevertheless, the tools for effective and safe gene transfer are now much improved, and we have started to see examples of clinical gene therapy successes. Leading the way has been the use of adeno-associated virus-based strategies for factor IX gene transfer in hemophilia B. Several small phase 1/2 clinical studies using this approach have shown prolonged expression of therapeutically beneficial levels of factor IX. Nevertheless, before the application of gene therapy for coagulation disorders becomes widespread, several obstacles need to be overcome. Immunologic responses to the vector and transgenic protein need to be mitigated, and production strategies for clinical grade vectors require enhancements. There is little doubt that with the development of more efficient and facile strategies for genome editing and the application of other nucleic acid-based approaches to influence the coagulation system, the future of genetic therapies for hemostasis is bright.
Cross Talk Pathways Between Coagulation and Inflammation.Friday, April 29, 2016
Foley JH, Conway EM,
Circulation research. 29-Apr-2016
Anatomic pathology studies performed over 150 years ago revealed that excessive activation of coagulation occurs in the setting of inflammation. However, it has taken over a century since these seminal observations were made to delineate the molecular mechanisms by which these systems interact and the extent to which they participate in the pathogenesis of multiple diseases. There is, in fact, extensive cross talk between coagulation and inflammation, whereby activation of one system may amplify activation of the other, a situation that, if unopposed, may result in tissue damage or even multiorgan failure. Characterizing the common triggers and pathways are key for the strategic design of effective therapeutic interventions. In this review, we highlight some of the key molecular interactions, some of which are already showing promise as therapeutic targets for inflammatory and thrombotic disorders.
Emergence of community-associated Methicillin-resistant Staphylococcus aureus strains in the neonatal intensive care unit: an infection prevention and patient Safety Challenge.Friday, April 29, 2016
Reich PJ, Boyle MG, Hogan PG, Johnson AJ, Wallace MA, Elward AM, Warner BB, Burnham CD, Fritz SA,
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 25-Apr-2016
Methicillin-resistant Staphylococcus aureus (MRSA) infections cause significant morbidity and mortality in neonatal intensive care units (NICUs). We characterized the clinical and molecular epidemiology of MRSA strains colonizing NICU patients. Nasal MRSA isolates (n=250, from 96 NICU patients) recovered through active surveillance from 2009-2014 were characterized with Staphylococcal cassette chromosome mec (SCCmec) typing and detection of mupA (marker of high-level mupirocin resistance) and qacA/B (marker associated with chlorhexidine resistance). Factors associated with community-associated (CA-) or healthcare-associated (HA-) MRSA were evaluated. The overall prevalence of MRSA nasal colonization was 3.9%. Of 96 neonates in our retrospective cohort, 60 (63%) were colonized with CA-MRSA strains and 35 (36%) were colonized with HA-MRSA strains. Patients colonized with HA-MRSA were more likely to develop MRSA infections than patients colonized with CA-MRSA (13/35 [37%] vs. 8/60 [13%], p=0.007), although the interval from colonization to infection was shorter in CA-MRSA-colonized infants (0 days [range -1 to 4] versus HA-MRSA-colonized infants, 7 days [-1 to 43], p=0.005). Maternal peripartum antibiotics were associated with CA-MRSA colonization (adjusted odds ratio [aOR] 8.7; 95% confidence interval [CI] 1.7, 45.0); intubation and surgical procedures were associated with HA-MRSA colonization (aOR 7.8; 95% CI 1.3, 47.6 and aOR 6.0; 95% CI 1.4, 24.4, respectively). Mupirocin- and chlorhexidine-resistant MRSA was isolated from 4 and 8 patients, respectively; carriage of a mupirocin-resistant strain precluded decolonization. CA-MRSA strains are prominent in the NICU and associated with distinct risk factors. Given community reservoirs for MRSA acquisition and transmission, novel infection prevention strategies are needed.
O-GlcNAcylation: A regulator of tau pathology and neurodegeneration.Friday, April 29, 2016
Gong CX, Liu F, Iqbal K,
Alzheimer's & dementia : the journal of the Alzheimer's Association. 25-Apr-2016
O-GlcNAcylation is the posttranslational modification of intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). The discovery of O-GlcNAc modification of tau and its impact on tau phosphorylation has attracted recent research interest in O-GlcNAc studies in the Alzheimer's disease (AD) field. Modification of proteins by O-GlcNAc occurs extensively in the brain. The expressions and activities of the enzymes catalyzing O-GlcNAc cycling are several-fold higher in the brain than in the peripheral tissues. The O-GlcNAcylation levels of brain proteins including tau are decreased in AD brain, probably due to decreased brain glucose metabolism. The reduction of brain O-GlcNAcylation appears to mediate the molecular mechanism by which decreased brain glucose metabolism contributes to neurodegeneration. Studies on mouse models of tauopathies suggest a neuroprotective role of pharmacological elevation of brain O-GlcNAc, which could potentially be a promising approach for treating AD and other neurodegenerative diseases.
Molecular mechanism of prion-like tau-induced neurodegeneration.Friday, April 29, 2016
Alonso AD, Beharry C, Corbo CP, Cohen LS,
Alzheimer's & dementia : the journal of the Alzheimer's Association. 25-Apr-2016
These findings suggest that phosphorylation of tau is a critical event in neurodegeneration. The combination of phosphorylation sites can generate a gain of toxic function for tau. The mechanism of tau toxicity might involve not only the microtubule system but also interference with other cellular compartments such as the nucleus and the actin cytoskeleton.
Constrictive Pericarditis Versus Restrictive Cardiomyopathy?Friday, April 29, 2016
Garcia MJ,
Journal of the American College of Cardiology. 3-May-2016
About one-half of the patients with congestive heart failure have preserved left ventricular ejection fraction (HFpEF). Although the etiology of HFpEF is most commonly related to long-standing hypertension and atherosclerosis, a significant number of suspected HFpEF patients have a restrictive cardiomyopathy or chronic pericardial disease. Recognizing these syndromes is important because early diagnosis may lead to instituting specific therapy that may prolong survival, improve quality of life, and/or recognize and treat an underlying systemic disorder. Advances in diagnostic imaging, biomarkers, and genetic testing today allow identification of the specific etiology in most cases. Novel pharmacological, immunologic, and surgical therapies are leading to improved quality of life and survival.
Prognostic Value of Plasma Soluble Corin in Patients With Acute Myocardial Infarction.Friday, April 29, 2016
Zhou X, Chen J, Zhang Q, Shao J, Du K, Xu X, Kong Y,
Journal of the American College of Cardiology. 3-May-2016
Our study demonstrates that corin is a valuable prognostic marker of MACE in patients with AMI, independent of established conventional risk factors.
Transcriptional characteristics of different sized follicles in relation to embryo-transferability: potential role of hepatocyte growth factor signalling.Friday, April 29, 2016
Nivet AL, Léveillé MC, Leader A, Sirard MA,
Molecular human reproduction. 28-Apr-2016
This study was supported by Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC) to MA Sirard. There are no competing interests to declare.
Short-Term Exposure to Air Pollution and Biomarkers of Oxidative Stress: The Framingham Heart Study.Friday, April 29, 2016
Li W, Wilker EH, Dorans KS, Rice MB, Schwartz J, Coull BA, Koutrakis P, Gold DR, Keaney JF, Lin H, Vasan RS, Benjamin EJ, Mittleman MA,
Journal of the American Heart Association. 2016
Our community-based investigation supports an association of select markers of ambient air pollution with circulating biomarkers of oxidative stress.
Two C-C Family Chemokines, Eotaxin and RANTES, Are Novel Independent Plasma Biomarkers for Abdominal Aortic Aneurysm.Friday, April 29, 2016
Jones GT, Phillips LV, Williams MJ, van Rij AM, Kabir TD,
Journal of the American Heart Association. 2016
Contrary to reports suggesting a distinct T helper 2-associated inflammatory profile in AAA, this current study suggests a more-generalized pattern of inflammation, albeit with some potentially distinct features, including elevated plasma eotaxin and decreased plasma RANTES. In combination with hsCRP, these markers may have potential utility as AAA biomarkers.
MicroRNAs and Drug-induced Kidney Injury.Friday, April 29, 2016
Pavkovic M, Vaidya VS,
Pharmacology & therapeutics. 25-Apr-2016
Drug-induced kidney injury (DIKI) is a severe complication in hospitalized patients associated with higher probabilities of developing progressive chronic kidney disease or end-stage renal diseases. Furthermore, DIKI is a problem during preclinical and clinical phases of drug development leading to high rates of project terminations. Understanding the molecular perturbations caused by DIKI would pave the way for a new class of therapeutics to mitigate the damage. Yet, another approach to ameliorate DIKI is identifying sensitive and specific translational biomarkers that outperform the current diagnostic analytes like serum creatinine and facilitate early diagnosis. MicroRNAs (miRNAs), a class of non-coding RNAs, are increasingly being recognized to have a two-pronged approach towards DIKI management: 1) miRNAs have a regulatory role in gene expression and signaling pathways thereby making them novel interventional targets and 2) miRNAs enable diagnosis and prognosis of DIKI because of their stable presence in biofluids. In this review, apart from summarizing the literature on miRNAs in DIKI, we report small RNA sequencing results showing miRNA expression profiles at baseline in normal kidney samples from mice and humans. Additionally, we also compared the miRNA expression in biopsies of normal human kidneys to patients with acute tubular necrosis, and found 76 miRNAs significantly downregulated and 47 miRNAs upregulated (FDR adjusted p<0.05, +/-2-fold change). In summary, we highlight the transformative potential of miRNAs in therapeutics and translational medicine with a focus on drug-induced kidney damage.
Cardiovascular risk stratification in familial hypercholesterolaemia.Friday, April 29, 2016
Sharifi M, Rakhit RD, Humphries SE, Nair D,
Heart (British Cardiac Society). 28-Apr-2016
Familial hypercholesterolaemia (FH) is a common autosomal-dominant disorder in most European countries. Patients with FH are characterised by a raised level of low-density lipoprotein cholesterol and a high risk of premature coronary heart disease (CHD). Currently there is no consensus regarding the clinical utility to predict future coronary events or testing for the presence of subclinical atherosclerotic disease in asymptomatic patients with FH. Family screening of patients with FH as recommended by the UK National Institute of Health and Care Excellence guideline would result in finding many young individuals with a diagnosis of FH who are clinically asymptomatic. The traditional CHD risk scores, that is, the Framingham score, are insufficient in risk prediction in this group of young individuals. In addition, a better understanding of the genetic aetiology of the FH phenotype and CHD risk in monogenic FH and polygenic hypercholesterolaemia is needed. Non-invasive imaging methods such as carotid intima-media thickness measurement might produce more reliable information in finding high-risk patients with FH. The potential market authorisation of novel therapeutic agents such as PCSK9 monoclonal inhibitors makes it essential to have a better screening programme to prioritise the candidates for treatment with the most severe form of FH and at higher risk of coronary events. The utility of new imaging techniques and new cardiovascular biomarkers remains to be determined in prospective trials.
Isolation and characterization of circulating tumor cells using a novel workflow combining the CellSearch® system and the CellCelector™.Friday, April 29, 2016
Neumann MH, Schneck H, Decker Y, Schömer S, Franken A, Endris V, Pfarr N, Weichert W, Niederacher D, Fehm T, Neubauer H,
Biotechnology progress. 29-Apr-2016
Circulating tumor cells (CTC) are rare cells which have left the primary tumor to enter the blood stream. Although only a small CTC subgroup is capable of extravasating, the presence of CTCs is associated with an increased risk of metastasis and a shorter overall survival. Understanding the heterogeneous CTC biology will optimize treatment decisions and will thereby improve patient outcome. For this, robust workflows for detection and isolation of CTCs are urgently required. Here, we present a workflow to characterize CTCs by combining the advantages of both the CellSearch® and the CellCelector™ micromanipulation system. CTCs were isolated from CellSearch® cartridges using the CellCelector™ system and were deposited into PCR tubes for subsequent molecular analysis (whole genome amplification (WGA) and massive parallel multigene sequencing). By a CellCelector™ screen we re-identified 97% of CellSearch® SKBR-3 cells. Furthermore, we isolated 97% of CellSearch®-proven patient CTCs using the CellCelector™ system. Therein, we found an almost perfect correlation of R(2) =0.98 (Spearman's rho correlation, n=20, p<0.00001) between the CellSearch® CTC count (n=271) and the CellCelector™ detected CTCs (n=252). Isolated CTCs were analyzed by WGA and massive parallel multigene sequencing. In total, single nucleotide polymorphisms (SNPs) could be detected in 50 genes in seven CTCs, twelve MCF-7 and three T47D cells, respectively. Taken together, CTC quantification via the CellCelector™ system ensures a comprehensive detection of CTCs pre-identified by the CellSearch® system. Moreover, the isolation of CTCs after CellSearch® using the CellCelector™ system guarantees for CTC enrichment without any contaminants enabling subsequent high throughput genomic analyses on single cell level. This article is protected by copyright. All rights reserved.
Using nanobiotechnology to increase the prevalence of epigenotyping assays in precision medicine.Friday, April 29, 2016
Heimer BW, Tam BE, Minkovsky A, Sikes HD,
Wiley interdisciplinary reviews. Nanomedicine and nanobiotechnology. 29-Apr-2016
Epigenetic silencing of genes that are important for DNA repair, cell cycle control, apoptosis, and cellular interactions with the extracellular matrix has been causally linked to several subtypes of cancer. Translating this knowledge of the implications of promoter methylation to wide and routine use in clinical pathology laboratories has been more challenging than the case of genetic analyses because epigenetic modifications do not change the underlying sequence of the affected nucleic acid, rendering polymerase chain reaction analysis alone uninformative. Two epigenotyping assays that detect promoter methylation are currently standard of care in treatment of two distinct tumor types in only a few top hospitals across the United States. Both rely on a harsh chemical step that degrades over 90% of tumor DNA samples, which are often available in limited quantities, and imparts the potential for false-negative or false-positive results if the reaction conditions are not exactly correct. Using nanotechnology and biotechnology to devise practical new analysis techniques that avoid the drawbacks of current techniques represents a powerful approach that is likely to significantly increase the clinical use of this class of biomarkers in the coming years. For further resources related to this article, please visit the WIREs website.
Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer.Friday, April 29, 2016
Das TP, Suman S, John AS, Pal D, Edwards A, Alatassi H, Ankem MK, Damodaran C,
Cancer letters. 25-Apr-2016
The activation of AKT governs many signaling pathways and promotes cell growth and inhibits apoptosis in human malignancies including prostate cancer (CaP). Here, we investigated the molecular association between AKT activation and the function of death-associated protein kinase 3 (DAPK3) in CaP. An inverse correlation of pAKT and DAPK3 expression were seen in a panel of CaP cell lines. Inhibition of AKT by wortmannin/LY294002 or overexpression of DAPK3 reverts the growth inhibitory function AKT in CaP cells. On the other hand, ectopic expression of AKT inhibited DAPK3 function and induced proliferation of Cap cells. In addition, AKT over-expressed tumors exhibit aggressive growth versus control vector-induced prostate tumors in xenograft models. The immunohistochemistry results revealed a down-regulation of DAPK3 expression in AKT over-expressed tumors. This was evident versus control tumors. Finally, we examined expression pattern of AKT and DAPK3 in human CaP specimens-the expected gradual increase and nuclear localization of pAKT was seen in higher Gleason score samples versus benign hyperplasia (BPH). On the contrary, reduced expression of DAPK3 was seen in higher Gleason stages versus BPH. This suggests that inhibition of DAPK3 may be a contributing factor to the carcinogenesis of the prostate. Understanding the mechanism by which AKT negatively regulates DAPK3 function may suggest whether DAPK3 can be therapeutic target for CaP.
Alkaline ceramidase 1 is essential for mammalian skin homeostasis and regulating whole body energy expenditure.Friday, April 29, 2016
Liakath-Ali K, Vancollie VE, Lelliott CJ, Speak AO, Lafont D, Protheroe HJ, Ingvorsen C, Galli A, Green A, Gleeson D, Ryder E, Glover L, Vizcay-Barrena G, Karp NA, Arends MJ, Brenn T, Spiegel S, Adams DJ, Watt FM, van der Weyden L,
The Journal of pathology. 29-Apr-2016
The epidermis is the outermost layer of skin that acts as a barrier to protect the body from the external environment and to control water and heat loss. This barrier function is established through the multistage differentiation of keratinocytes and the presence of bioactive sphingolipids such as ceramides, the levels of which are tightly regulated by a balance of ceramide synthase and ceramidase activities. Here we reveal the essential role of alkaline ceramidase 1 (Acer1) in the skin. Acer1-deficient (Acer1(-/-) ) mice showed elevated levels of ceramide in the skin, aberrant hair shaft cuticle formation and cyclic alopecia. We demonstrate that Acer1 is specifically expressed in differentiated interfollicular epidermis, infundibulum and sebaceous glands and consequently Acer1(-/-) mice have significant alterations in infundibulum and sebaceous gland architecture. Acer1(-/-) skin also shows perturbed hair follicle stem cell compartments. These alterations result in Acer1(-/-) mice showing increased trans-epidermal water loss and a hyper-metabolism phenotype with associated reduction of fat content with age. We conclude that Acer1 is indispensable for mammalian skin homeostasis and whole body energy homeostasis.
Retinal glial responses to optic nerve crush are attenuated in Bax-deficient mice and modulated by purinergic signaling pathways.Friday, April 29, 2016
Mac Nair CE, Schlamp CL, Montgomery AD, Shestopalov VI, Nickells RW,
Journal of neuroinflammation. 2016
RGC death in response to ONC plays a principal stimulatory role in the retinal glial activation response.
A systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure: rationale, design, and baseline characteristics of BIOSTAT-CHF.Friday, April 29, 2016
Voors AA, Anker SD, Cleland JG, Dickstein K, Filippatos G, van der Harst P, Hillege HL, Lang CC, Ter Maaten JM, Ng L, Ponikowski P, Samani NJ, van Veldhuisen DJ, Zannad F, Zwinderman AH, Metra M,
European journal of heart failure. 29-Apr-2016
By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure.
Development of a deregulating microRNA panel for the detection of early relapse in postoperative colorectal cancer patients.Friday, April 29, 2016
Yang IP, Tsai HL, Miao ZF, Huang CW, Kuo CH, Wu JY, Wang WM, Juo SH, Wang JY,
Journal of translational medicine. 2016
This study showed that the developed miR panel has the potential to improve predicting early relapse in CRC patients.
Durable coexistence of donor and recipient strains after fecal microbiota transplantation.Friday, April 29, 2016
Li SS, Zhu A, Benes V, Costea PI, Hercog R, Hildebrand F, Huerta-Cepas J, Nieuwdorp M, Salojärvi J, Voigt AY, Zeller G, Sunagawa S, de Vos WM, Bork P,
Science (New York, N.Y.). 29-Apr-2016
Fecal microbiota transplantation (FMT) has shown efficacy in treating recurrent Clostridium difficile infection and is increasingly being applied to other gastrointestinal disorders, yet the fate of native and introduced microbial strains remains largely unknown. To quantify the extent of donor microbiota colonization, we monitored strain populations in fecal samples from a recent FMT study on metabolic syndrome patients using single-nucleotide variants in metagenomes. We found extensive coexistence of donor and recipient strains, persisting 3 months after treatment. Colonization success was greater for conspecific strains than for new species, the latter falling within fluctuation levels observed in healthy individuals over a similar time frame. Furthermore, same-donor recipients displayed varying degrees of microbiota transfer, indicating individual patterns of microbiome resistance and donor-recipient compatibilities.
Cdh1 regulates craniofacial development via APC-dependent ubiquitination and activation of Goosecoid.Friday, April 29, 2016
Shao R, Liu J, Yan G, Zhang J, Han Y, Guo J, Xu Z, Yuan Z, Liu J, Malumbres M, Wan L, Wei W, Zou W,
Cell research. 29-Apr-2016
Craniofacial anomalies (CFAs) characterized by birth defects of skull and facial bones are the most frequent congenital disease. Genomic analysis has identified multiple genes responsible for CFAs; however, the underlying genetic mechanisms for the majority of CFAs remain largely unclear. Our previous study revealed that the Wwp2 E3 ubiquitin ligase facilitates craniofacial development in part through inducing monoubiquitination and activation of the paired-like homeobox transcription factor, Goosecoid (Gsc). Here we report that Gsc is also ubiquitinated and activated by the APC(Cdh1) E3 ubiquitin ligase, leading to transcriptional activation of various Gsc target genes crucial for craniofacial development. Consistenly, neural crest-specific Cdh1-knockout mice display similar bone malformation as Wwp2-deficient mice in the craniofacial region, characterized by a domed skull, a short snout and a twisted nasal bone. Mechanistically, like Wwp2-deficient mice, mice with Cdh1 deficiency in neural crest cells exhibit reduced Gsc/Sox6 transcriptional activities. Simultaneous deletion of Cdh1 and Wwp2 results in a more severe craniofacial defect compared with single gene deletion, suggesting a synergistic augmentation of Gsc activity by these two E3 ubiquitin ligases. Hence, our study reveals a novel role for Cdh1 in craniofacial development through promoting APC-dependent non-proteolytic ubiquitination and activation of Gsc.Cell Research advance online publication 29 April 2016; doi:10.1038/cr.2016.51.
Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia.Friday, April 29, 2016
Marsch E, Demandt JA, Theelen TL, Tullemans BM, Wouters K, Boon MR, van Dijk TH, Gijbels MJ, Dubois LJ, Meex SJ, Mazzone M, Hung G, Fisher EA, Biessen EA, Daemen MJ, Rensen PC, Carmeliet P, Groen AK, Sluimer JC,
European heart journal. 28-Apr-2016
Overall, PHD1 knockout mice display a metabolic phenotype that generally is deemed protective for cardiovascular disease. Future studies should focus on the efficacy, safety, and gender-specific effects of PHD1 inhibition in humans, and unravel the molecular actors responsible for PHD1-driven, likely intestinal, and regulation of cholesterol metabolism.
Source: NCBI - Disclaimer and Copyright notice
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