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Response of vitamins A, E, hematological and serum biochemical markers in Crucian carp (Carassius auratus gibelio) exposed to environmental Pb(2+) and Cd(2.)Thursday, September 03, 2015
Khan SA, Zhou P, Liu X, Li H, Li J, Rehman ZU, Ahmad I,
Acta biochimica Polonica. 3-Sep-2015
Toxicity of Pb(2+) and Cd(2+) is a widespread issue in the world; however, few studies have been conducted to understand their effect at environmentally realistic concentration in a mixture. In the present study, Crucian carp was exposed to Pb(2+) (30 µg · l(-1)), Cd(2+) (100 µg · l(-1)) and their mixture (30+100 µg · l(-1)) for 96h and 21d period to assess changes in the liver and muscle vitamin A and E content, and hematological and serum biochemical parameters. The results indicated significant decline in the level of antioxidant vitamins A, E and alterations in the hematological and serum biochemical indices. The toxicity revealed anemia, impairment of the liver and kidney with evident responses after 21d exposure due to additive effect of Pb(2+) and Cd(2+) in mixture. Moreover, the differential response of vitamins A, E and blood parameters to low levels of waterborne Pb(2+) and Cd(2+) in freshwater fish can be used as biomarkers for monitoring contamination of aquatic environment.
The relationship of female physical attractiveness to body fatness.Thursday, September 03, 2015
Wang G, Djafarian K, Egedigwe CA, El Hamdouchi A, Ojiambo R, Ramuth H, Wallner-Liebmann SJ, Lackner S, Diouf A, Sauciuvenaite J, Hambly C, Vaanholt LM, Faries MD, Speakman JR,
PeerJ. 03-9-2015
Aspects of the female body may be attractive because they signal evolutionary fitness. Greater body fatness might reflect greater potential to survive famines, but individuals carrying larger fat stores may have poor health and lower fertility in non-famine conditions. A mathematical statistical model using epidemiological data linking fatness to fitness traits, predicted a peaked relationship between fatness and attractiveness (maximum at body mass index (BMI) = 22.8 to 24.8 depending on ethnicity and assumptions). Participants from three Caucasian populations (Austria, Lithuania and the UK), three Asian populations (China, Iran and Mauritius) and four African populations (Kenya, Morocco, Nigeria and Senegal) rated attractiveness of a series of female images varying in fatness (BMI) and waist to hip ratio (WHR). There was an inverse linear relationship between physical attractiveness and body fatness or BMI in all populations. Lower body fat was more attractive, down to at least BMI = 19. There was no peak in the relationship over the range we studied in any population. WHR was a significant independent but less important factor, which was more important (greater r (2)) in African populations. Predictions based on the fitness model were not supported. Raters appeared to use body fat percentage (BF%) and BMI as markers of age. The covariance of BF% and BMI with age indicates that the role of body fatness alone, as a marker of attractiveness, has been overestimated.
Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls.Thursday, September 03, 2015
Castro-Nallar E, Bendall ML, Pérez-Losada M, Sabuncyan S, Severance EG, Dickerson FB, Schroeder JR, Yolken RH, Crandall KA,
PeerJ. 25-8-2015
The role of the human microbiome in schizophrenia remains largely unexplored. The microbiome has been shown to alter brain development and modulate behavior and cognition in animals through gut-brain connections, and research in humans suggests that it may be a modulating factor in many disorders. This study reports findings from a shotgun metagenomic analysis of the oropharyngeal microbiome in 16 individuals with schizophrenia and 16 controls. High-level differences were evident at both the phylum and genus levels, with Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria dominating both schizophrenia patients and controls, and Ascomycota being more abundant in schizophrenia patients than controls. Controls were richer in species but less even in their distributions, i.e., dominated by fewer species, as opposed to schizophrenia patients. Lactic acid bacteria were relatively more abundant in schizophrenia, including species of Lactobacilli and Bifidobacterium, which have been shown to modulate chronic inflammation. We also found Eubacterium halii, a lactate-utilizing species. Functionally, the microbiome of schizophrenia patients was characterized by an increased number of metabolic pathways related to metabolite transport systems including siderophores, glutamate, and vitamin B12. In contrast, carbohydrate and lipid pathways and energy metabolism were abundant in controls. These findings suggest that the oropharyngeal microbiome in individuals with schizophrenia is significantly different compared to controls, and that particular microbial species and metabolic pathways differentiate both groups. Confirmation of these findings in larger and more diverse samples, e.g., gut microbiome, will contribute to elucidating potential links between schizophrenia and the human microbiota.
Biomarkers for Predicting Illness Severity in Children With Acute Lower Respiratory Tract Infections.Thursday, September 03, 2015
Shah SS, Ambroggio L, Florin TA,
Journal of the Pediatric Infectious Diseases Society. Sep-2015
Anti-Oxidative Effect of Myrtenal in Prevention and Treatment of Colon Cancer Induced by 1, 2-Dimethyl Hydrazine (DMH) in Experimental Animals.Thursday, September 03, 2015
Lokeshkumar B, Sathishkumar V, Nandakumar N, Rengarajan T, Madankumar A, Balasubramanian MP,
Biomolecules & therapeutics. Sep-2015
Colon cancer is considered as the precarious forms of cancer in many developed countries, with few to no symptoms; the tumor is often diagnosed in the later stages of cancer. Monoterpenes are a major part of plant essential oils found largely in fruits, vegetables and herbs. The cellular and molecular activities show therapeutic progression that may reduce the risk of developing cancer by modulating the factors responsible for colon carcinogenesis. Colon cancer was induced with DMH with a dose of (20 mg/Kg/body weight) for 15 weeks by subcutaneous injection once in a week. Myrtenal treatment was started with (230 mg/Kg/body weight) by intragastric administration, one week prior to DMH induction and continued till the experimental period of 30 weeks. The Invivo results exhibit the elevated antioxidant and lipid peroxidation levels in DMH treated animals. The Histopathological analysis of colon tissues well supported the biochemical alterations and inevitably proves the protective role of Myrtenal. Treatment with myrtenal to cancer bearing animals resulted in a remarkable increase in the inherent antioxidants and excellent modulation in the morphological and physiological nature of the colon tissue. It is thus concluded that myrtenal exhibits excellent free radical scavenging activity and anticancer activity through the suppression of colon carcinoma in Wistar albino rats.
A New Histone Deacetylase Inhibitor, MHY219, Inhibits the Migration of Human Prostate Cancer Cells via HDAC1.Thursday, September 03, 2015
De U, Kundu S, Patra N, Ahn MY, Ahn JH, Son JY, Yoon JH, Moon HR, Lee BM, Kim HS,
Biomolecules & therapeutics. Sep-2015
Histone deacetylase (HDAC) inhibitors are considered novel agents for cancer chemotherapy. We previously investigated MHY219, a new HDAC inhibitor, and its potent anticancer activity in human prostate cancer cells. In the present study, we evaluated MHY219 molecular mechanisms involved in the regulation of prostate cancer cell migration. Similar to suberanilohydroxamic acid (SAHA), MHY219 inhibited HDAC1 enzyme activity in a dose-dependent manner. MHY219 cytotoxicity was higher in LNCaP (IC50=0.67 μM) than in DU145 cells (IC50=1.10 μM) and PC3 cells (IC50=5.60 μM) after 48 h of treatment. MHY219 significantly inhibited the HDAC1 protein levels in LNCaP and DU145 cells at high concentrations. However, inhibitory effects of MHY219 on HDAC proteins levels varied based on the cell type. MHY219 significantly inhibited LNCaP and DU145 cells migration by down-regulation of matrix metalloprotease-1 (MMP-1) and MMP-2 and induction of tissue inhibitor of metalloproteinases-1 (TIMP-1). These results suggest that MHY219 may potentially be used as an anticancer agent to block cancer cell migration through the repression of MMP-1 and MMP-2, which is related to the reduction of HDAC1.
Use of dressing with human fibrin and thrombin during resection of a right atrial angiosarcoma.Thursday, September 03, 2015
Filip G, Bochenek M, Kapelak B, Bartuś K, Urbańczyk M, Sadowski J,
Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. Jun-2015
Primary malignant cardiac tumors are rare and are usually detected at an advanced stage of disease. Their location and infiltration often hinder surgical resection. Tissue sarcomas, especially angiosarcomas, are composed of irregular and delicate vascular tissue. The resection of such tumors from the heart is associated with a high risk of life-threatening bleeding that cannot be stopped with traditional surgical methods. We present a case report of the application of a dressing containing human fibrin and thrombin in order to prevent bleeding during the partial resection of advanced cardiac angiosarcoma in a 40-year-old patient.
Oxidative stress and inflammatory markers - the future of heart failure diagnostics?Thursday, September 03, 2015
Szczurek W, Szyguła-Jurkiewicz B,
Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. Jun-2015
Heart failure remains one of the most important problems in cardiology despite the progress in its treatment. A number of recent studies have demonstrated the relationship between the intensification of oxidative stress and chronic inflammation and the severity of left ventricular dysfunction, development of heart failure symptoms, and prediction of future cardiac events. Early detection of changes developing in the heart is key in improving the treatment's effectiveness. It appears that determining specific, sensitive biomarkers reflecting the complex pathophysiology of heart failure and using them to detect asymptomatic cardiac alterations may become a crucial screening tool, assisting in the identification of patients requiring further diagnostic examinations. This article presents an overview of the current knowledge of the role of oxidative stress and inflammation in heart failure; it also discusses the potential role of oxidative stress and inflammatory markers as prognostic factors in heart failure that may be used in screening tests.
Severe multivessel coronary artery disease and high-sensitive troponin T.Thursday, September 03, 2015
Huziuk IM, Lelonek M,
Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. Jun-2015
In men with stable CAD, preserved systolic left ventricular function and non-high cardiovascular risk determined from the initial concentration of hsCRP, elevated level of hsTnT was independently associated with the risk of multivessel coronary artery disease.
Veno-venous extracorporeal membrane oxygenation in a patient with severe acute respiratory failure - case report.Thursday, September 03, 2015
Kubisa B, Dec PŁ, Lesińska AJ, Bocheńska A, Wasilewski P, Feldyk G, Kubisa A, Pieróg J, Bielewicz M, Grodzki T,
Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. Mar-2015
Acute respiratory failure resistant to conventional pulmonary therapy often requires intensive medical care. In rare cases, ventilator therapy proves insufficient, and only the option of employing veno-venous extracorporeal membrane oxygenation (ECMO V-V) remains. The present article describes the case of a 23-year-old patient who experienced severe acute respiratory distress syndrome with associated multiple organ failure. The patient was admitted to the pulmonary ward of the Alfred Sokołowski Regional Pulmonary Hospital in Szczecin-Zdunowo with suspected pneumonia of unknown etiology. After the initial 5 days of diagnostics at the pulmonary ward, the patient required a further 97 days of hospital treatment and spent 63 days at the Intensive Care Unit. There, he underwent ECMO V-V therapy lasting 22 days, which resulted in the improvement of his arterial blood gas parameters and clinical condition.
Prognostic value of sCD14-ST (presepsin) in cardiac surgery.Thursday, September 03, 2015
Popov D, Plyushch M, Ovseenko S, Abramyan M, Podshchekoldina O, Yaroustovsky M,
Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. Mar-2015
The use of modern biomarkers alongside integral severity-of-disease scores allows prediction of the risk of infectious complications and mortality in cardiosurgical patients.
Genetic basis of keloid formation in wounds after cardiac surgery.Thursday, September 03, 2015
Kulawczuk P, Czapla N, Bińczak-Kuleta A, Safranow K, Jaworska-Kulawczuk A, Gajewska D, Agata K, Brykczyński M, Bargiel P,
Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. Sep-2014
Keloid disease is the abnormal formation of scar tissue in genetically predisposed people. Among many genes which may be related to the development of keloids, transforming growth factor β1 (TGF-β1) is one of the most mentioned. It encodes cytokinin, which is responsible for the production of extracellular matrix and takes part in healing. Any abnormalities which arise during synthesis of the protein as a result of polymorphism or gene mutation may be the cause of healing disorders (scarring of the body); thus it is responsible for the development of keloids. The objective of this study is to determine the single nucleotide polymorphism of the gene TGF-β1, at the position -509(rs1800469)509, to compare the obtained results in the form of three different genotypes within the analysed group (keloids) and within the control group (healthy scars), and to analyse the correlation between obtained genotypes and the occurrence of keloid disease. Seventy-three patients after cardiac surgery with scars on their sternums were examined (22 women and 51 men) in the age group from 38 to 84 years. Two groups of patients were distinguished: 37 with keloids and 36 with healthy scars. DNA taken from patients was analysed and polymorphism C(-509)T of the gene TGF-β1 was determined. On the basis of the study it was found that the allele T in the position -509 of the gene TGF-β1 is associated with a lower risk of keloid formation regardless of age and gender.
The Evolving Medical and Veterinary Importance of the Gulf Coast tick (Acari: Ixodidae).Thursday, September 03, 2015
Paddock CD, Goddard J,
Journal of medical entomology. Mar-2015
Amblyomma maculatum Koch (the Gulf Coast tick) is a three-host, ixodid tick that is distributed throughout much of the southeastern and south-central United States, as well as several countries throughout Central and South America. A considerable amount of scientific literature followed the original description of A. maculatum in 1844; nonetheless, the Gulf Coast tick was not recognized as a vector of any known pathogen of animals or humans for >150 years. It is now identified as the principal vector of Hepatozoon americanum, the agent responsible for American canine hepatozoonosis, and Rickettsia parkeri, the cause of an emerging, eschar-associated spotted fever group rickettsiosis identified throughout much of the Western Hemisphere. Coincident with these discoveries has been recognition that the geographical distribution of A. maculatum in the United States is far more extensive than described 70 yr ago, supporting the idea that range and abundance of certain tick species, particularly those with diverse host preferences, are not fixed in time or space, and may change over relatively short intervals. Renewed interest in the Gulf Coast tick reinforces the notion that the perceived importance of a particular tick species to human or animal health can be relatively fluid, and may shift dramatically with changes in the distribution and abundance of the arthropod, its vertebrate hosts, or the microbial agents that transit among these organisms.
Comparison of Tick Feeding Success and Vector Competence for Borrelia burgdorferi Among Immature Ixodes scapularis (Ixodida: Ixodidae) of Both Southern and Northern Clades.Thursday, September 03, 2015
Goddard J, Embers M, Hojgaard A, Piesman J,
Journal of medical entomology. Jan-2015
Northern and southern Ixodes scapularis Say populations differ greatly in density, host utilization, and especially questing behavior of the immatures. Haplotypes of I. scapularis in North America can be divided into two major clades-the All American Clade (haplotypes A through J) and the Southern Clade (M through O). This genetic variation may affect feeding success and vector competence. This study compared feeding success of larval I. scapularis measured by time-to-drop-off and subsequent transmissibility success of Borrelia burgdorferi to mice using ticks from Mississippi, Connecticut (both F haplotype), and Louisiana (haplotype O). Northern ticks (CT) fed to repletion much faster than MS and LA ticks: overall, 73.6% of CT ticks had dropped off mice at Day 3 compared to only 1.7% and 6.6% of ticks dropped off for MS and LA ticks at that same time point. As for vector competence, 4 of the 4 mice in each case (MS or CT) that had been fed on by infected nymphs tested positive for B. burgdorferi. In a second experiment, 5 of the 6 mice tested positive for B. burgdorferi after exposure to infected LA ticks as compared with 3 of the 4 mice exposed to infected CT ticks. These data demonstrate that there is no difference in northern and southern populations of I. scapularis in their ability to transmit B. burgdorferi, but the ability of the northern populations to feed rapidly on rodents exceeds that of southern populations.
Population Genetic Structure of the Malaria Vector Anopheles sinensis (Diptera: Culicidae) Sensu Stricto and Evidence for Possible Introgression in the Republic of Korea.Thursday, September 03, 2015
Kang S, Jung J, Kim W,
Journal of medical entomology. 21-Aug-2015
Anopheles sinensis Wiedemann sensu stricto (s.s.) is a dominant mosquito and considered a secondary malaria vector in the Republic of Korea (ROK). Despite the potential significance for malaria control, population genetics studies have been conducted using only mitochondrial DNA (mtDNA), and studies of the genetics of hybridization have never been attempted. In this study, 346 specimens from 23 localities were subject to experiments. Among them, 305 An. sinensis s.s. specimens from 20 localities were used for mtDNA analysis, and 346 specimens comprising 341 An. sinensis s.s. from 22 localities and five Anopheles kleini Rueda from one locality were examined in the microsatellite study. Neighbor-joining analysis of pairwise FST and RST based on microsatellite results showed that the populations are divided into two groups, as did the mtDNA results. However, the Bayesian analysis and factorial correspondence analysis plots showed three distinct clusters. Among the mtDNA and microsatellite results, only microsatellites represented small but positive and significant isolation-by-distance patterns. Both molecular markers show the Taebaek and Sobaek Mountain ranges as barriers between the northern and southern parts of the ROK. The newly recognized third group suggests possible introgressive hybridization of An. sinensis s.s. with closely related species. The slightly different composition of populations in each group based on different markers is probably because of different population dynamics in each group. These results imply that there is restricted gene flow of epidemiologically important malaria-related genes between the northern and southern parts of the ROK.
A Faster cDNA Microarray Gene Expression Data Classifier for Diagnosing Diseases.Thursday, September 03, 2015
Hsieh SY, Chou YC,
IEEE/ACM transactions on computational biology and bioinformatics / IEEE, ACM. 28-Aug-2015
Profiling cancer molecules has several advantages; however, using microarray technology in routine clinical diagnostics is challenging for physicians. The classification of microarray data has two main limitations: 1) the data set is unreliable for building classifiers; and 2) the classifiers exhibit poor performance. Current microarray classification algorithms typically yield a high rate of false-positives cases, which is unacceptable in diagnostic applications. Numerous algorithms have been developed to detect falsepositive cases; however, they require a considerable computation time. To address this problem, this study enhanced a previously proposed gene expression graph (GEG)-based classifier to shorten the computation time. The modified classifier filters genes by using an edge weight to determine their significance, thereby facilitating accurate comparison and classification. This study experimentally compared the proposed classifier with a GEG-based classifier by using real data and benchmark tests. The results show that the proposed classifier is faster at detecting false-positives.
Screening and Monitoring for Infectious Complications When Immunosuppressive Agents Are Studied in the Treatment of Autoimmune Disorders.Thursday, September 03, 2015
Loechelt BJ, Green M, Gottlieb PA, Blumberg E, Weinberg A, Quinlan S, Baden LR,
Journal of the Pediatric Infectious Diseases Society. Sep-2015
Significant progress has been made in the development, investigation, and clinical application of immunosuppressive agents to treat a variety of autoimmune disorders. The expansion of clinical applications of these new agents requires the performance of large multicenter clinical trials. These large clinical trials are particularly important as one considers these agents for the treatment of type 1 diabetes, which although autoimmune in its pathogenesis, is not classically treated as an autoimmune disorder. Although these agents hold promise for amelioration or cure of this disease, they have the potential to facilitate infectious complications. There are limited data regarding the prospective assessment of infectious risks with these agents in trials of this nature. Pediatric subjects may be at greater risk due to the higher likelihood of primary infection. A subgroup of experts associated with TrialNet (a National Institutes of Health [NIH]-funded Type 1 diabetes mellitus research network) with expertise in infectious diseases, immunology, and diagnostics developed an approach for screening and monitoring of immunosuppression-associated infections for prospective use in clinical trials. The goals of these recommendations are to provide a structured approach to monitor for infections, to identify specific laboratory testing and surveillance methods, and to consider therapies for treatment of these potential complications. Prospective evaluations of these infectious risks allow for greater scientific rigor in the evaluation of risk, which must be balanced with the potential benefits of these therapies. Our experience supports an important role for investigators with expertise in infections in immunocompromised individuals in protocol development of immunosuppressive trials in type 1diabetes and potentially other autoimmune diseases.
Initial Hyperleukocytosis and Neutrophilia in Nasopharyngeal Carcinoma: Incidence and Prognostic Impact.Thursday, September 03, 2015
Su Z, Mao YP, OuYang PY, Tang J, Xie FY,
PloS one. 26-6-2014
Initial hyperleukocytosis and neutrophilia were independent, poor prognostic factors and may be convenient and useful biological markers for survival of patients with nasopharyngeal carcinoma.
Gaucher disease in Syrian children: common mutations identification, and clinical futures.Thursday, September 03, 2015
Alasmar D,
Annals of Saudi medicine. 3-9-2015
L444P/L444P was the most common genotype in the studied patients. GD3 with severe visceral presentation in childhood was the dominant phenotype; N370S was found in the heterozygote state in 1 case and in the homozygote state in 1 case. This phenotype and genotype pattern is encountered in the Middle East. There was no genotype-phenotype correlation.
Use of qualitative integrative cycler PCR (qicPCR) to identify optimal therapeutic dosing time-points in a Respiratory Syncytial Virus Human Viral Challenge Model (hVCM).Thursday, September 03, 2015
Kelly G, Laxton C, Garelnabi M, Alton B, Addan F, Catchpole A, Thomas E, Borley D, Dee K, Boyers A, Bringas E, Noulin N, Lambkin-Williams R, Murray EJ,
Journal of virological methods. 31-Aug-2015
Retroscreen (hVIVO) have developed an RSV human viral challenge model (hVCM) for testing the efficacy of novel antiviral therapies by monitoring changes in viral load and symptoms. The integrated cycler technology and Simplexa™ kits (Focus Diagnostics) currently provide fast, qualitative and sensitive diagnostic testing in hospitals and other healthcare facilities for patients with well-established respiratory illness. We have developed a novel use of qualitative integrated cycler PCR (qicPCR) technology to identify onset of RSV infection enabling an informed dosing clinical protocol in the RSV hVCM. We have validated qicPCR detection of RSV in spiked nasal wash aspirates and demonstrate that the qicPCR assay is 94% concordant with RSV plaque assay data in nasal wash samples from 53 RSV inoculated human volunteers in the hVCM. The use of qicPCR for informed dosing was successfully implemented in a recent clinical trial demonstrating efficacy of the RSV entry inhibitor GS-5806 in the hVCM (NCT01756482). Comparison of qicPCR positivity in relation to nasal wash viral load measured by both RT-qPCR and plaque assay shows that the therapeutic exposure was correctly initiated prior to onset and peak of RSV viral shedding and symptoms in the majority of volunteers.
Arterial Pressure Variation as a Biomarker of Preload Dependency in Spontaneously Breathing Subjects - A Proof of Principle.Thursday, September 03, 2015
Bronzwaer AG, Ouweneel DM, Stok WJ, Westerhof BE, van Lieshout JJ,
PloS one. 31-8-2015
Under conditions of progressive central hypovolemia, the application of an external respiratory resistance at a breathing frequency of 6/min enhanced PPV and SPV and is worth further study for detection of preload dependency from arterial pressure variations in non-ventilated subjects.
The Italian external quality assessment for RAS testing in colorectal carcinoma identifies methods-related inter-laboratory differences.Thursday, September 03, 2015
Normanno N, Pinto C, Castiglione F, Fenizia F, Barberis M, Marchetti A, Fontanini G, De Rosa G, Taddei GL,
Journal of translational medicine. 3-9-2015
The results of the Italian RAS EQA scheme indicate that the mutational analyses are performed with good quality in many Italian centers, although significant differences in the methods used were highlighted. The relatively high number of centers failing the first round underlines the fundamental role in continued education covered by EQA schemes.
[Expert Meeting Obstructive Airway Disease Measuring and Evaluating in COPD].Thursday, September 03, 2015
Lorenz J, Bals R, Ewert R, Heussel CP, Kauczor HU, Randerath W, Steinkamp G, Watz H, Worth H,
Pneumologie (Stuttgart, Germany). Sep-2015
This report gives an overview on the contributions presented in an expert meeting in February, 2015. They deal with the analysis and evaluation of the multiple dimensions of COPD. This complex disease not only interferes with pulmonary mechanics and gas exchange, but also with cardiopulmonary crosstalk and the ventilator pump. A bulk of inflammatory and microbial activity develops during the progression of disease. As a consequence, systemic effects on muscles, metabolism and psyche develop.The sections consider the value of multiple endpoints in clinical research. Quantifiable parameters of lung mechanics and gas exchange, of exercise tolerance and biomarkers improve the measurability of effects in interventions. However, do we really know in a biological sense what we are measuring? What conclusions can we draw in terms of prognosis?Vice versa, we have to look into the origin and meaning of integrative endpoints e.g. quality or life, dyspnoea and spontaneous physical activity. As a new dimension, the clinical significance of morphological findings in HRCT and MRT is analyzed.
FUS Interacts with HSP60 to Promote Mitochondrial Damage.Thursday, September 03, 2015
Deng J, Yang M, Chen Y, Chen X, Liu J, Sun S, Cheng H, Li Y, Bigio EH, Mesulam M, Xu Q, Du S, Fushimi K, Zhu L, Wu JY,
PLoS genetics. Sep-2015
FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.
Activation of 5-HT4 receptors facilitates neurogenesis from transplanted neural stem cells in the anastomotic ileum.Thursday, September 03, 2015
Goto K, Kawahara I, Inada H, Misawa H, Kuniyasu H, Nabekura J, Takaki M,
The journal of physiological sciences : JPS. 3-Sep-2015
An orally administered serotonin-4 (5-HT4) receptor agonist, mosapride citrate (MOS), promotes enteric neurogenesis in anastomoses after gut surgery. We performed gut surgery and transplanted 2 × 10(5) neural stem cells (NSCs) from the embryonic central nervous system after marking them with the cell linker, PKH26. We found that neurons differentiated from transplanted NSCs (PKH [+]) and newborn enteric neurons differentiated from mobilized (host) NSCs (YFP [+]) in the deep granulation tissue of the anastomotic ileum. MOS significantly increased the number of PKH (+) and YFP (+) neurons by 2.5-fold (P < 0.005) (n = 4). The distribution patterns of PKH (+) neurons and YFP (+) neurons were similar along the depth of the anastomosis. A 5-HT4 receptor antagonist, SB-207266, abolished these effects of MOS (n = 4). Our results indicate that neurogenesis from transplanted NSCs is potentiated by activation of 5-HT4 receptors. Thus, a combination of drug administration and cell transplantation could be more beneficial than cell transplantation alone in treating Hirschsprung's disease and related disorders.
Inhibition of autophagy in EBV-positive Burkitt's lymphoma cells enhances EBV lytic genes expression and replication.Thursday, September 03, 2015
De Leo A, Colavita F, Ciccosanti F, Fimia GM, Lieberman PM, Mattia E,
Cell death & disease. 3-9-2015
Autophagy, an important degradation system involved in maintaining cellular homeostasis, serves also to eliminate pathogens and process their fragments for presentation to the immune system. Several viruses have been shown to interact with the host autophagic machinery to suppress or make use of this cellular catabolic pathway to enhance their survival and replication. Epstein Barr virus (EBV) is a γ-herpes virus associated with a number of malignancies of epithelial and lymphoid origin in which establishes a predominantly latent infection. Latent EBV can periodically reactivate to produce infectious particles that allow the virus to spread and can lead to the death of the infected cell. In this study, we analyzed the relationship between autophagy and EBV reactivation in Burkitt's lymphoma cells. By monitoring autophagy markers and EBV lytic genes expression, we demonstrate that autophagy is enhanced in the early phases of EBV lytic activation but decreases thereafter concomitantly with increased levels of EBV lytic proteins. In a cell line defective for late antigens expression, we found an inverse correlation between EBV early antigens expression and autophagosomes formation, suggesting that early after activation, the virus is able to suppress autophagy. We report here for the first time that inhibition of autophagy by Bafilomycin A1 or shRNA knockdown of Beclin1 gene, highly incremented EBV lytic genes expression as well as intracellular viral DNA and viral progeny yield. Taken together, these findings indicate that EBV activation induces the autophagic response, which is soon inhibited by the expression of EBV early lytic products. Moreover, our findings open the possibility that pharmacological inhibitors of autophagy may be used to enhance oncolytic viral therapy of EBV-related lymphomas.
Meta-Analysis of Large-Scale Toxicogenomic Data Finds Neuronal Regeneration Related Protein and Cathepsin D to Be Novel Biomarkers of Drug-Induced Toxicity.Thursday, September 03, 2015
Kim H, Kim JH, Kim SY, Jo D, Park HJ, Kim J, Jung S, Kim HS, Lee K,
PloS one. 3-9-2015
Undesirable toxicity is one of the main reasons for withdrawing drugs from the market or eliminating them as candidates in clinical trials. Although numerous studies have attempted to identify biomarkers capable of predicting pharmacotoxicity, few have attempted to discover robust biomarkers that are coherent across various species and experimental settings. To identify such biomarkers, we conducted meta-analyses of massive gene expression profiles for 6,567 in vivo rat samples and 453 compounds. After applying rigorous feature reduction procedures, our analyses identified 18 genes to be related with toxicity upon comparisons of untreated versus treated and innocuous versus toxic specimens of kidney, liver and heart tissue. We then independently validated these genes in human cell lines. In doing so, we found several of these genes to be coherently regulated in both in vivo rat specimens and in human cell lines. Specifically, mRNA expression of neuronal regeneration-related protein was robustly down-regulated in both liver and kidney cells, while mRNA expression of cathepsin D was commonly up-regulated in liver cells after exposure to toxic concentrations of chemical compounds. Use of these novel toxicity biomarkers may enhance the efficiency of screening for safe lead compounds in early-phase drug development prior to animal testing.
Liquid biopsy: will it be the 'magic tool' for monitoring response of solid tumors to anticancer therapies?Thursday, September 03, 2015
Gingras I, Salgado R, Ignatiadis M,
Current opinion in oncology. 1-Sep-2015
CTCs and ctDNA are promising new biomarkers in oncology, with potential clinical applications for monitoring and for comprehensive molecular profiling of cancer. For each assay, demonstration of analytical and clinical validity, as well as clinical utility in prospective clinical trials is needed before implementation in clinical practice.
Postmenopausal mammographic breast density and subsequent breast cancer risk according to selected tissue markers.Thursday, September 03, 2015
Yaghjyan L, Pettersson A, Colditz GA, Collins LC, Schnitt SJ, Beck AH, Rosner B, Vachon C, Tamimi RM,
British journal of cancer. 3-Sep-2015
Breast density influences the risk of breast cancer subtypes by potentially different mechanisms.British Journal of Cancer advance online publication 3 September 2015; doi:10.1038/bjc.2015.315 www.bjcancer.com.
Potential of DNA methylation in rectal cancer as diagnostic and prognostic biomarkers.Thursday, September 03, 2015
Exner R, Pulverer W, Diem M, Spaller L, Woltering L, Schreiber M, Wolf B, Sonntagbauer M, Schröder F, Stift J, Wrba F, Bergmann M, Weinhäusel A, Egger G,
British journal of cancer. 3-Sep-2015
The newly defined methylation markers will be suitable for early disease detection and monitoring of rectal cancer.British Journal of Cancer advance online publication 3 September 2015; doi:10.1038/bjc.2015.303 www.bjcancer.com.
Identification of differential anti-neoplastic activity of copper bis(thiosemicarbazones) that is mediated by intracellular reactive oxygen species generation and lysosomal membrane permeabilization.Thursday, September 03, 2015
Stefani C, Al-Eisawi Z, Jansson PJ, Kalinowski DS, Richardson DR,
Journal of inorganic biochemistry. 17-Aug-2015
Bis(thiosemicarbazones) and their copper (Cu) complexes possess unique anti-neoplastic properties. However, their mechanism of action remains unclear. We examined the structure-activity relationships of twelve bis(thiosemicarbazones) to elucidate factors regarding their anti-cancer efficacy. Importantly, the alkyl substitutions at the diimine position of the ligand backbone resulted in two distinct groups, namely, unsubstituted/monosubstituted and disubstituted bis(thiosemicarbazones). This alkyl substitution pattern governed their: (1) Cu(II/I) redox potentials; (2) ability to induce cellular (64)Cu release; (3) lipophilicity; and (4) anti-proliferative activity. The potent anti-cancer Cu complex of the unsubstituted bis(thiosemicarbazone) analog, glyoxal bis(4-methyl-3-thiosemicarbazone) (GTSM), generated intracellular reactive oxygen species (ROS), which was attenuated by Cu sequestration by a non-toxic Cu chelator, tetrathiomolybdate, and the anti-oxidant, N-acetyl-l-cysteine. Fluorescence microscopy suggested that the anti-cancer activity of Cu(GTSM) was due, in part, to lysosomal membrane permeabilization (LMP). For the first time, this investigation highlights the role of ROS and LMP in the anti-cancer activity of bis(thiosemicarbazones).
Metabolic profiling as a tool for prioritizing antimicrobial compounds.Thursday, September 03, 2015
Wu C, Choi YH, van Wezel GP,
Journal of industrial microbiology & biotechnology. 3-Sep-2015
Metabolomics is an analytical technique that allows scientists to globally profile low molecular weight metabolites between samples in a medium- or high-throughput environment. Different biological samples are statistically analyzed and correlated to a bioactivity of interest, highlighting differentially produced compounds as potential biomarkers. Here, we review NMR- and MS-based metabolomics as technologies to facilitate the identification of novel antimicrobial natural products from microbial sources. Approaches to elicit the production of poorly expressed (cryptic) molecules are thereby a key to allow statistical analysis of samples to identify bioactive markers, while connection of compounds to their biosynthetic gene cluster is a determining step in elucidating the biosynthetic pathway and allows downstream process optimization and upscaling. The review focuses on approaches built around NMR-based metabolomics, which enables efficient dereplication and guided fractionation of (antimicrobial) compounds.
One-pot synthesis of highly greenish-yellow fluorescent nitrogen-doped graphene quantum dots for pyrophosphate sensing via competitive coordination with Eu(3+) ions.Thursday, September 03, 2015
Lin L, Song X, Chen Y, Rong M, Zhao T, Jiang Y, Wang Y, Chen X,
Nanoscale. 3-Sep-2015
Highly fluorescent nitrogen-doped graphene quantum dots (N-GQDs) with greenish-yellow emission and quantum yield of 13.2% have been synthesized via a one-pot hydrothermal method. The obtained N-GQDs displayed excellent optical properties, high photostability and resistance to strong ion strength. Based on the higher affinity of pyrophosphate (PPi) than carboxyl and amido groups on the surface of the N-GQDs to Eu(3+), a Eu(3+)-modulated N-GQD off-on fluorescent probe for PPi detection was constructed with a detection limit of 0.074 μM. The detection process was simple in design, easy to operate, and showed a highly selective response to PPi in the presence of co-existing anions. This work widens the applications of N-GQDs with versatile functionality and reactivity in clinical diagnostics and as biosensors.
Environmental phenols and pubertal development in girls.Thursday, September 03, 2015
Wolff MS, Teitelbaum SL, McGovern K, Pinney SM, Windham GC, Galvez M, Pajak A, Rybak M, Calafat AM, Kushi LH, Biro FM,
Environment international. 31-Aug-2015
Environmental exposures to many phenols are documented worldwide and exposures can be quite high (>1μM of urine metabolites). Phenols have a range of hormonal activity, but knowledge of effects on child reproductive development is limited, coming mostly from cross-sectional studies. We undertook a prospective study of pubertal development among 1239 girls recruited at three U.S. sites when they were 6-8years old and were followed annually for 7years to determine age at first breast or pubic hair development. Ten phenols were measured in urine collected at enrollment (benzophenone-3, enterolactone, bisphenol A, three parabens (methyl-, ethyl-, propyl-), 2,5-dichlorophenol, triclosan, genistein, daidzein). We used multivariable adjusted Cox proportional hazards ratios (HR (95% confidence intervals)) and Kaplan-Meier survival analyses to estimate relative risk of earlier or later age at puberty associated with phenol exposures. For enterolactone and benzophenone-3, girls experienced breast development 5-6months later, adjusted HR 0.79 (0.64-0.98) and HR 0.80 (0.65-0.98) respectively for the 5th vs 1st quintiles of urinary biomarkers (μg/g-creatinine). Earlier breast development was seen for triclosan and 2,5-dichlorophenol: 4-9months sooner for 5th vs 1st quintiles of urinary concentrations (HR 1.17 (0.96-1.43) and HR 1.37 (1.09-1.72), respectively). Association of breast development with enterolactone, but not the other three phenols, was mediated by body size. These phenols may be antiadipogens (benzophenone-3 and enterolactone) or thyroid agonists (triclosan and 2,5-dichlorophenol), and their ubiquity and relatively high levels in children would benefit from further investigation to confirm these findings and to establish whether there are certain windows of susceptibility during which exposure can affect pubertal development.
Comparison of a Real-Time Multiplex PCR and Sequetyping Assay for Pneumococcal Serotyping.Thursday, September 03, 2015
Dube FS, van Mens SP, Robberts L, Wolter N, Nicol P, Mafofo J, Africa S, Zar HJ, Nicol MP,
PloS one. 31-8-2015
The rmPCR assay performed well for the 21 serotypes/-groups included in the assay. However, in our study setting, a large proportion of serotypes were not detected by rmPCR. The sequetyping assay performed well, but did misassign specific serotypes. It may be useful for regions where vaccine serotypes are less common, however confirmatory testing is advisable.
Enhanced Human Epidermal Growth Factor Receptor 2 Degradation in Breast Cancer Cells by Lysosome-Targeting Gold Nanoconstructs.Thursday, September 03, 2015
Lee H, Dam DH, Ha JW, Yue J, Odom TW,
ACS nano. 3-Sep-2015
This paper describes how gold nanoparticle nanoconstructs can enhance anticancer effects of lysosomal targeting aptamers in breast cancer cells. Nanoconstructs consisting of anti-HER2 aptamer (human epidermal growth factor receptor 2, HApt) densely grafted on gold nanostars (AuNS) first targeted HER2 and then were internalized via HER2-mediated endocytosis. As incubation time increased, the nanoconstruct complexes were found in vesicular structures, starting from early endosomes to lysosomes as visualized by confocal fluorescence and differential interference contrast microscopy. Within the target organelle, lysosomes, HER2 was degraded by enzymes at low pH, which resulted in apoptosis. At specific time points related to the doubling time of the cancer cells, we found that accumulation of HER2-HApt-AuNS complexes in lysosomes, lysosomal activity, and lysosomal degradation of HER2 were positively correlated. Increased HER2 degradation by HApt-AuNS triggered cell death and cell cycle arrest in the G0/G1 phase inhibition of cell proliferation. This work shows how a perceived disadvantage of nanoparticle-based therapeutics-the inability of nanoconstructs to escape from vesicles and thus induce a biological response-can be overcome by both targeting lysosomes and exploiting lysosomal degradation of the biomarkers.
Lambdoid Synostosis Versus Positional Posterior Plagiocephaly, a Comparison of Skull Base and Shape of Calvarium Using Computed Tomography Imaging.Thursday, September 03, 2015
Hurmerinta K, Kiukkonen A, Hukki J, Saarikko A, Leikola J,
The Journal of craniofacial surgery. 26-Aug-2015
The differential diagnostics between the common positional posterior plagiocephaly and relatively rare lambdoid synostosis is important due to the differences in their treatment plan and clinical management. However, the clinical criteria for the diagnosis of lambdoid synostosis are not clear since there is a considerable overlap in the features of positional posterior plagiocephaly and unilateral lambdoid synostosis. To systematically evaluate the clinical findings in these 2 patient groups, we quantitatively compared the characteristics of endocranial skull base and ectocranial calvarium in 3D computed tomography, in 9 children (mean age 2.9 years) with unilateral lambdoid synostosis and 9 children with positional posterior plagiocephaly. The groups were sex and age matched. Our results show that the skull bases in the lambdoid synostosis are posteriorly shorter and more twisted than in positional posterior plagiocephaly. Anterior twisting was mild in both skull types. Our study confirmed earlier suggested diagnostic feature: prominent ipsilateral mastoidal bossing downward and laterally in all lambdoid skulls. In positional posterior plagiocephaly the bossing was typically not detected. Interestingly, there was a great variation in the position of the ipsilateral ear and external auditory meatus in both patient groups. Thus, neither antero-posterior nor vertical position of ear is a reliable differential diagnostic feature between lambdoid synostosis or positional posterior plagiocephaly.
Laboratory Medicine Meets Precision Medicine: the Paradigm of Metabolomics in Perinatology. Proposals from the 4th International Conference on Neonatal and Pediatric Laboratory Medicine.Thursday, September 03, 2015
Mussap M, Ferrari M, Fanos V,
Clinica chimica acta; international journal of clinical chemistry. 31-Aug-2015
The use of a new hybrid stentgraft for the repair of extensive thoracic aortic aneurysms with the frozen elephant trunk method - first Polish experiences.Thursday, September 03, 2015
Zembala M, Krasoń M, Hrapkowicz T, Przybylski R, Filipiak K, Borowicz M, Niklewski T, Głowacki J, Wolny T, Nadziakiewicz P, Walas R, Zembala M,
Kardiochirurgia i torakochirurgia polska = Polish journal of cardio-thoracic surgery. Sep-2014
The frozen elephant trunk (FET) technique is a modification of the traditional elephant trunk method, which was introduced by Borst in 1983 in order to treat extensive thoracic aortic aneurysms. The crux of the new method is the different type of aortic prosthesis, consisting of a Dacron part (with or without branches leading to the arterial vessels which exit the aortic arch) and a port for extracorporeal circulation with a self-expanding nitinol stentgraft. This combination enables a complete one-stage treatment of the pathologies within the arch and the proximal segment of the descending aorta; moreover, it facilitates the performance of a two-stage hybrid treatment of extensive thoracic aortic aneurysms involving a significant part of the descending aorta. This article presents the cases of four patients with extensive aortic disease, who were implanted with Thoraflex prostheses (Vascutek, Scotland).
Differential targeting of the cyclin-dependent kinase inhibitor, p21CIP1/WAF1, by chelators with anti-proliferative activity in a range of tumor cell-types.Thursday, September 03, 2015
Moussa RS, Kovacevic Z, Richardson DR,
Oncotarget. 22-Aug-2015
Chelators such as 2-hydroxy-1-napthylaldehyde isonicotinoyl hydrazone (311) and di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT) target tumor cell iron pools and inhibit proliferation. These agents also modulate multiple targets, one of which is the cyclin-dependent kinase inhibitor, p21. Hence, this investigation examined the mechanism of action of these compounds in targeting p21. All the chelators up-regulated p21 mRNA in the five tumor cell-types assessed. In contrast, examining their effect on total p21 protein levels, these agents induced either: (1) down-regulation in MCF-7 cells; (2) up-regulation in SK-MEL-28 and CFPAC-1 cells; or (3) had no effect in LNCaP and SK-N-MC cells. The nuclear localization of p21 was also differentially affected by the ligands depending upon the cell-type, with it being decreased in MCF-7 cells, but increased in SK-MEL-28 and CFPAC-1 cells. Further studies assessing the mechanisms responsible for these effects demonstrated that p21 expression was not correlated with p53 status, suggesting a p53-independent mechanism. Considering this, we examined proteins that modulate p21 independently of p53, namely NDRG1, MDM2 and ΔNp63. These studies demonstrated that a dominant negative MDM2 isoform (p75MDM2) closely resembled p21 expression in response to chelation in three cell lines. These data suggest MDM2 may be involved in the regulation of p21 by chelators.
Expression of Mammalian Target of Rapamycin and Downstream Targets in Normal and Gestational Diabetic Human Term Placenta.Thursday, September 03, 2015
Sati L, Soygur B, Celik-Ozenci C,
Reproductive sciences (Thousand Oaks, Calif.). 2-Sep-2015
Mammalian target of rapamycin (mTOR) signaling serves as a central regulator of cell growth, proliferation, and survival by interacting with various proteins. To date, few studies implicated mTOR in placenta. Human placenta in gestational diabetes mellitus (GDM) shows several alterations including villous immaturity, impaired placental function, and overgrowth. Hence, we aimed to investigate the expression of mTOR, phospho-mTOR (p-mTOR), and the 2 phosphorylated downstream targets of mTOR, ribosomal protein S6 kinase 1 (p-p70S6K), and eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1) in normal term and gestational diabetic human placentas. Immunohistochemistry and Western blot were performed with antibodies against mTOR, p-mTOR, p-p70S6K, and p-4EBP1 (Thr37/46) in normal and diabetic placentas (n = 6 each) and quantified by ImageJ. All mTOR pathway components that we studied were immunolocalized in both normal and diabetic placenta groups. Syncytiotrophoblast and the vascular wall in villi displayed cytoplasmic mTOR and p-mTOR (S2448) immunoreactivities in all placenta samples. However, increased expression of p70S6K in syncytiotrophoblast and p-4EBP1 (Thr37/46) in villous stromal cells was observed in gestational diabetic placentas. Western blot analysis also confirmed the statistically significant increase in p-p70S6K (T389) expression in diabetic placentas. The altered expression of downstream components of mTOR signaling in gestational diabetic placentas suggests an involvement of mTOR activity in the placental pathology of GDM. However, whether increased nutrient transport via this pathway will stimulate fetal and placental overgrowth is still unknown. Although this is a descriptive study, further studies with a functional analysis to highlight the molecular mechanisms underlying this placental pathology are proposed.
A novel apoptosis-inducing mechanism of 5-aza-2'-deoxycitidine in melanoma cells: demethylation of TNF-α and activation of FOXO1.Thursday, September 03, 2015
Noguchi S, Mori T, Igase M, Mizuno T,
Cancer letters. 31-Aug-2015
Melanoma is a poor-prognosis cancer in both humans and dogs, and so the anti-tumor effects of 5-aza-2'-deoxycitidine (5-aza) on solid tumors such as melanoma have gained much attention. However, its anti-tumor mechanism remains entirely unclear. This present study revealed a part of the anti-tumor effects of 5-aza, focusing on apoptosis induction, on human and canine melanoma cells. Treatment with 5-aza markedly induced obvious apoptosis in melanoma cells. 5-Aza-induced apoptosis was possibly due to induced expression of cytotoxic cytokines such as TNF-α. We revealed hypermethylation of the promoter region of TNF-α as a consequence of treatment with 5-aza. Concurrently, we evaluated the effect of 5-aza on the Akt/FOXO1 signaling cascade, which plays a pivotal role in the transcription of cytokine genes. As a result, 5-aza inactivated Akt and inversely activated FOXO1, which contributed to up-regulation of TNF-α. Furthermore, up-regulation of TNF-α by 5-aza administration was found in in vivo experiments. These current data suggest a novel apoptosis-inducing mechanism of 5-aza and indicate that 5-aza could be a promising therapeutic agent for the treatment of human and canine melanomas.
Skin Wound Trauma, Following High-Dose Radiation Exposure, Amplifies and Prolongs Skeletal Tissue Loss.Thursday, September 03, 2015
Swift JM, Swift SN, Smith JT, Kiang JG, Allen MR,
Bone. 1-Sep-2015
The present study investigated the detrimental effects of non-lethal, high-dose (whole body) γ-irradiation on bone, and the impact that radiation combined with skin trauma (i.e. combined injury) has on long-term skeletal tissue health. Recovery of bone after an acute dose of radiation (RI; 8 Gy), skin wounding (15-20% of total body skin surface), or combined injury (RI+Wound; CI) was determined 3, 7, 30, and 120 days post-irradiation in female B6D2F1 mice and compared to non-irradiated mice (SHAM) at each time-point. CI mice demonstrated long-term (day 120) elevations in serum TRAP 5b (osteoclast number) and sclerostin (bone formation inhibitor), and suppression of osteocalcin levels through 30 days as compared to SHAM (p<0.05). Radiation-induced reductions in distal femur trabecular bone volume fraction and trabecular number through 120 days post-exposure were significantly greater than non-irradiated mice (p<0.05) and were exacerbated in CI mice by day 30 (p<0.05). Negative alterations in trabecular bone microarchitecture were coupled with extended reductions in cancellous bone formation rate in both RI and CI mice as compared to Sham (p<0.05). Increased osteoclast surface in CI animals was observed by 3 days after irradiation and remained elevated through 120 days (p<0.01). These results demonstrate a long-term, exacerbated response of bone to radiation when coupled with non-lethal wound trauma. Changes in cancellous bone after combined trauma were derived from extended reductions in osteoblast-driven bone formation and increases in osteoclast activity.
Serum transferrin carrying the xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a biomarker of ALG1-CDG.Thursday, September 03, 2015
Bengtson P, Ng BG, Jaeken J, Matthijs G, Freeze HH, Eklund EA,
Journal of inherited metabolic disease. 3-Sep-2015
ALG1-CDG (formerly CDG-Ik) is a subtype of congenital disorders of glycosylation (CDG) where the genetic defect disrupts the synthesis of the lipid-linked oligosaccharide precursor required for N-glycosylation. The initial step in the investigation for these disorders involves the demonstration of hypoglycosylated serum transferrin (TF). There are no specific biomarkers of this CDG subtype known to date. An LC/MS approach was used to analyze sera from patients with ALG1-CDG, PMM2-CDG, suspected CDG, and individuals with alcohol abuse. We show mass spectrometric data combined with data from enzymatic digestions that suggest the presence of a tetrasaccharide consisting of two N-acetylglucosamines, one galactose, and one sialic acid, appearing on serum TF, is a biomarker of this particular CDG subtype. This is the first time analysis of serum TF can suggest a specific CDG type I subtype and we suggest this tetrasaccharide be used in the clinic to guide the ALG1-CDG diagnostic process.
Post-mortem brain analyses of the Lothian Birth Cohort 1936: extending lifetime cognitive and brain phenotyping to the level of the synapse.Thursday, September 03, 2015
Henstridge CM, Jackson RJ, Kim JM, Herrmann AG, Wright AK, Harris SE, Bastin ME, Starr JM, Wardlaw J, Gillingwater TH, Smith C, McKenzie CA, Cox SR, Deary IJ, Spires-Jones TL,
Acta neuropathologica communications. 3-9-2015
Our novel post-mortem protocol facilitates high-resolution neuropathological analysis of the well-characterized LBC1936 cohort, extending phenotyping beyond cognition and in vivo imaging to nowinclude neuropathological changes, at the level of single synapses. This approach offers an unprecedentedopportunity to study synaptic and axonal integrity during ageing and how it contributes to differences in agerelatedcognitive change.
Clinical Outcomes of Patients with Resected Oral Cavity Cancer and Simultaneous Second Primary Malignancies.Thursday, September 03, 2015
Liao CT, Fan KH, Kang CJ, Lin CY, Chang JT, Tsang NM, Huang BS, Chao YK, Lee LY, Hsueh C, Wang HM, Liau CT, Hsu CL, Hsieh CH, Ng SH, Lin CH, Tsao CK, Fang TJ, Huang SF, Chang KP, Yen TC,
PloS one. 4-9-2015
OSCC patients with neck nodal ECS and esophageal cancer or hepatocellular carcinoma as SSPT have a dismal short-term prognosis.
Increased glycolipid storage produced by the inheritance of a complex intronic haplotype in the α-galactosidase A (GLA) gene.Thursday, September 03, 2015
Gervas-Arruga J, Cebolla JJ, Irun P, Perez-Lopez J, Plaza L, Roche JC, Capablo JL, Rodriguez-Rey JC, Pocovi M, Giraldo P,
BMC genetics. 3-9-2015
Thus, inheritance of the CIH caused an mRNA deregulation altering the GLA expression pattern, producing a tissue glycolipid storage.
Decreased activation-induced cell death by EBV-transformed B cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation.Thursday, September 03, 2015
Ruiz-García R, Mora S, Lozano-Sánchez G, Martínez-Lostao L, Paz-Artal E, Ruiz-Contreras J, Anel A, González-Granado LI, Moreno D, Allende LM,
Pediatric research. 3-Sep-2015
Patients with autosomal recessive inheritance of ALPS-FASLG have a severe phenotype and a partial defect in AICD in T- and B-cell lines. The Fasligand could play a key role in immune surveillance preventing malignancy.Pediatric Research (2015); doi:10.1038/pr.2015.170.
Plasma N-glycome signature of Down syndrome.Thursday, September 03, 2015
Borelli V, Vanhooren V, Lonardi E, Reiding KR, Capri M, Libert C, Garagnani P, Salvioli S, Franceschi C, Wuhrer M,
Journal of proteome research. 3-Sep-2015
In recent years, plasma N-glycans have emerged as biomarkers for health and disease. Here, we studied N-glycomic changes in Down Syndrome (DS). Due to the progeroid phenotype of DS, we focused on the dissection of syndrome- and aging-associated glycomic changes, as well as the interaction thereof. We analyzed the plasma N-glycome of 76 DS persons, 37 siblings (DSS) and 42 mothers (DSM) of DS persons by DNA-Sequencer-Aided, Fluorophore-Assisted-Carbohydrate-Electrophoresis, as well as by MALDI-TOF-MS. The results showed an overall decrease of galactosylation and alpha2,3 sialylation, a concomitant increase of the level of fucosylated N-glycans as well as of monogalactosylated diantennary N-glycans in DS, while the GlycoAgeTest and the ratio of the two core-fucosylated, monogalactosylated diantennary isomers (galactose positioned on alpha1,6 arm versus alpha1,3 arm) were the strongest DS discriminators. Hypogalactosylation is a characteristic of both DS and aging of control individuals. A decrease in alpha2,3-sialylated species is also common to DS and aging of controls. However, regarding to alpha2,6-sialylated tri- and tetragalactosylated N-glycan species, we found those to be lowered in DS, but showed an increase with age in the same persons, while these glycans were not affected by aging in control individuals. In conclusion, we identified specific glycomic changes associated with DS, aging in DS as well as aging in controls, identifying glycomic features in line with accelerated aging in DS. Notably, our data demonstrate an aging phenotype in DS which only in part overlaps with aging in controls, but reveals DS-specificity.
Targeting Cancer Cells Using LNA-Modified Aptamer-siRNA Chimeras.Thursday, September 03, 2015
Subramanian N, Kanwar JR, Kanwar RK, Krishnakumar S,
Nucleic acid therapeutics. 3-Sep-2015
Aptamers are chimerized with drug or antisense oligos or nanoparticles to generate targeted therapeutics for cancer. Aptamer chimerized siRNA rescues nonspecific delivery and, thereby, enhances the availability of siRNA to target cells. EpCAM RNA aptamer (EpApt or Ep) has potential for siRNA chimerization due to its secondary structure. Stathmin and survivin proteins are reported to aid oncogenicity in retinoblastoma (RB), breast cancer and other cancers. Thus, chimerization of EpCAM Apt with siRNA against survivin and stathmin, respectively, was performed by incorporating Locked Nucleic Acid (LNA) modification. The LNA-modified chimeric aptamers were stable until 96 h and got internalized into RB, WERI-Rb1 and breast cancer, MDAMB453 cell lines. The constructs were studied using the recombinant dicer enzyme for the siRNA generation. Quantitative polymerase chain reaction and immunofluorescence by microscopic analysis of chimeras in vitro exhibited silencing of stathmin and survivin in the RB and breast cancer model. The chimeric constructs showed significant inhibition of cell proliferation of breast cancer cells. Thus, LNA-modified aptamer-based siRNA delivery aids in cell targeting and necessitates further studies in animal models.
Ischaemia Reperfusion, Does Temperature matter? Laboratory Perspective.Thursday, September 03, 2015
Mas VR,
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 3-Sep-2015
Liver transplantation is the best available treatment option for patients with end-stage liver disease. The large gap between patients waiting for a liver transplant and the availability of donor organs limited its utilization and has powered efforts to maximize the donor pool. Alternative approaches to expand donor pool include the use of suboptimal or extended criteria donor (ECD) livers and living donors. It is well known that ECD livers present increased vulnerability to ischemia reperfusion injury, and are associated with graft dysfunction and poorer long-term survival. Aiming to expand the donor pool through the use of ECD livers and minimizing ischemia-related complications, machine perfusion has gained interest as a technique to optimize preservation of grafts. This technology also provides a unique opportunity to assess graft quality in real-time by measuring the degree of ischemic injury and organ viability at pre-implantation time. However, standardized and accurate biomarkers that can be timely applied to assess donor quality at pre-implantation are still lacking. This review analyze the published reports showing current biomarkers used to asses liver graft quality during preservation and its potential utilization as a tool for a safe expansion of the ECD use. This article is protected by copyright. All rights reserved.
Cytoplasmic mislocalization of RNA splicing factors and aberrant neuronal gene splicing in TDP-43 transgenic pig brain.Thursday, September 03, 2015
Wang G, Yang H, Yan S, Wang CE, Liu X, Zhao B, Ouyang Z, Yin P, Liu Z, Zhao Y, Liu T, Fan N, Guo L, Li S, Li XJ, Lai L,
Molecular neurodegeneration. 3-9-2015
Our findings from a large mammalian model suggest that cytoplasmic mutant TDP-43 could reduce the nuclear function of RNA splicing factors, contributing to neuropathology.
Combined Effects of 2 Interleukin 28B Polymorphisms on the Therapeutic Outcome of Hepatitis C Patients With Circulating Cryoglobulins.Thursday, September 03, 2015
Bellanti F, Lauletta G, Villani R, Lipsi MR, Natalicchio MI, Sansonno D, Vendemiale G, Serviddio G,
Medicine. Sep-2015
Chronic hepatitis C is commonly associated with extrahepatic manifestations. Cryoglobulins are observed in 40% to 60% of such patients and their presence seems to modify response to therapy. The new antivirals are greatly improving the sustained virological response (SVR); however, their high cost limits the use, leaving pegylated interferon plus ribavirin (PR) still the standard-of-care therapy worldwide. Since PR therapy is burdened with several side effects, pretreatment predictions of patients who are unlikely to respond to this regimen may avoid ineffective treatment. Variants of the interleukin-28B (IL28B) gene correlate with an SVR to PR, and combined IL28B polymorphisms may improve the prediction of treatment outcome.The potential role of both rs8099917 and rs12979860 IL28B single nucleotide polymorphisms (SNPs) combined with presence of cryoglobulins in predicting SVR to PR in hepatitis C virus (HCV)-chronically infected patients was analyzed in the present study.Single and combined IL28B SNPs (rs12979860 and rs8099917) were analyzed in 64 chronic HCV patients treated with PR showing circulating cryoglobulins and compared to 108 noncryoglobulinemic subjects to verify the predictive value on the SVR.The association of rs12979860CC or rs8099917TT with SVR was confirmed in the noncryoglobulinemic group but not in cryoglobulinemic patients. Moreover, the combined determination of both SNPs improved the prediction of SVR in noncryoglobulinemic patients but not in the cryoglobulinemic subgroup.We report that both single and combined determination of IL28B rs12979860 and rs8099917 SNPs in chronic HCV patients with circulating cryoglobulins treated with PR may have a reduced predictive value of SVR.
Case Report: Atrial Fibrillation After Intravenous Administration of Iodinated Contrast Medium in a Patient With Hepatocellular Carcinoma.Thursday, September 03, 2015
Maimone S, Filomia R, Saitta C, Raimondo G, Squadrito G,
Medicine. Sep-2015
We describe the case of a 73-year-old woman with liver cirrhosis and hepatocellular carcinoma (HCC) who developed 2 distinct episodes of paroxystic atrial fibrillation (AF) each of which occurred 1 to 4 hours after iodine medium contrast-enhanced computed tomography. Sinus rhythm was restored by amiodarone therapy after the first AF episode and by electrical cardioversion after the second one. A careful clinical, biochemical, and instrumental examination showed that the patient had subclinical hyperthyroidism and moderate mitral insufficiency with mild atrial enlargement.Thus, the coexistence of both subclinical disthyroidism and of cardiac anatomical alterations may have predisposed the patient to AF that in fact occurred when exogenous iodine administration triggered a hyperthyroidism status.
Molecular Detection of Rickettsia Species Within Ticks (Acari: Ixodidae) Collected from Arkansas United States.Thursday, September 03, 2015
Trout Fryxell RT, Steelman CD, Szalanski AL, Billingsley PM, Williamson PC,
Journal of medical entomology. May-2015
Rocky Mountain spotted fever (RMSF), caused by the etiological agent Rickettsia rickettsii, is the most severe and frequently reported rickettsial illness in the United States, and is commonly diagnosed throughout the southeast. With the discoveries of Rickettsia parkeri and other spotted fever group rickettsiae (SFGR) in ticks, it remains inconclusive if the cases reported as RMSF are truly caused by R. rickettsii or other SFGR. Arkansas reports one of the highest incidence rates of RMSF in the country; consequently, to identify the rickettsiae in Arkansas, 1,731 ticks, 250 white-tailed deer, and 189 canines were screened by polymerase chain reaction (PCR) for the rickettsial genes gltA, rompB, and ompA. None of the white-tailed deer were positive, while two of the canines (1.1%) and 502 (29.0%) of the ticks were PCR positive. Five different tick species were PCR positive: 244 (37%) Amblyomma americanum L., 130 (38%) Ixodes scapularis Say, 65 (39%) Amblyomma maculatum (Koch), 30 (9%) Rhipicephalus sanguineus Latreille, 7 (4%) Dermacentor variabilis Say, and 26 (44%) unidentified Amblyomma ticks. None of the sequenced products were homologous to R. rickettsii. The most common Rickettsia via rompB amplification was Rickettsia montanensis and nonpathogenic Candidatus Rickettsia amblyommii, whereas with ompA amplification the most common Rickettsia was Ca. R. amblyommii. Many tick specimens collected in northwest Arkansas were PCR positive and these were commonly A. americanum harboring Ca. R. amblyommii, a currently nonpathogenic Rickettsia. Data reported here indicate that pathogenic R. rickettsii was absent from these ticks and suggest by extension that other SFGR are likely the causative agents for Arkansas diagnosed RMSF cases.
Effects of Cohabitation on the Population Performance and Survivorship of the Invasive Mosquito Aedes albopictus and the Resident Mosquito Aedes notoscriptus (Diptera: Culicidae) in Australia.Thursday, September 03, 2015
Nicholson J, Ritchie SA, Russell RC, Webb CE, Cook A, Zalucki MP, Williams CR, Ward P, van den Hurk AF,
Journal of medical entomology. May-2015
The presence of Aedes albopictus (Skuse) in the Torres Strait of northern Australia increases the potential for colonization and establishment on the mainland. However, there is a possibility that native species that occupy the same habitats may influence the population performance of Ae. albopictus, potentially affecting the establishment of this species in Australia. Cohabitation experiments were performed with the endemic Aedes notoscriptus (Skuse), which has been found occupying the same larval habitats as Ae. albopictus in the Torres Strait and is the most widespread container-inhabiting Aedes species in Australia. The influence of environmental factors and cohabitation between the two species was examined using different climates, food resource levels, food resource types, and species densities. Survivorship proportions and a population performance index (λ') were calculated and compared. The consequences of increased Ae. notoscriptus densities were reduced survivorship and λ' for Ae. albopictus. Despite this, the mean λ' of Ae. albopictus and Ae. notoscriptus was consistently ≥ 1.06, indicating both species could increase under all conditions, potentially due to increasing conspecific densities negatively affecting Ae. notoscriptus. The outcomes from this study suggest that the preexisting presence of Ae. notoscriptus may not prevent the establishment of Ae. albopictus in Australia.
Real-time PCR Tests in Dutch Exotic Mosquito Surveys; Implementation of Aedes aegypti and Aedes albopictus Identification Tests, and the Development of Tests for the Identification of Aedes atropalpus and Aedes japonicus japonicus (Diptera: Culicidae).Thursday, September 03, 2015
van de Vossenberg BT, Ibáñez-Justicia A, Metz-Verschure E, van Veen EJ, Bruil-Dieters ML, Scholte EJ,
Journal of medical entomology. May-2015
Since 2009, The Netherlands Food and Consumer Product Safety Authority carries out surveys focusing on, amongst others, the presence of invasive mosquito species (IMS). Special attention is given to exotic container-breeding Aedes species Aedes aegypti (L.), Aedes albopictus (Skuse), Aedes atropalpus (Coquillett), and Aedes japonicus japonicus (Theobald). This study describes the implementation of real-time PCR tests described by Hill et al. (2008) for the identification of Ae. aegypti and Ae. albopictus, and the development of two novel real-time PCR tests for the identification of Ae. atropalpus and Ae. j. japonicus. Initial test showed that optimization of elements of the Ae. aegypti and Ae. albopictus tests was needed. Method validation tests were performed to determine if the implemented and newly developed tests are fit for routine diagnostics. Performance criteria of analytical sensitivity, analytical specificity, selectivity, repeatability, and reproducibility were determined. In addition, experiments were performed to determine the influence of environmental conditions on the usability of DNA extracted from mosquito specimens trapped in BG-Sentinel traps. The real-time PCR tests were demonstrated to be sensitive, specific, repeatable, reproducible, and are less prone to false negative results compared to partial cytochrome c oxidase I gene sequencing owing to the DNA fragmentation caused by environmental influences.
RIFM Fragrance ingredient safety assessment, Linalyl isovalerate, CAS Registry Number 1118-27-0.Thursday, September 03, 2015
Api AM, Belsito D, Bhatia S, Bruze M, Calow P, Dagli ML, Dekant W, Fryer AD, Kromidas L, La Cava S, Lalko JF, Lapczynski A, Liebler DC, Miyachi Y, Politano VT, Ritacco G, Salvito D, Schultz TW, Shen J, Sipes IG, Wall B, Wilcox DK,
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 31-Aug-2015
The use of this material under current use conditions is supported by the existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity, skin sensitization potential, as well as, environmental safety. Reproductive toxicity was based on the Threshold of Toxicological Concern (TTC) of 0.03 mg/kg/day for a Cramer Class I material. The estimated systemic exposure is determined to be equal to this value while assuming 100% absorption from skin contact and inhalation. A systemic exposure at or below the TTC value is acceptable.
Factors associated with real time RT-PCR cycle threshold values among medically attended influenza episodes.Thursday, September 03, 2015
Spencer S, Clippard J, Thompson M, Piedra PA, Jewell A, Avadhanula V, Mei M, Jackson ML, Meece J, Sundaram M, Belongia EA, Cross R, Johnson E, Bullotta A, Rinaldo C, Gaglani M, Murthy K, Clipper L, Berman L, Flannery B,
Journal of medical virology. 3-Sep-2015
We evaluated the cycle threshold (CT) values of 1160 influenza A positive and 806 influenza B positive specimens from two seasons of the US Flu VE Network to identify factors associated with CT values. Low CT values (high genomic load) were associated with shorter intervals between illness onset and specimen collection, young age (ages 3-8 years old), and self-rated illness severity for both influenza A and B. Low CT values were also associated with reported fever/feverishness and age ≥65 years for influenza A. This article is protected by copyright. All rights reserved.
EGFR MutationImpact on DefinitiveConcurrent Chemoradiation Therapy for Inoperable Stage III Adenocarcinoma.Thursday, September 03, 2015
Tanaka K, Hida T, Oya Y, Oguri T, Yoshida T, Shimizu J, Horio Y, Hata A, Kaji R, Fujita 2, Sekido Y, Kodaira T, Kokubo M, Katakami N, Yatabe Y,
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 2-Sep-2015
Concurrent CRT resulted in shorter PFS in EGFR-mutant stage III adenocarcinoma patients than in wild-type patients, mainly due to distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-TKIs for EGFR-mutant, locally advanced adenocarcinoma patients receiving definitive CRT may be needed.
Structure of Neurotropic Adeno-Associated Virus AAVrh.8.Thursday, September 03, 2015
Halder S, Van Vliet K, Kennon Smith J, Duong TT, McKenna R, Wilson JM, Agbandje-McKenna M,
Journal of structural biology. 31-Aug-2015
Adeno-associated virus rhesus isolate 8 (AAVrh.8) is a leading vector for the treatment of neurological diseases due to its efficient transduction of neuronal cells and reduced peripheral tissue tropism. Toward identification of the capsid determinants for these properties, the structure of AAVrh.8 was determined by X-ray crystallography to 3.5 Å resolution and compared to those of other AAV isolates. The capsid viral protein (VP) structure consists of an αA helix and an eight-stranded anti-parallel β-barrel core conserved in parvoviruses, and large insertion loop regions between the β-strands form the capsid surface topology. The AAVrh.8 capsid exhibits the surface topology conserved in all AAVs: depressions at the icosahedral twofold axis and surrounding the cylindrical channel at the fivefold axis, and three protrusions around the threefold axis. A structural comparison to serotypes AAV2, AAV8, and AAV9, to which AAVrh.8 shares ∼84, ∼91, and ∼87% VP sequence identity, respectively, revealed differences in the surface loops known to affect receptor binding, transduction efficiency, and antigenicity. Consistent with this observation, biochemical assays showed that AAVrh.8 is unable to bind heparin and does not cross-react with conformational monoclonal antibodies directed against the other AAVs compared. This structure of AAVrh.8 thus identified capsid surface differences which can serve as template regions for rational design of vectors with enhanced transduction for specific tissues and escape pre-existing antibody recognition. These features are essential for the creation of an AAV vector toolkit that is amenable to personalized disease treatment.
Deregulation of SYCP2 predicts early stage HPV+ oropharyngeal carcinoma - a prospective whole transcriptome analysis.Thursday, September 03, 2015
Masterson L, Sorgeloos F, Winder D, Lechner M, Marker A, Malhotra S, Sudhoff H, Jani P, Goon P, Sterling J,
Cancer science. 3-Sep-2015
This study was designed to identify significant differences in gene expression profiles of HPV-positive (HPV+) and HPV-negative (HPV-) oropharyngeal squamous cell carcinomas (OPSCC) and to better understand the functional and biological effects of HPV infection in the pre-malignant pathway. Twenty-four consecutive patients with locally advanced primary OPSCC were included in a prospective clinical trial. Fresh tissue samples (tumor versus matched normal epithelium) were subjected to whole transcriptome analysis and the results validated on the same cohort with reverse transcription-quantitative real-time PCR (RT-qPCR). In a separate retrospective cohort of twenty-seven OPSCC patients, laser capture micro-dissection of FFPE tissue allowed RNA extraction from adjacent regions of normal epithelium, carcinoma in situ (pre-malignant) and invasive SCC tissue. In all patients, the majority displayed evidence of high risk HPV16 positivity (80.4%). Predictable fold changes of RNA expression in HPV-associated disease included multiple transcripts within the p53 oncogenic pathway (e.g. CDKN2A / CCND1). Other candidate transcripts found to have altered levels of expression in this study have not previously been established (SFRP1, CRCT1, DLG2, SYCP2 and CRNN). SYCP2 showed the most consistent fold change from baseline in pre-malignant tissue and aberrant expression of this protein may contribute to genetic instability during HPV-associated cancer development. If further corroborated, this data may contribute to the development of a non-invasive screening tool. This study is registered with the United Kingdom Clinical Research Network (ref: 11945). This article is protected by copyright. All rights reserved.
Enhanced Expression of Integrin αvβ3 Induced by TGF-β Is Required for the Enhancing Effect of Fibroblast Growth Factor 1 (FGF1) in TGF-β-Induced Epithelial-Mesenchymal Transition (EMT) in Mammary Epithelial Cells.Thursday, September 03, 2015
Mori S, Kodaira M, Ito A, Okazaki M, Kawaguchi N, Hamada Y, Takada Y, Matsuura N,
PloS one. 3-9-2015
Epithelial-to-mesenchymal transition (EMT) plays a critical role in cancer metastasis, and is regulated by growth factors such as transforming growth factor β (TGF-β) and fibroblast growth factors (FGF) secreted from the stromal and tumor cells. However, the role of growth factors in EMT has not been fully established. Several integrins are upregulated by TGF-β1 during EMT. Integrins are involved in growth factor signaling through integrin-growth factor receptor crosstalk. We previously reported that FGF1 directly binds to integrin αvβ3 and the interaction was required for FGF1 functions such as cell proliferation and migration. We studied the role of αvβ3 induced by TGF-β on TGF-β-induced EMT. Here, we describe that FGF1 augmented EMT induced by TGF-β1 in MCF10A and MCF12A mammary epithelial cells. TGF-β1 markedly amplified integrin αvβ3 and FGFR1 (but not FGFR2). We studied if the enhancing effect of FGF1 on TGF-β1-induced EMT requires enhanced levels of both integrin αvβ3 expression and FGFR1. Knockdown of β3 suppressed the enhancement by FGF1 of TGF-β1-induced EMT in MCF10A cells. Antagonists to FGFR suppressed the enhancing effect of FGF1 on EMT. Integrin-binding defective FGF1 mutant did not augment TGF-β1-induced EMT in MCF10A cells. These findings suggest that enhanced integrin αvβ3 expression in addition to enhanced FGFR1 expression is critical for FGF1 to augment TGF-β1-induced EMT in mammary epithelial cells.
Diagnostic and prognostic value of serum thioredoxin and DJ-1 in non-small cell lung carcinoma patients.Thursday, September 03, 2015
Fan J, Yu H, Lv Y, Yin L,
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 3-Sep-2015
In response to reactive oxygen species (ROS), thioredoxin and DJ-1 are upregulated to counteract the detrimental effect of ROS under normal condition. However, cancer cells can take advantage of thioredoxin and DJ-1 against ROS-induced cell damage. In several human cancer types, thioredoxin and DJ-1 were found to be overexpressed. The present study aimed to explore the serum levels of thioredoxin and DJ-1 in non-small cell lung cancer (NSCLC) patients and its relationship to the diagnosis and prognosis of this particular malignancy. Sera from 134 NSCLC patients and 168 healthy controls were obtained. Using the enzyme-linked immunosorbent assay (ELISA) method, the levels of serum thioredoxin and DJ-1 were measured and correlated to the clinicopathological characteristics of NSCLC patients. The diagnostic and prognostic significance of the biomarkers were evaluated by using receiver operating curve (ROC), Kaplan-Meier curve, and log-rank analyses and the Cox proportional hazard model, respectively. Serum thioredoxin and DJ-1 levels were significantly higher in the NSCLC patients than that in the controls (23.5 ± 6.57 vs. 13.8 ± 2.49 and 7.11 ± 2.02 vs. 5.18 ± 1.26, respectively). NSCLC patients at later stage cancer showed significantly higher levels of serum thioredoxin and DJ-1 than those at the early stages (P < 0.01 and P < 0.05, respectively). Multivariate logistic regression analysis showed that high serum thioredoxin level was an independent risk factor for lymph nodal metastases and distant metastases (OR = 2.18, 95 % CI 1.26-3.41 and OR = 3.68, 95 % CI 2.16-5.33, respectively). In addition, an increase in the serum DJ-1 level was also identified as an independent risk factor for nodal metastases (OR = 1.37, 95 % CI 1.11-3.04). For predicting the development of NSCLC, ROC/area under the curve (AUC) analysis for thioredoxin indicated an AUC of 0.80 (sensitivity 0.62, specificity 0.92), and ROC/AUC analysis for DJ-1 showed an AUC of 0.78 (sensitivity 0.66, specificity 0.89). NSCLC patients with high serum thioredoxin and DJ-1 levels had lower survival rates than those with low levels, and multivariate analyses for overall survival revealed that high serum thioredoxin levels served as an independent prognostic factor for NSCLC (HR = 2.07, 95 % CI 1.19-3.48). Serum levels of thioredoxin and DJ-1 were significantly higher in NSCLC patients; therefore, these may be utilized as novel diagnostic and prognostic biomarkers for NSCLC.
Epigenetic silencing of NTSR1 is associated with lateral and noninvasive growth of colorectal tumors.Thursday, September 03, 2015
Kamimae S, Yamamoto E, Kai M, Niinuma T, Yamano HO, Nojima M, Yoshikawa K, Kimura T, Takagi R, Harada E, Harada T, Maruyama R, Sasaki Y, Tokino T, Shinomura Y, Sugai T, Imai K, Suzuki H,
Oncotarget. 17-Aug-2015
Our aim was to identify DNA methylation changes associated with the growth pattern and invasiveness of colorectal cancers (CRCs). Comparison of the methylation statuses of large (≥20 mm in diameter along the colonic surface) noninvasive tumors (NTs) and small (<20 mm in diameter along the colonic surface) invasive tumors (ITs) using CpG island microarray analysis showed neurotensin receptor 1 (NTSR1) to be hypermethylated in large NTs. Quantitative bisulfite pyrosequencing revealed that NTSR1 is frequently methylated in colorectal tumors, with large NTs exhibiting the highest methylation levels. The higher NTSR1 methylation levels were associated with better prognoses. By contrast, NTSR1 copy number gains were most frequent among small ITs. Methylation of NTSR1 was associated with the gene's silencing in CRC cell lines, whereas ectopic expression of NTSR1 promoted proliferation and invasion by CRC cells. Analysis of primary tumors composed of adenomatous and malignant portions revealed that NTSR1 is frequently methylated in the adenomatous portion, while methylation levels are generally lower in the cancerous portions. These results suggest that NTSR1 methylation is associated with lateral and noninvasive growth of colorectal tumors, while low levels of methylation may contribute to the malignant potential through activation of NTSR1. Our data also indicate that NTSR1 methylation may be a prognostic biomarker in CRC.
A Systematic Review of Health Economic Evaluations of Diagnostic Biomarkers.Thursday, September 03, 2015
Oosterhoff M, van der Maas ME, Steuten LM,
Applied health economics and health policy. 3-Sep-2015
Published health economic evaluations of biomarkers used for diagnosing, staging diseases, and guiding treatment selection are characterized by a large number of comparators to model the potential clinical applications and to determine their value. Assessing outcomes beyond health as well as specific issues, such as different payer perspectives and patient preferences, is crucial to fully capture the potential health economic impact of diagnostic biomarkers and to inform value-based reimbursement.
Protective properties of lysozyme on β-amyloid pathology; implications for Alzheimer disease.Thursday, September 03, 2015
Helmfors L, Boman A, Civitelli L, Nath S, Sandin L, Janefjord C, McCann H, Zetterberg H, Blennow K, Halliday G, Brorsson AC, Kågedal K,
Neurobiology of disease. 31-Aug-2015
The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.
Loss of miR-200b promotes invasion via activating the Kindlin-2/integrin β1/AKT pathway in esophageal squamous cell carcinoma: An E-cadherin-independent mechanism.Thursday, September 03, 2015
Zhang HF, Alshareef A, Wu C, Li S, Jiao JW, Cao HH, Lai R, Xu LY, Li EM,
Oncotarget. 20-Aug-2015
Our previous studies have shown that loss of miR-200b enhances the invasiveness of esophageal squamous cell carcinoma (ESCC) cells. However, whether the miR-200-ZEB1/2-E-cadherin regulatory cascade, a master regulator of epithelial-to-mesenchymal transition (EMT), is involved in the regulation of ESCC invasion remains elusive. Here, we show that miR-200b represses ESCC cell invasion in vivo without altering the expression of E-cadherin and vimentin, two surrogate markers of EMT. However, an inverse correlation was observed between the expression levels of miR-200b and ZEB1/2 in both ESCC cell lines (n = 7, P < 0.05) and ESCC tumor samples (n = 88, P < 0.05). Methylation of E-cadherin gene was found to block the regulation of E-cadherin by the miR-200b-ZEB1/2 axis, indicating that an E-cadherin-independent mechanism can mediate the biological function of miR-200b in ESCC. We revealed that miR-200b suppresses the integrin β1-AKT pathway via targeting Kindlin-2 to mitigate ESCC cell invasiveness. In two independent cohorts of ESCC samples (n = 20 and n = 53, respectively), Kindlin-2 expression positively correlated with the activation status of both the integrin signaling pathway and the PI3K-AKT signaling pathway (both P < 0.01). These data highlight that suppression of the Kindlin-2-integrin β1-AKT regulatory axis is an alternative mechanism underlying the tumor suppressor function of miR-200b in ESCC.
Targeted anti-inflammatory therapeutics in asthma and chronic obstructive lung disease.Thursday, September 03, 2015
Durham AL, Caramori G, Chung KF, Adcock IM,
Translational research : the journal of laboratory and clinical medicine. 20-Aug-2015
Asthma and chronic obstructive pulmonary disease (COPD) are chronic inflammatory diseases of the airway, although the drivers and site of the inflammation differ between diseases. Asthmatics with a neutrophilic airway inflammation are associated with a poor response to corticosteroids, whereas asthmatics with eosinophilic inflammation respond better to corticosteroids. Biologicals targeting the Th2-eosinophil nexus such as anti-interleukin (IL)-4, anti-IL-5, and anti-IL-13 are ineffective in asthma as a whole but are more effective if patients are selected using cellular (eg, eosinophils) or molecular (eg, periostin) biomarkers. This highlights the key role of individual inflammatory mediators in driving the inflammatory response and for accurate disease phenotyping to allow greater understanding of disease and development of patient-oriented antiasthma therapies. In contrast to asthmatic patients, corticosteroids are relatively ineffective in COPD patients. Despite stratification of COPD patients, the results of targeted therapy have proved disappointing with the exception of recent studies using CXCR2 antagonists. Currently, several other novel mediator-targeted drugs are undergoing clinical trials. As with asthma specifically targeted treatments may be of most benefit in specific COPD patient endotypes. The use of novel inflammatory mediator-targeted therapeutic agents in selected patients with asthma or COPD and the detection of markers of responsiveness or nonresponsiveness will allow a link between clinical phenotypes and pathophysiological mechanisms to be delineated reaching the goal of endotyping patients.
Phenoxide-bridged Zinc(II)-Bis(dipicolylamine) Probes for Molecular Imaging of Cell Death.Thursday, September 03, 2015
Clear K, Harmatys K, Rice DR, Wolter WR, Suckow M, Wang Y, Rusckowski M, Smith BD,
Bioconjugate chemistry. 3-Sep-2015
Cell death is involved in many pathological conditions, and there is a need for clinical and preclinical imaging agents that can target and report cell death. One of the best known biomarkers of cell death is exposure of the anionic phospholipid phosphatidylserine (PS) on the surface of dead and dying cells. Synthetic zinc(II)-bis(dipicolylamine) (Zn2BDPA) coordination complexes are known to selectively recognize PS-rich membranes and act as cell death molecular imaging agents. However, there is a need to improve in vivo imaging performance by selectively increasing target affinity and decreasing off-target accumulation. This present study compared the cell death targeting ability of two new deep-red fluorescent probes containing phenoxide-bridged Zn2BDPA complexes. One probe was a bivalent version of the other, and associated more strongly with PS-rich liposome membranes. But, the bivalent probe exhibited self-quenching on the membrane surface, so the monovalent version produced brighter micrographs of dead and dying cells in cell culture and also better fluorescence imaging contrast in two living animal models of cell death (rat implanted tumor with necrotic core and mouse thymus atrophy). An 111In-labelled radiotracer version of the monovalent probe also exhibited selective cell death targeting ability in the mouse thymus atrophy model, with relatively high amounts in dead and dying tissue and low off-target accumulation in non-clearance organs. The in vivo biodistribution profile is the most favorable yet reported for a Zn2BDPA complex and thus the monovalent phenoxide-bridged Zn2BDPA scaffold is a promising candidate for further development as a cell death imaging agent in living subjects.
From Barrett metaplasia to esophageal adenocarcinoma: the molecular background.Thursday, September 03, 2015
Saraggi D, Fassan M, Bornschein J, Farinati F, Realdon S, Valeri N, Rugge M,
Histology and histopathology. 3-Sep-2015
The molecular landscape of Barrett's esophagus and Barrett-related neoplastic lesions is still far from being completely elucidated. Both in vitro and in vivo studies pinpointed the pathogenetic role of different morphogenic pathways (the para-homeobox, the Notch and the Sonic Hedgehog families in particular) implicated in the acquisition of the metaplastic phenotype of the esophageal mucosa. On the other hand, the most common genetic alterations observed during Barrett's carcinogenesis include disorders of major regulators of the cell cycle, as well as deregulation of the TGF-β/Smad and receptor tyrosine kinases signalling pathways. Recent comprehensive mutational profiling studies identified that the inactivation of the TP53 and of the SMAD4 tumour suppressor genes occurred in a stage-specific manner, confined to (high grade) dysplastic and neoplastic lesions, respectively. The next step will be the correlation of these findings into multidisciplinary diagnostic approaches integrating endoscopy, histology, molecular profiling and liquid biopsies. This will allow the introduction of innovative strategies for secondary prevention of esophageal adenocarcinoma based on biological rationales, and the implementation of potential novel therapeutic targets.
Histological study of chronic pulmonary aspergillosis.Thursday, September 03, 2015
Tochigi N, Ishiwatari T, Okubo Y, Ando T, Shinozaki M, Aki K, Gocho K, Hata Y, Murayama SY, Wakayama M, Nemoto T, Hori Y, Shibuya K,
Diagnostic pathology. 3-9-2015
In conclusion, acute inflammatory exudate along the terminal respiratory tract is most significant pathophysiolocial complication of the CPA, caused to organizing pneumonia, which derives fatal respiratory failure. In addition, the viability of fungus does not concern extension of exudative inflammation at the site of erosion along terminal airway.
Biomarkers of Chondrocyte Apoptosis and Autophagy in Osteoarthritis.Thursday, September 03, 2015
Musumeci G, Castrogiovanni P, Trovato FM, Weinberg AM, Al-Wasiyah MK, Alqahtani MH, Mobasheri A,
International journal of molecular sciences. 3-9-2015
Cell death with morphological and molecular features of apoptosis has been detected in osteoarthritic (OA) cartilage, which suggests a key role for chondrocyte death/survival in the pathogenesis of OA. Identification of biomarkers of chondrocyte apoptosis may facilitate the development of novel therapies that may eliminate the cause or, at least, slow down the degenerative processes in OA. The aim of this review was to explore the molecular markers and signals that induce chondrocyte apoptosis in OA. A literature search was conducted in PubMed, Scopus, Web of Science and Google Scholar using the keywords chondrocyte death, apoptosis, osteoarthritis, autophagy and biomarker. Several molecules considered to be markers of chondrocyte apoptosis will be discussed in this brief review. Molecular markers and signalling pathways associated with chondroycte apoptosis may turn out to be therapeutic targets in OA and approaches aimed at neutralizing apoptosis-inducing molecules may at least delay the progression of cartilage degeneration in OA.
Whole-transcriptome analysis links trastuzumab sensitivity of breast tumors to both HER2 dependence and immune cell infiltration.Thursday, September 03, 2015
Triulzi T, De Cecco L, Sandri M, Prat A, Giussani M, Paolini B, Carcangiu ML, Canevari S, Bottini A, Balsari A, Menard S, Generali D, Campiglio M, Di Cosimo S, Tagliabue E,
Oncotarget. 1-Jul-2015
While results thus far demonstrate the clinical benefit of trastuzumab, some patients do not respond to this therapy. To identify a molecular predictor of trastuzumab benefit, we conducted whole-transcriptome analysis of primary HER2+ breast carcinomas obtained from patients treated with trastuzumab-containing therapies and correlated the molecular portrait with treatment benefit.The estimated association between gene expression and relapse-free survival allowed development of a trastuzumab risk model (TRAR), with ERBB2 and ESR1 expression as core elements, able to identify patients with high and low risk of relapse. Application of the TRAR model to 24 HER2+ core biopsies from patients treated with neo-adjuvant trastuzumab indicated that it is predictive of trastuzumab response. Examination of TRAR in available whole-transcriptome datasets indicated that this model stratifies patients according to response to trastuzumab-based neo-adjuvant treatment but not to chemotherapy alone. Pathway analysis revealed that TRAR-low tumors expressed genes of the immune response, with higher numbers of CD8-positive cells detected immunohistochemically compared to TRAR-high tumors.The TRAR model identifies tumors that benefit from trastuzumab-based treatment as those most enriched in CD8-positive immune infiltrating cells and with high ERBB2 and low ESR1 mRNA levels, indicating the requirement for both features in achieving trastuzumab response.
Sense and nonsense in the process of accreditation of a pathology laboratory.Thursday, September 03, 2015
Long-Mira E, Washetine K, Hofman P,
Virchows Archiv : an international journal of pathology. 3-Sep-2015
The aim of accreditation of a pathology laboratory is to control and optimize, in a permanent manner, good professional practice in clinical and molecular pathology, as defined by internationally established standards. Accreditation of a pathology laboratory is a key element in fine in increasing recognition of the quality of the analyses performed by a laboratory and in improving the care it provides to patients. One of the accreditation standards applied to clinical chemistry and pathology laboratories in the European Union is the ISO 15189 norm. Continued functioning of a pathology laboratory might in time be determined by whether or not it has succeeded the accreditation process. Necessary requirements for accreditation, according to the ISO 15189 norm, include an operational quality management system and continuous control of the methods used for diagnostic purposes. Given these goals, one would expect that all pathologists would agree on the positive effects of accreditation. Yet, some of the requirements stipulated in the accreditation standards, coming from the bodies that accredit pathology laboratories, and certain normative issues are perceived as arduous and sometimes not adapted to or even useless in daily pathology practice. The aim of this review is to elaborate why it is necessary to obtain accreditation but also why certain requirements for accreditation might be experienced as inappropriate.
LINE-1 in cancer: multifaceted functions and potential clinical implications.Thursday, September 03, 2015
Xiao-Jie L, Hui-Ying X, Qi X, Jiang X, Shi-Jie M,
Genetics in medicine : official journal of the American College of Medical Genetics. 3-Sep-2015
Long interspersed nuclear element-1 (L1) retrotransposons are jumping genes that comprise 17% of human DNA. They utilize a ''copy-and-paste'' mechanism to propagate themselves throughout the genome via RNA intermediates, a process termed retrotransposition. L1s are active in the germ line and during embryogenesis, yet they are epigenetically suppressed in somatic cells. In cancer cells, however, L1s are aberrantly activated and may have a role in genome instability, one of the hallmarks of cancer pathogenesis. Their methylation states and retrotransposition activities are associated with and fluctuate during cancer initiation and progression, thus representing promising diagnostic biomarkers and therapeutic targets. During tumorigenesis, L1s exert both retrotransposition-dependent and retrotransposition-independent functions. The former may result in alterations in target gene expression or chromosomal rearrangement, or drive Alu and SVA, events that could function in tumorigenesis, whereas the latter can potentially exert epigenetic regulation by generating endo-siRNAs, forming chimeric L1 transcripts or changing the expression of adjacent genes by providing novel splicing sites or alternative promoters. Moreover, the L1 encoded proteins, ORF1p and ORF2p, may have pro-oncogenic potential by, for example, activating oncogenic transcriptional factors or sequestering oncosuppressors. Herein, we introduce the components and mechanisms of L1 retrotransposition, discuss the landscape, possible functions, and regulation of L1 activity in cancer, and seek their potential as diagnostic biomarkers and therapeutic targets.Genet Med advance online publication 03 September 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.119.
Expanded genetic screening panel for the Ashkenazi Jewish population.Thursday, September 03, 2015
Baskovich B, Hiraki S, Upadhyay K, Meyer P, Carmi S, Barzilai N, Darvasi A, Ozelius L, Peter I, Cho JH, Atzmon G, Clark L, Yu J, Lencz T, Pe'er I, Ostrer H, Oddoux C,
Genetics in medicine : official journal of the American College of Medical Genetics. 3-Sep-2015
Screening for a broader range of disorders not only could further reduce the incidence of autosomal recessive disorders but also could offer the benefits of early or presymptomatic diagnosis.Genet Med advance online publication 03 September 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.123.
Deregulation of ARID1A, CDH1, cMET and PIK3CA and target-related microRNA expression in gastric cancer.Thursday, September 03, 2015
Ibarrola-Villava M, Llorca-Cardeñosa MJ, Tarazona N, Mongort C, Fleitas T, Perez-Fidalgo JA, Roselló S, Navarro S, Ribas G, Cervantes A,
Oncotarget. 27-Jul-2015
Genetic and epigenetic alterations play an important role in gastric cancer (GC) pathogenesis. Aberrations of the phosphatidylinositol-3-kinase signaling pathway are well described. However, emerging genes have been described such as, the chromatin remodeling gene ARID1A. Our aim was to determine the expression levels of four GC-related genes, ARID1A, CDH1, cMET and PIK3CA, and 14 target-related microRNAs (miRNAs). We compared mRNA and miRNA expression levels among 66 gastric tumor and normal adjacent mucosa samples using quantitative real-time reverse transcription PCR. Moreover, ARID1A, cMET and PIK3CA protein levels were assessed by immunohistochemistry (IHC). Finally, gene and miRNAs associations with clinical characteristics and outcome were also evaluated. An increased cMET and PIK3CA mRNA expression was found in 78.0% (P = 2.20 × 10-5) and 73.8% (P = 1.00 × 10-3) of the tumors, respectively. Moreover, IHC revealed that cMET and PIK3CA expression was positive in 63.6% and 87.8% of the tumors, respectively. Six miRNAs had significantly different expression between paired-samples, finding five up-regulated [miR-223-3p (P = 1.65 × 10-6), miR-19a-3p (P = 1.23 × 10-4), miR-128-3p (P = 3.49 × 10-4), miR-130b-3p (P = 1.00 × 10-3) and miR-34a-5p (P = 4.00 × 10-3)] and one down-regulated [miR-124-3p (P = 0.03)]. Our data suggest that cMET, PIK3CA and target-related miRNAs play an important role in GC and may serve as potential targets for therapy.
The emerging threat of multidrug-resistant Gram-negative bacteria in urology.Thursday, September 03, 2015
Zowawi HM, Harris PN, Roberts MJ, Tambyah PA, Schembri MA, Pezzani MD, Williamson DA, Paterson DL,
Nature reviews. Urology. 1-Sep-2015
Antibiotic resistance in Gram-negative uropathogens is a major global concern. Worldwide, the prevalence of Enterobacteriaceae that produce extended-spectrum β-lactamase or carbapenemase enzymes continues to increase at alarming rates. Likewise, resistance to other antimicrobial agents including aminoglycosides, sulphonamides and fluoroquinolones is also escalating rapidly. Bacterial resistance has major implications for urological practice, particularly in relation to catheter-associated urinary tract infections (UTIs) and infectious complications following transrectal-ultrasonography-guided biopsy of the prostate or urological surgery. Although some new drugs with activity against Gram-negative bacteria with highly resistant phenotypes will become available in the near future, the existence of a single agent with activity against the great diversity of resistance is unlikely. Responding to the challenges of Gram-negative resistance will require a multifaceted approach including considered use of current antimicrobial agents, improved diagnostics (including the rapid detection of resistance) and surveillance, better adherence to basic measures of infection prevention, development of new antibiotics and research into non-antibiotic treatment and preventive strategies.
Highlights of This Issue.Thursday, September 03, 2015
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. Sep-2015
Phosphoinositide 3-kinase gamma controls inflammation-induced myocardial depression via sequential cAMP- and iNOS- signaling.Thursday, September 03, 2015
Ndongson-Dongmo B, Heller R, Hoyer D, Brodhun M, Bauer M, Winning J, Hirsch E, Wetzker R, Schlattmann P, Bauer R,
Cardiovascular research. 2-Sep-2015
This study reveals the lipid kinase-independent scaffold function of PI3Kγ as a mediator of SIMD during inflammation-induced SIRS. Activation of cardiac phosphodiesterases via PI3Kγ is shown to restrict myocardial hypercontractility early after SIRS induction as well as the subsequent inflammatory responses.
Necroinflammation in Kidney Disease.Thursday, September 03, 2015
Mulay SR, Linkermann A, Anders HJ,
Journal of the American Society of Nephrology : JASN. 2-Sep-2015
The bidirectional causality between kidney injury and inflammation remains an area of unexpected discoveries. The last decade unraveled the molecular mechanisms of sterile inflammation, which established danger signaling via pattern recognition receptors as a new concept of kidney injury-related inflammation. In contrast, renal cell necrosis remained considered a passive process executed either by the complement-related membrane attack complex, exotoxins, or cytotoxic T cells. Accumulating data now suggest that renal cell necrosis is a genetically determined and regulated process involving specific outside-in signaling pathways. These findings support a unifying theory in which kidney injury and inflammation are reciprocally enhanced in an autoamplification loop, referred to here as necroinflammation. This integrated concept is of potential clinical importance because it offers numerous innovative molecular targets for limiting kidney injury by blocking cell death, inflammation, or both. Here, the contribution of necroinflammation to AKI is discussed in thrombotic microangiopathies, necrotizing and crescentic GN, acute tubular necrosis, and infective pyelonephritis or sepsis. Potential new avenues are further discussed for abrogating necroinflammation-related kidney injury, and questions and strategies are listed for further exploration in this evolving field.
Novel mutations in PIEZO1 cause an autosomal recessive generalized lymphatic dysplasia with non-immune hydrops fetalis.Thursday, September 03, 2015
Fotiou E, Martin-Almedina S, Simpson MA, Lin S, Gordon K, Brice G, Atton G, Jeffery I, Rees DC, Mignot C, Vogt J, Homfray T, Snyder MP, Rockson SG, Jeffery S, Mortimer PS, Mansour S, Ostergaard P,
Nature communications. 2015
Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis and childhood onset of facial and four limb lymphoedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant dehydrated hereditary stomatocytosis and non-immune hydrops of unknown aetiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.
Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities.Thursday, September 03, 2015
Itakura H, Achrol AS, Mitchell LA, Loya JJ, Liu T, Westbroek EM, Feroze AH, Rodriguez S, Echegaray S, Azad TD, Yeom KW, Napel S, Rubin DL, Chang SD, Harsh GR, Gevaert O,
Science translational medicine. 2-Sep-2015
Glioblastoma (GBM) is the most common and highly lethal primary malignant brain tumor in adults. There is a dire need for easily accessible, noninvasive biomarkers that can delineate underlying molecular activities and predict response to therapy. To this end, we sought to identify subtypes of GBM, differentiated solely by quantitative magnetic resonance (MR) imaging features, that could be used for better management of GBM patients. Quantitative image features capturing the shape, texture, and edge sharpness of each lesion were extracted from MR images of 121 single-institution patients with de novo, solitary, unilateral GBM. Three distinct phenotypic "clusters" emerged in the development cohort using consensus clustering with 10,000 iterations on these image features. These three clusters-pre-multifocal, spherical, and rim-enhancing, names reflecting their image features-were validated in an independent cohort consisting of 144 multi-institution patients with similar tumor characteristics from The Cancer Genome Atlas (TCGA). Each cluster mapped to a unique set of molecular signaling pathways using pathway activity estimates derived from the analysis of TCGA tumor copy number and gene expression data with the PARADIGM (Pathway Recognition Algorithm Using Data Integration on Genomic Models) algorithm. Distinct pathways, such as c-Kit and FOXA, were enriched in each cluster, indicating differential molecular activities as determined by the image features. Each cluster also demonstrated differential probabilities of survival, indicating prognostic importance. Our imaging method offers a noninvasive approach to stratify GBM patients and also provides unique sets of molecular signatures to inform targeted therapy and personalized treatment of GBM.
The Optimized Fabrication of Nanobubbles as Ultrasound Contrast Agents for Tumor Imaging.Thursday, September 03, 2015
Cai WB, Yang HL, Zhang J, Yin JK, Yang YL, Yuan LJ, Zhang L, Duan YY,
Scientific reports. 2015
Nanobubbles, which have the potential for ultrasonic targeted imaging and treatment in tumors, have been a research focus in recent years. With the current methods, however, the prepared uniformly sized nanobubbles either undergo post-formulation manipulation, such as centrifugation, after the mixture of microbubbles and nanobubbles, or require the addition of amphiphilic surfactants. These processes influence the nanobubble stability, possibly create material waste, and complicate the preparation process. In the present work, we directly prepared uniformly sized nanobubbles by modulating the thickness of a phospholipid film without the purification processes or the addition of amphiphilic surfactants. The fabricated nanobubbles from the optimal phospholipid film thickness exhibited optimal physical characteristics, such as uniform bubble size, good stability, and low toxicity. We also evaluated the enhanced imaging ability of the nanobubbles both in vitro and in vivo. The in vivo enhancement intensity in the tumor was stronger than that of SonoVue after injection (UCA; 2 min: 162.47 ± 8.94 dB vs. 132.11 ± 5.16 dB, P < 0.01; 5 min: 128.38.47 ± 5.06 dB vs. 68.24 ± 2.07 dB, P < 0.01). Thus, the optimal phospholipid film thickness can lead to nanobubbles that are effective for tumor imaging.
Dissecting the Heterogeneity of Treatment Response in First-Episode Schizophrenia.Thursday, September 03, 2015
Malhotra AK,
Schizophrenia bulletin. 2-Sep-2015
The Mental Health Centers for Intervention Development and Applied Research (CIDAR) program prioritized research to provide an evidence base for biomarker development. At the Zucker Hillside Hospital (ZHH), our CIDAR grant supported research on a comprehensive investigation of treatment response and outcome in first episode schizophrenia. Results provide evidence that baseline neuroimaging, neurocognitive, and genetic measures are significantly associated with clinical response to treatment, and that our currently available interventions can effectively treat aspects of psychotic illness, as well as potentially reduce comorbidity associated with illness. Future research may include combining modalities to more robustly predict response and identify treatment targets, as well as to further develop more effective intervention strategies for these devastating and disabling disorders.
Type 2 diabetes mellitus and biomarkers of neurodegeneration.Thursday, September 03, 2015
Moran C, Beare R, Phan TG, Bruce DG, Callisaya ML, Srikanth V,
Neurology. 2-Sep-2015
T2DM may promote neurodegeneration independent of AD dementia diagnosis, and its effect may be driven by tau phosphorylation. The mechanisms through which T2DM may promote tau phosphorylation deserve further study.
In Response.Thursday, September 03, 2015
Mejia R,
The American journal of tropical medicine and hygiene. 2-Sep-2015
Identification of disrupted AUTS2 and EPHA6 genes by array painting in a patient carrying a de novo balanced translocation t(3;7) with intellectual disability and neurodevelopment disorder.Thursday, September 03, 2015
Schneider A, Puechberty J, Ng BL, Coubes C, Gatinois V, Tournaire M, Girard M, Dumont B, Bouret P, Magnetto J, Baghdadli A, Pellestor F, Geneviève D,
American journal of medical genetics. Part A. 3-Sep-2015
Intellectual disability (ID) is a frequent feature but is highly clinically and genetically heterogeneous. The establishment of the precise diagnosis in patients with ID is challenging due to this heterogeneity but crucial for genetic counseling and appropriate care for the patients. Among the etiologies of patients with ID, apparently balanced de novo rearrangements represent 0.6%. Several mechanisms explain the ID in patients with apparently balanced de novo rearrangement. Among them, disruption of a disease gene at the breakpoint, is frequently evoked. In this context, technologies recently developed are used to characterize precisely such chromosomal rearrangements. Here, we report the case of a boy with ID, facial features and autistic behavior who is carrying a de novo balanced reciprocal translocation t(3;7)(q11.2;q11.22)dn. Using microarray analysis, array painting (AP) technology combined with molecular study, we have identified the interruption of the autism susceptibility candidate 2 gene (AUTS2) and EPH receptor A6 gene (EPHA6). We consider that the disruption of AUTS2 explains the phenotype of the patient; the exact role of EPHA6 in human pathology is not well defined. Based on the observation of recurrent germinal and somatic translocations involving AUTS2 and the molecular environment content, we put forward the hypothesis that the likely chromosomal mechanism responsible for the translocation could be due either to replicative stress or to recombination-based mechanisms. © 2015 Wiley Periodicals, Inc.
Among the S100 proteins, S100A12 is the most significant marker for psoriasis disease activity.Thursday, September 03, 2015
Wilsmann-Theis D, Wagenpfeil J, Holzinger D, Roth J, Koch S, Schnautz S, Bieber T, Wenzel J,
Journal of the European Academy of Dermatology and Venereology : JEADV. 2-Sep-2015
Among the investigated S100-proteins, S100A12 showed the closest association with disease activity and therapeutic response and might therefore provide a valuable biomarker for psoriasis.
[Discovery of novel protein biomarkers in early silicosis by proteomics and identification of alpha B-crystallin].Thursday, September 03, 2015
Chu L, Wang T, Hu Y, Jiang H, Gu Y, Su Z,
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences. 28-Aug-2015
To establish 2-dimensional gel electrophoresis (2-DE) image for the early lung injury rats induced by silica dioxide and to identify differentially expressed protein biomarkers during the early stage of silicosis.
 Methods: The animal models of silicosis were established and morphology changes were observed by HE staining, and then the key protein biomarkers in silicosis were identified by 2-DE and matrix-assisted laser desorption/ionization time of flight tandem mass spectrometry (MALDI-TOF-MS) and verified by Western blot.
 Results: The well qualified 2-DE gel images for experimental and control lung tissues were successfully established, and 40 different protein spots was observed when comparing the gel images between the experimental and control groups. Twenty of them were analyzed by MALDI-TOF-MS. A total of 13 altered proteins were identified, including alpha B-crystallin, mast cell protease 6, annexin 1, etc. The expression of alpha B-crystallin in lung was further verified by Western blot.
 Conclusion: The protein expression of alpha B-crystallin was increased significantly, suggesting that it might play an important role in the progress of silicosis.
The emerging roles of inositol pyrophosphates in eukaryotic cell physiology.Thursday, September 03, 2015
Thota SG, Bhandari R,
Journal of biosciences. Sep-2015
Inositol pyrophosphates are water soluble derivatives of inositol that contain pyrophosphate or diphosphate moieties in addition to monophosphates. The best characterised inositol pyrophosphates, are IP7 (diphosphoinositol pentakisphosphate or PP-IP5), and IP8 (bisdiphosphoinositol tetrakisphosphate or (PP)2-IP4). These energy-rich small molecules are present in all eukaryotic cells, from yeast to mammals, and are involved in a wide range of cellular functions including apoptosis, vesicle trafficking, DNA repair, osmoregulation, phosphate homeostasis, insulin sensitivity, immune signalling, cell cycle regulation, and ribosome synthesis. Identified more than 20 years ago, there is still only a rudimentary understanding of the mechanisms by which inositol pyrophosphates participate in these myriad pathways governing cell physiology and homeostasis. The unique stereochemical and bioenergetic properties these molecules possess as a consequence of the presence of one or two pyrophosphate moieties in the vicinity of densely packed monophosphates are likely to form the molecular basis for their participation in multiple signalling and metabolic pathways. The aim of this review is to provide first time researchers in this area with an introduction to inositol pyrophosphates and a comprehensive overview on their cellular functions.
Contrast-Induced Sustained Kidney Injury: Defining a Disease.Thursday, September 03, 2015
Dauerman HL,
Circulation. Cardiovascular interventions. Sep-2015
This is what COPD looks like.Thursday, September 03, 2015
Sheikh K, Coxson HO, Parraga G,
Respirology (Carlton, Vic.). 26-Aug-2015
Despite decades of research, and the growing healthcare and societal burden of chronic obstructive pulmonary disease (COPD), therapeutic COPD breakthroughs have not occurred. Sub-optimal COPD patient phenotyping, an incomplete understanding of COPD pathogenesis and a scarcity of sensitive tools that provide patient-relevant intermediate endpoints likely all play a role in the lack of new, efficacious COPD interventions. In other words, COPD patients are still diagnosed based on the presence of persistent airflow limitation measured using spirometry. Spirometry measurements reflect the global sum of all the different possible COPD pathologies and perhaps because of this, we lose sight of the different contributions of airway and parenchymal abnormalities. With recent advances in thoracic X-ray computed tomography (CT) and magnetic resonance imaging (MRI), lung structure and function abnormalities may be regionally identified and measured. These imaging endpoints may serve as biomarkers of COPD that can be used to better phenotype patients. Therefore, here we review novel CT and MRI measurements that help reveal COPD phenotypes and what COPD really 'looks' like, beyond spirometric indices. We discuss MR and CT imaging approaches for generating reproducible and sensitive measurements of COPD phenotypes related to pulmonary ventilation and perfusion as well as airway and parenchyma anatomical and morphological features. These measurements may provide a way to advance the development and testing of new COPD interventions and therapies.
Mapping epitopes of U1-70K autoantibodies at single-amino acid resolution.Thursday, September 03, 2015
Haddon DJ, Jarrell JA, Diep VK, Wand HE, Price JV, Tangsombatvisit S, Credo GM, Mackey S, Dekker CL, Baechler EC, Liu CL, Varma M, Utz PJ,
Autoimmunity. 3-Sep-2015
The mechanisms underlying development of ribonucleoprotein (RNP) autoantibodies are unclear. The U1-70K protein is the predominant target of RNP autoantibodies, and the RNA binding domain has been shown to be the immunodominant autoantigenic region of U1-70K, although the specific epitopes are not known. To precisely map U1-70K epitopes, we developed silicon-based peptide microarrays with >5700 features, corresponding to 843 unique peptides derived from the U1-70K protein. The microarrays feature overlapping peptides, with single-amino acid resolution in length and location, spanning amino acids 110-170 within the U1-70K RNA binding domain. We evaluated the serum IgG of a cohort of patients with systemic lupus erythematosus (SLE; n = 26) using the microarrays, and identified multiple reactive epitopes, including peptides 116-121 and 143-148. Indirect peptide ELISA analysis of the sera of patients with SLE (n = 88) revealed that ∼14% of patients had serum IgG reactivity to 116-121, while reactivity to 143-148 appeared to be limited to a single patient. SLE patients with serum reactivity to 116-121 had significantly lower SLE Disease Activity Index (SLEDAI) scores at the time of sampling, compared to non-reactive patients. Minimal reactivity to the peptides was observed in the sera of healthy controls (n = 92). Competitive ELISA showed antibodies to 116-121 bind a common epitope in U1-70K (68-72) and the matrix protein M1 of human influenza B viruses. Institutional Review Boards approved this study. Knowledge of the precise epitopes of U1-70K autoantibodies may provide insight into the mechanisms of development of anti-RNP, identify potential clinical biomarkers and inform ongoing clinical trails of peptide-based therapeutics.
FDG μPET Fails to Detect a Disease-Specific Phenotype in Rats Transgenic for Huntington's Disease – A 15 Months Follow-up Study.Wednesday, September 02, 2015
Reilmann R, Lippross V, Hölzner E, Gigengack F, Bohlen S, Kugel H, Deppe M, Osada N, Lücke M, Riess O, Nguyen HP, Von Hörsten S, Schäfers K, Schäfers M, Jacobs AH, Hermann S,
Journal of Huntington's disease. 2015
In this transgenic rat model of HD FDG-μPET imaging does not detect significant alterations at the ages investigated. Further investigations are warranted employing other age groups and alternative imaging biomarkers for neuronal degeneration, respectively.
Lymphatic endothelial cells derived from metastatic and non-metastatic lymph nodes of human colorectal cancer reveal phenotypic differences in culture.Wednesday, September 02, 2015
Garrafa E, De Francesco M, Solaini L, Giulini SM, Bonfanti C, Ministrini S, Caimi L, Tiberio GA,
Lymphology. Mar-2015
Colorectal cancer is one of the most frequent causes of death in Western countries. Most patients develop metastasis traveling through the lymphatic system, and regional lymph node metastasis is considered a marker for dissemination, increased stage, and worse prognosis. Despite rapid advances in tumor biology, the processes that underpin lymphatic invasion and lymph node metastasis remain poorly understood. The aim of this study was to establish an easy protocol for isolation of pure tumor lymphatic endothelial cells derived from lymph nodes to study differences compared with normal endothelial cells of uninvolved tissue from the same patients. Cells were isolated with very high purity via magnetic cell sorting and express the specific lymphatic markers Prox-1 and Lyve-1. They show differences in expression of adhesion molecules, chemokines, and growth factor secretion, and capability to form capillaries when seeded on basal membrane, thereby, revealing important differences between the two cell type. These cultures may provide a promising platform for the comparative analysis of both cell types at the molecular and biological level and to optimize treatment strategies.
Humoral response against sialyl-Le(a) glycosylated protein species in esophageal cancer: insights for immunoproteomic studies Short Communication.Wednesday, September 02, 2015
Fernandes E, Peixoto A, Neves M, Afonso LP, Santos LL, Ferreira JA,
Electrophoresis. 1-Sep-2015
Esophageal cancers (EC) show poor prognosis and decreased overall survival due to late diagnosis and ineffective therapeutics, urging the introduction of novel biomarkers to aid disease management. The levels of sialyl-Lewis(a) antigen (sLe(a) ) are frequently increased in digestive tumours, which has been explored in serological non-invasive prognostication (CA19-9 test); however with low sensitivity and specificity. Autoantibodies against cancer antigens are considered the next generation biomarkers, as they are present in circulation long before tumour-associated proteins. Based on these observations we have mined the serum of EC patients (n = 7) for antibodies against sLe(a) -glycosylated protein species. All EC were positive for sLe(a) , irrespectively of their histological nature but only two patients showed elevated CA19-9. Moreover, IgG titers, with emphasis on IgG1, were elevated in EC patients in comparison to the control group. SLe(a) -glycoproteins were then extracted from tumours of patients with negative CA19-9, isolated by immunoprecipitation and blotted with patients IgG. Autoantibodies against sLe(a) -glycosylated proteins were detected in all cases. Different SLe(a) -glycoproteins were observed for tumours of distinct histological natures, which now require identification and validation in larger patient sets. This preliminary data suggests that antoantibodies against sLe(a) glycosylated proteins hold potential for non-invasive diagnosis in CA19-9 negative cases and sets the rational for future immunoproteomic studies envisaging highly specific EC biomarkers. This article is protected by copyright. All rights reserved.
Multifunctional Theranostic Nanoplatform for Cancer Combined Therapy Based on Gold Nanorods.Wednesday, September 02, 2015
Chen WH, Yang CX, Qiu WX, Luo GF, Jia HZ, Lei Q, Wang XY, Liu G, Zhuo RX, Zhang XZ,
Advanced healthcare materials. 1-Sep-2015
Nanomaterials that integrate diagnostic and therapeutic functions within a single nanoplatform promise great advances in revolutionizing cancer therapy. A smart multifunctional theranostic drug-delivery system (DDS) based on gold nanorods (abbreviated as GNR/TSDOX) is designed for cancer-targeted imaging and imaging-guided therapy. In this intelligent theranostic DDS, the active targeting ligand biotin is introduced to track cancer sites in vivo. With the aid of photothermal/photoacoustic imaging, GNR/TSDOX can ablate cancer specifically and effectively. When stimulated with a single near-infrared (NIR) light source, this NIR light energy is effectively absorbed and converted into heat by GNR/TSDOX for localized photothermal therapy and the increase in temperature also further triggers the cascaded release of the anticancer drug for combined thermo-chemotherapy. More importantly, the in vivo cure effect can be well guided by regulating the irradiation time and intensity of the NIR light.
Evaluation of pro-inflammatory markers plasma C-reactive protein and urinary prostaglandin-E2 metabolite in colorectal adenoma risk.Wednesday, September 02, 2015
Davenport JR, Cai Q, Ness RM, Milne G, Zhao Z, Smalley WE, Zheng W, Shrubsole MJ,
Molecular carcinogenesis. 31-Aug-2015
C-reactive protein (CRP) is a pro-inflammatory protein with potential as a biomarker in predicting colon cancer risk. However, little is known regarding its association with risk of colorectal adenomas, particularly by subtypes. We conducted a colonoscopy-based matched case-control study to assess whether elevated plasma CRP levels may be associated with colorectal adenoma risk and further whether this association may be modified by urinary prostaglandin E2 metabolite (PGE-M), a biomarker of systemic prostaglandin E2 production. Included in the study were 226 cases with a single small tubular adenoma, 198 cases with multiple small tubular adenomas, 283 cases with at least one advanced adenoma, and 395 polyp-free controls. No apparent association between CRP level and risk of single small tubular adenomas was found (ptrend  = 0.59). A dose-response relationship with CRP level was observed for risk of either multiple small tubular adenomas (OR = 2.01, 95%CI = 1.10-3.68 for the highest versus lowest tertile comparison; ptrend   = 0.03) or advanced adenomas (OR = 1.81, 95%CI = 1.10-2.96 for the highest versus lowest tertile comparison; ptrend  = 0.02). In a joint analysis of CRP level and PGE-M, risk of multiple or advanced adenoma was greatest among those with highest levels of both CRP and PGE-M in comparison to those with low CRP and low PGE-M (OR = 3.72, 95%CI = 1.49-9.72). Our results suggest that elevated CRP, particularly in the context of concurrent elevated PGE-M, may be a biomarker of multiple or advanced adenoma risk in a screening age population. © 2015 Wiley Periodicals, Inc.
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