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TitleDate Created
A computational approach for studying antibody-antigen interactions without prior structural information: The anti-testosterone binding antibody as a case study.Friday, December 09, 2016
Koivuniemi A, Takkinen K, Nevanen T,
Proteins. 09-Dec-2016
Given the increasing exploitation of antibodies in different contexts such as molecular diagnostics and therapeutics, it would be beneficial to unravel the atomistic level properties of antibody-antigen complexes with the help of computational modeling. Thus, here we have studied the feasibility of computational tools to gather atomic scale information regarding the antibody-antigen complexes solely starting from an amino acid sequence. First, we constructed a homology model for the anti-testosterone binding antibody based on the knowledge based classification of complementary determining regions (CDRs) and implicit solvent molecular dynamics simulations. To further examine whether the generated homology model is suitable for studying antibody-antigen interactions, docking calculations were carried out followed by binding free-energy simulations. Our results indicate that with the antibody modeling approach presented here it is possible to construct accurate homology models for antibodies which correctly describes the antibody-antigen interactions, and produces absolute binding free-energies that are comparable with experimental values. In addition, our simulations suggest that the conformations of complementary determining regions (CDRs) may considerably change from the X-ray configuration upon solvation. In conclusion, here we have introduced an antibody modeling workflow that can be used in studying the interactions between antibody and antigen solely based on an amino acid sequence, which in turn provides novel opportunities to tune the properties of antibodies in different applications. This article is protected by copyright. All rights reserved.
"Novel biomarkers for the assessment of pediatric Systemic Lupus Erythematosus nephritis".Friday, December 09, 2016
Koutsonikoli A, Trachana M, Farmaki E, Tzimouli V, Pratsidou-Gertsi P, Printza N, Garyphallos A, Galanopoulou V, Kanakoudi-Tsakalidou F, Papachristou F,
Clinical and experimental immunology. 09-Dec-2016
These findings suggest that the serum anti-NCS, anti-GBM and HMGB1 may serve as biomarkers specific for the presence of nephritis in pSLE. The HMGB1 emerged as a useful biomarker for the assessment of pLN and pSLE activity, whereas the anti-C1q only of pSLE activity. This article is protected by copyright. All rights reserved.
The GALAD scoring algorithm based on AFP, AFP-L3, and DCP significantly improves detection of BCLC early stage hepatocellular carcinoma.Friday, December 09, 2016
Best J, Bilgi H, Heider D, Schotten C, Manka P, Bedreli S, Gorray M, Ertle J, van Grunsven LA, Dechêne A,
Zeitschrift fur Gastroenterologie. Dec-2016
Background: Hepatocellular carcinoma (HCC) is one of the leading causes of death in cirrhotic patients worldwide. The detection rate for early stage HCC remains low despite screening programs. Thus, the majority of HCC cases are detected at advanced tumor stages with limited treatment options. To facilitate earlier diagnosis, this study aims to validate the added benefit of the combination of AFP, the novel biomarkers AFP-L3, DCP, and an associated novel diagnostic algorithm called GALAD. Material and methods: Between 2007 and 2008 and from 2010 to 2012, 285 patients newly diagnosed with HCC and 402 control patients suffering from chronic liver disease were enrolled. AFP, AFP-L3, and DCP were measured using the µTASWako i30 automated immunoanalyzer. The diagnostic performance of biomarkers was measured as single parameters and in a logistic regression model. Furthermore, a diagnostic algorithm (GALAD) based on gender, age, and the biomarkers mentioned above was validated. Results: AFP, AFP-L3, and DCP showed comparable sensitivities and specifities for HCC detection. The combination of all biomarkers had the highest sensitivity with decreased specificity. In contrast, utilization of the biomarker-based GALAD score resulted in a superior specificity of 93.3 % and sensitivity of 85.6 %. In the scenario of BCLC 0/A stage HCC, the GALAD algorithm provided the highest overall AUROC with 0.9242, which was superior to any other marker combination. Conclusions: We could demonstrate in our cohort the superior detection of early stage HCC with the combined use of the respective biomarkers and in particular GALAD even in AFP-negative tumors.
DPP4/CD26 overexpression in urothelial carcinoma confers an independent prognostic impact and correlates with intrinsic biological aggressiveness.Friday, December 09, 2016
Liang PI, Yeh BW, Li WM, Chan TC, Chang IW, Huang CN, Li CC, Ke HL, Yeh HC, Wu WJ, Li CF,
Oncotarget. 07-Dec-2016
Urothelial carcinoma (UC) is common cancer worldwide. The molecular aberrations regarding tumor progression remain unclear. Pericellular proteolysis is crucial in tumorigenesis, but its significance is unexplored in UC. By data mining the datasets in Gene Expression Omnibus, specifically focus on the proteolysis pathway, and followed by a preliminary validation in a pilot batch of tumor samples, we identified that the upregulation of dipeptidyl peptidase 4 (DPP4) was most significantly associated with clinical aggressiveness of UCs. Quantitative RT-PCR confirmed upregulation of DPP4 mRNA in advanced stage UCs. The clinical significance of DPP4 expression was validated in our large cohort consists of 635 UCs from upper urinary tract and urinary bladder. Univariate and multivariate analyses show that DPP4 is an independent prognosticatory biomarker for disease-specific survival and metastasis-free survival. Comparing the DPP4 expression level of three urothelial cell lines with normal urothelial cells, J82 and RTCC-1 showed a significantly increased in transcript and protein expression. DPP4 knockdown as conducted by using short-hairpin RNA resulted in a significantly decreased cell viability, proliferation, migration, and invasion in J82 and RTCC-1 cells. These findings implicate that DPP4 plays a role in the aggressiveness of UCs, and can serve as a novel prognostic marker and therapeutic target.
Sinu virus, a novel and divergent orthomyxovirus related to members of the genus Thogotovirus isolated from mosquitoes in Colombia.Friday, December 09, 2016
Contreras-Gutiérrez MA, Nunes MR, Guzman H, Uribe S, Gallego Gómez JC, Suaza Vasco JD, Cardoso JF, Popov VL, Widen SG, Wood TG, Vasilakis N, Tesh RB,
Virology. 06-Dec-2016
The genome and structural organization of a novel insect-specific orthomyxovirus, designated Sinu virus, is described. Sinu virus (SINUV) was isolated in cultures of C6/36 cells from a pool of mosquitoes collected in northwestern Colombia. The virus has six negative-sense ssRNA segments. Genetic analysis of each segment demonstrated the presence of six distinct ORFs encoding the following genes: PB2 (Segment 1), PB1, (Segment 2), PA protein (Segment 3), envelope GP gene (Segment 4), the NP (Segment 5), and M-like gene (Segment 6). Phylogenetically, SINUV appears to be most closed related to viruses in the genus Thogotovirus.
Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis.Friday, December 09, 2016
Duarte TL, Caldas C, Santos AG, Silva-Gomes S, Santos-Gonçalves A, Martins MJ, Porto G, Lopes JM,
Redox biology. 01-Dec-2016
The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe(-/-) mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.
Label-free colorimetric detection of cancer related gene based on two-step amplification of molecular machine.Friday, December 09, 2016
Xu H, Wu D, Li CQ, Lu Z, Liao XY, Huang J, Wu ZS,
Biosensors & bioelectronics. 02-Dec-2016
Highly sensitive detection of K-ras gene is of great significance in biomedical research and clinical diagnosis. Here, we developed a colorimetric biosensing system for the detection of proto-oncogene K-ras based on enhanced amplification effect of DNA molecular machine, where dual isothermal circular strand-displacement amplification (D-SDA) occurs on two arms in one-to-one correspondence. Specifically, we designed a primer-locked hairpin probe (HP) and a primer-contained linear polymerization template (PPT). In the presence of target gene, HP can hybridize with PPT, forming a DNA molecular machine with dual functional arms (called DFA-machine). Each of the two probes in this machine is able to be extended by polymerase on its counterpart species. Moreover, with the help of nicking endonuclease, the dual isothermal polymerization is converted into dual circular strand-displacement amplification, generating a large amount of anti-hemin aptamer-contained products. After binding to hemins, the aptamer/hemin duplex, horseradish peroxidase (HRP)-mimicking DNAzyme, was formed and catalyzed the oxidation of colorless ABTS by H2O2, producing a visible green color. The proposed colorimetric assay exhibits a wide linear range from 0.01 to 150nM with a low detection limit of 10pM. More interestingly, the mutations existing in target gene are easily observed by the naked eye. It should be noted that this colorimetric system was proved by the analysis of K-ras gene of SW620 cell lines. The simple and powerful DFA-machine is expected to provide promising potential in the sensitive detection of biomarkers for cancer diagnosis, prognosis and therapy.
GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.Friday, December 09, 2016
Barton JC, Chen WP, Emond MJ, Phatak PD, Subramaniam VN, Adams PC, Gurrin LC, Anderson GJ, Ramm GA, Powell LW, Allen KJ, Phillips JD, Parker CJ, McLaren GD, McLaren CE,
Blood cells, molecules & diseases. 12-Nov-2016
GNPAT p.D519G is strongly associated with markedly increased iron stores in p.C282Y homozygotes after correction for age, iron-related variables, and alcohol consumption.
An association of serum ALT with elevated blood pressure in senior adults: a case-control study.Friday, December 09, 2016
Hong X, Wongtongkam N, Ward PR, Xiao S, Wang S, Peng Q, Zuo Q, Zeng D, Wang J, Wang C, Chen J, Zhang N,
Clinical and experimental hypertension (New York, N.Y. : 1993). 09-Dec-2016
Hypertension is a major risk factor for cardiovascular diseases in China; hence, identifying good serum markers might provide cost benefits in terms of reducing morbidity rates. In this population-based case-control study, participants were recruited from five districts in Hunan province, and 416 cases were matched with an equal number of controls. Markers related to elevated blood pressure were assessed: Body Mass Index, total cholesterol, triglycerides, fasting blood glucose, and creatinine. Three potential serum markers homocysteine (HCY), C-reactive protein (CRP), and alanine aminotransferase (ALT) were dichotomized as normal or high level. Binary logistic regression was used to determine odds ratios (ORs) and 95% confidence intervals (CIs). The findings showed that ALT is a powerful serum marker for predicting high risk of high blood pressure with OR = 2.94, 95% CI (1.44-6.02), while there were no significant differences between cases and controls for HCY and CRP. Additionally, it seems likely that high concentrations of HCY conferred a protective effect against elevated blood pressure. When adjusted for sex, ORs for hypertensive females were nearly five times higher than for hypertensive males (OR = 4.34, 95% CI = 1.17-16.04). The study strongly supports findings showing ALT is a potential indicator for patients with hypertension.
Evaluation of Antigens for Development of a Serological Test for Human African Trypanosomiasis.Friday, December 09, 2016
Biéler S, Waltenberger H, Barrett MP, McCulloch R, Mottram JC, Carrington M, Schwaeble W, McKerrow J, Phillips MA, Michels PA, Büscher P, Sanchez JC, Bishop R, Robinson DR, Bangs J, Ferguson M, Nerima B, Albertini A, Michel G, Radwandska M, Ndung'u JM,
PloS one. 2016
This study identified antigens that were highly reactive to T. b. gambiense sera, which could be considered for developing a serological test for gambiense HAT, either individually or in combination. Antigens with potential for inclusion in a test for T. b. rhodesiense HAT were also identified, but because their reactivity was comparatively lower, a search for additional antigens would be required before developing a test for this form of the disease.
Circulating Microvesicles Are Elevated Acutely following Major Burns Injury and Associated with Clinical Severity.Friday, December 09, 2016
O'Dea KP, Porter JR, Tirlapur N, Katbeh U, Singh S, Handy JM, Takata M,
PloS one. 2016
Microvesicles are cell-derived signaling particles emerging as important mediators and biomarkers of systemic inflammation, but their production in severe burn injury patients has not been described. In this pilot investigation, we measured circulating microvesicle levels following severe burns, with severe sepsis patients as a comparator group. We hypothesized that levels of circulating vascular cell-derived microvesicles are elevated acutely following burns injury, mirroring clinical severity due to the early onset and prevalence of systemic inflammatory response syndrome (SIRS) in these patients. Blood samples were obtained from patients with moderate to severe thermal injury burns, with severe sepsis, and from healthy volunteers. Circulating microvesicles derived from total leukocytes, granulocytes, monocytes, and endothelial cells were quantified in plasma by flow cytometry. All circulating microvesicle subpopulations were elevated in burns patients on day of admission (day 0) compared to healthy volunteers (leukocyte-microvesicles: 3.5-fold, p = 0.005; granulocyte-microvesicles: 12.8-fold, p<0.0001; monocyte-microvesicles: 20.4-fold, p<0.0001; endothelial- microvesicles: 9.6-fold, p = 0.01), but decreased significantly by day 2. Microvesicle levels were increased with severe sepsis, but less consistently between patients. Leukocyte- and granulocyte-derived microvesicles on day 0 correlated with clinical assessment scores and were higher in burns ICU non-survivors compared to survivors (leukocyte MVs 4.6 fold, p = 0.002; granulocyte MVs 4.8 fold, p = 0.003). Mortality prediction analysis of area under receiver operating characteristic curve was 0.92 (p = 0.01) for total leukocyte microvesicles and 0.85 (p = 0.04) for granulocyte microvesicles. These findings demonstrate, for the first time, acute increases in circulating microvesicles following burns injury in patients and point to their potential role in propagation of sterile SIRS-related pathophysiology.
Two Isoforms of Yersinia pestis Plasminogen Activator Pla: Intraspecies Distribution, Intrinsic Disorder Propensity, and Contribution to Virulence.Friday, December 09, 2016
Dentovskaya SV, Platonov ME, Svetoch TE, Kopylov PK, Kombarova TI, Ivanov SA, Shaikhutdinova RZ, Kolombet LV, Chauhan S, Ablamunits VG, Motin VL, Uversky VN, Anisimov AP,
PloS one. 2016
It has been shown previously that several endemic Y. pestis isolates with limited virulence contained the I259 isoform of the outer membrane protease Pla, while the epidemic highly virulent strains possessed only the T259 Pla isoform. Our sequence analysis of the pla gene from 118 Y. pestis subsp. microtus strains revealed that the I259 isoform was present exclusively in the endemic strains providing a convictive evidence of more ancestral origin of this isoform. Analysis of the effects of the I259T polymorphism on the intrinsic disorder propensity of Pla revealed that the I259T mutation slightly increases the intrinsic disorder propensity of the C-terminal tail of Pla and makes this protein slightly more prone for disorder-based protein-protein interactions, suggesting that the T259 Pla could be functionally more active than the I259 Pla. This assumption was proven experimentally by assessing the coagulase and fibrinolytic activities of the two Pla isoforms in human plasma, as well as in a direct fluorometric assay with the Pla peptide substrate. The virulence testing of Pla-negative or expressing the I259 and T259 Pla isoforms Y. pestis subsp. microtus and subsp. pestis strains did not reveal any significant difference in LD50 values and dose-dependent survival assays between them by using a subcutaneous route of challenge of mice and guinea pigs or intradermal challenge of mice. However, a significant decrease in time-to-death was observed in animals infected with the epidemic T259 Pla-producing strains as compared to the parent Pla-negative variants. Survival curves of the endemic I259 Pla+ strains fit between them, but significant difference in mean time to death post infection between the Pla-strains and their I259 Pla+ variants could be seen only in the isogenic set of subsp. pestis strains. These findings suggest an essential role for the outer membrane protease Pla evolution in Y. pestis bubonic infection exacerbation that is necessary for intensification of epidemic process from endemic natural focality with sporadic cases in men to rapidly expanding epizootics followed by human epidemic outbreaks, local epidemics or even pandemics.
The Slavic NBN Founder Mutation: A Role for Reproductive Fitness?Friday, December 09, 2016
Seemanova E, Varon R, Vejvalka J, Jarolim P, Seeman P, Chrzanowska KH, Digweed M, Resnick I, Kremensky I, Saar K, Hoffmann K, Dutrannoy V, Karbasiyan M, Ghani M, Barić I, Tekin M, Kovacs P, Krawczak M, Reis A, Sperling K, Nothnagel M,
PloS one. 2016
The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.
Anti-TNF-α Drugs Differently Affect the TNFα-sTNFR System and Monocyte Subsets in Patients with Psoriasis.Friday, December 09, 2016
Gibellini L, De Biasi S, Bianchini E, Bartolomeo R, Fabiano A, Manfredini M, Ferrari F, Albertini G, Trenti T, Nasi M, Pinti M, Iannone A, Salvarani C, Cossarizza A, Pellacani G,
PloS one. 2016
TNF-α has a central role in the development and maintenance of psoriatic plaques, and its serum levels correlate with disease activity. Anti-TNF-α drugs are, however, ineffective in a relevant percentage of patients for reasons that are currently unknown. To understand whether the response to anti-TNF-α drugs is influenced by the production of anti-drug antibodies or by the modulation of the TNFα-TNFα receptor system, and to identify changes in monocyte phenotype and activity, we analysed 119 psoriatic patients who either responded or did not respond to different anti-TNF-α therapies (adalimumab, etanercept or infliximab), and measured plasma levels of TNF-α, TNF-α soluble receptors, drug and anti-drug antibodies. Moreover, we analyzed the production of TNF-α and TNF-α soluble receptors by peripheral blood mononuclear cells (PBMCs), and characterized different monocyte populations. We found that: i) the drug levels varied between responders and non-responders; ii) anti-infliximab antibodies were present in 15% of infliximab-treated patients, while anti-etanercept or anti-adalimumab antibodies were never detected; iii) plasma TNF-α levels were higher in patients treated with etanercept compared to patients treated with adalimumab or infliximab; iv) PBMCs from patients responding to adalimumab and etanercept produced more TNF-α and sTNFRII in vitro than patients responding to infliximab; v) PBMCs from patients not responding to infliximab produce higher levels of TNF-α and sTNFRII than patients responding to infliximab; vi) anti- TNF-α drugs significantly altered monocyte subsets. A complex remodelling of the TNFα-TNFα receptor system thus takes place in patients treated with anti-TNF-α drugs, that involves either the production of anti-drug antibodies or the modulation of monocyte phenotype or inflammatory activity.
Genome-Wide Association of Heroin Dependence in Han Chinese.Friday, December 09, 2016
Kalsi G, Euesden J, Coleman JR, Ducci F, Aliev F, Newhouse SJ, Liu X, Ma X, Wang Y, Collier DA, Asherson P, Li T, Breen G,
PloS one. 2016
Drug addiction is a costly and recurring healthcare problem, necessitating a need to understand risk factors and mechanisms of addiction, and to identify new biomarkers. To date, genome-wide association studies (GWAS) for heroin addiction have been limited; moreover they have been restricted to examining samples of European and African-American origin due to difficulty of recruiting samples from other populations. This is the first study to test a Han Chinese population; we performed a GWAS on a homogeneous sample of 370 Han Chinese subjects diagnosed with heroin dependence using the DSM-IV criteria and 134 ethnically matched controls. Analysis using the diagnostic criteria of heroin dependence yielded suggestive evidence for association between variants in the genes CCDC42 (coiled coil domain 42; p = 2.8x10-7) and BRSK2 (BR serine/threonine 2; p = 4.110-6). In addition, we found evidence for risk variants within the ARHGEF10 (Rho guanine nucleotide exchange factor 10) gene on chromosome 8 and variants in a region on chromosome 20q13, which is gene-poor but has a concentration of mRNAs and predicted miRNAs. Gene-based association analysis identified genome-wide significant association between variants in CCDC42 and heroin addiction. Additionally, when we investigated shared risk variants between heroin addiction and risk of other addiction-related and psychiatric phenotypes using polygenic risk scores, we found a suggestive relationship with variants predicting tobacco addiction, and a significant relationship with variants predicting schizophrenia. Our genome wide association study of heroin dependence provides data in a novel sample, with functionally plausible results and evidence of genetic data of value to the field.
Characterization of Arginase Expression in Glioma-Associated Microglia and Macrophages.Friday, December 09, 2016
Zhang I, Alizadeh D, Liang J, Zhang L, Gao H, Song Y, Ren H, Ouyang M, Wu X, D'Apuzzo M, Badie B,
PloS one. 2016
Microglia (MG) and macrophages (MPs) represent a significant component of the inflammatory response to gliomas. When activated, MG/MP release a variety of pro-inflammatory cytokines, however, they also secrete anti-inflammatory factors that limit their cytotoxic function. The balance between pro and anti-inflammatory functions dictates their antitumor activity. To evaluate potential variations in MG and MP function in gliomas, we isolated these cells (and other Gr1+ cells) from intracranial GL261 murine gliomas by FACS and evaluated their gene expression profiles by microarray analysis. As expected, arginase 1 (Arg1, M2 marker) was highly expressed by tumor-associated Gr1+, MG and MP. However, in contrast to MP and Gr1+ cells that expressed Arg1 shortly after tumor trafficking, Arg1 expression in MG was delayed and occurred in larger tumors. Interestingly, depletion of MPs in tumors did not prevent MG polarization, suggesting direct influence of tumor-specific factors on MG Arg1 upregulation. Finally, Arg1 expression was confirmed in human GBM samples, but most Arg1+ cells were neutrophils and not MPs. These findings confirm variations in tumor MG and MP polarization states and its dependency on tumor microenvironmental factors.
Objectives and Design of BLEEDS: A Cohort Study to Identify New Risk Factors and Predictors for Major Bleeding during Treatment with Vitamin K Antagonists.Friday, December 09, 2016
van Rein N, Lijfering WM, Bos MH, Herruer MH, Vermaas HW, van der Meer FJ, Reitsma PH,
PloS one. 2016
BLEEDS is generalizable to other VKA treated populations and will permit innovative and unbiased research of biomarkers that may predict major bleeding during VKA treatment.
Molecular Characterization of Resistance to Soybean Rust (Phakopsora pachyrhizi Syd. & Syd.) in Soybean Cultivar DT 2000 (PI 635999).Friday, December 09, 2016
Vuong TD, Walker DR, Nguyen BT, Nguyen TT, Dinh HX, Hyten DL, Cregan PB, Sleper DA, Lee JD, Shannon JG, Nguyen HT,
PloS one. 2016
Resistance to soybean rust (SBR), caused by Phakopsora pachyrhizi Syd. & Syd., has been identified in many soybean germplasm accessions and is conferred by either dominant or recessive genes that have been mapped to six independent loci (Rpp1 -Rpp6), but No U.S. cultivars are resistant to SBR. The cultivar DT 2000 (PI 635999) has resistance to P. pachyrhizi isolates and field populations from the United States as well as Vietnam. A F6:7 recombinant inbred line (RIL) population derived from Williams 82 × DT 2000 was used to identify genomic regions associated with resistance to SBR in the field in Ha Noi, Vietnam, and in Quincy, Florida, in 2008. Bulked segregant analysis (BSA) was conducted using the soybean single nucleotide polymorphism (SNP) USLP 1.0 panel along with simple sequence repeat (SSR) markers to detect regions of the genome associated with resistance. BSA identified four BARC_SNP markers near the Rpp3 locus on chromosome (Chr.) 6. Genetic analysis identified an additional genomic region around the Rpp4 locus on Chr. 18 that was significantly associated with variation in the area under disease progress curve (AUDPC) values and sporulation in Vietnam. Molecular markers tightly linked to the DT 2000 resistance alleles on Chrs. 6 and 18 will be useful for marker-assisted selection and backcrossing in order to pyramid these genes with other available SBR resistance genes to develop new varieties with enhanced and durable resistance to SBR.
Prevalence of Primary Ciliary Dyskinesia in consecutive referrals of suspect cases and the Transmission Electron Microscopy detection rate: A systematic review and meta-analysis.Friday, December 09, 2016
Kouis P, Yiallouros PK, Middleton N, Evans JS, Kyriacou K, Papatheodorou SI,
Pediatric research. 09-Dec-2016
BackgroundDiagnostic testing for Primary Ciliary Dyskinesia (PCD) usually includes Transmission Electron Microscopy (TEM), nasal Nitric Oxide, High Speed Video Microscopy and genetics. Diagnostic performance of each test should be assessed towards the development of PCD diagnostic algorithms. We systematically reviewed the literature and quantified PCD prevalence among referrals and TEM detection rate in confirmed PCD patients.MethodsMajor electronic databases were searched until December 2015 using appropriate terms. Included studies described cohorts of consecutive PCD referrals in which PCD was confirmed by at least TEM and one additional test, in order to compare the index test performance with other test(s). Meta-analyses of pooled PCD prevalence and TEM detection rate across studies were performed.ResultsPCD prevalence among referrals was 32% (95%CI:25%-39%, I(2)=92%). TEM detection rate among PCD patients was 83% (95%CI:75%-90%, I(2)=90%). Exclusion of studies reporting isolated inner dynein arm defects as PCD, reduced TEM detection rate and explained an important fraction of observed heterogeneity (74%, 95%CI:66%-83%, I(2)=66%).ConclusionApproximately, one third of referrals, are diagnosed with PCD. Among PCD patients, a significant percentage, at least as high as 26%, is missed by TEM, a limitation that should be accounted towards the development of an efficacious PCD diagnostic algorithm.Pediatric Research (2016); doi:10.1038/pr.2016.263.
A ruthenium anticancer compound interacts with histones and impacts differently on epigenetic and death pathways compared to cisplatin.Friday, December 09, 2016
Cynthia L, Marie-Elodie S, Antonella C, Moussa A, Rita S, Olivier A, Francois D, Dorsselaer Alain V, Sarah C, John S, Michel P, Georg M, Christian G,
Oncotarget. 30-Nov-2016
Ruthenium complexes are considered as potential replacements for platinum compounds in oncotherapy. Their clinical development is handicapped by a lack of consensus on their mode of action. In this study, we identify three histones (H3.1, H2A, H2B) as possible targets for an anticancer redox organoruthenium compound (RDC11). Using purified histones, we confirmed an interaction between the ruthenium complex and histones that impacted on histone complex formation. A comparative study of the ruthenium complex versus cisplatin showed differential epigenetic modifications on histone H3 that correlated with differential expression of histone deacetylase (HDAC) genes. We then characterized the impact of these epigenetic modifications on signaling pathways employing a transcriptomic approach. Clustering analyses showed gene expression signatures specific for cisplatin (42%) and for the ruthenium complex (30%). Signaling pathway analyses pointed to specificities distinguishing the ruthenium complex from cisplatin. For instance, cisplatin triggered preferentially p53 and folate biosynthesis while the ruthenium complex induced endoplasmic reticulum stress and trans-sulfuration pathways. To further understand the role of HDACs in these regulations, we used suberanilohydroxamic acid (SAHA) and showed that it synergized with cisplatin cytotoxicity while antagonizing the ruthenium complex activity. This study provides critical information for the characterization of signaling pathways differentiating both compounds, in particular, by the identification of a non-DNA direct target for an organoruthenium complex.
T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice.Friday, December 09, 2016
Liu W, Guo W, Shen L, Chen Z, Luo Q, Luo X, Feng GS, Shu Y, Gu Y, Xu Q, Sun Y,
Oncotarget. 07-Dec-2016
Nonresolving inflammation is involved in the initiation and progression process of tumorigenesis. Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is known to inhibit acute inflammation but its role in chronic inflammation-associated cancer remains unclear. The role of SHP2 in T cells in dextran sulfate sodium (DSS)-induced colitis and azoxymethane-DSS-induced colitis-associated carcinogenesis was examined using SHP2CD4-/- conditional knockout mice. SHP2 deficiency in T cells aggravated colitis with increased level of pro-inflammatory cytokines including IFN-γ and IL-17A. In contrast, the SHP2CD4-/- mice developed much fewer and smaller tumors than wild type mice with higher level of IFN-γ and enhanced cytotoxicity of CD8+ T cells in the tumor and peritumoral areas. At the molecular level, STAT1 was hyper-phosphorylated in T cells lacking SHP2, which may account for the increased Th1 differentiation and IFN-γ secretion. IFN-γ neutralization or IFN-γ receptor knockout but not IL-17A neutralization, abrogated the anti-tumor effect of SHP2 knockout with lowered levels of perforin 1, FasL and granzyme B. Finally, the expression of granzyme B was negatively correlated with the malignancy of colon cancer in human patients. In conclusion, these findings suggest a new strategy to treat colitis-associated cancer via targeting SHP2.
Second-trimester maternal serum markers in the prediction of preeclampsia.Friday, December 09, 2016
Luo Q, Han X,
Journal of perinatal medicine. 09-Dec-2016
Maternal serum levels of PP13, sFlt-1 and FSLT3 play an important role in predicting late-onset preeclampsia, and the combination of these three markers significantly increases the detection rate for prediction.
Stromal Hedgehog signaling maintains smooth muscle and hampers micro-invasive prostate cancer.Friday, December 09, 2016
Yang Z, Peng YC, Gopalan A, Gao D, Chen Y, Joyner AL,
Disease models & mechanisms. 30-Nov-2016
It is widely appreciated that reactive stroma or carcinoma-associated fibroblasts can influence epithelial tumor progression. In prostate cancer (PCa), the second most common male malignancy worldwide, the amount of reactive stroma is variable and has predictive value for tumor recurrence. By analyzing human PCa protein and RNA expression databases, we found smooth muscle cells (SMCs) are decreased in advanced tumors, whereas fibroblasts are maintained. In three mouse models of PCa, we found the composition of the stroma is distinct. SMCs are greatly depleted in advanced PB-MYC tumors and locally reduced in ERG/PTEN prostates, whereas in TRAMP tumors the SMC layers are increased. In addition, interductal fibroblast-like cells expand in PB-MYC and ERG/PTEN tumors, whereas in TRAMP PCa they expand little and stromal cells invade into intraductal adenomas. Fate mapping of SMCs showed that in PB-MYC tumors the cells are depleted, whereas they expand in TRAMP tumors and interestingly contribute to the stromal cells in intraductal adenomas. Hedgehog (HH) ligands secreted by epithelial cells are known to regulate prostate mesenchyme expansion differentially during development and regeneration. Any possible role of HH signaling in stromal cells during PCa progression is poorly understood. We found that HH signaling is high in SMCs and fibroblasts near tumor cells in all models, and epithelial Shh expression is decreased while Ihh and Dhh are increased. In human primary PCa IHH is expressed the highest, and elevated HH signaling correlates with high stromal gene expression. Moreover, increasing HH signaling in the stroma of PB-MYC PCa resulted in more intact SMC layers and decreased tumor progression (micro-invasive carcinoma). Thus, we propose HH signaling restrains tumor progression by maintaining the smooth muscle and preventing invasion by tumor cells. Our studies highlight the importance of understanding how HH signaling and stromal composition impact on PCa to optimize drug treatments.
A novel brain tumour model in zebrafish reveals the role of YAP activation in MAPK/PI3K induced malignant growth.Friday, December 09, 2016
Mayrhofer M, Gourain V, Reischl M, Affaticati P, Jenett A, Joly JS, Benelli M, Demichelis F, Poliani PL, Sieger D, Mione M,
Disease models & mechanisms. 24-Nov-2016
Somatic mutations activating MAPK/PI3K signalling play a pivotal role in both tumours and brain developmental disorders. We developed a zebrafish model of brain tumour based on somatic expression of oncogenes that activate MAPK/PI3K signalling in neural progenitor cells. HRAS(V12) was the most effective in inducing both heterotopia and invasive tumours. Tumours, but not heterotopias, require persistent activation of phospho‑(p)ERK and express a gene signature similar to the mesenchymal glioblastoma subtype, with a strong YAP component. Application of a 8-gene signature to human brain tumours establishes that YAP activation distinguishes between mesenchymal glioblastoma and low grade glioma in a wide TCGA sample set including gliomas and glioblastomas (GBMs). This suggests that the activation of YAP may be an important event in brain tumour development, promoting malignant versus benign brain lesions. Indeed, co-expression of dominant active YAP (YAP(S5A)) and HRAS(V12) abolishes the development of heterotopias and leads to the sole development of aggressive tumours. Thus, we have developed a model proving that neurodevelopmental disorders and brain tumours may originate from the same somatic mutations activating oncogenes and established that YAP activation is a hallmark of malignant brain tumours.
ATF4 Targets RET for Degradation and is a Candidate Tumor Suppressor Gene in Medullary Thyroid Cancer.Friday, December 09, 2016
Bagheri-Yarmand R, Williams MD, Grubbs EG, Gagel RF,
The Journal of clinical endocrinology and metabolism. 09-Dec-2016
ATF4 was identified as a negative regulator of RET, a candidate tumor suppressor gene, and may be a molecular marker that distinguishes patients at high risk of MTC from those with a longer survival prognosis.
Quantification of ATP7B Protein in Dried Blood Spots by Peptide Immuno-SRM as a Potential Screen for Wilson's Disease.Friday, December 09, 2016
Jung S, Whiteaker JR, Zhao L, Yoo HW, Paulovich AG, Hahn SH,
Journal of proteome research. 09-Dec-2016
Wilson's Disease (WD), a copper transport disorder caused by a genetic defect in the ATP7B gene, has been a long time strong candidate for newborn screening (NBS), since early interventions can give better results by preventing irreversible neurological disability or liver cirrhosis. Several previous pilot studies measuring ceruloplasmin (CP) in infants or children showed that this marker alone was insufficient to meet the universal screening for WD. WD results from mutations that cause absent or markedly diminished levels of ATP7B. Therefore, ATP7B could serve as a marker for the screening of WD, if the protein can be detected from dried blood spots (DBS). This study demonstrates that the immuno-SRM platform can quantify ATP7B in DBS in the picomolar range, and that the assay readily distinguishes affected cases from normal controls (p < 0.0001). The assay precision was <10% CV, and the protein was stable for a week in DBS at room temperature. These promising proof-of-concept data open up the possibility of screening WD in newborns and the potential for a multiplexed assay for screening a variety of congenital disorders using proteins as biomarkers in DBS.
AN INTERNATIONAL INTER-LABORATORY DIGITAL PCR STUDY DEMONSTRATES HIGH REPRODUCIBILITY FOR THE MEASUREMENT OF A RARE SEQUENCE VARIANT.Friday, December 09, 2016
Whale AS, Devonshire AS, Karlin-Neumann GA, Regan J, Javier L, Cowen S, Fernandez-Gonzalez A, Jones GM, Redshaw N, Beck J, Berger AW, Combaret V, Dahl Kjersgaard N, Davis L, Fina F, Forshew T, Fredslund Andersen R, Galbiati S, González Hernández Á, Haynes CA, Janku F, Lacave R, Lee J, Mistry V, Pender A, Pradines A, Proudhon C, Saal LH, Stieglitz E, Ulrich B, Foy CA, Parkes H, Tzonev S, Huggett JF,
Analytical chemistry. 09-Dec-2016
This study tested the claim that digital PCR (dPCR) can offer highly reproducible quantitative measurements in disparate labs. Twenty-one laboratories measured four blinded samples containing different quantities of a KRAS fragment encoding G12D, an important genetic marker for guiding therapy of certain cancers. This marker is challenging to quantify reproducibly using qPCR or NGS due to the presence of competing wild type sequences and the need for calibration. Using dPCR, eighteen laboratories were able to quantify the G12D marker within 12% of each other in all samples. Three laboratories appeared to measure consistently outlying results; however, proper application of a follow-up analysis recommendation rectified their data. Our findings show that dPCR has demonstrable reproducibility across a large number of laboratories without calibration. This could enable the reproducible application of molecular stratification to guide therapy and, potentially, for molecular diagnostics.
Depleting stabilized GOF mutant p53 proteins by inhibiting molecular folding chaperones: a new promise in cancer therapy.Friday, December 09, 2016
Alexandrova EM, Moll UM,
Cell death and differentiation. 09-Dec-2016
Elevation of Peripheral BDNF Promoter Methylation Predicts Conversion from Amnestic Mild Cognitive Impairment to Alzheimer's Disease: A 5-Year Longitudinal Study.Friday, December 09, 2016
Xie B, Xu Y, Liu Z, Liu W, Jiang L, Zhang R, Cui D, Zhang Q, Xu S,
Journal of Alzheimer's disease : JAD. 05-Dec-2016
Epigenetic aberrations have been identified as biomarkers to predict the risk of Alzheimer's disease (AD). This study aimed to evaluate whether altered DNA methylation status of BDNF promoter could be used as potential epigenetic biomarkers for predicting the progression from amnestic mild cognitive impairment (aMCI) to AD. A total of 506 aMCI patients and 728 cognitively normal controls were recruited in the cross-sectional analyses. Patients (n = 458) from aMCI cohort were classified into two groups after 5-year follow-up: aMCI-stable group (n = 330) and AD-conversion group (n = 128). DNA methylation of BDNF promoter was detected by bisulfite-PCR amplification and pyrosequencing. The DNA methylation levels of CpG1 and CpG2 in promoter I and CpG5 and CpG6 in promoter IV of BDNF gene were significantly higher in the aMCI group than in the control group at baseline and also were increased in the conversion group compared with the non-conversion group at 5-year follow up time point. CpG5 in BDNF promoter IV had the highest AUC of 0.910 (95% CI: 0.817-0.983, p < 0.05). Kaplan-Meier analysis showed a significant AD conversion propensity for aMCI patients with high methylation levels of CpG5 (HR = 1.96, 95% CI: 1.07-2.98, p < 0.001). Multivariate Cox regression analysis revealed elevated methylation status of CpG5 was a significant independent predictor for AD conversion (HR = 3.51, p = 0.013). These results suggest that elevation of peripheral BDNF promoter methylation might be used as potential epigenetic biomarkers for predicting the conversion from aMCI to AD.
Identification of early-stage lung adenocarcinoma prognostic signatures based on statistical modeling.Friday, December 09, 2016
Wu C, Zhang D,
Cancer biomarkers : section A of Disease markers. 02-Dec-2016
Our results show that the prognostic models could successfully predict patients' outcome and serve as biomarkers for early-stage lung adenocarcinoma overall survival analysis.
Role of Chlamydia pneumoniae in the pathogenesis of hypertrophy and adenoid tissue inflammation in children.Friday, December 09, 2016
Bielicka A, Zielnik-Jurkiewicz B, Podsiadły E, Prochorec-Sobieszek M, Rogulska J, Demkow U,
Otolaryngologia polska = The Polish otolaryngology. 31-Oct-2016
A presence of C. pneumoniae in lymphocytes and epithelial cells of the adenoid first of all in older children with adenoid hypertrophy confirms the participation of this bacteria in adenoid pathology.
The role of nutritional biomarkers in prediction and understanding the etiology of type 2 diabetes.Friday, December 09, 2016
Abbasi A,
The American journal of clinical nutrition. Dec-2016
Preoperative transdural collateral vessels in moyamoya as radiographic biomarkers of disease.Friday, December 09, 2016
Storey A, Michael Scott R, Robertson R, Smith E,
Journal of neurosurgery. Pediatrics. 09-Dec-2016
OBJECTIVE The prevalence of angiographically evident preoperative transdural collateral vessels in moyamoya is not well documented. The authors hypothesized that transdural collaterals could be used as radiographic biomarkers of disease, and that their presence is associated with more advanced moyamoya arteriopathy at diagnosis, which is a harbinger of more frequent operative complications and a predictor of better long-term angiographic results following surgery. METHODS The study consists of a single-institution case series of patients with moyamoya who underwent pial synangiosis between 2005 and 2013. RESULTS Moyamoya was diagnosed in a total of 204 patients (n = 121 [59%] female, 83 [41%] male); the average age at surgery was 9.5 years (range 0.4-35 years). Radiographically, 154 (75%) had bilateral disease for a total of 308 affected hemispheres; 152 (75%) had radiographic stroke; and 190 (93%) had "ivy sign" on FLAIR MRI, indicating slow flow. Of the 358 hemispheres, 324 were treated operatively. On preoperative angiography, 107 patients (52%) had transdural collaterals in 176 affected hemispheres (49%). The Suzuki stage was higher in patients with collaterals (3.4 vs 3.0, p = 0.002). Of 324 treated hemispheres, 84 (26%) had collaterals within the surgical field. Complications included 12 strokes (3.7% stroke rate/hemisphere), with 5 (42%) directly attributable to interruption of transdural collaterals. On 1-year postoperative arteriograms available in 222 hemispheres, Matsushima grades trended better in patients with preoperative collaterals (1.5 vs 1.8 [A = 1, B = 2, C = 3]; p < 0.003). CONCLUSIONS Transdural collaterals are present in nearly half of all preoperative arteriograms in patients with moyamoya. These collaterals are more common in advanced disease, are associated with stroke as a perioperative complication, and may suggest increased capacity to produce surgical collaterals postoperatively. These data support the utility of preoperative arteriography.
Update on bipolar disorder biomarker candidates: what about uric acid/adenosine hypothesis?Friday, December 09, 2016
Bartoli F, Carrà G, Clerici M,
Expert review of molecular diagnostics. 09-Dec-2016
Identification of novel disulfide adducts between the thiol containing leaving group of the nerve agent VX and cysteine containing tripeptides derived from human serum albumin.Friday, December 09, 2016
Kranawetvogl A, Küppers J, Gütschow M, Worek F, Thiermann H, Elsinghorst PW, John H,
Drug testing and analysis. 09-Dec-2016
Chemical warfare agents represent a continuous and considerable threat to military personnel and the civilian population. Such compounds are prohibited by the Chemical Weapons Convention, to which adherence by the member states is strictly controlled. Therefore, reliable analytical methods for verification of an alleged use of banned substances are required. Accordingly, current research focuses on long-term biomarkers derived from covalent adducts with biomolecules such as proteins. Recently, we have introduced a microbore liquid chromatography/electrospray ionization high-resolution tandem mass spectrometry method allowing for the investigation of two different classes of adducts of the nerve agent VX with human serum albumin (HSA). Phosphonylated tyrosine residues and novel disulfide adducts at cysteine residues of HSA were produced by enzymatic cleavage with pronase and detected simultaneously. Notably, the thiol containing leaving group of VX (2-(diisopropylamino)ethanethiol, DPAET) formed disulfide adducts that were released as cysteine and proline containing dipeptides originating from at least two different sites of HSA. Aim of this study was to identify assumed and novel adducts of DPAET with HSA using synthetic peptide reference compounds. Two novel tripeptides were identified representing disulfide adducts with DPAET (Met-Pro-Cys-DPAET, MPC-DPAET and Asp-Ile-Cys-DPAET, DIC-DPAET). MPC-DPAET was shown to undergo partial in-source decay during electrospray ionization for MS detection thereby losing the N-terminal Met residue. This results in the more stable Pro-Cys-DPAET (PC-DPAET) dipeptide detectable as protonated ion. The limit of detection for MPC-DPAET was evaluated, revealing toxicologically relevant VX plasma concentrations. The results provide novel insights into the reactivity of VX and its endogenous targets.
Does cell phone use increase the chances of parotid gland tumor development? A systematic review and meta-analysis.Friday, December 09, 2016
de Siqueira EC, de Souza FT, Gomez RS, Gomes CC, de Souza RP,
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 09-Dec-2016
Initial screening included 37 articles and three were included in meta-analysis. Using three independent samples including 5087 subjects from retrospective case-control studies, cell phone use seems to be associated with greater odds (1.28, 95%- confidence interval 1.09 - 1.51) to develop salivary gland tumor. Results should be read with caution due to the limited number of studies available and their retrospective design. This article is protected by copyright. All rights reserved.
GPNMB ameliorates mutant TDP-43-induced motor neuron cell death.Friday, December 09, 2016
Nagahara Y, Shimazawa M, Ohuchi K, Ito J, Takahashi H, Tsuruma K, Kakita A, Hara H,
Journal of neuroscience research. 09-Dec-2016
Glycoprotein nonmetastatic melanoma protein B (GPNMB) aggregates are observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, but the detailed localization is still unclear. Mutations of transactive response DNA binding protein 43kDa (TDP-43) are associated with neurodegenerative diseases including ALS. In this study, we evaluated the localization of GPNMB aggregates in the spinal cord of ALS patients and the effect of GPNMB against mutant TDP-43 induced motor neuron cell death. GPNMB aggregates were not localized in the glial fibrillary acidic protein (GFAP)-positive astrocyte and ionized calcium binding adaptor molecule-1 (Iba1)-positive microglia. GPNMB aggregates were localized in the microtubule-associated protein 2 (MAP-2)-positive neuron and neurofilament H non-phosphorylated (SMI-32)-positive neuron, and these were co-localized with TDP-43 aggregates in the spinal cord of ALS patients. Mock or TDP-43 (WT, M337V, and A315T) plasmids were transfected into mouse motor neuron cells (NSC34). The expression level of GPNMB was increased by transfection of mutant TDP-43 plasmids. Recombinant GPNMB ameliorated motor neuron cell death induced by transfection of mutant TDP-43 plasmids and serum-free stress. Furthermore, the expression of phosphorylated ERK1/2 and phosphorylated Akt were decreased by this stress, and these expressions were increased by recombinant GPNMB. These results indicate that GPNMB has protective effects against mutant TDP-43 stress via activating the ERK1/2 and Akt pathways, and GPNMB may be a therapeutic target for TDP-43 proteinopathy in familial and sporadic ALS. © 2016 Wiley Periodicals, Inc.
Endometrial cancer risk prediction including serum-based biomarkers: Results from the EPIC cohort.Friday, December 09, 2016
Fortner RT, Hüsing A, Kühn T, Konar M, Overvad K, Tjønneland A, Hansen L, Boutron-Ruault MC, Severi G, Fournier A, Boeing H, Trichopoulou A, Benetou V, Orfanos P, Masala G, Agnoli C, Mattiello A, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, Peeters PH, Weiderpass E, Gram IT, Gavrilyuk O, Quirós JR, Huerta JM, Ardanaz E, Larrañaga N, Lujan-Barroso L, Sánchez-Cantalejo E, Butt ST, Borgquist S, Idahl A, Lundin E, Khaw KT, Allen NE, Rinaldi S, Dossus L, Gunter M, Merritt MA, Tzoulaki I, Riboli E, Kaaks R,
International journal of cancer. 09-Dec-2016
Endometrial cancer risk prediction models including lifestyle, anthropometric, and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines, and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p<0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination. This article is protected by copyright. All rights reserved.
Damaging Effects of Ultraviolet Radiation on the Cornea.Friday, December 09, 2016
Delic NC, Lyons JG, Di Girolamo N, Halliday GM,
Photochemistry and photobiology. 09-Dec-2016
The cornea sits at the anterior aspect of the eye and additionally to the skin, is highly exposed to ultraviolet radiation (UVR). The cornea blocks a significant proportion of UVB from reaching the posterior structures of the eye. However, UVA can penetrate the full thickness of the cornea, even reaching the anterior portion of the lens. Epidemiological data indicate that UVR is a contributing factor for a multitude of corneal diseases of the cornea including pterygium, photokeratitis, climatic droplet keratopathy, (CDK) and ocular surface squamous neoplasia (OSSN), although the pathogenic mechanisms of each require further elucidation. UVR is a well-known genotoxic agent and its effects have been well characterized in organs such as the skin. However, we are only beginning to identify its effects on the cornea, such as the UVR signature C→T and CC→TT transversions identified by sequencing and increased proliferative and shedding rates in response to UVR exposure. Alarmingly, a single low dose exposure of UVR to the cornea is sufficient to elicit genetic, molecular and cellular changes, supporting the consideration of using protective measures, such as wearing sunglasses when outdoors. The aim of this review is to describe the adverse effects of UVR on the cornea. This article is protected by copyright. All rights reserved.
Integrated Analysis and microRNA Expression Profiling Identified Seven miRNAs Associated With Progression of Oral Squamous Cell Carcinoma.Friday, December 09, 2016
Yan ZY, Luo ZQ, Zhang LJ, Li J, Liu JQ,
Journal of cellular physiology. 09-Dec-2016
MicroRNAs have been used as diagnostic and prognostic biomarkers for many cancers including oral squamous cell carcinoma (OSCC). Several studies have been shown that microRNA (miRNA) play important roles during the progression of OSCC. However, the results vary largely in different studies due to different platforms and sample sizes. In this study, we systematically evaluated a large scale of miRNA profiles from current qualified OSCC samples, and further investigated the functions of genes regulated by these key miRNAs as well as the signaling pathways through which these miRNA effect carcinogenesis. Seven key miRNAs were identified, and of which 3 were significantly up-regulated, including hsa-miR-21, hsa-miR-31, hsa-miR-338, and 4 were down-regulated, namely hsa-miR-125b, hsa-miR-133a, hsa-miR-133b and hsa-miR-139. The function enrichment analysis revealed that target genes of up-regulated miRNAs were associated with cellular protein metabolic process, macromolecule metabolic process and TGF-beta pathway, while the targets of down-regulated were enriched in negative regulation of macromolecule biosynthetic process and gene expression, and p53, Long-term potentiation and adherens junction pathways. Transcription factor analysis revealed that there were 67 (51.1%) transcription factors influenced by both up and down-regulated miRNAs. To summary, 7 key miRNAs were found to play essential role in progression of OSCC, as well as the target genes and transcription factors of these miRNAs. The potential functions of these target genes identified in our study may be profitable to diagnosis and prognostic prediction of OSCC as biomarkers. This article is protected by copyright. All rights reserved.
Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers.Friday, December 09, 2016
Wilhelmsen M, Christensen IJ, Rasmussen L, Jørgensen LN, Madsen MR, Vilandt J, Hillig T, Klaerke M, Nielsen KT, Laurberg S, Brünner N, Gawel S, Yang X, Davis G, Heijboer AM, Martens F, Nielsen HJ,
International journal of cancer. 09-Dec-2016
Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed 8 cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia. Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3, and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of: 1: CRC and high risk adenoma and 2: CRC. Logistic regression was performed. Final reduced models were constructed selecting the 4 biomarkers with the highest likelihood scores. Subjects (N=4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer (CC) and 193 rectal cancer (RC). Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1342 had non-neoplastic bowell disease, and 1978 subjects had "clean" colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUC's were 0.76 and, 0.84, respectively. The postive predictive value (PPV) at 90% sensitivity was 25% for endpoint 1 and the negative predictive value (NPV) was 93%. For endpoint 2 the PPV was 18% and the NPV was 97%. Combinations of serological protein biomarkers provided a significant identification of subjects with high-risk of presence of colorectal neoplasia. The present set of biomarkers could become important adjunct in early detection of CRC. This article is protected by copyright. All rights reserved.
Importance of specimen pretreatment for the low-level detection of mycobacterial lipoarabinomannan in human serum.Friday, December 09, 2016
Laurentius LB, Crawford AC, Mulvihill TS, Granger JH, Robinson R, Spencer JS, Chatterjee D, Hanson KE, Porter MD,
The Analyst. 09-Dec-2016
Patient care and prevention of disease outbreaks rely heavily on the performance of diagnostic tests. These tests are typically carried out in serum, urine, and other complex sample matrices, but are often plagued by a number of matrix effects such as nonspecific adsorption and complexation with circulating proteins. This paper demonstrates the importance of sample pretreatment to overcome matrix effects, enabling the low-level detection of a disease marker for tuberculosis (TB). The impact of pretreatment is illustrated by detecting a cell wall component unique to mycobacteria, lipoarabinomannan (LAM). LAM is a major virulence factor in the infectious pathology of Mycobacterium tuberculosis (Mtb) and has been successfully detected in the body fluids of TB-infected individuals; however, its clinical sensitivity - identifying patients with active infection - remains problematic. This and the companion paper show that the detection of LAM in an immunoassay is plagued by its complexation with proteins and other components in serum. Herein, we present the procedures and results from an investigation of several different pretreatment schemes designed to disrupt complexation and thereby improve detection. These sample pretreatment studies, aimed at determining the optimal conditions for complex disruption, were carried out by using a LAM simulant derived from the nonpathogenic M. smegmatis, a mycobacterium often used as a model for Mtb. We have found that a perchloric acid-based pretreatment step improves the ability to detect this simulant by ∼1500× with respect to that in untreated serum. This paper describes the approach to pretreatment, how pretreatment improves the detection of the LAM simulant in human serum, and the results from a preliminary investigation to identify possible contributors to complexation by fractionating serum according to molecular weight. The companion paper applies this pretreatment approach to assays of TB patient samples.
Quantitative HDL Proteomics Identifies Peroxiredoxin-6 as a Biomarker of Human Abdominal Aortic Aneurysm.Friday, December 09, 2016
Burillo E, Jorge I, Martínez-López D, Camafeita E, Blanco-Colio LM, Trevisan-Herraz M, Ezkurdia I, Egido J, Michel JB, Meilhac O, Vázquez J, Martin-Ventura JL,
Scientific reports. 09-Dec-2016
High-density lipoproteins (HDLs) are complex protein and lipid assemblies whose composition is known to change in diverse pathological situations. Analysis of the HDL proteome can thus provide insight into the main mechanisms underlying abdominal aortic aneurysm (AAA) and potentially detect novel systemic biomarkers. We performed a multiplexed quantitative proteomics analysis of HDLs isolated from plasma of AAA patients (N = 14) and control study participants (N = 7). Validation was performed by western-blot (HDL), immunohistochemistry (tissue), and ELISA (plasma). HDL from AAA patients showed elevated expression of peroxiredoxin-6 (PRDX6), HLA class I histocompatibility antigen (HLA-I), retinol-binding protein 4, and paraoxonase/arylesterase 1 (PON1), whereas α-2 macroglobulin and C4b-binding protein were decreased. The main pathways associated with HDL alterations in AAA were oxidative stress and immune-inflammatory responses. In AAA tissue, PRDX6 colocalized with neutrophils, vascular smooth muscle cells, and lipid oxidation. Moreover, plasma PRDX6 was higher in AAA (N = 47) than in controls (N = 27), reflecting increased systemic oxidative stress. Finally, a positive correlation was recorded between PRDX6 and AAA diameter. The analysis of the HDL proteome demonstrates that redox imbalance is a major mechanism in AAA, identifying the antioxidant PRDX6 as a novel systemic biomarker of AAA.
K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and dictates H3K56 acetylation promoting hypoxia-induced tumour progression.Friday, December 09, 2016
Wu HT, Kuo YC, Hung JJ, Huang CH, Chen WY, Chou TY, Chen Y, Chen YJ, Chen YJ, Cheng WC, Teng SC, Wu KJ,
Nature communications. 09-Dec-2016
Intratumoural hypoxia induces HIF-1α and promotes tumour progression, metastasis and treatment resistance. HIF-1α stability is regulated by VHL-E3 ligase-mediated ubiquitin-dependent degradation; however, the hypoxia-regulated deubiquitinase that stabilizes HIF-1α has not been identified. Here we report that HAUSP (USP7) deubiquitinase deubiquitinates HIF-1α to increase its stability, induce epithelial-mesenchymal transition and promote metastasis. Hypoxia induces K63-linked polyubiquitinated HAUSP at lysine 443 to enhance its functions. Knockdown of HAUSP decreases acetylation of histone 3 lysine 56 (H3K56Ac). K63-polyubiquitinated HAUSP interacts with a ubiquitin receptor CBP to specifically mediate H3K56 acetylation. ChIP-seq analysis of HAUSP and HIF-1α binding reveals two motifs responsive to hypoxia. HectH9 is the E3 ligase for HAUSP and a prognostic marker together with HIF-1α. This report demonstrates that hypoxia-induced K63-polyubiquitinated HAUSP deubiquitinates HIF-1α and causes CBP-mediated H3K56 acetylation on HIF-1α target gene promoters to promote EMT/metastasis, further defining HAUSP as a therapeutic target in hypoxia-induced tumour progression.
The defining DNA methylation signature of Floating-Harbor Syndrome.Friday, December 09, 2016
Hood RL, Schenkel LC, Nikkel SM, Ainsworth PJ, Pare G, Boycott KM, Bulman DE, Sadikovic B,
Scientific reports. 09-Dec-2016
Floating-Harbor syndrome (FHS) is an autosomal dominant genetic condition characterized by short stature, delayed osseous maturation, expressive language impairment, and unique facial dysmorphology. We previously identified mutations in the chromatin remodeling protein SRCAP (SNF2-related CBP Activator Protein) as the cause of FHS. SRCAP has multiple roles in chromatin and transcriptional regulation; however, specific epigenetic consequences of SRCAP mutations remain to be described. Using high resolution genome-wide DNA methylation analysis, we identified a unique and highly specific DNA methylation "epi-signature" in the peripheral blood of individuals with FHS. Both hyper and hypomethylated loci are distributed across the genome, preferentially occurring in CpG islands. Clonal bisulfite sequencing of two hypermethylated (FIGN and STPG2) and two hypomethylated (MYO1F and RASIP1) genes confirmed these findings. The identification of a unique methylation signature in FHS provides further insight into the biological function of SRCAP and provides a unique biomarker for this disorder.
Rapid, Affordable and Portable Medium-Throughput Molecular Device for Zika Virus.Friday, December 09, 2016
Chan K, Weaver SC, Wong PY, Lie S, Wang E, Guerbois M, Vayugundla SP, Wong S,
Scientific reports. 09-Dec-2016
Zika virus (ZIKV) has gained global attention as an etiologic agent of fetal microcephaly and Guillain-Barré syndrome. Existing immuno-based rapid tests often fail to distinguish between Zika and related flaviviruses that are common in affected regions of Central and South Americas and the Caribbean. The US CDC and qualified state health department laboratories can perform the reverse transcription polymerase chain reaction (RT-PCR) ZIKV test using highly sophisticated instruments with long turnaround times. The preliminary results of a portable and low-cost molecular diagnostics system for ZIKV infection are reported here. In less than 15 minutes, this low-cost platform can automatically perform high quality RNA extraction from up to 12 ZIKV-spiked urine samples simultaneously. It can also perform reverse transcription recombinase polymerase amplification reaction (RT-RPA) in ≤15 minutes. The fluorescent signal produced from probe-based RT-RPA or RT-PCR assays can be monitored using LEDs and a smartphone camera. In addition, the RT-RPA and RT-PCR assays do not cross-react with dengue and chikungunya viral RNA. This low-cost system lacks complicated, sensitive and high cost components, making it suitable for resource-limited settings. It has the potential to offer simple sample-to-answer molecular diagnostics and can inform healthcare workers of patients' diagnosis promptly.
Stable knockdown of CREB, HIF-1 and HIF-2 by replication-competent retroviruses abrogates the responses to hypoxia in hepatocellular carcinoma.Friday, December 09, 2016
Shneor D, Folberg R, Pe'er J, Honigman A, Frenkel S,
Cancer gene therapy. 09-Dec-2016
The fast proliferation of tumor cells develops faster than the vasculature, resulting, in most malignant tumors, in generation of hypoxic regions. Hypoxia renders solid tumors resistant to radiation and chemotherapeutics while providing opportunities for tumor-selective therapies targeting tumor hypoxia. Here we exploit two properties of tumors: propagation of tumor cells and ongoing generation of hypoxic regions to construct a system that preferentially leads to the death of tumor cells and thus hinders tumor growth. We constructed murine leukemia virus replication-competent (RCR) viruses that infect only propagating cells. These viruses express small hairpin RNAs (shRNAs) targeting cyclic AMP-response-element binding protein (CREB), hypoxia-inducible factors 1 (HIF)-1 or HIF-2 individually or all three together (X3). These viruses efficiently infected in vitro human hepatocellular carcinoma (HepG2 and FLC4) cells and established persistence of the virus and knocked down the expression of the regulators of the hypoxia-responding genes. Knockdown of either HIF-1 or CREB or both in hypoxia reduced the expression of hypoxia-response elements- and CRE-mediated gene expression, diminished cell proliferation and increased caspase-3 activity. We did not detect any significant effect of the efficiently knocked down HIF-2 on any of the functions tested in vitro. Moreover, severe combined immunodeficiency mice implanted subcutaneously with HepG2 stably infected with recombinant RCRs showed reduction of tumor growth and vascular endothelial growth factor expression, and no hypoxia-guided neovascularization. Combined treatment (RCRs+doxorubicin) improved efficacy in the context of in vitro hypoxia and in vivo (with either vACE-CREB or vACE-X3). This synergistic effect may lead to an improved efficacy and safety profile of the treatment that may result in fewer side effects.Cancer Gene Therapy advance online publication, 9 December 2016; doi:10.1038/cgt.2016.68.
Xp11.2 translocation renal cell carcinoma with NONO-TFE3 gene fusion: morphology, prognosis, and potential pitfall in detecting TFE3 gene rearrangement.Friday, December 09, 2016
Xia QY, Wang Z, Chen N, Gan HL, Teng XD, Shi SS, Wang X, Wei X, Ye SB, Li R, Ma HH, Lu ZF, Zhou XJ, Rao Q,
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 09-Dec-2016
Xp11 translocation renal cell carcinomas are characterized by several different translocations involving the TFE3 gene. Tumors with different specific gene fusions may have different clinicopathological manifestations. Fewer than 10 renal cell carcinoma cases with NONO-TFE3 have been described. Here we examined eight additional cases of this rare tumor using clinicopathological, immunohistochemical, and molecular analyses. The male-to-female ratio of our study cohort was 1:1, and the median age was 30 years. The most distinctive feature of the tumors was that they exhibited glandular/tubular or papillary architecture that was lined with small-to-medium cuboidal to high columnar cells with indistinct cell borders and an abundantly clear or flocculent eosinophilic cytoplasm. The nuclei were oriented toward the luminal surface and were round and uniform in shape, which resulted in the appearance of secretory endometrioid subnuclear vacuolization. The distinct glandular/tubular or papillary architecture was often accompanied by sheets of epithelial cells that presented a biphasic pattern. Immunohistochemically, all eight cases demonstrated moderate (2+) or strong (3+) positive staining for TFE3, CD10, RCC marker, and PAX-8. None of the tumors were immunoreactive for CK7, Cathepsin K, Melan-A, HMB45, Ksp-cadherin, Vimentin, CA9, 34βE12 or CD117. NONO-TFE3 fusion transcripts were identified in six cases by RT-PCR. All eight cases showed equivocal split signals with a distance of nearly 2 signal diameters and sometimes had false-negative results. Furthermore, we developed a fluorescence in situ hybridization (FISH) assay to serve as an adjunct diagnostic tool for the detection of the NONO-TFE3 fusion gene and used this method to detect the fusion gene in all eight cases. Long-term follow-up (range, 10-102 months) was available for 7 patients. All 7 patients were alive with no evidence of recurrent disease or disease progression after their initial resection. This report adds to the known data regarding NONO-TFE3 renal cell carcinoma.Modern Pathology advance online publication, 9 December 2016; doi:10.1038/modpathol.2016.204.
Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1(+) immune cells in Epstein-Barr virus-associated gastric cancer: the prognostic implications.Friday, December 09, 2016
Saito R, Abe H, Kunita A, Yamashita H, Seto Y, Fukayama M,
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 09-Dec-2016
Cancer cells use PD-L1 to evade antitumor immunity through interaction with programmed cell death protein 1 (PD-1) on T cells. Recent whole-genome sequence studies revealed frequent gene amplification of PD-L1 in Epstein-Barr virus-associated gastric cancer (EBVaGC). To investigate the significance of PD-L1 in cancer cells and their microenvironment in EBVaGC, we studied PD-L1 expression by analysis of the public database and immunohistochemistry with fluorescent in situ hybridization (FISH) of the PD-L1 gene. Analysis of the database from The Cancer Genome Atlas also disclosed high expression of PD-L1 in EBVaGC compared with other molecular subtypes of GC. Expression of PD-L1 was frequently detected in cancer cells of EBVaGC (33/96; 34%), with infiltration of PD-L1(+) immune cells in its stroma (43/96; 45%). Both expression of PD-L1 in cancer cells and PD-L1(+) immune cell infiltration in EBVaGC were significantly correlated with diffuse histology according to Lauren's classification and tumor invasion (pT1b or more). As a prognostic indicator, PD-L1 expression in cancer cells correlated with poor outcomes in both overall survival and disease-specific survival (P=0.0498, 0.007). PD-L1-positive cancers had dense infiltration of PD-L1(+) immune cells as well as CD8(+) and PD-1(+) cells in EBVaGC. FISH analysis of representative samples of the tumor demonstrated gene amplification of PD-L1 in 11% of cases. PD-L1-amplified cells corresponded to PD-L1-positive cells showing high-intensity immunohistochemical staining among cancer cells showing weak or moderate intensities. Taken together, PD-L1 expression in cancer cells and their microenvironment may contribute to the progression of EBVaGC, and gene amplification occurs as clonal evolution during progression. This specific subtype of GC infected with EBV is potentially a good candidate for immunotherapy targeting of the PD-L1/PD-1 axis.Modern Pathology advance online publication, 9 December 2016; doi:10.1038/modpathol.2016.202.
Internalisation of hepatitis C virus core protein by human conjunctival fibroblasts.Friday, December 09, 2016
Rajalakshmy AR, Malathi J, Madhavan HN, Bhaskar S, Iyer GK,
Indian journal of medical microbiology. 09-12-2016
Recent studies indicate that hepatitis C virus (HCV) proteins can mediate innate immune response and inflammation in conjunctival fibroblasts which contributes to the pathology of dry eye condition associated with chronic HCV infection. The present study investigates the phagocytic potential of human conjunctival fibroblasts (HCFj) for HCV core protein. HCFj cells were incubated with HCV core antigen for different periods of time, and fluorescent micrographs were taken to observe protein internalisation. HCFj cells were capable of internalising HCV core antigen within 1 h; this gives an insight into another molecular mechanism which may contribute towards HCV-associated conjunctival inflammation.
Molecular characterisation of Panton-Valentine leucocidin-producing methicillin-resistant Staphylococcus aureus clones isolated from the main hospitals in Taif, KSA.Friday, December 09, 2016
Eed EM, Ghonaim MM, Hussein YM, Al-Shehri SS, Khalifa AS,
Indian journal of medical microbiology. 10-12-2016
PVL is more frequent among CA-MRSA than MSSA. All the HA-MRSA and 25% of CA-MRSA strains were negative for PVL. The pvl gene was related to the severity of infection but not related to coa gene RFLP pattern.
Circulating heat shock protein mRNA profile in gestational hypertension, pre-eclampsia & foetal growth restriction.Friday, December 09, 2016
Hromadnikova I, Dvorakova L, Kotlabova K, Kestlerova A, Hympanova L, Novotna V, Doucha J, Krofta L,
The Indian journal of medical research. Aug-2016
These data support that maternal circulation can reflect both maternal and foetal pathologic conditions. Hsp70 represents the sole plasmatic marker, and increased Hsp70 mRNA levels reflect maternal and placental stress response to pregnancy-related complications such as GH and PE, irrespective of the severity of the disease.
Safety and Tolerability of Leucine Supplementation in Elderly Men.Friday, December 09, 2016
Elango R, Rasmussen B, Madden K,
The Journal of nutrition. Dec-2016
Leucine, a branched-chain amino acid, has been shown to stimulate muscle protein synthesis and has been suggested to play a role in the prevention of age-related muscle atrophy (sarcopenia). Although leucine supplementation may be beneficial, the efficacious dose of leucine is unknown. Before conducting studies with increased doses of leucine, the Tolerable Upper Intake Level (UL) for leucine needs to be determined. The objective of this review is to describe 2 current studies to determine the UL for leucine in young and elderly men. Initially, in young men we tested the conceptual model of determining the maximum oxidative capacity of an amino acid to be an ideal marker for identifying the UL. Leucine oxidation, measured with the use of l-[1-(13)C]leucine, increased with increasing leucine intakes and reached a plateau at higher intakes. Two-phase linear regression analysis identified a breakpoint of 550 mg ⋅ kg(-1) ⋅ d(-1) (95% CI: 454, 646 mg ⋅ kg(-1) ⋅ d(-1)), with a simultaneous increase in blood ammonia concentrations above normal values (35 μmol/L). Recently, a similar study was conducted in elderly men (∼72 y old). A breakpoint in leucine oxidation was observed at 431 mg ⋅ kg(-1) ⋅ d(-1) (95% CI: 351, 511 mg ⋅ kg(-1) ⋅ d(-1)), with blood ammonia concentrations above normal (35 μmol/L) at leucine intakes >550 mg ⋅ kg(-1) ⋅ d(-1) Taking the data together, the UL for leucine intake in healthy elderly men could be set at a value similar to young men, at 500 mg ⋅ kg(-1) ⋅ d(-1), or ∼35 g/d for an individual weighing 70 kg; or, as a cautious estimate, the leucine UL could also be considered as 351 mg ⋅ kg(-1) ⋅ d(-1) (the lower 95% CI), which would be ∼24.5 g/d for an elderly individual weighing 70 kg. These studies to determine the UL for leucine in humans are acute diet studies, and future studies with additional biomarkers and long-term supplementation of leucine will be necessary.
Comparative evaluation of dehydroepiandrosterone sulfate (DHEAS) potential to predict hepatic OATP transporter-based drug-drug interactions.Friday, December 09, 2016
Nishizawa K, Nakanishi T, Tamai I,
Drug metabolism and disposition: the biological fate of chemicals. 01-Dec-2016
Pharmacokinetic drug-drug interactions (DDIs) on hepatic organic anion transporting polypeptides (OATPs) are important clinical issues. Previously we reported that plasma dehydroepiandrosterone sulfate (DHEAS) could serve as an endogenous probe to predict OATP-based DDIs in monkeys using rifampicin as an OATP inhibitor. However, since the contribution of hepatic OATPs to the changes of plasma DHEAS by rifampicin remains unclear, here, we evaluated by an in vivo pharmacokinetic study. Since plasma DHEAS concentrations were unexpectedly low in our rat model, disposition of externally administered DHEAS was evaluated. Intravenously administered DHEAS was mainly recovered in bile (29.1 %) and less in urine (2.95 %). The liver tissue to plasma concentration ratio (Kpliver) decreased from 41.8 to 5.07 by rifampicin, and this decrement was consistent with the decrease of distribution volume from 247 to 59 mL/rat. Comparison of in vitro IC50 of rifampicin for DHEAS uptake by isolated rat hepatocytes and in vivo plasma rifampicin concentration suggested that rifampicin effect on the plasma DHEAS concentration was mostly explained by inhibition of hepatic OATPs, demonstrating that DHEAS could be a biomarker of hepatic OATP activity. Next, previously reported rifampicin-induced changes of plasma concentrations evaluated as an AUC ratio (AUCR) of possible probe compounds were compared on the basis of rifampicin dose/body surface area. The AUCR values of endogenous compounds and intravenously administered statins, for which possible DDIs in the intestinal absorption process can be excluded, increased proportionally to rifampicin dose. Simultaneous measurement of these endogenous compounds could be effective biomarkers for prediction of OATP-based DDIs.
Generation of an Abcc8 heterozygous mutation human embryonic stem cell line using CRISPR/Cas9.Friday, December 09, 2016
Guo D, Liu H, Gao G, Ruzi A, Wang K, Wu H, Lai K, Liu Y, Yang F, Lai L, Li YX,
Stem cell research. 05-Nov-2016
The gene of ATP-binding cassette subfamily C member 8 (Abcc8) is cytogenetically located at 11p15.1 and encodes the sulfonylurea receptor (SUR1). SUR1 is a subunit of ATP-sensitive potassium channel (KAPT) in the β-cell regulating insulin secretion. Mutations of ABCC8 are responsible for congenital hyperinsulinism (CHI). Here we reported that an Abcc8 heterozygous mutant cell line was generated by CRISPR/Cas9 technique with 1bp insertion resulting in abnormal splicing on human embryonic stem cell line H1. The phenotypic characteristics of this cell line reveal defective KATP channel and diazoxide-responsive that provides ideal model for molecular pathology research and drug screening for CHI.
Generation and characterization of an induced pluripotent stem cell (iPSC) line from a patient with clozapine-resistant Schizophrenia.Friday, December 09, 2016
Marsoner F, Marcatili M, Karnavas T, Bottai D, D'Agostino A, Scarone S, Conti L,
Stem cell research. 10-Nov-2016
Peripheral Blood Mononuclear Cells (PBMCs) were collected from a patient with clozapine-resistant (also known as "super-refractory") Schizophrenia. iPSCs were established with a non-integrating Sendai virus-based reprogramming system. A footprint-free hiPSC line was characterized to express the main endogenous pluripotency markers and to retain a normal karyotype. Cells showed pluripotency competency by giving rise to progeny of differentiated cells belonging to the three germ layers. This hiPSC line represents a valuable tool to obtain mature, pathology-relevant neuronal populations in vitro that are suitable to investigate the molecular background of the schizophrenic disorder and the resultant patients' response to treatments.
Generation of an Abcc8 homozygous mutation human embryonic stem cell line using CRISPR/Cas9.Friday, December 09, 2016
Guo D, Liu H, Gao G, Ruzi A, Wang K, Wu H, Lai K, Liu Y, Yang F, Lai L, Li YX,
Stem cell research. 09-Nov-2016
The gene of ATP-binding cassette subfamily C member 8 (Abcc8) is cytogenetically located at 11p15.1 and encodes the sulfonylurea receptor (SUR1). SUR1 is a subunit of ATP-sensitive potassium channel (KAPT) in the β-cell regulating insulin secretion. Mutations of ABCC8 are responsible for congenital hyperinsulinism (CHI). Here we generated an Abcc8 homozygous mutant cell line by CRISPR/Cas9 technique with 22bp deletion resulting in abnormal splicing on human embryonic stem cell line H1. The phenotypic characteristics of this cell line reveal defective KATP channel and diazoxide-unresponsive that provides an ideal model for molecular pathology research and drug screening for CHI.
Cerebrospinal-fluid Alzheimer's Disease Biomarkers and Blood-Brain Barrier Integrity in a natural population of cognitive intact Parkinson's Disease patients.Friday, December 09, 2016
Liguori C, Olivola E, Pierantozzi M, Cerroni R, Galati S, Saviozzi V, Mercuri NB, Stefani A,
CNS & neurological disorders drug targets. 05-Dec-2016
This study performed in cognitive intact PD patients confirms the progressive increase of CSF tau proteins levels and BBB impairment along with the evolution of PD pathology. Since the BBB ensures the clearance of tau proteins from brain, we hypothesize that the dysfunction of the BBB throughout the disease progression may possibly cause the concurrent increase of CSF tau proteins levels in PD, which could be irrespective of cognitive decline.
ARHGEF10 gene polymorphism is closely associated with the risk of ischemic stroke in Northern Han Chinese population.Friday, December 09, 2016
Li H, Yu S, Wang R, Sun Z, Zhou X, Zheng L, Yin Z, Zhang X, Sun Y,
Neurological research. 09-Dec-2016
Stroke is a common disease with high mortality and morbidity. It is of high importance to identify biomarkers of stroke. Rho guanine nucleotide-exchange factor(GEF) 10 (ARHGEF10) gene polymorphism has been found to be associated with various human diseases, but its correlation with stroke remains unknown. This study aims to evaluate the potential association of the single nucleotide polymorphisms (SNPs) of ARHGEF10 with ischemic stroke (IS) in northern Han Chinese population. Three SNPs of ARHGEF10 gene were analyzed in 385 IS patients and 362 hypertension control patients using the ligase detection reaction (LDR) method. Logistic regression analysis demonstrated that GG genotypes of SNP rs2280887 were associated with an increased risk of IS in dominant, recessive, and additive models. Moreover, SNP rs9657362 and SNP rs4480162 were significantly associated with IS in dominant and additive models. These results indicate that ARHGEF10 gene polymorphisms may affect IS risk in northern Han Chinese.
Aspirin-Based Carbon Dots, a Good Biocompatibility of Material Applied for Bioimaging and Anti-Inflammation.Friday, December 09, 2016
Xu X, Zhang K, Zhao L, Li C, Bu W, Shen Y, Gu Z, Chang B, Zheng C, Lin C, Sun H, Yang B,
ACS applied materials & interfaces. 07-Dec-2016
The emerging photoluminescent carbon-based nanomaterials are promising in various fields besides cell imaging and carrier transport. Carbon nanomaterials with specific biological functions, however, are rarely investigated. Aspirin is a very common anti-inflammatory medication to relieve aches and pains. In this study, we have tried to create a carbon nanoparticle with aspirin, and we expect that this new carbon nanoparticle will have both anti-inflammatory and fluorescent biomarker functions. Fluorescent aspirin-based carbon dots (FACDs) were synthesized by condensing aspirin and hydrazine through a one-step microwave-assisted method. Imaging data demonstrated that FACDs efficiently entered into human cervical carcinoma and mouse monocyte macrophage cells in vitro with low cell toxicity. Results from quantitative polymerase chain reaction and histological analysis indicated that FACDs possessed effective anti-inflammatory effects in vitro and in vivo compared to aspirin only. Hematology, serum biochemistry, and histology results suggested that FACDs also had no significant toxicity in vivo. Our results clearly demonstrate that FACDs have dual functions, cellular imaging/bioimaging and anti-inflammation, and suggest that FACDs have great potential in future clinical applications.
Cancer Cell Hyperactivity and Membrane Dipolarity Monitoring via Raman Mapping of Interfaced Graphene: Toward Non-Invasive Cancer Diagnostics.Friday, December 09, 2016
Keisham B, Cole A, Nguyen P, Mehta A, Berry V,
ACS applied materials & interfaces. 07-Dec-2016
Ultrasensitive detection, mapping, and monitoring of the activity of cancer cells is critical for treatment evaluation and patient care. Here, we demonstrate that a cancer cell's glycolysis-induced hyperactivity and enhanced electronegative membrane (from sialic acid) can sensitively modify the second-order overtone of in-plane phonon vibration energies (2D) of interfaced graphene via a hole-doping mechanism. By leveraging ultrathin graphene's high quantum capacitance and responsive phononics, we sensitively differentiated the activity of interfaced Glioblastoma Multiforme (GBM) cells, a malignant brain tumor, from that of human astrocytes at a single-cell resolution. GBM cell's high surface electronegativity (potential ∼310 mV) and hyperacidic-release induces hole-doping in graphene with a 3-fold higher 2D vibration energy shift of approximately 6 ± 0.5 cm(-1) than astrocytes. From molecular dipole-induced quantum coupling, we estimate that the sialic acid density on the cell membrane increases from one molecule per ∼17 nm(2) to one molecule per ∼7 nm(2). Furthermore, graphene phononic response also identified enhanced acidity of cancer cell's growth medium. Graphene's phonon-sensitive platform to determine interfaced cell's activity/chemistry will potentially open avenues for studying activity of other cancer cell types, including metastatic tumors, and characterizing different grades of their malignancy.
Application of LC-MS-Based Global Metabolomic Profiling Methods to Human Mental Fatigue.Friday, December 09, 2016
Chen Z, Xu X, Zhang J, Liu Y, Xu X, Li L, Wang W, Xu H, Jiang W, Wang Y,
Analytical chemistry. 06-Dec-2016
Mental fatigue is characterized by a reduced capacity for work and a loss of capacity to respond to stimulation and is usually accompanied by a feeling of tiredness and drowsiness. Mental fatigue at work is a serious problem and can raise safety concerns especially in the transportation system. It is believed that mental fatigue is a direct or contributing cause of road and air related accidents and incidents. Psychological studies indicate that fatigue results in reduced work efficiency, alertness, and impaired mental performance. However, its underlying biochemical mechanisms are poorly understood. We hypothesized that the human body is an integrated system, and mental fatigue results in changes not only in psychology but also in biochemistry of the human body. These biochemical changes are detectable in metabolites. We employed global metabolomic profiling methods to screen biochemical changes that occur with mental fatigue in air traffic controllers (ATCs) in civil aviation. A total of 45, all male, ATCs (two batches) were recruited as two mental fatigue groups and 23 executive staff acted as a control group for this study. The volunteers' urine samples were collected before and after their work. The samples were analyzed with liquid chromatography/mass spectrometry equipped with a polar, a weak polar, and a nonpolar column, respectively. Three candidate biomarkers were selected on the basis of statistical significance, coefficient of variance, and compared with data of the three groups. The results suggest that urine metabolites may provide a complete new clue from biochemistry to understand, monitor, and manage human mental fatigue.
Hybrid Synthetic Receptors on MOSFET Devices for Detection of Prostate Specific Antigen in Human Plasma.Friday, December 09, 2016
Tamboli VK, Bhalla N, Jolly P, Bowen CR, Taylor JT, Bowen JL, Allender CJ, Estrela P,
Analytical chemistry. 06-Dec-2016
The study reports the use of extended gate field-effect transistors (FET) for the label-free and sensitive detection of prostate cancer (PCa) biomarkers in human plasma. The approach integrates for the first time hybrid synthetic receptors comprising of highly selective aptamer-lined pockets (apta-MIP) with FETs for sensitive detection of prostate specific antigen (PSA) at clinically relevant concentrations. The hybrid synthetic receptors were constructed by immobilizing an aptamer-PSA complex on gold and subjecting it to 13 cycles of dopamine electropolymerization. The polymerization resulted in the creation of highly selective polymeric cavities that retained the ability to recognize PSA post removal of the protein. The hybrid synthetic receptors were subsequently used in an extended gate FET setup for electrochemical detection of PSA. The sensor was reported to have a limit of detection of 0.1 pg/mL with a linear detection range from 0.1 pg/mL to 1 ng/mL PSA. Detection of 1-10 pg/mL PSA was also achieved in diluted human plasma. The present apta-MIP sensor developed in conjunction with FET devices demonstrates the potential for clinical application of synthetic hybrid receptors for the detection of clinically relevant biomarkers in complex samples.
Fixation and Permeabilization Approaches for Scanning Electrochemical Microscopy of Living Cells.Friday, December 09, 2016
Bondarenko A, Lin TE, Stupar P, Lesch A, Cortés-Salazar F, Girault HH, Pick H,
Analytical chemistry. 06-Dec-2016
Scanning electrochemical microscopy (SECM) has been widely used for the electrochemical imaging of dynamic topographical and metabolic changes in alive adherent mammalian cells. However, extracting intracellular information by SECM is challenging, since it requires redox species to travel in and out the lipid cell membrane. Herein, we present cell fixation and permeabilization approaches as an alternative tool for visualizing cell properties by SECM. With this aim, adherent cells were analyzed in the SECM feedback mode in three different conditions: (i) alive; (ii) fixed, and (iii) fixed and permeabilized. The fixation was carried out with formaldehyde and does not damage lipid membranes. Therefore, this strategy can be used for the SECM investigation of cell topography or the passive transport of the redox mediator into the cells. Additional permeabilization of the cell membrane after fixation enables the analysis of the intracellular content through the coupling of SECM with immunoassay strategies for the detection of specific biomarkers. The latter was successfully applied as an easy and fast screening approach to detect the expression of the melanoma-associated marker tyrosinase in adherent melanoma cell lines corresponding to different cancer progression stages using the SECM substrate generation-tip collection mode. The present approach is simple, fast, and reliable and can open new ways to analyze cell cultures with electrochemically based scanning probe techniques.
Highly Sensitive and Quick Detection of Acute Myocardial Infarction Biomarkers Using In2O3 Nanoribbon Biosensors Fabricated Using Shadow Masks.Friday, December 09, 2016
Liu Q, Aroonyadet N, Song Y, Wang X, Cao X, Liu Y, Cong S, Wu F, Thompson ME, Zhou C,
ACS nano. 22-Nov-2016
We demonstrate a scalable and facile lithography-free method for fabricating highly uniform and sensitive In2O3 nanoribbon biosensor arrays. Fabrication with shadow masks as the patterning method instead of conventional lithography provides low-cost, time-efficient, and high-throughput In2O3 nanoribbon biosensors without photoresist contamination. Combined with electronic enzyme-linked immunosorbent assay for signal amplification, the In2O3 nanoribbon biosensor arrays are optimized for early, quick, and quantitative detection of cardiac biomarkers in diagnosis of acute myocardial infarction (AMI). Cardiac troponin I (cTnI), creatine kinase MB (CK-MB), and B-type natriuretic peptide (BNP) are commonly associated with heart attack and heart failure and have been selected as the target biomarkers here. Our approach can detect label-free biomarkers for concentrations down to 1 pg/mL (cTnI), 0.1 ng/mL (CK-MB), and 10 pg/mL (BNP), all of which are much lower than clinically relevant cutoff concentrations. The sample collection to result time is only 45 min, and we have further demonstrated the reusability of the sensors. With the demonstrated sensitivity, quick turnaround time, and reusability, the In2O3 nanoribbon biosensors have shown great potential toward clinical tests for early and quick diagnosis of AMI.
Blood-Brain-Barrier-Penetrating Albumin Nanoparticles for Biomimetic Drug Delivery via Albumin-Binding Protein Pathways for Antiglioma Therapy.Friday, December 09, 2016
Lin T, Zhao P, Jiang Y, Tang Y, Jin H, Pan Z, He H, Yang VC, Huang Y,
ACS nano. 22-Nov-2016
Nutrient transporters have been explored for biomimetic delivery targeting the brain. The albumin-binding proteins (e.g., SPARC and gp60) are overexpressed in many tumors for transport of albumin as an amino acid and an energy source for fast-growing cancer cells. However, their application in brain delivery has rarely been investigated. In this work, SPARC and gp60 overexpression was found on glioma and tumor vessel endothelium; therefore, such pathways were explored for use in brain-targeting biomimetic delivery. We developed a green method for blood-brain barrier (BBB)-penetrating albumin nanoparticle synthesis, with the capacity to coencapsulate different drugs and no need for cross-linkers. The hydrophobic drugs (i.e., paclitaxel and fenretinide) yield synergistic effects to induce albumin self-assembly, forming dual drug-loaded nanoparticles. The albumin nanoparticles can penetrate the BBB and target glioma cells via the mechanisms of SPARC- and gp60-mediated biomimetic transport. Importantly, by modification with the cell-penetrating peptide LMWP, the albumin nanoparticles display enhanced BBB penetration, intratumoral infiltration, and cellular uptake. The LMWP-modified nanoparticles exhibited improved treatment outcomes in both subcutaneous and intracranial glioma models, with reduced toxic side effects. The therapeutic mechanisms were associated with induction of apoptosis, antiangiogenesis, and tumor immune microenvironment regulation. It provides a facile method for dual drug-loaded albumin nanoparticle preparation and a promising avenue for biomimetic delivery targeting the brain tumor based on combination therapy.
Nanopores and Nanochannels: From Gene Sequencing to Genome Mapping.Friday, December 09, 2016
Howorka S, Siwy Z,
ACS nano. 22-Nov-2016
DNA strands can be analyzed at the single-molecule level by isolating them inside nanoscale holes. The strategy is used for the label-free and portable sequencing with nanopores. Nanochannels can also be applied to map genomes with high resolution, as shown by Jeffet et al. in this issue of ACS Nano. Here, we compare the two strategies in terms of biophysical similarities and differences and describe that both are complementary and can improve the DNA analysis for genomic research and diagnostics.
(18)F-Labeled Benzyldiamine Derivatives as Novel Flexible Probes for Positron Emission Tomography of Cerebral β-Amyloid Plaques.Friday, December 09, 2016
Li Z, Zhang X, Zhang X, Cui M, Lu J, Pan X, Zhang X,
Journal of medicinal chemistry. 08-Dec-2016
Early noninvasive visualization of cerebral β-amyloid (Aβ) plaques with positron emission tomography (PET) is the most feasible way to diagnose Alzheimer's disease (AD). In this study, a series of flexible benzyldiamine derivatives (BDA) were proposed for binding to aggregated β-amyloid 1-42 (Aβ1-42) with high adaptability, high binding affinity (6.8 ± 0.6 nM), and rapid body excretion. The methylthio (12) and ethoxyl (10) derivatives were further labeled with (18)F directly on their benzene ring and examined as PET probes for Aβ plaque imaging. [(18)F]12 displayed 4.87 ± 0.52% ID/g initial uptake and prompt washout from normal brain in biodistribution studies. MicroPET-CT imaging indicated sufficient retention of [(18)F]12 but lower white matter uptake in the brain of an AD transgenic mouse model compared with that of commercial [(18)F]AV-45. Our experimental results provide new insights for developing targeting ligands possessing a flexible framework for use as efficient Aβ probes for PET imaging of AD brain.
Three-Dimensionally Functionalized Reverse Phase Glycoprotein Array for Cancer Biomarker Discovery and Validation.Friday, December 09, 2016
Pan L, Aguilar HA, Wang L, Iliuk A, Tao WA,
Journal of the American Chemical Society. 30-Nov-2016
Glycoproteins have vast structural diversity that plays an important role in many biological processes and have great potential as disease biomarkers. Here, we report a novel functionalized reverse phase protein array (RPPA), termed polymer-based reverse phase glycoprotein array (polyGPA), to capture and profile glycoproteomes specifically, and validate glycoproteins. Nitrocellulose membrane functionalized with globular hydroxyaminodendrimers was used to covalently capture preoxidized glycans on glycoproteins from complex protein samples such as biofluids. The captured glycoproteins were subsequently detected using the same validated antibodies as in RPPA. We demonstrated the outstanding specificity, sensitivity, and quantitative capabilities of polyGPA by capturing and detecting purified as well as endogenous α-1-acid glycoprotein (AGP) in human plasma. We further applied quantitative N-glycoproteomics and the strategy to validate a panel of glycoproteins identified as potential biomarkers for bladder cancer by analyzing urine glycoproteins from bladder cancer patients or matched healthy individuals.
Global Analysis of Secreted Proteins and Glycoproteins in Saccharomyces cerevisiae.Friday, December 09, 2016
Smeekens JM, Xiao H, Wu R,
Journal of proteome research. 09-Dec-2016
Protein secretion is essential for numerous cellular activities, and secreted proteins in bodily fluids are a promising and non-invasive source of biomarkers for disease detection. Systematic analysis of secreted proteins and glycoproteins will provide insight into protein function and cellular activities. Yeast (Saccharomyces cerevisiae) is an excellent model system for eukaryotic cells, but global analysis of secreted proteins and glycoproteins in yeast is challenging due to the low abundances of secreted proteins and contamination from high-abundance intracellular proteins. Here, by using mild separation of secreted proteins from cells, we comprehensively identified and quantified secreted proteins and glycoproteins through inhibition of glycosylation and mass spectrometry-based proteomics. In biological triplicate experiments, 245 secreted proteins were identified, and comparison with previous experimental and computational results demonstrated that many identified proteins were located in the extracellular space. Most quantified secreted proteins were down-regulated from cells treated with an N-glycosylation inhibitor (tunicamycin). The quantitative results strongly suggest that the secretion of these down-regulated proteins was regulated by glycosylation while, the secretion of proteins with minimal abundance changes was contrarily irrelevant to protein glycosylation, likely being secreted through non-classical pathways. Glycoproteins in the yeast secretome were globally analyzed for the first time. A total of 27 proteins were quantified in at least two protein and glycosylation triplicate experiments, and all except one were down-regulated under N-glycosylation inhibition, which is solid experimental evidence to further demonstrate that the secretion of these proteins is regulated by their glycosylation. These results provide valuable insight into protein secretion, which will further advance protein secretion and disease studies.
Peptide-Mediated Platelet Capture at Gold Micropore Arrays.Friday, December 09, 2016
Adamson K, Spain E, Prendergast U, Moran N, Forster RJ, Keyes TE,
ACS applied materials & interfaces. 30-Nov-2016
Ordered spherical cap gold cavity arrays with 5.4, 1.6, and 0.98 μm diameter apertures were explored as capture surfaces for human blood platelets to investigate the impact of surface geometry and chemical modification on platelet capture efficiency and their potential as platforms for surface enhanced Raman spectroscopy of single platelets. The substrates were chemically modified with single-constituent self-assembled monolayers (SAM) or mixed SAMs comprised of thiol-functionalized arginine-glycine-aspartic acid (RGD, a platelet integrin target) with or without 1-octanethiol (adhesion inhibitor). As expected, platelet adhesion was promoted and inhibited at RGD and alkanethiol modified surfaces, respectively. Platelet adhesion was reversible, and binding efficiency at the peptide modified substrates correlated inversely with pore diameter. Captured platelets underwent morphological change on capture, the extent of which depended on the topology of the underlying substrate. Regioselective capture of the platelets enabled study for the first time of the surface enhanced Raman spectroscopy of single blood platelets, yielding high quality Raman spectroscopy of individual platelets at 1.6 μm diameter pore arrays. Given the medical importance of blood platelets across a range of diseases from cancer to psychiatric illness, such approaches to platelet capture may provide a useful route to Raman spectroscopy for platelet related diagnostics.
Structural Insight into the Anti-prion Compound Inhibition Mechanism of Native Prion Folding over Misfolding.Friday, December 09, 2016
Choi J, Govindaraj RG, Hyeon JW, Lee K, Ma S, Kim SY, Lee J, No KT,
Chemical biology & drug design. 09-Dec-2016
Transition of a physiological folded prion (PrP(C) ) into a pathogenic misfolded prion (PrP(S)(c) ) causes lethal neurodegenerative disorders and prion diseases. Anti-prion compounds have been developed to prevent this conversion; however, their mechanism of action remains unclear. Recently, we reported two anti-prion compounds, BMD29 and 35, identified by in silico and in vitro screening. In this study, we used extensive explicit-solvent molecular dynamics simulations to investigate ligand binding inhibition by anti-prion compounds in prion folding over misfolding behavior at acidic pH. The two anti-prion compounds and the previously reported GN8 compound resulted in a remarkably stabilized intermediate by binding to the hotspot region of PrP(C) , whereas free PrP(C) and the inactive compound BMD01 destabilized the structure of PrP(C) leading to the misfolded form. The results uncovered a secondary structural transition of free PrP(C) and transition suppression by the anti-prion compounds. One of the major misfolding processes in PrP(C) , alternation of hydrophobic core residues, disruption of intramolecular interactions, and the increase in residue solvent exposure were significantly inhibited by both anti-prion compounds. These findings provide insights into prion misfolding and inhibition by anti-prion compounds. This article is protected by copyright. All rights reserved.
Shared molecular networks in orofacial and neural tube development.Friday, December 09, 2016
Kousa YA, Mansour TA, Seada H, Matoo S, Schutte BC,
Birth defects research. Part A, Clinical and molecular teratology. 09-Dec-2016
These data suggest that key developmental factors and pathways are shared between orofacial and neural tube defects. We conclude that it might be most beneficial to focus on common regulatory factors and pathways to better understand pathology and develop preventative measures for these birth defects. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc.
White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy.Friday, December 09, 2016
Fiford CM, Manning EN, Bartlett JW, Cash DM, Malone IB, Ridgway GR, Lehmann M, Leung KK, Sudre C, Ourselin S, Jan Biessels G, Carmichael OT, Fox NC, Cardoso MJ, Barnes J,
Hippocampus. 09-Dec-2016
This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 Mild Cognitive Impairment (MCI) and 154 AD subjects with serial volumetric 1.5T MRI. CSF Aβ42 and total tau were measured (n=353). Brain and hippocampal loss were quantified from serial MRI using the Boundary Shift Integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for a) concurrent brain/hippocampal atrophy rates and b) CSF Aβ42 and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (p=0.002) and MCI subjects (p=0.03), and with brain atrophy rate in controls (p=0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (p= 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in non-demented older adults. This article is protected by copyright. All rights reserved.
Are nutraceuticals the modern panacea? From myth to science.Friday, December 09, 2016
Minuz P, Velo G, Violi F, Ferro A,
British journal of clinical pharmacology. Jan-2017
Aflatoxin biomarkers in hair may facilitate long-term exposure studies.Friday, December 09, 2016
Mupunga I, Izaaks CD, Shai LJ, Katerere DR,
Journal of applied toxicology : JAT. 09-Dec-2016
Aflatoxins are highly toxic fungal metabolites produced by some members of the Aspergillus species. They are low molecular weight lipophilic compounds that are easily absorbed from the gastrointestinal tract. They contaminate most staple foods, including maize, peanuts, peanut butter and sorghum mainly in the tropics where hot and humid conditions promote fungal growth. Absorbed aflatoxins are metabolized by the cytochrome P450 enzyme system in the liver into toxic metabolites. Aflatoxin B (AFB)1 is the most toxic, carcinogenic and mutagenic naturally occurring toxin. Aflatoxin exposure assessment has been traditionally achieved through food use frequency questionnaires and laboratory analysis of food samples. However, estimation of individual exposure to aflatoxins based on these methods may not be accurate. The use of aflatoxin biomarkers in urine and blood for use in exposure studies has emerged in more recent times. However, the current biomarkers (e.g., AFB-N(7) -guanine and AFB1 -albumin adduct) in use have a short half-life and are only practically useful to indicate levels over 24 h-3 months post-exposure. There is therefore an immediate need to study and evaluate alternative biomarkers in non-conventional matrices such as hair and nails. Hair analysis revealed considerable interest in forensic analysis particularly in the detection of drugs of abuse where it has emerged as a sensitive and specific technique complementary to blood and urinalysis. This article provides an overview of aflatoxins, current aflatoxin biomarkers and proposes the use of hair as a potential matrix for biomarkers of long-term aflatoxin exposure. Copyright © 2016 John Wiley & Sons, Ltd.
An Appraisal of Novel Biomarkers for Evaluating and Monitoring Neurologic Diseases: Editorial Introduction.Friday, December 09, 2016
Shefner JM, Sabbagh MN,
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 08-Dec-2016
Fluid-Based Biomarkers for Amyotrophic Lateral Sclerosis.Friday, December 09, 2016
Vu LT, Bowser R,
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 08-Dec-2016
Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous disease with no effective treatment. Drug development has been hampered by the lack of biomarkers that aid in early diagnosis, demonstrate target engagement, monitor disease progression, and can serve as surrogate endpoints to assess the efficacy of treatments. Fluid-based biomarkers may potentially address these issues. An ideal biomarker should exhibit high specificity and sensitivity for distinguishing ALS from control (appropriate disease mimics and other neurologic diseases) populations and monitor disease progression within individual patients. Significant progress has been made using cerebrospinal fluid, serum, and plasma in the search for ALS biomarkers, with urine and saliva biomarkers still in earlier stages of development. A few of these biomarker candidates have demonstrated use in patient stratification, predicting disease course (fast vs slow progression) and severity, or have been used in preclinical and clinical applications. However, while ALS biomarker discovery has seen tremendous advancements in the last decade, validating biomarkers and moving them towards the clinic remains more elusive. In this review, we highlight biomarkers that are moving towards clinical utility and the challenges that remain in order to implement biomarkers at all stages of the ALS drug development process.
High Percentage of IBD Patients with Indefinite Fecal Calprotectin Levels: Additional Value of a Combination Score.Friday, December 09, 2016
Bodelier AG, Jonkers D, van den Heuvel T, de Boer E, Hameeteman W, Masclee AA, Pierik MJ,
Digestive diseases and sciences. 08-Dec-2016
A combination of FC with clinical activity indices or CRP may aid in classifying patients with indefinite disease activity according to FC alone.
Conditional screening for ultra-high dimensional covariates with survival outcomes.Friday, December 09, 2016
Hong HG, Kang J, Li Y,
Lifetime data analysis. 08-Dec-2016
Identifying important biomarkers that are predictive for cancer patients' prognosis is key in gaining better insights into the biological influences on the disease and has become a critical component of precision medicine. The emergence of large-scale biomedical survival studies, which typically involve excessive number of biomarkers, has brought high demand in designing efficient screening tools for selecting predictive biomarkers. The vast amount of biomarkers defies any existing variable selection methods via regularization. The recently developed variable screening methods, though powerful in many practical setting, fail to incorporate prior information on the importance of each biomarker and are less powerful in detecting marginally weak while jointly important signals. We propose a new conditional screening method for survival outcome data by computing the marginal contribution of each biomarker given priorily known biological information. This is based on the premise that some biomarkers are known to be associated with disease outcomes a priori. Our method possesses sure screening properties and a vanishing false selection rate. The utility of the proposal is further confirmed with extensive simulation studies and analysis of a diffuse large B-cell lymphoma dataset. We are pleased to dedicate this work to Jack Kalbfleisch, who has made instrumental contributions to the development of modern methods of analyzing survival data.
Characterization of the first fully human anti-TEM1 scFv in models of solid tumor imaging and immunotoxin-based therapy.Friday, December 09, 2016
Yuan X, Yang M, Chen X, Zhang X, Sukhadia S, Musolino N, Bao H, Chen T, Xu C, Wang Q, Santoro S, Ricklin D, Hu J, Lin R, Yang W, Li Z, Qin W, Zhao A,
Cancer immunology, immunotherapy : CII. 08-Dec-2016
Tumor endothelial marker 1 (TEM1) has been identified as a novel surface marker upregulated on the blood vessels and stroma in many solid tumors. We previously isolated a novel single-chain variable fragment (scFv) 78 against TEM1 from a yeast display scFv library. Here, we evaluated the potential applications of scFv78 as a tool for tumor molecular imaging, immunotoxin-based therapy and nanotherapy. Epitope mapping, three-dimensional structure docking and affinity measurements indicated that scFv78 could bind to both human and murine TEM1, with equivalent affinity, at a well-conserved conformational epitope. The rapid internalization of scFv78 and scFv78-labeled nanoparticles was triggered after specific TEM1 binding. The scFv78-saporin immunoconjugate also exerted dose-dependent cytotoxicity with high specificity to TEM1-positive cells in vitro. Finally, specific and sensitive tumor localization of scFv78 was confirmed with optical imaging in a tumor mouse model that has highly endogenous mTEM1 expression in the vasculature. Our data indicated that scFv78, the first fully human anti-TEM1 recombinant antibody, recognizes both human and mouse TEM1 and has unique and favorable features that are advantageous for the development of imaging probes or antibody-toxin conjugates for a large spectrum of human TEM1-positive solid tumors.
Positron emission tomography in amyotrophic lateral sclerosis: Towards targeting of molecular pathological hallmarks.Friday, December 09, 2016
Willekens SM, Van Weehaeghe D, Van Damme P, Van Laere K,
European journal of nuclear medicine and molecular imaging. 08-Dec-2016
During the past decades, extensive efforts have been made to expand the knowledge of amyotrophic lateral sclerosis (ALS). However, clinical translation of this research, in terms of earlier diagnosis and improved therapy, remains challenging. Since more than 30% of motor neurons are lost when symptoms become clinically apparent, techniques allowing non-invasive, in vivo detection of motor neuron degeneration are needed in the early, pre-symptomatic disease stage. Furthermore, it has become apparent that non-motor signs play an important role in the disease and there is an overlap with cognitive disorders, such as frontotemporal dementia (FTD). Radionuclide imaging, such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), form an attractive approach to quantitatively monitor the ongoing neurodegenerative processes. Although [(18)F]-FDG has been recently proposed as a potential biomarker for ALS, active targeting of the underlying pathologic molecular processes is likely to unravel further valuable disease information and may help to decipher the pathogenesis of ALS. In this review, we provide an overview of radiotracers that have already been applied in ALS and discuss possible novel targets for in vivo imaging of various pathogenic processes underlying ALS onset and progression.
Investigation on genetic thrombophilic factors in FFPE autopsy tissue from subjects who died from pulmonary embolism.Friday, December 09, 2016
Brandimarti F, Alessandrini F, Pesaresi M, Catalani C, De Angelis L, Galeazzi R, Giovagnetti S, Gesuita R, Righi E, Giorgetti R, Tagliabracci A,
International journal of legal medicine. 09-Dec-2016
Venous thromboembolism (VTE) is a multifactorial disease determined by a combination of inherited and acquired factors. Inherited factors include mutations in the genes coding for coagulation factors, some of which seem to exert a differential influence on the risk of developing deep vein thrombosis (DVT) and pulmonary embolism (PE). In post-mortem studies of subjects who have died from pulmonary embolism (PE), the analysis of the factors that may have augmented the VTE risk is often limited to acquired factors. This is due to the complexity-and sometimes the unfeasibility-of analyzing genetic factors and to insufficient knowledge of their individual roles in PE development. The present study used formalin-fixed paraffin-embedded (FFPE) tissue to investigate a panel of 12 polymorphisms-the largest ever studied-that affect the VTE risk. Tissue samples came from post-mortem examinations performed by the specialists of the Section of Legal Medicine of the Department of Pathology of Marche's Polytechnic University, and by the specialists of Health Care District Hospital of Imola, on 44 subjects who died from PE in the period 1997-2014. All individuals were found to have at least one mutation affecting the VTE risk. The present study demonstrates that genetic analysis can be performed post-mortem and the results are useful for forensic investigations, especially from MTHFR C677T and PAI-1 4G/5G polymorphisms. Broader studies using the techniques described herein are needed to determine the relative influence of the individual polymorphisms and their interaction in PE deaths.
Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.Friday, December 09, 2016
Chapuis J, Flaig A, Grenier-Boley B, Eysert F, Pottiez V, Deloison G, Vandeputte A, Ayral AM, Mendes T, Desai S, Goate AM, Kauwe JS, Leroux F, Herledan A, Demiautte F, Bauer C, Checler F, Petersen RC, Blennow K, Zetterberg H, Minthon L, Van Deerlin VM, Lee VM, Shaw LM, Trojanowski JQ, Albert M, Moghekar A, O'Brien R, Peskind ER, Malmanche N, Schellenberg GD, Dourlen P, Song OR, Cruchaga C, Amouyel P, Deprez B, Brodin P, Lambert JC,
Acta neuropathologica. 08-Dec-2016
Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a β3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aβ peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aβ peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aβ peptide production.
Implementation of clinical decision support in young children with acute gastroenteritis: a randomized controlled trial at the emergency department.Friday, December 09, 2016
Geurts D, de Vos-Kerkhof E, Polinder S, Steyerberg E, van der Lei J, Moll H, Oostenbrink R,
European journal of pediatrics. 08-Dec-2016
Implementation of nurse-guided clinical decision support system on rehydration treatment in children with AGE showed high compliance and increase standardized use of ORS, without differences in other outcome measures. What is Known: • Acute gastroenteritis is one of the most frequently encountered problems in pediatric emergency departments. • Guidelines advocate standardized oral treatment in children with mild to moderate dehydration, but appear to be applied infrequently in clinical practice. What is New: • Implementation of a nurse-guided clinical decision support system on treatment of AGE in young children showed good feasibility, resulting in a more standardized ORS use in children with mild to moderate dehydration, compared to usual care. • Given the challenges to perform research in emergency care setting, the ED should be experienced and adequately equipped, especially during peak times.
Thyroid autoimmunity: is really associated with papillary thyroid carcinoma?Friday, December 09, 2016
Selek A, Cetinarslan B, Tarkun I, Canturk Z, Ustuner B, Akyay Z,
European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 08-Dec-2016
The incidence of thyroid cancer has been greatly increasing. Several studies aimed to investigate biomarkers for prediction of thyroid cancer. Some of these studies have suggested that thyroid autoantibodies (TAb) could be used as predictors of thyroid cancer risk, but the correlation between TAb and PTC is still a matter of debate. The aim of this study is to evaluate thyroid autoimmunity and TAbs in patients with PTC and benign multinodular goiter (MNG) to investigate if TAbs and autoimmune thyroid disease (ATD) could predict thyroid malignancy. A total of 577 patients with thyroid papillary carcinoma (PTC) and 293 patients with benign MNG disease were enrolled postoperatively. Demographic features, thyroglobulin (TgAb) and thyroid peroxidase antibodies (TPOAb) and histologic outcome of the patients were evaluated. The prevalence of ATD and TgAb or TPOAb measurements was not statistically different in PTC and MNG groups. However, tumors were significantly smaller and tumor capsule invasion was seen less frequently in patients with PTC and ATD than without ATD. Patients without ATD had more advanced stage (TNM stage III/IV) tumors than with ATD. Only one of the 11 patients with distant organ metastasis had ATD. The present study demonstrated that the prevalence of ATD diagnosed even with histology or TAb positivity was not different in patients with PTC and MNG. However, having ATD might be associated with a better prognosis in PTC patients.
Doxorubicin-induced chronic dilated cardiomyopathy-the apoptosis hypothesis revisited.Friday, December 09, 2016
Kankeu C, Clarke K, Passante E, Huber HJ,
Journal of molecular medicine (Berlin, Germany). 08-Dec-2016
The chemotherapeutic agent doxorubicin (DOX) has significantly increased survival rates of pediatric and adult cancer patients. However, 10% of pediatric cancer survivors will 10-20 years later develop severe dilated cardiomyopathy (DCM), whereby the exact molecular mechanisms of disease progression after this long latency time remain puzzling. We here revisit the hypothesis that elevated apoptosis signaling or its increased likelihood after DOX exposure can lead to an impairment of cardiac function and cause a cardiac dilation. Based on recent literature evidence, we first argue why a dilated phenotype can occur when little apoptosis is detected. We then review findings suggesting that mature cardiomyocytes are protected against DOX-induced apoptosis downstream, but not upstream of mitochondrial outer membrane permeabilisation (MOMP). This lack of MOMP induction is proposed to alter the metabolic phenotype, induce hypertrophic remodeling, and lead to functional cardiac impairment even in the absence of cardiomyocyte apoptosis. We discuss findings that DOX exposure can lead to increased sensitivity to further cardiomyocyte apoptosis, which may cause a gradual loss in cardiomyocytes over time and a compensatory hypertrophic remodeling after treatment, potentially explaining the long lag time in disease onset. We finally note similarities between DOX-exposed cardiomyocytes and apoptosis-primed cancer cells and propose computational system biology as a tool to predict patient individual DOX doses. In conclusion, combining recent findings in rodent hearts and cardiomyocytes exposed to DOX with insights from apoptosis signal transduction allowed us to obtain a molecularly deeper insight in this delayed and still enigmatic pathology of DCM.
Genetic engineering of chimeric antigen receptors using lamprey derived variable lymphocyte receptors.Friday, December 09, 2016
Moot R, Raikar SS, Fleischer L, Querrey M, Tylawsky DE, Nakahara H, Doering CB, Spencer HT,
Molecular therapy oncolytics. 2016
Chimeric antigen receptors (CARs) are used to redirect effector cell specificity to selected cell surface antigens. Using CARs, antitumor activity can be initiated in patients with no prior tumor specific immunity. Although CARs have shown promising clinical results, the technology remains limited by the availability of specific cognate cell target antigens. To increase the repertoire of targetable tumor cell antigens we utilized the immune system of the sea lamprey to generate directed variable lymphocyte receptors (VLRs). VLRs serve as membrane bound and soluble immune effectors analogous but not homologous to immunoglobulins. They have a fundamentally different structure than immunoglobulin (Ig)-based antibodies while still demonstrating high degrees of specificity and affinity. To test the functionality of VLRs as the antigen recognition domain of CARs, two VLR-CARs were created. One contained a VLR specific for a murine B cell leukemia and the other contained a VLR specific for the human T cell surface antigen, CD5. The CAR design consisted of the VLR sequence, myc-epitope tag, CD28 transmembrane domain, and intracellular CD3ζ signaling domain. We demonstrate proof of concept, including gene transfer, biosynthesis, cell surface localization, and effector cell activation for multiple VLR-CAR designs. Therefore, VLRs provide an alternative means of CAR-based cancer recognition.
Branched-Chain Amino Acid Levels Are Related with Surrogates of Disturbed Lipid Metabolism among Older Men.Friday, December 09, 2016
Kujala UM, Peltonen M, Laine MK, Kaprio J, Heinonen OJ, Sundvall J, Eriksson JG, Jula A, Sarna S, Kainulainen H,
Frontiers in medicine. 2016
The findings provided further support for our hypothesis by strengthening the idea that the efficiency of BCAA catabolism may be mechanistically involved in the regulation of fat oxidation, thus affecting the levels of metabolic disease risk factors.
Is There a Role for Genetic Information in Risk Assessment and Decision Making in Prostate Cancer?Friday, December 09, 2016
Nowroozi M, Ayati M, Amini E, Mahdian R, Yousefi B, Arbab A, Jamali Zawarei M, Niroomand H, Ghorbani H, Ghadian A,
Nephro-urology monthly. Nov-2016
Genetic information combined with clinical data can be useful in risk assessment and treatment planning. Based on the results of the current study, the decreased expression of AMACR was a sign of poor prognosis.
Prognostic Value of Plasma and Urine Glycosaminoglycan Scores in Clear Cell Renal Cell Carcinoma.Friday, December 09, 2016
Gatto F, Maruzzo M, Magro C, Basso U, Nielsen J,
Frontiers in oncology. 2016
This is the first report on an association between plasma or urine GAG scores and the prognosis of ccRCC patients. Prospective trials validating the prognostic and predictive role of this novel systems biomarker are warranted.
Functional Significance of Aurora Kinases-p53 Protein Family Interactions in Cancer.Friday, December 09, 2016
Sasai K, Treekitkarnmongkol W, Kai K, Katayama H, Sen S,
Frontiers in oncology. 2016
Aurora kinases play critical roles in regulating spindle assembly, chromosome segregation, and cytokinesis to ensure faithful segregation of chromosomes during mitotic cell division cycle. Molecular and cell biological studies have revealed that Aurora kinases, at physiological levels, orchestrate complex sequential cellular processes at distinct subcellular locations through functional interactions with its various substrates. Aberrant expression of Aurora kinases, on the other hand, cause defects in mitotic spindle assembly, checkpoint response activation, and chromosome segregation leading to chromosomal instability. Elevated expression of Aurora kinases correlating with chromosomal instability is frequently detected in human cancers. Recent genomic profiling of about 3000 human cancer tissue specimens to identify various oncogenic signatures in The Cancer Genome Atlas project has reported that recurrent amplification and overexpression of Aurora kinase-A characterize distinct subsets of human tumors across multiple cancer types. Besides the well-characterized canonical pathway interactions of Aurora kinases in regulating assembly of the mitotic apparatus and chromosome segregation, growing evidence also supports the notion that deregulated expression of Aurora kinases in non-canonical pathways drive transformation and genomic instability by antagonizing tumor suppressor and exacerbating oncogenic signaling through direct interactions with critical proteins. Aberrant expression of the Aurora kinases-p53 protein family signaling axes appears to be critical in the abrogation of p53 protein family mediated tumor suppressor pathways frequently deregulated during oncogenic transformation process. Recent findings reveal the existence of feedback regulatory loops in mRNA expression and protein stability of these protein families and their consequences on downstream effectors involved in diverse physiological functions, such as mitotic progression, checkpoint response pathways, as well as self-renewal and pluripotency in embryonic stem cells. While these investigations have focused on the functional consequences of Aurora kinase protein family interactions with wild-type p53 family proteins, those involving Aurora kinases and mutant p53 remain to be elucidated. This article presents a comprehensive review of studies on Aurora kinases-p53 protein family interactions along with a prospective view on the possible functional consequences of Aurora kinase-mutant p53 signaling pathways in tumor cells. Additionally, we also discuss therapeutic implications of these findings in Aurora kinases overexpressing subsets of human tumors.
A Novel Method for Quantitative Serial Autofluorescence Analysis in Retinitis Pigmentosa Using Image Characteristics.Friday, December 09, 2016
Jolly JK, Wagner SK, Moules J, Gekeler F, Webster AR, Downes SM, MacLaren RE,
Translational vision science & technology. Dec-2016
Spatial extraction software can be a valuable tool in the assessment of ophthalmic imaging data.
Quality to rely on: meeting report of the 5th Meeting of External Quality Assessment, Naples 2016.Friday, December 09, 2016
van Krieken H, Deans S, Hall JA, Normanno N, Ciardiello F, Douillard JY,
ESMO open. 2016
Molecular pathology of cancer: how to communicate with disease.Friday, December 09, 2016
Birner P, Prager G, Streubel B,
ESMO open. 2016
EK1541/2012.
Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-coding HLA-DRB1 allele.Friday, December 09, 2016
Gehlot P, Volk SL, Rios HF, Jepsen KJ, Holoshitz J,
RMD open. 2016
A human SE-coding allele increases the propensity to spontaneous bone-destructive periodontal inflammation and skeletal bone damage in transgenic mice. These findings provide new insights into the previously documented but poorly understood association of the SE with accelerated bone erosion in RA and several other human diseases.
Effect of type and amount of dietary carbohydrate on biomarkers of glucose homeostasis and C reactive protein in overweight or obese adults: results from the OmniCarb trial.Friday, December 09, 2016
Juraschek SP, Miller ER, Selvin E, Carey VJ, Appel LJ, Christenson RH, Sacks FM,
BMJ open diabetes research & care. 2016
NCT00608049.
Profiling lung adenocarcinoma by liquid biopsy: can one size fit all?Friday, December 09, 2016
Clifford HW, Cassidy AP, Vaughn C, Tsai ES, Seres B, Patel N, O'Neill HL, Hewage E, Cassidy JW,
Cancer nanotechnology. 2016
With further optimisation, this hotspot panel could allow molecular diagnostics laboratories to build curated primer banks for 'off-the-shelf' monitoring of ctDNA by droplet-based digital PCR or similar techniques, in a time- and cost-effective manner.
Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response.Friday, December 09, 2016
Schaller MA, Allen RM, Kimura S, Day CL, Kunkel SL,
Frontiers in immunology. 2016
The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4(+) T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCG Mycobacterium. Transfer of DLL4(+) progenitor cells from infected hosts resulted in an increase DLL4(+) myeloid cells in the spleen, indicating that expression of the dll4 gene is propagated throughout hematopoiesis. We also found an increase in DLL4(+) monocytes from individuals who were infected with Mycobacterium tuberculosis. In latent individuals, DLL4 expression correlated with increased cytokine production from T cells in response to PPD stimulation. Finally, antibody blockade of DLL4 reduced T cell cytokine production from naïve T cells stimulated with antigen. These results demonstrate that the Notch ligand DLL4 can influence T cell cytokine production in both humans and mice, and further reveal that expression of DLL4 is upregulated on early hematopoietic progenitors in response to chronic mycobacterial infection. These data suggest that widespread DLL4 expression may occur as a result of mycobacterial infection, and that this expression may alter CD4(+) T cell responses to both previously encountered and novel antigens.
Aire Downregulation Is Associated with Changes in the Posttranscriptional Control of Peripheral Tissue Antigens in Medullary Thymic Epithelial Cells.Friday, December 09, 2016
Oliveira EH, Macedo C, Collares CV, Freitas AC, Donate PB, Sakamoto-Hojo ET, Donadi EA, Passos GA,
Frontiers in immunology. 2016
Autoimmune regulator (Aire) is a transcriptional regulator of peripheral tissue antigens (PTAs) and microRNAs (miRNAs) in medullary thymic epithelial cells (mTECs). In this study, we tested the hypothesis that Aire also played a role as an upstream posttranscriptional controller in these cells and that variation in its expression might be associated with changes in the interactions between miRNAs and the mRNAs encoding PTAs. We demonstrated that downregulation of Aire in vivo in the thymuses of BALB/c mice imbalanced the large-scale expression of these two RNA species and consequently their interactions. The expression profiles of a large set of mTEC miRNAs and mRNAs isolated from the thymuses of mice subjected (or not) to small-interfering-induced Aire gene knockdown revealed that 87 miRNAs and 4,558 mRNAs were differentially expressed. The reconstruction of the miRNA-mRNA interaction networks demonstrated that interactions between these RNAs were under Aire influence and therefore changed when this gene was downregulated. Prior to Aire-knockdown, only members of the miR-let-7 family interacted with a set of PTA mRNAs. Under Aire-knockdown conditions, a larger set of miRNA families and their members established this type of interaction. Notably, no previously described Aire-dependent PTA interacted with the miRNAs, indicating that these PTAs were somehow refractory. The miRNA-mRNA interactions were validated by calculating the minimal free energy of the pairings between the miRNA seed regions and the mRNA 3' UTRs and within the cellular milieu using the luciferase reporter gene assay. These results suggest the existence of a link between transcriptional and posttranscriptional control because Aire downregulation alters the miRNA-mRNA network controlling PTAs in mTEC cells.
Source: NCBI - Disclaimer and Copyright notice
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