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Showing 100 Latest Publications
TitleDate Created
Environmental Chemicals in Urine and Blood: Improving Methods for Creatinine and Lipid Adjustment.Tuesday, July 28, 2015
O'Brien KM, Upson K, Cook NR, Weinberg CR,
Environmental health perspectives. 24-Jul-2015
To control measurement error bias due to variations in serum lipids or urinary diluteness, we recommend improved methods for standardizing exposure concentrations across individuals.
Tooth matrix analysis for biomonitoring of organic chemical exposure: Current status, challenges, and opportunities.Tuesday, July 28, 2015
Andra SS, Austin C, Arora M,
Environmental research. 24-Jul-2015
Epidemiological evidence supports associations between prenatal exposure to environmental organic chemicals and childhood health impairments. Unlike the common choice of biological matrices such as urine and blood that can be limited by short half-lives for some chemicals, teeth provide a stable repository for chemicals with half-life in the order of decades. Given the potential of the tooth bio-matrix to study long-term exposures to environmental organic chemicals in human biomonitoring programs, it is important to be aware of possible pitfalls and potential opportunities to improve on the current analytical method for tooth organics analysis. We critically review previous results of studies of this topic. The major drawbacks and challenges in currently practiced concepts and analytical methods in utilizing tooth bio-matrix are (i) no consideration of external (from outer surface) or internal contamination (from micro-odontoblast processes), (ii) the misleading assumption that whole ground teeth represent prenatal exposures (latest formed dentine is lipid rich and therefore would absorb and accumulate more organic chemicals), (iii) reverse causality in exposure assessment due to whole ground teeth, and (iv) teeth are a precious bio-matrix and grinding them raises ethical concerns about appropriate use of a very limited resource in exposure biology and epidemiology studies. These can be overcome by addressing the important limitations and possible improvements with the analytical approach associated at each of the following steps: (i) tooth sample preparation to retain exposure timing, (ii) organics extraction and pre-concentration to detect ultra-trace levels of analytes, (iii) chromatography separation, (iv) mass spectrometric detection to detect multi-class organics simultaneously, and (v) method validation, especially to exclude chance findings. To highlight the proposed improvements we present findings from a pilot study that utilizes tooth matrix biomarkers to obtain trimester-specific exposure information for a range of organic chemicals.
Learning the Structure of Biomedical Relationships from Unstructured Text.Tuesday, July 28, 2015
Percha B, Altman RB,
PLoS computational biology. Jul-2015
The published biomedical research literature encompasses most of our understanding of how drugs interact with gene products to produce physiological responses (phenotypes). Unfortunately, this information is distributed throughout the unstructured text of over 23 million articles. The creation of structured resources that catalog the relationships between drugs and genes would accelerate the translation of basic molecular knowledge into discoveries of genomic biomarkers for drug response and prediction of unexpected drug-drug interactions. Extracting these relationships from natural language sentences on such a large scale, however, requires text mining algorithms that can recognize when different-looking statements are expressing similar ideas. Here we describe a novel algorithm, Ensemble Biclustering for Classification (EBC), that learns the structure of biomedical relationships automatically from text, overcoming differences in word choice and sentence structure. We validate EBC's performance against manually-curated sets of (1) pharmacogenomic relationships from PharmGKB and (2) drug-target relationships from DrugBank, and use it to discover new drug-gene relationships for both knowledge bases. We then apply EBC to map the complete universe of drug-gene relationships based on their descriptions in Medline, revealing unexpected structure that challenges current notions about how these relationships are expressed in text. For instance, we learn that newer experimental findings are described in consistently different ways than established knowledge, and that seemingly pure classes of relationships can exhibit interesting chimeric structure. The EBC algorithm is flexible and adaptable to a wide range of problems in biomedical text mining.
The Tragedy of the Implementation of ICD-10-CM as ICD-10: Is the Cart Before the Horse or Is There a Tragic Paradox of Misinformation and Ignorance?Tuesday, July 28, 2015
Manchikanti L, Kaye AD, Singh V, Boswell MV,
Pain physician. 28-7-2015
ICD-10-CM, ICD-10, ICD-9-CM (International Classification of Diseases, 10th Revision, Ninth revision, Clinical Modification), Health Insurance Portability and Accountability Act (HIPAA), Health Information Technology (HIT), costs of implementation.
Trinucleotide Repeat Expansion in the TCF4 Gene in Fuchs' Endothelial Corneal Dystrophy in Japanese.Tuesday, July 28, 2015
Nakano M, Okumura N, Nakagawa H, Koizumi N, Ikeda Y, Ueno M, Yoshii K, Adachi H, Aleff RA, Butz ML, Highsmith WE, Tashiro K, Wieben ED, Kinoshita S, Baratz KH,
Investigative ophthalmology & visual science. 1-Jul-2015
These findings show for the first time in a Japanese population the association of the TNR expansion in TCF4 with FECD. In contrast to Caucasian cohorts in whom the TNR expansion is present in most patients with FECD, a CTG expansion is present in a minority of Japanese subjects, indicating other genetic variants as common causes of phenotypically identical disease in this population.
Recent Developments in Transplantation and Transfusion Medicine.Tuesday, July 28, 2015
Edinur HA, Chambers GK, Dunn PP,
Annals of transplantation : quarterly of the Polish Transplantation Society. 29-7-2015
Transplantation and transfusion are related and clinically important areas of multidisciplinary expertise, including pre-operative treatment, donor recruitment, tissue matching, and post-operative care. We have seen significant developments in these areas, especially in the late 20th and early 21st century. This paper reviews the latest advances in modern transplantation and transfusion medicine, including several new genetic markers (e.g., major histocompatibility complex class I chain-related gene A, killer cell immunoglobulin-like receptor, and human platelet antigens) for donor and recipient matching, genotyping platforms (e.g., next-generation sequencer and Luminex technology), donor recruitment strategies, and several clinical applications in which genotyping has advantages over agglutination tests (e.g., genotyping of weakly expressed antigens and determination of blood groups and human leukocyte antigen types in multi-transfused patients). We also highlight the roles of population studies and international collaborations in moving towards more efficient donor recruitment strategies.
PKCζ Promotes Breast Cancer Invasion by Regulating Expression of E-cadherin and Zonula Occludens-1 (ZO-1) via NFκB-p65.Tuesday, July 28, 2015
Paul A, Danley M, Saha B, Tawfik O, Paul S,
Scientific reports. 28-7-2015
Atypical Protein Kinase C zeta (PKCζ) forms Partitioning-defective (PAR) polarity complex for apico-basal distribution of membrane proteins essential to maintain normal cellular junctional complexes and tissue homeostasis. Consistently, tumor suppressive role of PKCζ has been established for multiple human cancers. However, recent studies also indicate pro-oncogenic function of PKCζ without firm understanding of detailed molecular mechanism. Here we report a possible mechanism of oncogenic PKCζ signaling in the context of breast cancer. We observed that depletion of PKCζ promotes epithelial morphology in mesenchymal-like MDA-MB-231 cells. The induction of epithelial morphology is associated with significant upregulation of adherens junction (AJ) protein E-cadherin and tight junction (TJ) protein Zonula Occludens-1 (ZO-1). Functionally, depletion of PKCζ significantly inhibits invasion and metastatic progression. Consistently, we observed higher expression and activation of PKCζ signaling in invasive and metastatic breast cancers compared to non-invasive diseases. Mechanistically, an oncogenic PKCζ- NFκB-p65 signaling node might be involved to suppress E-cadherin and ZO-1 expression and ectopic expression of a constitutively active form of NFκB-p65 (S536E-NFκB-p65) significantly rescues invasive potential of PKCζ-depleted breast cancer cells. Thus, our study discovered a PKCζ - NFκB-p65 signaling pathway might be involved to alter cellular junctional dynamics for breast cancer invasive progression.
Molecular markers and pathway analysis of colorectal carcinoma in the Middle East.Tuesday, July 28, 2015
Beg S, Siraj AK, Prabhakaran S, Bu R, Al-Rasheed M, Sultana M, Qadri Z, Al-Assiri M, Sairafi R, Al-Dayel F, Al-Sanea N, Uddin S, Al-Kuraya KS,
Cancer. 28-Jul-2015
The serrated pathway was found to account for a very low percentage of the CRC patient cohort in the current study. The unassigned group accounted for the majority of Middle Eastern CRC cases, and therefore methods of CRC pathway analysis might not be applicable to this ethnic group. The current study demonstrates the need to unravel the molecular genetic basis of this disease to further subcategorize these CRC cases. It also identifies a need for further studies on different populations for a better understanding of their exact role and incidence. Cancer 2015. © 2015 American Cancer Society.
Influence of galacto-oligosaccharide mixture (B-GOS) on gut microbiota, immune parameters and metabonomics in elderly persons.Tuesday, July 28, 2015
Vulevic J, Juric A, Walton GE, Claus SP, Tzortzis G, Toward RE, Gibson GR,
The British journal of nutrition. 28-Jul-2015
It is recognised that ageing induces various changes to the human colonic microbiota. Most relevant is a reduction in bifidobacteria, which is a health-positive genus. Prebiotics, such as galacto-oligosaccharides (GOS), are dietary ingredients that selectively fortify beneficial gut microbial groups. Therefore, they have the potential to reverse the age-related decline in bifidobacteria and modulate associated health parameters. We assessed the effect of GOS mixture (Bimuno (B-GOS)) on gut microbiota, markers of immune function and metabolites in forty elderly (age 65-80 years) volunteers in a randomised, double-blind, placebo (maltodextrin)-controlled, cross-over study. The intervention periods consisted of 10 weeks with daily doses of 5·5 g/d with a 4-week washout period in between. Blood and faecal samples were collected for the analyses of faecal bacterial populations and immune and metabolic biomarkers. B-GOS consumption led to significant increases in bacteroides and bifidobacteria, the latter correlating with increased lactic acid in faecal waters. Higher IL-10, IL-8, natural killer cell activity and C-reactive protein and lower IL-1β were also observed. Administration of B-GOS to elderly volunteers may be useful in positively affecting the microbiota and some markers of immune function associated with ageing.
Determination of alkylresorcinols and their metabolites in biological samples by gas chromatography-mass spectrometry.Tuesday, July 28, 2015
Wierzbicka R, Wu H, Franek M, Kamal-Eldin A, Landberg R,
Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 15-Jul-2015
High throughput GC-MS methods for quantification of alkylresorcinols (AR), biomarkers of whole grain wheat and rye intake, in plasma and adipose tissue and their metabolites in urine were developed and optimised. Alkylresorcinols in plasma (200μL) and adipose tissues (10-50mg) were extracted with diethyl ether, whereas main AR metabolites such as DHBA and DHPPA and newly identified metabolites in urine (50μL) were extracted with ethyl acetate after enzymatic deconjugation. All extracts were purified on OASIS-MAX solid phase extraction cartridges. Plasma and adipose tissue sample extracts were then derivatised with trifluoroacetic anhydride and reconstituted in undecane, whereas AR metabolites in urine samples were derivatised with BSTFA+TMCS (99:1, v/v, 100μL). Prepared samples were quantified by GC-MS (EI-SIM). Analysis of all compounds in the different matrices showed good selectivity, sensitivity, linearity, precision (<15% within and between batches), adequate recovery (75-108%), and short total run time (10-12min). The methods developed are applicable to large-scale sample sets such as epidemiological studies.
A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis.Tuesday, July 28, 2015
Whitfield MG, Soeters HM, Warren RM, York T, Sampson SL, Streicher EM, van Helden PD, van Rie A,
PloS one. 15-7-2015
PZA resistance is ubiquitous, with an estimated one in six incident TB cases and more than half of all MDR-TB cases resistant to PZA globally. The diversity of SNPs across the pncA gene complicates the development of rapid molecular diagnostics. These findings caution against relying on PZA in current and future TB drug regimens, especially in MDR-TB patients.
The Identification of Circulating MiRNA in Bovine Serum and Their Potential as Novel Biomarkers of Early Mycobacterium avium subsp paratuberculosis Infection.Tuesday, July 28, 2015
Farrell D, Shaughnessy RG, Britton L, MacHugh DE, Markey B, Gordon SV,
PloS one. 28-7-2015
Mycobacterium avium subspecies paratuberculosis (MAP) is the aetiological agent of Johne's disease (JD), a chronic enteritis in ruminants that causes substantial economic loses to agriculture worldwide. Current diagnostic assays are hampered by low sensitivity and specificity that seriously complicate disease control; a new generation of diagnostic and prognostic assays are therefore urgently needed. Circulating microRNAs (miRNAs) have been shown to have significant potential as novel biomarkers for a range of human diseases, but their potential application in the veterinary sphere has been less well characterised. The aim of this study was therefore to apply RNA-sequencing approaches to serum from an experimental JD infection model as a route to identify novel diagnostic and prognostic miRNA biomarkers. Sera from experimental MAP-challenged calves (n = 6) and age-matched controls (n = 6) were used. We identified a subset of known miRNAs from bovine serum across all samples, with approximately 90 being at potentially functional abundance levels. The majority of known bovine miRNAs displayed multiple isomiRs that differed from the canonical sequences. Thirty novel miRNAs were identified after filtering and were found within sera from all animals tested. No significant differential miRNA expression was detected when comparing sera from MAP-challenged animals to their age-matched controls at six-month's post-infection. However, comparing sera from pre-infection bleeds to six-month's post-infection across all 12 animals did identify increased miR-205 (2-fold) and decreased miR-432 (2-fold) within both challenged and control groups, which suggests changes in circulating miRNA profiles due to ageing or development (P<0.00001). In conclusion our study has identified a range of novel miRNA in bovine serum, and shown the utility of small RNA sequencing approaches to explore the potential of miRNA as novel biomarkers for infectious disease in cattle.
Loss of C. elegans GON-1, an ADAMTS9 Homolog, Decreases Secretion Resulting in Altered Lifespan and Dauer Formation.Tuesday, July 28, 2015
Yoshina S, Mitani S,
PloS one. 28-7-2015
ADAMTS9 is a metalloprotease that cleaves components of the extracellular matrix and is also implicated in transport from the endoplasmic reticulum (ER) to the Golgi. It has been reported that an ADAMTS9 gene variant is associated with type 2 diabetes. The underlying pathology of type 2 diabetes is insulin resistance and beta-cell dysfunction. However, the molecular mechanisms underlying ADAMTS9 function in beta cells and peripheral tissues are unknown. We show that loss of C. elegans GON-1, an ADAMTS9 homolog, alters lifespan and dauer formation. GON-1 loss impairs secretion of proteins such as insulin orthologs and TGF-beta, and additionally impacts insulin/IGF-1 signaling in peripheral tissues. The function of the GON domain, but not the protease domain, is essential for normal lifespan and dauer formation in these scenarios. We conclude that the GON domain is critical for ADAMTS9/GON-1 function across species, which should help the understanding of type 2 diabetes in humans.
Genetic subtypes of invasive bladder cancer.Tuesday, July 28, 2015
McConkey DJ, Choi W, Dinney CP,
Current opinion in urology. Sep-2015
Like their breast cancer counterparts, basal bladder cancers are characterized by poor clinical outcomes in the absence of effective systemic therapy, but a large fraction of them do respond to neoadjuvant chemotherapy, suggesting that the tumors should be managed aggressively. On the contrary, tumors that belong to the 'p53-like' subtype tend to be chemoresistant, so patients with these tumors should probably be managed differently. It seems likely that prospective identification of tumor intrinsic subtype membership could complement the use of DNA-based biomarkers to identify the groups of patients who will benefit the most from chemotherapy and targeted agents.
Methylenetetrahydrofolate reductase C677T and A1298C gene polymorphisms in oral squamous cell carcinoma in south-east Iran.Tuesday, July 28, 2015
Miri-Moghaddam E, Saravani S, Garme Y, Khosravi A, Bazi A, Motazedian J,
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 27-Jul-2015
Our results highlight the possible impact of C677T polymorphism in increasing the risk of OSCC development.
Atherogenic lipids and macrophage subsets.Tuesday, July 28, 2015
Getz GS, Reardon CA,
Current opinion in lipidology. 25-Jul-2015
Although we are beginning to appreciate the heterogeneity of macrophages present in atherosclerotic plaques, further work is required to fully understand the molecular basis for the differential ability of macrophage subsets to form foam cells and to respond to bioactive lipids.
Breast Implant-Associated Anaplastic Large Cell Lymphoma: Proposal for a Monitoring Protocol.Tuesday, July 28, 2015
Santanelli di Pompeo F, Laporta R, Sorotos M, Di Napoli A, Giovagnoli MR, Cox MC, Campanale A, Longo B,
Plastic and reconstructive surgery. Aug-2015
Therapeutic, V.
Eosinophils and IL-33 Perpetuate Chronic Inflammation and Fibrosis in a Pediatric Population with Stricturing Crohn's Ileitis.Tuesday, July 28, 2015
Masterson JC, Capocelli KE, Hosford L, Biette K, McNamee EN, de Zoeten EF, Harris R, Fernando SD, Jedlicka P, Protheroe C, Lee JJ, Furuta GT,
Inflammatory bowel diseases. 25-Jul-2015
Our study of specimens from pediatric patients with ileal CD linked eosinophil patterns and IL-33 to fibrosis and suggested that these may contribute to the perpetuation of inflammation and subsequent stricture in pediatric CD.
The effects of poly(dimethylsiloxane) surface silanization on the mesenchymal stem cell fate.Tuesday, July 28, 2015
Chuah YJ, Kuddannaya S, Lee MH, Zhang Y, Kang Y,
Biomaterials science. 20-Feb-2015
In recent years, poly(dimethylsiloxane) (PDMS)-based microfluidic devices have become very popular for on-chip cell investigation. Maintenance of mammalian cell adhesion on the substrate surface is crucial in determining the cell viability, proliferation and differentiation. However, the inherent hydrophobicity of PDMS is unfavourable for cell culture, causing cells to eventually dislodge from the surface. Although physically adsorbed matrix proteins can promote initial cell adhesion, this effect is usually short-lived. To address this critical issue, in this study, we employed (3-aminopropyl) triethoxy silane (APTES) and cross-linker glutaraldehyde (GA) chemistry to immobilize collagen type 1 (Col1) on PDMS. These modified surfaces are highly efficient to support the adhesion of mesenchymal stem cells (MSCs) with no deterioration of their potency. Significant changes of the native PDMS surface properties were observed with the proposed surface functionalization, and MSC adhesion was improved on PDMS surfaces modified with APTES + GA + Protein. Therefore, this covalent surface modification could generate a more biocompatible platform for stabilized cell adhesion. Furthermore, this modification method facilitated long-term cell attachment, which is favourable for successful induction of osteogenesis and cell sheet formation with an increased expression of osteogenic biomarkers and comparable extracellular matrix (ECM) constituent biomarkers, respectively. The surface silanization can be applied to PDMS-based microfluidic systems for long-term study of cellular development. Similar strategies could also be applied to several other substrate materials by appropriate combinations of self-assembled monolayers (SAMs) and ECM proteins.
Asymmetric Signal Amplification for Simultaneous SERS Detection of Multiple Cancer Markers with Significantly Different Levels.Tuesday, July 28, 2015
Ye S, Wu Y, Zhai X, Tang B,
Analytical chemistry. 28-Jul-2015
Simultaneous detection of cancer biomarkers holds great promise for the early diagnosis of different cancers. However, in the presence of high concentration biomarkers, the signals of lower-expression biomarkers are overlapped. Existing techniques are not suitable for simultaneously detecting multiple biomarkers at concentrations with significantly different orders of magnitude. Here, we propose an asymmetric signal amplification method for simultaneously detecting multiple biomarkers with significantly different levels. Using the bifunctional probe, a linear amplification mode responds to high-concentration markers and quadratic amplification mode responds to low-concentration markers. With the Combined bio-barcode probe and hybridization chain reaction (HCR) amplification method, the detection limits of mRNA and ATP via surface-enhanced Raman scattering (SERS) detection are 0.15 fM and 20 nM on, respectively, with a breakthrough of detection concentration difference over 11 orders magnitude. Furthermore, successful determination of mRNA and ATP in cancer cells supports the practicability of the assay. This methodology promises to open an exciting new avenue for the detection of various types of biomolecules.
Patient-Derived Gastric Carcinoma Xenograft Mouse Models Faithfully Represent Human Tumor Molecular Diversity.Tuesday, July 28, 2015
Zhang T, Zhang L, Fan S, Zhang M, Fu H, Liu Y, Yin X, Chen H, Xie L, Zhang J, Gavine PR, Gu Y, Ni X, Su X,
PloS one. 28-7-2015
Patient-derived cancer xenografts (PDCX) generally represent more reliable models of human disease in which to evaluate a potential drugs preclinical efficacy. However to date, only a few patient-derived gastric cancer xenograft (PDGCX) models have been reported. In this study, we aimed to establish additional PDGCX models and to evaluate whether these models accurately reflected the histological and genetic diversities of the corresponding patient tumors. By engrafting fresh patient gastric cancer (GC) tissues into immune-compromised mice (SCID and/or nude mice), thirty two PDGCX models were established. Histological features were assessed by a qualified pathologist based on H&E staining. Genomic comparison was performed for several biomarkers including ERBB1, ERBB2, ERBB3, FGFR2, MET and PTEN. These biomarkers were profiled to assess gene copy number by fluorescent in situ hybridization (FISH) and/or protein expression by immunohistochemistry (IHC). All 32 PDGCX models retained the histological features of the corresponding human tumors. Furthermore, among the 32 models, 78% (25/32) highly expressed ERBB1 (EGFR), 22% (7/32) were ERBB2 (HER2) positive, 78% (25/32) showed ERBB3 (HER3) high expression, 66% (21/32) lost PTEN expression, 3% (1/32) harbored FGFR2 amplification, 41% (13/32) were positive for MET expression and 16% (5/32) were MET gene amplified. Between the PDGCX models and their parental tumors, a high degree of similarity was observed for FGFR2 and MET gene amplification, and also for ERBB2 status (agreement rate = 94~100%; kappa value = 0.81~1). Protein expression of PTEN and MET also showed moderate agreement (agreement rate = 78%; kappa value = 0.46~0.56), while ERBB1 and ERBB3 expression showed slight agreement (agreement rate = 59~75%; kappa value = 0.18~0.19). ERBB2 positivity, FGFR2 or MET gene amplification was all maintained until passage 12 in mice. The stability of the molecular profiles observed across subsequent passages within the individual models provides confidence in the utility and translational significance of these models for in vivo testing of personalized therapies.
Prediction model for regional or distant recurrence in endometrial cancer based on classical pathological and immunological parameters.Tuesday, July 28, 2015
Versluis MA, de Jong RA, Plat A, Bosse T, Smit VT, Mackay H, Powell M, Leary A, Mileshkin L, Kitchener HC, Crosbie EJ, Edmondson RJ, Creutzberg CL, Hollema H, Daemen T, de Bock GH, Nijman HW,
British journal of cancer. 28-Jul-2015
In high-risk EC, clinicopathological or immunological variables can predict regional or distant recurrence with equal accuracy, but the use of these variables in combination is more powerful.British Journal of Cancer advance online publication, 28 July 2015; doi:10.1038/bjc.2015.268
Data from human salivary proteome - A resource of potential biomarkers for oral cancer.Tuesday, July 28, 2015
Sivadasan P, Kumar Gupta M, Sathe GJ, Balakrishnan L, Palit P, Gowda H, Suresh A, Abraham Kuriakose M, Sirdeshmukh R,
Data in brief. Sep-2015
Salivary proteins are an important source for developing marker-based assays for oral cancers. To get an insight into the proteins present in human saliva, we applied multiple strategies involving affinity-based depletion of abundant proteins, fractionation of the resulting proteins or their tryptic peptides followed by LC-MS/MS analysis, using high resolution mass spectrometry. By integrating the protein identifications observed by us with those from similar workflows employed in earlier investigations, we compiled an updated salivary proteome. We have mapped the salivary proteome to the published data on differentially expressed proteins from oral cancer tissues and also for their secretory features using prediction tools, SignalP 4.1, TMHMM 2c and Exocarta. Proteotypic peptides for the subset of proteins implicated in oral cancer and mapped to any two of the prediction tools for secretory potential have been listed. The data here are related to the research article "Human saliva proteome - a resource of potential biomarkers for oral cancer" in the Journal of Proteomics [1].
Data set of the protein expression profiles of Luminal A, Claudin-low and overexpressing HER2(+) breast cancer cell lines by iTRAQ labelling and tandem mass spectrometry.Tuesday, July 28, 2015
Calderón-González KG, Valero Rustarazo ML, Labra-Barrios ML, Bazán-Méndez CI, Tavera-Tapia A, Herrera-Aguirre Ma, Sánchez Del Pino MM, Gallegos-Pérez JL, González-Márquez H, Hernández-Hernández JM, León-Ávila G, Rodríguez-Cuevas S, Guisa-Hohenstein F, Luna-Arias JP,
Data in brief. Sep-2015
Breast cancer is the most common and the leading cause of mortality in women worldwide. There is a dire necessity of the identification of novel molecules useful in diagnosis and prognosis. In this work we determined the differentially expression profiles of four breast cancer cell lines compared to a control cell line. We identified 1020 polypeptides labelled with iTRAQ with more than 95% in confidence. We analysed the common proteins in all breast cancer cell lines through IPA software (IPA core and Biomarkers). In addition, we selected the specific overexpressed and subexpressed proteins of the different molecular classes of breast cancer cell lines, and classified them according to protein class and biological process. Data in this article is related to the research article "Determination of the protein expression profiles of breast cancer cell lines by Quantitative Proteomics using iTRAQ Labelling and Tandem Mass Spectrometry" (Calderón-González et al. [1] in press).
Data from identification of diagnostic biomarkers and metabolic pathway shifts of heat-stressed lactating dairy cows.Tuesday, July 28, 2015
Tian H, Wang W, Zheng N, Cheng J, Li S, Zhang Y, Wang J,
Data in brief. Sep-2015
Controlling heat stress (HS) is a global challenge for the dairy industry. In this work, an integrated metabolomics and lipidomics approach using (1)H nuclear magnetic resonance (NMR) and ultra-fast LC-MS in combination with multivariate analyses was employed to investigate the discrimination of plasma metabolic profiles between HS-free and HS lactating dairy cows. Here we provide the information about the acquiring and processing of raw data obtained by (1)H NMR and LC-MS techniques. The data of present study are related to the research article "Identification of diagnostic biomarkers and metabolic pathway shifts of heat-stressed lactating dairy cows" in the Journal of Proteomics (Tian et al., J. Proteomics, (2015), doi:10.1016/j.jprot.2015.04.014).
Data in support of enhancing metabolomics research through data mining.Tuesday, July 28, 2015
Martínez-Arranz I, Mayo R, Pérez-Cormenzana M, Mincholé I, Salazar L, Alonso C, Mato JM,
Data in brief. Jun-2015
Metabolomics research has evolved considerably, particularly during the last decade. Over the course of this evolution, the interest in this 'omic' discipline is now more evident than ever. However, the future of metabolomics will depend on its capability to find biomarkers. For that reason, data mining constitutes a challenging task in metabolomics workflow. This work has been designed in support of the research article entitled "Enhancing metabolomics research through data mining", which proposed a methodological data handling guideline. An aging research in healthy population was used as a guiding thread to illustrate this process. Here we provide a further interpretation of the obtained statistical results. We also focused on the importance of graphical visualization tools as a clue to understand the most common univariate and multivariate data analyses applied in metabolomics.
Experimental evidences of the NO action on a recombinant PrxII F from pea plant and its effect preventing the citrate synthase aggregation.Tuesday, July 28, 2015
Camejo D, Ortiz-Espín A, Lázaro JJ, Romero-Puertas MC, Lázaro-Payo A, Sevilla F, Jiménez A,
Data in brief. Jun-2015
S-nitrosylation is emerging as a key post-translational protein modification for the transduction of NO as a signaling molecule in plants. This data article supports the research article entitled "Functional and structural changes in plant mitochondrial PrxII F caused by NO" [1]. To identify the Cys residues of the recombinant PrxII F modified after the treatment with S-nitrosylating agents we performed the LC ESI-QTOF tandem MS and MALDI peptide mass fingerprinting analysis. Change in A 650 nm was monitored to estimate the thermal aggregation of citrate synthase in the presence S-nitrosylated PrxII F. The effect of the temperature on the oligomerization pattern and aggregation of PrxII F was analysed by SDS-PAGE and changes in absorbance at 650 nm, respectively.
Comparative secretome analysis of rat stomach under different nutritional status.Tuesday, July 28, 2015
Senin LL, Roca-Rivada A, Castelao C, Alonso J, Folgueira C, Casanueva FF, Pardo M, Seoane LM,
Data in brief. Jun-2015
The fact that gastric surgery is at the moment the most effective treatment to fight against obesity highlights the relevance of gastric derived proteins as potential targets to treat this pathology. Taking advantage of a previously established gastric explant model for endocrine studies, the proteomic analysis of gastric secretome was performed. To validate this gastric explant system for proteomic analysis, the identification of ghrelin, a classical gastric derived peptide, was performed by MS. In addition, the differential analysis of gastric secretomes under differential nutritional status (control feeding vs fasting vs re-feeding) was performed. The MS identified proteins are showed in the present manuscript. The data supplied in this article is related to the research article entitled "Comparative secretome analysis of rat stomach under different nutritional status" [1].
Biochemical and computational analyses of two phenotypically related GALT mutations (S222N and S135L) that lead to atypical galactosemia.Tuesday, July 28, 2015
Cocanougher B, Aypar U, McDonald A, Hasadsri L, Bennett MJ, Edward Highsmith W, D׳Aco K,
Data in brief. Jun-2015
Galactosemia is a metabolic disorder caused by mutations in the GALT gene [1,2]. We encountered a patient heterozygous for a known pathogenic H132Q mutation and a novel S222N variant of unknown significance [3]. Reminiscent of patients with the S135L mutation, our patient had loss of GALT enzyme activity in erythrocytes but a very mild clinical phenotype [3-8]. We performed splicing experiments and computational structural analyses to investigate the role of the novel S222N variant. Alamut software data predicted loss of splicing enhancers for the S222N and S135L mutations [9,10]. A cDNA library was generated from our patient׳s RNA to investigate for splicing errors, but no change in transcript length was seen [3]. In silico structural analysis was performed to investigate enzyme stability and attempt to understand the mechanism of the atypical galactosemia phenotype. Stability results are publicly available in the GALT Protein Database 2.0 [11-14]. Animations were created to give the reader a dynamic view of the enzyme structure and mutation locations. Protein database files and python scripts are included for further investigation.
Data set from the phosphoproteomic analysis of Magnaporthe oryzae-responsive proteins in susceptible and resistant rice cultivars.Tuesday, July 28, 2015
Li Y, Ye Z, Nie Y, Zhang J, Wang GL, Wang Z,
Data in brief. Jun-2015
Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is the most destructive disease of rice and causes tremendous losses of rice yield worldwide. To explore the molecular mechanisms involved in the rice-M. oryzae interaction, we conducted a time-course phosphoproteomic analysis of leaf samples from resistant and susceptible rice cultivars infected with M. oryzae. This data article contains additional results and analysis of M. oryzae-regulated phosphoproteins in rice leaves [1]. We report the analysis of M. oryzae-regulated phosphoproteins at all time points, including Venn diagram analysis, close-up views, relative intensities, and functional category, and the MS spectra of representative phosphoprotein and representative phosphorylated peptides.
Data for chicken semen proteome and label free quantitative analyses displaying sperm quality biomarkers.Tuesday, July 28, 2015
Labas V, Grasseau I, Cahier K, Gargaros A, Harichaux G, Teixeira-Gomes AP, Alves S, Bourin M, Gérard N, Blesbois E,
Data in brief. Dec-2014
Understanding of biology of the avian male gamete is essential to improve the conservation of genetic resources and performances in farming. In this study, the semen proteome of the main domestic avian species (Gallus gallus) and evaluation of the molecular phenotype related to sperm quality were investigated using GeLC-MS/MS approach and label-free quantitative proteomic based on Spectral Counting (SC) and extracted ion chromatograms (XIC) methods. Here we describe in details the peptide/protein inventory of chicken ejaculated spermatozoa (SPZ) and seminal plasma (SP). We also show differential analyses of chicken semen (SPZ and corresponding SP) from 11 males demonstrating different levels of fertilizing capacity and sperm motility. The interpretation and description of these data can be found in a research article published by Labas and colleagues in the Journal of Proteomics in 2014 [1]. This is a new resource for exploring the molecular mechanisms involved in fertilizing capacity and to reveal new sets of fertility biomarkers.
Understanding the Key to Targeting the IGF Axis in Cancer: A Biomarker Assessment.Tuesday, July 28, 2015
Lodhia KA, Tienchaiananda P, Haluska P,
Frontiers in oncology. 2015
Type 1 insulin like growth factor receptor (IGF-1R) targeted therapies showed compelling pre-clinical evidence; however, to date, this has failed to translate into patient benefit in Phase 2/3 trials in unselected patients. This was further complicated by the toxicity, including hyperglycemia, which largely results from the overlap between IGF and insulin signaling systems and associated feedback mechanisms. This has halted the clinical development of inhibitors targeting IGF signaling, which has limited the availability of biopsy samples for correlative studies to understand biomarkers of response. Indeed, a major factor contributing to lack of clinical benefit of IGF targeting agents has been difficulty in identifying patients with tumors driven by IGF signaling due to the lack of predictive biomarkers. In this review, we will describe the IGF system, rationale for targeting IGF signaling, the potential liabilities of targeting strategies, and potential biomarkers that may improve success.
Can cell proliferation of umbilical cord blood cells reflect environmental exposures?Tuesday, July 28, 2015
Novack L, Manor E, Gurevich E, Yitshak-Sade M, Landau D, Sarov B, Hershkovitz R, Dukler D, Vodonos T, Karakis I,
SpringerPlus. 2015
Environmental hazards were shown to have an impact on cell proliferation (CP). We investigated CP of lymphocytes in umbilical cord blood in relation to prenatal environmental exposures in a sample of 346 Arab-Bedouin women giving birth in a local hospital. Information on subjects' addresses at pregnancy, potential household exposures and demographical status was collected in an interview during hospitalization. This population is usually featured by high rates of neonatal morbidity and multiple environmental exposures, originating from the local industrial park (IP), household hazards and frequent male smoking. A geometric mean CP ratio 2.17 (2.06; 2.29), and was high in women residing in a direction of prevailing winds from the local IP (p value = 0.094) and who gave birth during fall-winter season (p value = 0.024). Women complaining on disturbing exposure to noise had lower CP (p value = 0.015), compared to other women. CP was not indicative of neonatal morbidity. However, our findings suggest that CP of umbilical cord might be modified by environmental exposures. A long-term follow-up of the children is required to assess their developmental outcomes.
Dose and time responses of vitamin D biomarkers to monthly vitamin D3 supplementation in overweight/obese African Americans with suboptimal vitamin d status: a placebo controlled randomized clinical trial.Tuesday, July 28, 2015
Bhagatwala J, Zhu H, Parikh SJ, Guo DH, Kotak I, Huang Y, Havens R, Pham M, Afari E, Kim S, Cutler C, Pollock NK, Dong Y, Raed A, Dong Y,
BMC obesity. 2015 number: NCT01583621, Registered on April 3, 2012.
Prevalence of obesity and overweight, its clinical markers and associated factors in a high risk South-Asian population.Tuesday, July 28, 2015
Amin F, Fatima SS, Islam N, Gilani AH,
BMC obesity. 2015
Considering lower cut-offs for South-Asians BMI and WC, this study showed a high prevalence of obesity among a sub-urban population of Karachi, which was even higher when BF% was measured. Considering the rising prevalence of non-communicable diseases, BF%, WC, WHR and BMI measurements are convenient and feasible means of identifying population at risk and hence addressing it through public awareness and early detection.
Associations of total and abdominal adiposity with risk marker patterns in children at high-risk for cardiovascular disease.Tuesday, July 28, 2015
de Koning L, Denhoff E, Kellogg MD, de Ferranti SD,
BMC obesity. 2015
In children at high-risk for CVD, BMI% or WC% explained similar variance in an adverse lipid pattern; however, the combination of BMI% and WC% explained greater variance in a pro-inflammatory pattern than either alone. Both WC% and BMI% should both be used in anthropometric assessments of high-risk children.
Cpipe: a shared variant detection pipeline designed for diagnostic settings.Tuesday, July 28, 2015
Sadedin SP, Dashnow H, James PA, Bahlo M, Bauer DC, Lonie A, Lunke S, Macciocca I, Ross JP, Siemering KR, Stark Z, White SM, Taylor G, Gaff C, Oshlack A, Thorne NP,
Genome medicine. 2015
The benefits of implementing high throughput sequencing in the clinic are quickly becoming apparent. However, few freely available bioinformatics pipelines have been built from the ground up with clinical genomics in mind. Here we present Cpipe, a pipeline designed specifically for clinical genetic disease diagnostics. Cpipe was developed by the Melbourne Genomics Health Alliance, an Australian initiative to promote common approaches to genomics across healthcare institutions. As such, Cpipe has been designed to provide fast, effective and reproducible analysis, while also being highly flexible and customisable to meet the individual needs of diverse clinical settings. Cpipe is being shared with the clinical sequencing community as an open source project and is available at
Corrigendum: Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example.Tuesday, July 28, 2015
Goldstein BA, Knowles JW, Salfati E, Ioannidis JP, Assimes TL,
Frontiers in genetics. 10-07-2015
[This corrects the article on p. 254 in vol. 5, PMID: 25136350.].
The Evolution of the Scavenger Receptor Cysteine-Rich Domain of the Class A Scavenger Receptors.Tuesday, July 28, 2015
Yap NV, Whelan FJ, Bowdish DM, Golding GB,
Frontiers in immunology. 2015
The class A scavenger receptor (cA-SR) family is a group of five evolutionarily related innate immune receptors. The cA-SRs are known for their promiscuous ligand binding; as they have been shown to bind bacteria, such as Streptococcus pneumoniae and Escherichia coli, as well as different modified forms of low-density lipoprotein. Three of the five family members possess a scavenger receptor cysteine-rich (SRCR) domain while the remaining two receptors lack the domain. Previous work has suggested that the macrophage-associated receptor with collagenous structure (MARCO) shares a recent common ancestor with the non-SRCR-containing receptors; however, the origin of the SRCR domain within the cA-SRs remains unknown. We hypothesize that the SRCR domains of the cA-SRs have a common origin that predates teleost fish. Using the newly available sequence data from sea lamprey and ghost shark genome projects, we have shown that MARCO shares a common ancestor with the SRCR-containing proteins. In addition, we explored the evolutionary relationships within the SRCR domain by reconstructing the ancestral SRCR domains of the cA-SRs. We identified a motif that is highly conserved between the cA-SR SRCR domains and the ancestral SRCR domain that consist of WGTVCDD. We also show that the GRAEVYY motif, a functionally important motif within MARCO, is poorly conserved in the other cA-SRs and in the reconstructed ancestral domain. Further, we identified three sites within MARCO's SRCR domain, which are under positive selection. Two of these sites lie adjacent to the conserved WGTVCDD motif, and may indicate a potential biological function for these sites. Together, these findings indicate a common origin of the SRCR domain within the cA-SRs; however, different selective pressures between the proteins may have caused MARCOs SRCR domain to evolve to contain different functional motifs when compared to the other SRCR-containing cA-SRs.
Antibody-Based Strategies to Prevent and Treat Influenza.Tuesday, July 28, 2015
Shriver Z, Trevejo JM, Sasisekharan R,
Frontiers in immunology. 2015
Passive immunization using antibodies is a promising alternative to other antiviral treatment options. The potential for seasonal protection arising from a single injection of antibodies is appealing and has been pursued for a number of infectious agents. However, until recently, antibody-based strategies to combat infectious agents have been hampered due to the fact that most antibodies have been found to be strain specific, with the virus evolving resistance in many cases. The discovery of broadly neutralizing antibodies (bNAbs) in influenza, dengue virus, and HIV, which bind to multiple, structurally diverse strains, has provided renewed interest in this area. This review will focus on new technologies that enable the discovery of bNAbs, the challenges and opportunities of immunotherapies as an important addition to existing antiviral therapy, and the role of antibody discovery in informing rational vaccine discovery - with agents targeting influenza specifically addressed. Multiple candidates have entered the clinic and raise the possibility that a single antibody or small combination of antibodies can effectively neutralize a wide variety of strains. However, challenges remain - including combating escape variants, pharmacodynamics of antibody distribution, and development of efficacy biomarkers beyond virologic endpoints.
microRNA-Based Biomarkers and the Diagnosis of Alzheimer's Disease.Tuesday, July 28, 2015
Zhao Y, Bhattacharjee S, Dua P, Alexandrov PN, Lukiw WJ,
Frontiers in neurology. 2015
Chasing the Effects of Pre-Analytical Confounders - A Multicenter Study on CSF-AD Biomarkers.Tuesday, July 28, 2015
Leitão MJ, Baldeiras I, Herukka SK, Pikkarainen M, Leinonen V, Simonsen AH, Perret-Liaudet A, Fourier A, Quadrio I, Veiga PM, de Oliveira CR,
Frontiers in neurology. 2015
This systematic study reinforces the need for CSF centrifugation at 4°C prior to storage and highlights the influence of storage conditions in Aβ42 levels. This study contributes to the establishment of harmonized standard operating procedures that will help reducing inter-lab variability of CSF-AD biomarkers evaluation.
Serum PINP, PIIINP, galectin-3, and ST2 as surrogates of myocardial fibrosis and echocardiographic left venticular diastolic filling properties.Tuesday, July 28, 2015
Lepojärvi ES, Piira OP, Pääkkö E, Lammentausta E, Risteli J, Miettinen JA, Perkiömäki JS, Huikuri HV, Junttila MJ,
Frontiers in physiology. 2015
Elevated serum levels of gal-3 reflect the degree of myocardial fibrosis assessed by LGE CMR. Gal-3, ST2, and PIIINP are also elevated in patients with impaired LV diastolic function, suggesting that these biomarkers are useful surrogates of structural and functional abnormality of the myocardium.
A novel, dynamic pattern-based analysis of NF-κB binding during the priming phase of liver regeneration reveals switch-like functional regulation of target genes.Tuesday, July 28, 2015
Cook DJ, Patra B, Kuttippurathu L, Hoek JB, Vadigepalli R,
Frontiers in physiology. 2015
Following partial hepatectomy, a coordinated series of molecular events occurs to regulate hepatocyte entry into the cell cycle to recover lost mass. In rats during the first 6 h following resection, hepatocytes are primed by a tightly controlled cytokine response to prepare hepatocytes to begin replication. Although it appears to be a critical element driving regeneration, the cytokine response to resection has not yet been fully characterized. Specifically, the role of one of the key response elements to cytokine signaling (NF-κB) remains incompletely characterized. In this study, we present a novel, genome-wide, pattern-based analysis characterizing NF-κB binding during the priming phase of liver regeneration. We interrogated the dynamic regulation of priming by NF-κB through categorizing NF-κB binding in different temporal profiles: immediate sustained response, early transient response, and delayed response to partial hepatectomy. We then identified functional regulation of NF-κB binding by relating the temporal response profile to differential gene expression. We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. NF-κB also transiently regulates genes responsible for lipid biosynthesis and transport as well as induction of apoptosis following hepatectomy. By the end of the priming phase, NF-κB regulation of genes involved in inflammatory response, negative regulation of cell death, and extracellular structure organization became prominent. These results suggest that NF-κB regulates target genes through binding and unbinding in immediate, transient, and delayed patterns. Such dynamic switch-like patterns of NF-κB binding may govern different functional transitions that drive the onset of regeneration.
Oxidative stress and Parkinson's disease.Tuesday, July 28, 2015
Blesa J, Trigo-Damas I, Quiroga-Varela A, Jackson-Lewis VR,
Frontiers in neuroanatomy. 2015
Parkinson disease (PD) is a chronic, progressive neurological disease that is associated with a loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. The molecular mechanisms underlying the loss of these neurons still remain elusive. Oxidative stress is thought to play an important role in dopaminergic neurotoxicity. Complex I deficiencies of the respiratory chain account for the majority of unfavorable neuronal degeneration in PD. Environmental factors, such as neurotoxins, pesticides, insecticides, dopamine (DA) itself, and genetic mutations in PD-associated proteins contribute to mitochondrial dysfunction which precedes reactive oxygen species formation. In this mini review, we give an update of the classical pathways involving these mechanisms of neurodegeneration, the biochemical and molecular events that mediate or regulate DA neuronal vulnerability, and the role of PD-related gene products in modulating cellular responses to oxidative stress in the course of the neurodegenerative process.
Understanding the role of P2X7 in affective disorders-are glial cells the major players?Tuesday, July 28, 2015
Stokes L, Spencer SJ, Jenkins TA,
Frontiers in cellular neuroscience. 2015
Pathophysiology associated with several psychiatric disorders has been linked to inflammatory biomarkers. This has generated a theory of major depressive disorders as an inflammatory disease. The idea of pro-inflammatory cytokines altering behavior is now well accepted however many questions remain. Microglia can produce a plethora of inflammatory cytokines and these cells appear to be critical in the link between inflammatory changes and depressive disorders. Microglia play a known role in sickness behavior which has many components of depressive-like behavior such as social withdrawal, sleep alterations, and anorexia. Numerous candidate genes have been identified for psychiatric disorders in the last decade. Single nucleotide polymorphisms (SNPs) in the human P2X7 gene have been linked to bipolar disorder, depression, and to the severity of depressive symptoms. P2X7 is a ligand-gated cation channel expressed on microglia with lower levels found on astrocytes and on some neuronal populations. In microglia P2X7 is a major regulator of pro-inflammatory cytokines of the interleukin-1 family. Genetic deletion of P2X7 in mice is protective for depressive behavior in addition to inflammatory responses. P2X7(-/-) mice have been shown to demonstrate anti-depressive-like behavior in forced swim and tail suspension behavioral tests and stressor-induced behavioral responses were blunted. Both neurochemical (norepinephrine, serotonin, and dopamine) and inflammatory changes have been observed in the brains of P2X7(-/-) mice. This review will discuss the recent evidence for involvement of P2X7 in the pathophysiology of depressive disorders and propose mechanisms by which altered signaling through this ion channel may affect the inflammatory state of the brain.
Physical biology of human brain development.Tuesday, July 28, 2015
Budday S, Steinmann P, Kuhl E,
Frontiers in cellular neuroscience. 2015
Neurodevelopment is a complex, dynamic process that involves a precisely orchestrated sequence of genetic, environmental, biochemical, and physical events. Developmental biology and genetics have shaped our understanding of the molecular and cellular mechanisms during neurodevelopment. Recent studies suggest that physical forces play a central role in translating these cellular mechanisms into the complex surface morphology of the human brain. However, the precise impact of neuronal differentiation, migration, and connection on the physical forces during cortical folding remains unknown. Here we review the cellular mechanisms of neurodevelopment with a view toward surface morphogenesis, pattern selection, and evolution of shape. We revisit cortical folding as the instability problem of constrained differential growth in a multi-layered system. To identify the contributing factors of differential growth, we map out the timeline of neurodevelopment in humans and highlight the cellular events associated with extreme radial and tangential expansion. We demonstrate how computational modeling of differential growth can bridge the scales-from phenomena on the cellular level toward form and function on the organ level-to make quantitative, personalized predictions. Physics-based models can quantify cortical stresses, identify critical folding conditions, rationalize pattern selection, and predict gyral wavelengths and gyrification indices. We illustrate that physical forces can explain cortical malformations as emergent properties of developmental disorders. Combining biology and physics holds promise to advance our understanding of human brain development and enable early diagnostics of cortical malformations with the ultimate goal to improve treatment of neurodevelopmental disorders including epilepsy, autism spectrum disorders, and schizophrenia.
Regulated phosphorylation of the K-Cl cotransporter KCC3 is a molecular switch of intracellular potassium content and cell volume homeostasis.Tuesday, July 28, 2015
Adragna NC, Ravilla NB, Lauf PK, Begum G, Khanna AR, Sun D, Kahle KT,
Frontiers in cellular neuroscience. 2015
The defense of cell volume against excessive shrinkage or swelling is a requirement for cell function and organismal survival. Cell swelling triggers a coordinated homeostatic response termed regulatory volume decrease (RVD), resulting in K(+) and Cl(-) efflux via activation of K(+) channels, volume-regulated anion channels (VRACs), and the K(+)-Cl(-) cotransporters, including KCC3. Here, we show genetic alanine (Ala) substitution at threonines (Thr) 991 and 1048 in the KCC3a isoform carboxyl-terminus, preventing inhibitory phosphorylation at these sites, not only significantly up-regulates KCC3a activity up to 25-fold in normally inhibitory isotonic conditions, but is also accompanied by reversal of activity of the related bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter isoform 1 (NKCC1). This results in a rapid (<10 min) and significant (>90%) reduction in intracellular K(+) content (Ki) via both Cl-dependent (KCC3a + NKCC1) and Cl-independent [DCPIB (VRAC inhibitor)-sensitive] pathways, which collectively renders cells less prone to acute swelling in hypotonic osmotic stress. Together, these data demonstrate the phosphorylation state of Thr991/Thr1048 in KCC3a encodes a potent switch of transporter activity, Ki homeostasis, and cell volume regulation, and reveal novel observations into the functional interaction among ion transport molecules involved in RVD.
Contra-Directional Expression of Serum Homocysteine and Uric Acid as Important Biomarkers of Multiple System Atrophy Severity: A Cross-Sectional Study.Tuesday, July 28, 2015
Chen D, Wei X, Zou J, Wang R, Liu X, Xu X, Lu J, Wang Z, Tang B, Wang B, Jin K, Wang Q,
Frontiers in cellular neuroscience. 2015
Our findings suggest that the inflammatory mediators Hcy and UA may play important roles in the pathogenesis of MSA. The measurement of serum Hcy and UA levels could then be a useful tool to accurately distinguish MSA from healthy subjects.
SLITRK3 expression correlation to gastrointestinal stromal tumor risk rating and prognosis.Tuesday, July 28, 2015
Wang CJ, Zhang ZZ, Xu J, Wang M, Zhao WY, Tu L, Zhuang C, Liu Q, Shen YY, Cao H, Zhang ZG,
World journal of gastroenterology : WJG. 21-Jul-2015
SLITRK3 expression is a highly significant predictor of GIST recurrence and metastasis. Combinations of SLITRK3 and NIH stage have strong predictive and prognostic value, and are feasible markers for clinical practice in gastrointestinal stromal tumor.
Screening for genes involved in antibody response to sheep red blood cells in the chicken, Gallus gallus.Tuesday, July 28, 2015
Geng T, Guan X, Smith EJ,
Poultry science. 27-Jul-2015
Antibody response, an important trait in both agriculture and biomedicine, plays a part in protecting animals from infection. Dissecting molecular basis of antibody response may improve artificial selection for natural disease resistance in livestock and poultry. A number of genetic markers associated with antibody response have been identified in the chicken and mouse by linkage-based association studies, which only define genomic regions by genetic markers but do not pinpoint genes for antibody response. In contrast, global expression profiling has been applied to define the molecular bases of a variety of biological traits through identification of differentially expressed genes (DEGs). Here, we employed Affimetrix GeneChip Chicken Genome Arrays to identify differentially expressed genes for antibody response to sheep red blood cells (SRBC) using chickens challenged with and without SRBC or chickens with high and low anti-SRBC titers. The DEGs include those with known (i.e., MHC class I and IgH genes) or unknown function in antibody response. Classification test of these genes suggested that the response of the chicken to intravenous injection of SRBC involved multiple biological processes, including response to stress or other different stimuli, sugar, carbohydrate or protein binding, and cell or soluble fraction, in addition to antibody response. This preliminary study thus provides an insight into molecular basis of antibody response to SRBC in the chicken.
CRB3A controls the morphology and cohesion of cancer cells through Ehm2/p114RhoGEF-dependent signaling.Tuesday, July 28, 2015
Loie E, Charrier LE, Sollier K, Masson JY, Laprise P,
Molecular and cellular biology. 27-Jul-2015
The transmembrane protein CRB3A controls epithelial cell polarization. Elucidating the molecular mechanisms of CRB3A function is essential, as this protein prevents epithelial to mesenchymal transition (EMT), which contributes to tumor progression. To investigate the functional impact of altered CRB3A expression in cancer cells, we expressed CRB3A in HeLa cells, which are devoid of endogenous CRB3A. While control HeLa cells display a patchy F-actin distribution, CRB3A-expressing cells form a circumferential actomyosin belt. This re-organization of the cytoskeleton is accompanied by a transition from an ameboid cell shape to an epithelial-like morphology. In addition, CRB3A increases the cohesion of HeLa cells. To perform these functions, CRB3A recruits p114RhoGEF and its activator Ehm2 to the cell periphery using both functional motifs of its cytoplasmic tail, and increases RhoA activation levels. ROCK1/2, which are critical effectors of RhoA, are also essential to modulate the cytoskeleton and cell shape downstream of CRB3A. Overall, our study highlights novel roles for CRB3A, and deciphers the signaling pathway conferring to CRB3A the ability to fulfill these functions. Thereby, our data will facilitate further investigation of CRB3A functions, and increase our understanding of the cellular defects associated with the loss of CRB3A expression in cancer cells.
Novel serologic biomarkers provide accurate estimates of recent Plasmodium falciparum exposure for individuals and communities.Tuesday, July 28, 2015
Helb DA, Tetteh KK, Felgner PL, Skinner J, Hubbard A, Arinaitwe E, Mayanja-Kizza H, Ssewanyana I, Kamya MR, Beeson JG, Tappero J, Smith DL, Crompton PD, Rosenthal PJ, Dorsey G, Drakeley CJ, Greenhouse B,
Proceedings of the National Academy of Sciences of the United States of America. 27-Jul-2015
Tools to reliably measure Plasmodium falciparum (Pf) exposure in individuals and communities are needed to guide and evaluate malaria control interventions. Serologic assays can potentially produce precise exposure estimates at low cost; however, current approaches based on responses to a few characterized antigens are not designed to estimate exposure in individuals. Pf-specific antibody responses differ by antigen, suggesting that selection of antigens with defined kinetic profiles will improve estimates of Pf exposure. To identify novel serologic biomarkers of malaria exposure, we evaluated responses to 856 Pf antigens by protein microarray in 186 Ugandan children, for whom detailed Pf exposure data were available. Using data-adaptive statistical methods, we identified combinations of antibody responses that maximized information on an individual's recent exposure. Responses to three novel Pf antigens accurately classified whether an individual had been infected within the last 30, 90, or 365 d (cross-validated area under the curve = 0.86-0.93), whereas responses to six antigens accurately estimated an individual's malaria incidence in the prior year. Cross-validated incidence predictions for individuals in different communities provided accurate stratification of exposure between populations and suggest that precise estimates of community exposure can be obtained from sampling a small subset of that community. In addition, serologic incidence predictions from cross-sectional samples characterized heterogeneity within a community similarly to 1 y of continuous passive surveillance. Development of simple ELISA-based assays derived from the successful selection strategy outlined here offers the potential to generate rich epidemiologic surveillance data that will be widely accessible to malaria control programs.
Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors.Tuesday, July 28, 2015
Daemen A, Peterson D, Sahu N, McCord R, Du X, Liu B, Kowanetz K, Hong R, Moffat J, Gao M, Boudreau A, Mroue R, Corson L, O'Brien T, Qing J, Sampath D, Merchant M, Yauch R, Manning G, Settleman J, Hatzivassiliou G, Evangelista M,
Proceedings of the National Academy of Sciences of the United States of America. 27-Jul-2015
Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors.
MALDI mass spectrometry imaging analysis of pituitary adenomas for near-real-time tumor delineation.Tuesday, July 28, 2015
Calligaris D, Feldman DR, Norton I, Olubiyi O, Changelian AN, Machaidze R, Vestal ML, Laws ER, Dunn IF, Santagata S, Agar NY,
Proceedings of the National Academy of Sciences of the United States of America. 27-Jul-2015
We present a proof of concept study designed to support the clinical development of mass spectrometry imaging (MSI) for the detection of pituitary tumors during surgery. We analyzed by matrix-assisted laser desorption/ionization (MALDI) MSI six nonpathological (NP) human pituitary glands and 45 hormone secreting and nonsecreting (NS) human pituitary adenomas. We show that the distribution of pituitary hormones such as prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH), and thyroid stimulating hormone (TSH) in both normal and tumor tissues can be assessed by using this approach. The presence of most of the pituitary hormones was confirmed by using MS/MS and pseudo-MS/MS methods, and subtyping of pituitary adenomas was performed by using principal component analysis (PCA) and support vector machine (SVM). Our proof of concept study demonstrates that MALDI MSI could be used to directly detect excessive hormonal production from functional pituitary adenomas and generally classify pituitary adenomas by using statistical and machine learning analyses. The tissue characterization can be completed in fewer than 30 min and could therefore be applied for the near-real-time detection and delineation of pituitary tumors for intraoperative surgical decision-making.
The behavioural variant frontotemporal dementia (bvFTD) syndrome in psychiatry.Tuesday, July 28, 2015
Lanata SC, Miller BL,
Journal of neurology, neurosurgery, and psychiatry. 27-Jul-2015
The primary goal of this article is to critically discuss the syndromic overlap that exists between early behavioural variant frontotemporal dementia (bvFTD)-the most common clinical syndrome associated with frontotemporal lobar degeneration (FTLD)-and several primary psychiatric disorders. We begin by summarising the current state of knowledge regarding FTLD, including the recent discovery of FTLD-causative genetic mutations. Clinicopathological correlations in FTLD are subsequently discussed, while emphasising that clinical syndromes of FTD are dictated by the distribution of FTLD pathology in the brain. We then review a large number of cases with suspected and confirmed bvFTD that had previously been diagnosed with a primary psychiatric disorder. The clinical and neuroscientific implications of this overlap are discussed, focusing on the importance of early diagnosis for clinical and therapeutic reasons. We propose that largely due to the paucity of biomarkers for primary psychiatric disorders, and the limited use of FTLD-related biomarkers by psychiatrists at present, it is very difficult to separate patients with early bvFTD from those with primary psychiatric disorders based on clinical grounds. Furthermore, specific limitations of the Diagnostic and Statistical Manual of Mental Disorders (DSM) 5 criteria for bvFTD may inadvertently discourage recognition of bvFTD in mental health settings. Clinically, more research is needed to develop tools that allow early differentiation of bvFTD from primary psychiatric disease, as bvFTD therapies will likely be most effective in the earliest stages of disease. From a neuroscience perspective, we argue that bvFTD provides an excellent paradigm for investigating the neural basis of psychiatric disorders.
Elevations in Circulating Methylated and Unmethylated Preproinsulin DNA in New-Onset Type 1 Diabetes.Tuesday, July 28, 2015
Fisher MM, Watkins RA, Blum J, Evans-Molina C, Chalasani N, DiMeglio LA, Mather KJ, Tersey SA, Mirmira RG,
Diabetes. 27-Jul-2015
Elevated ratios of circulating unmethylated to methylated preproinsulin (INS) DNA have been suggested to reflect β-cell death in type 1 diabetes (T1D). We tested the hypothesis that absolute levels (rather than ratios) of unmethylated and methylated INS DNA differ between new-onset T1D subjects and controls, and assessed longitudinal changes in these parameters. We used droplet digital PCR to measure levels of unmethylated and methylated INS DNA in serum from subjects at T1D onset, and at 8 weeks and one year post-onset. Compared to controls, levels of both unmethylated and methylated INS DNA were elevated at T1D onset. At 8 weeks post-onset, methylated INS DNA remained elevated, but unmethylated INS DNA fell. At one year post-onset, both unmethylated and methylated INS DNA returned to control levels. Subjects with obesity, type 2 diabetes (T2D), and autoimmune hepatitis exhibited lower levels of unmethylated and methylated INS compared to T1D subjects at-onset and no differences compared to controls. Our study shows that elevations in both unmethylated and methylated INS DNA occurs in new-onset T1D and that levels of these DNA species change during T1D evolution. Our work emphasizes the need to consider absolute levels of differentially methylated DNA species as potential biomarkers of disease.
Chlamydia trachomatis type III secretion proteins regulate transcription.Tuesday, July 28, 2015
Hanson BR, Slepenkin A, Peterson EM, Tan M,
Journal of bacteriology. 27-Jul-2015
This study investigates a novel mechanism for regulating gene expression in the pathogenic bacterium Chlamydia. The Chlamydia type III secretion (T3S) chaperone Scc4 has been shown to inhibit transcription by RNA polymerase. This study describes physical interactions between Scc4 and the T3S proteins Scc1 and CopN. Furthermore Chlamydia Scc1 and CopN antagonized the inhibitory effects of Scc4 on transcription and growth in a heterologous E. coli system. These results provide evidence that transcription in Chlamydia can be regulated by the T3S system through interactions between T3S proteins.
Genetics and Genetic Biomarkers in Sporadic Colorectal Cancer.Tuesday, July 28, 2015
Carethers JM, Jung BH,
Gastroenterology. 24-Jul-2015
Sporadic colorectal cancer (CRC) is a somatic genetic disease in which pathogenesis is influenced by the local colonic environment and the patient's genetic background. Consolidating the knowledge of genetic and epigenetic events that occur with initiation, progression, and metastasis of sporadic CRC has identified some biomarkers that might be utilized to predict behavior and prognosis beyond staging, and inform treatment approaches. Modern next generation sequencing of sporadic CRCs has confirmed prior identified genetic alterations, and has classified new alterations. Each patient's CRC is genetically unique, propelled by 2 to 8 driver gene alterations that have accumulated within the CRC since initiation. Commonly observed alterations across sporadic CRCs have allowed classification into a: (1) hypermutated group that includes defective DNA mismatch repair with microsatellite instability (MSI) and POLE mutations in ∼15%, containing multiple frameshifted genes and BRAF(V600E); (2) non-hypermutated group with multiple somatic copy number alterations and aneuploidy in ∼85%, containing oncogenic activation of KRAS and PIK3CA and mutation and loss of heterozygosity of tumor suppressor genes such as APC and TP53; (3) CpG Island Methylator Phenotype CRCs in ∼20% that overlap greatly with MSI CRCs and some non-hypermutated CRCs; and (4) elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) in ∼60% that associates with metastatic behavior in both hypermutated and non-hypermutated groups. Components from these classifications are now used as diagnostic, prognostic and treatment biomarkers. Additional common biomarkers may come from genome-wide association studies and microRNAs among other sources, as well as from the unique alteration profile of an individual CRC to apply a precision medicine approach to care.
Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers.Tuesday, July 28, 2015
Okugawa Y, Grady WM, Goel A,
Gastroenterology. 24-Jul-2015
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colon epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer "epigenome" has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, is presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.
Scavenger Receptors: Emerging Roles in Cancer Biology and Immunology.Tuesday, July 28, 2015
Yu X, Guo C, Fisher PB, Subjeck JR, Wang XY,
Advances in cancer research. 2015
Scavenger receptors constitute a large family of evolutionally conserved protein molecules that are structurally and functionally diverse. Although scavenger receptors were originally identified based on their capacity to scavenge modified lipoproteins, these molecules have been shown to recognize and bind to a broad spectrum of ligands, including modified and unmodified host-derived molecules or microbial components. As a major subset of innate pattern recognition receptors, scavenger receptors are mainly expressed on myeloid cells and function in a wide range of biological processes, such as endocytosis, adhesion, lipid transport, antigen presentation, and pathogen clearance. In addition to playing a crucial role in maintenance of host homeostasis, scavenger receptors have been implicated in the pathogenesis of a number of diseases, e.g., atherosclerosis, neurodegeneration, or metabolic disorders. Emerging evidence has begun to reveal these receptor molecules as important regulators of tumor behavior and host immune responses to cancer. This review summarizes our current understanding on the newly identified, distinct functions of scavenger receptors in cancer biology and immunology. The potential of scavenger receptors as diagnostic biomarkers and novel targets for therapeutic interventions to treat malignancies is also highlighted.
Proteomics driven biomarker discovery in gestational diabetes mellitus: A review.Tuesday, July 28, 2015
Singh A, Subramani E, DattaRay C, Rapole S, Chaudhury K,
Journal of proteomics. 24-Jul-2015
GDM refers to glucose intolerance which develops in women after 20weeks of gestation. The lack of uniformity in screening standards has led to rise in percentage of undetected cases in GDM. Thus, owing to the limitations of the current early pregnancy screening tools to identify women at risk of developing GDM, it is crucial to discover new biomarkers which can aid in disease identification and subsequent development. Proteomics relies on analysis of complete set of proteome for comprehensive understanding of complex biological processes and helps to gain insights into the molecular mechanisms of disease initiation and progression through monitoring cell activity in real time. Therefore, accurate early prediction of those destined to develop GDM would allow for early initiation of measures that may ameliorate the effects of this condition.
Bioprinting for cancer research.Tuesday, July 28, 2015
Knowlton S, Onal S, Yu CH, Zhao JJ, Tasoglu S,
Trends in biotechnology. 24-Jul-2015
Bioprinting offers the ability to create highly complex 3D architectures with living cells. This cutting-edge technique has significantly gained popularity and applicability in several fields. Bioprinting methods have been developed to effectively and rapidly pattern living cells, biological macromolecules, and biomaterials. These technologies hold great potential for applications in cancer research. Bioprinted cancer models represent a significant improvement over previous 2D models by mimicking 3D complexity and facilitating physiologically relevant cell-cell and cell-matrix interactions. Here we review bioprinting methods based on inkjet, microextrusion, and laser technologies and compare 3D cancer models with 2D cancer models. We discuss bioprinted models that mimic the tumor microenvironment, providing a platform for deeper understanding of cancer pathology, anticancer drug screening, and cancer treatment development.
[MicroRNAs in kidney fibrosis].Tuesday, July 28, 2015
Van der Hauwaert C, Savary G, Hennino MF, Pottier N, Glowacki F, Cauffiez C,
Nephrologie & therapeutique. 24-Jul-2015
Renal fibrosis represents the final stage of most chronic kidney diseases and contributes to the progressive and irreversible decline in kidney function with accumulation of extracellular matrix components in the renal parenchyma. The molecular mechanisms governing the renal fibrosis process are complex and remain poorly understood. Recently, the profibrotic role of several microRNAs (miRNAs) has been described in kidney fibrosis. MiRNAs are a new class of, small non-coding RNAs of about 20 nucleotides that act as gene expression negative regulators at the post-transcriptional level. Seminal studies have highlighted the potential importance of miRNA as new therapeutic targets and innovative diagnostic and/or prognostic biomarkers. This review summarizes recent scientific advances on the role played by miRNAs in kidney fibrogenesis and discusses potential clinical applications as well as future research directions.
Microelectrode bioimpedance analysis distinguishes basal and claudin-low subtypes of triple negative breast cancer cells.Tuesday, July 28, 2015
Srinivasaraghavan V, Strobl J, Agah M,
Biomedical microdevices. Aug-2015
Triple negative breast cancer (TNBC) is highly aggressive and has a poor prognosis when compared to other molecular subtypes. In particular, the claudin-low subtype of TNBC exhibits tumor-initiating/cancer stem cell like properties. Here, we seek to find new biomarkers to discriminate different forms of TNBC by characterizing their bioimpedance. A customized bioimpedance sensor with four identical branched microelectrodes with branch widths adjusted to accommodate spreading of individual cells was fabricated on silicon and pyrex/glass substrates. Cell analyses were performed on the silicon devices which showed somewhat improved inter-electrode and intra-device reliability. We performed detailed analysis of the bioimpedance spectra of four TNBC cell lines, comparing the peak magnitude, peak frequency and peak phase angle between claudin-low TNBC subtype represented by MDA-MB-231 and Hs578T with that of two basal cells types, the TNBC MDA-MB-468, and an immortalized non-malignant basal breast cell line, MCF-10A. The claudin-low TNBC cell lines showed significantly higher peak frequencies and peak phase angles than the properties might be useful in distinguishing the clinically significant claudin-low subtype of TNBC.
The Aggregatibacter actinomycetemcomitans cytolethal distending toxin active subunit, CdtB, contains a cholesterol recognition sequence required for toxin binding and subunit internalization.Tuesday, July 28, 2015
Boesze-Battaglia K, Walker LP, Zekavat A, Dlakić M, Scuron MD, Nygren P, Shenker BJ,
Infection and immunity. 27-Jul-2015
Induction of cell cycle arrest in lymphocytes following exposure to the Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) is dependent upon the integrity of lipid membrane microdomains. Moreover, we have previously demonstrated that the associaton of Cdt with target cells involves the CdtC subunit which binds to cholesterol via a cholesterol recognition amino acid consensus sequence (CRAC site). In this study we demonstrate that the active Cdt subunit, CdtB, also is capable of binding to large unilamellar vesicles (LUVs) containing cholesterol. Furthermore, CdtB binding to cholesterol involves a similar CRAC site as that demonstrated for CdtC. Mutation of the CRAC site reduces binding to model membranes as well as toxin binding and CdtB internalization in both Jurkat cells and human macrophages. A concomitant reduction in Cdt-induced toxicity was also noted indicated by reduced cell cycle arrest and apoptosis in Jurkat cells and a reduction in the pro-inflammatory response in macrophages (IL-1β and TNFα release). Collectively, these observations indicate that membrane cholesterol serves as an essential ligand for both CdtC and CdtB and further, that this binding is necessary for both internalization of CdtB and subsequent molecular events leading to intoxication of cells.
Acylation enhances, but is not required for, the cytotoxic activity of Mannheimia haemolytica leukotoxin in bighorn sheep.Tuesday, July 28, 2015
Batra SA, Shanthalingam S, Munske GR, Raghavan B, Kugadas A, Bavanthasivam J, Highlander SK, Srikumaran S,
Infection and immunity. 27-Jul-2015
Mannheimia haemolytica causes pneumonia in domestic and wild ruminants. Leukotoxin (Lkt) is the most important virulence factor of this bacterium. It is encoded within the four-gene lktCABD operon: lktA encodes the structural pro-toxin and lktC encodes a trans-acylase that adds fatty acid chains to internal lysine residues in the pro-toxin, which is then secreted from the cell by a type 1 secretion system apparatus encoded by lktB and lktD. It has been reported that LktC-mediated acylation is necessary for the biological effects of the toxin. However, an LktC mutant that we developed previously was only partially attenuated in its virulence for cattle. The objective of this study was to elucidate the role of LktC-mediated acylation in Lkt-induced cytotoxicity. We performed this study in bighorn sheep (Ovis canadensis; BHS) since they are highly susceptible to M. haemolytica infection. The LktC mutant caused fatal pneumonia in 40% of inoculated BHS. On necropsy, a large number of necrotic PMNs were observed in the lungs. Lkt from the mutant was cytotoxic to BHS PMNs in an in vitro cytotoxicity assay. Flow cytometric analysis of mutant Lkt-treated PMNs revealed the induction of necrosis. Scanning electron microscopic analysis revealed the presence of pores and blebs on mutant-Lkt-treated PMNs. Mass spectrometric analysis confirmed that the mutant secreted an un-acylated Lkt. Taken together, these results suggest that acylation is not necessary for the cytotoxic activity of M. haemolytica Lkt, but that it enhances the potency of the toxin.
Effects of Dietary Different Doses of Copper and High Fructose Feeding on Rat Fecal Metabolome.Tuesday, July 28, 2015
Wei X, Song M, Yin X, Schuschke DA, Koo I, McClain CJ, Zhang X,
Journal of proteome research. 28-Jul-2015
The gut microbiota play a critical role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Increased fructose consumption and inadequate copper intake are two critical risk factors in the development of NAFLD. To gain insights into the role of gut microbiota, fecal metabolites, obtained from rats exposed to dietary different levels of copper with and without high fructose intake for 4 weeks, were analyzed by GC×GC-TOF MS. In parallel, liver tissues were assessed by histology and triglyceride assay. Our data showed that high fructose feeding led to obvious hepatic steatosis in both marginal copper deficient rats and copper supplementation rats. Among the 38 metabolites detected with significant abundance alteration between groups, short chain fatty acids (SCFAs) were markedly decreased with excessive fructose intake, irrespective of copper levels. C15:0 and C17:0 long chain fatty acids (LCFAs), produced only by bacteria, were increased by either high copper level or high fructose intake. In addition, increased fecal urea and malic acid paralleled the increased hepatic fat accumulation. Collectively, GC×GC-TOF MS analysis of rat fecal samples revealed distinct fecal metabolome profiles associated with the dietary high fructose and copper level, with some metabolites possibly serving as potential noninvasive biomarkers of fructose induced-NAFLD.
MicroRNAs in Ovarian Cancer.Tuesday, July 28, 2015
Katz B, Tropé CG, Reich R, Davidson B,
Human pathology. 30-Jun-2015
Ovarian cancer, consisting predominantly of ovarian carcinoma, is the eighth most common cancer in women and the most lethal gynecologic malignancy. Efforts focus on identifying biomarkers which may aid in early diagnosis and reduce mortality, as well as on characterizing therapeutic targets with the aim of circumventing chemoresistance and prolonging survival at advanced-stage disease. MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression, and have been found to play an important role in ovarian carcinoma. Recent research has identified multiple miRNAs involved in the biology and progression of the disease, and supports a role for miRNAs as potential biomarkers, predictive markers and prognostic factors. Many of the studies published to date nevertheless suffer from critical weaknesses which affect data quality and reproducibility, including the comparison of normal ovaries to tumor tissue without compensation for the highly discrepant target cell fraction in these two specimen types and the inclusion of carcinomas of different histotypes, non-epithelial tumors or tumors of non-specified histology. These shortcomings highlight the critical role of pathologists as part of the team in the setting of such research. This review summarizes current knowledge in this area and discusses the potential clinical relevance of miRNAs in ovarian carcinoma, with focus on studies of clinical specimens in which tissue selection has been deemed adequate.
HNF4α Regulates Claudin-7 Protein Expression during Intestinal Epithelial Differentiation.Tuesday, July 28, 2015
Farkas AE, Hilgarth RS, Capaldo CT, Gerner-Smidt C, Powell DR, Vertino PM, Koval M, Parkos CA, Nusrat A,
The American journal of pathology. Aug-2015
The intestinal epithelium is a dynamic barrier that maintains the distinct environments of intestinal tissue and lumen. Epithelial barrier function is defined principally by tight junctions, which, in turn, depend on the regulated expression of claudin family proteins. Claudins are expressed differentially during intestinal epithelial cell (IEC) differentiation. However, regulatory mechanisms governing claudin expression during epithelial differentiation are incompletely understood. We investigated the molecular mechanisms regulating claudin-7 during IEC differentiation. Claudin-7 expression is increased as epithelial cells differentiate along the intestinal crypt-luminal axis. By using model IECs we observed increased claudin-7 mRNA and nascent heteronuclear RNA levels during differentiation. A screen for potential regulators of the CLDN7 gene during IEC differentiation was performed using a transcription factor/DNA binding array, CLDN7 luciferase reporters, and in silico promoter analysis. We identified hepatocyte nuclear factor 4α as a regulatory factor that bound endogenous CLDN7 promoter in differentiating IECs and stimulated CLDN7 promoter activity. These findings support a role of hepatocyte nuclear factor 4α in controlling claudin-7 expression during IEC differentiation.
Role of Platelet-Derived Growth Factor-CC in Capillary Rarefaction in Renal Fibrosis.Tuesday, July 28, 2015
Boor P, Bábíčková J, Steegh F, Hautvast P, Martin IV, Djudjaj S, Nakagawa T, Ehling J, Gremse F, Bücher E, Eriksson U, van Roeyen CR, Eitner F, Lammers T, Floege J, Peutz-Kootstra CJ, Ostendorf T,
The American journal of pathology. Aug-2015
We have identified platelet-derived growth factor (PDGF)-CC as a potent profibrotic mediator in kidney fibrosis and pro-angiogenic mediator in glomeruli. Because renal fibrosis is associated with progressive capillary rarefaction, we asked whether PDGF-CC neutralization in fibrosis might have detrimental anti-angiogenic effects leading to aggravated peritubular capillary loss. We analyzed capillary rarefaction in mice with and without PDGF-CC neutralization (using genetically deficient mice and neutralizing antibodies), in three different models of renal interstitial fibrosis, unilateral ureteral obstruction, unilateral ischemia-reperfusion, Col4a3-deficient (Alport) mice, and healthy animals. Independent of the effect of PDGF-CC neutralization on renal fibrosis, we found no difference in capillary rarefaction between PDGF-CC-neutralized mice and mice with intact PDGF-CC. We also found no differences in microvascular leakage (determined by extravasation of Evans Blue Dye) and in renal relative blood volume quantified using in vivo microcomputed tomography. PDGF-CC neutralization had no effects on renal microvasculature in healthy animals. Capillary endothelium did not express PDGF receptor-α, suggesting that potential PDGF-CC effects would have to be indirect. PDGF-CC neutralization or deficiency was not associated with preservation or accelerated loss of peritubular capillaries, suggesting no significant pro-angiogenic effects of PDGF-CC during renal fibrosis. From a clinical perspective, the profibrotic effects of PDGF-CC outweigh the pro-angiogenic effects and, thus, do not limit a potential therapeutic use of PDGF-CC inhibition in renal fibrosis.
A group ICA based framework for evaluating resting fMRI markers when disease categories are unclear: Application to schizophrenia, bipolar, and schizoaffective disorders.Tuesday, July 28, 2015
Du Y, Pearlson GD, Liu J, Sui J, Yu Q, He H, Castro E, Calhoun VD,
NeuroImage. 24-Jul-2015
Schizophrenia (SZ), bipolar disorder (BP) and schizoaffective disorder (SAD) share some common symptoms, and there is a debate about whether SAD is an independent category. To the best of our knowledge, no study has been done to differentiate these three disorders or to investigate the distinction of SAD as an independent category using fMRI data. The present study is aimed to explore biomarkers from resting-state fMRI networks for differentiating these disorders and investigate the relationship among these disorders based on fMRI networks with an emphasis on SAD. Firstly, a novel group ICA method, group information guided independent component analysis (GIG-ICA), was applied to extract subject-specific brain networks from fMRI data of 20 healthy controls (HC), 20 SZ patients, 20 BP patients, 20 patients suffering SAD with manic episodes (SADM), and 13 patients suffering SAD with depressive episodes exclusively (SADD). Then, five-level one-way analysis of covariance and multiclass support vector machine recursive feature elimination were employed to identify discriminative regions from the networks. Subsequently, the t-distributed stochastic neighbor embedding (t-SNE) projection and the hierarchical clustering methods were implemented to investigate the relationship among those groups. Finally, to evaluate the generalization ability, 16 new subjects were classified based on the found regions and the trained model using original 93 subjects. Results show that the discriminative regions mainly include frontal, parietal, precuneus, cingulate, supplementary motor, cerebellar, insula and supramarginal cortices, which performed well in distinguishing different groups. SADM and SADD were the most similar to each other, although SADD had greater similarity to SZ compared to other groups, which indicates SAD may be an independent category. BP was closer to HC compared with other psychotic disorders. In summary, resting-state fMRI brain networks extracted via GIG-ICA provide a promising potential to differentiate SZ, BP, and SAD.
The Effect of Viral Infection on Exhaled Nitric Oxide in Children with Acute Asthma Exacerbations.Tuesday, July 28, 2015
Malka J, Covar R, Faino A, Fish J, Pickering P, Ramamoorthy P, Gleason M, Spahn JD,
The journal of allergy and clinical immunology. In practice. 24-Jul-2015
Higher Feno concentration in PCR (-) exacerbations suggests an eosinophilic predominance in nonviral compared with viral exacerbations.
Epigenetic inheritance and the missing heritability.Tuesday, July 28, 2015
Trerotola M, Relli V, Simeone P, Alberti S,
Human genomics. 2015
Genome-wide association studies of complex physiological traits and diseases consistently found that associated genetic factors, such as allelic polymorphisms or DNA mutations, only explained a minority of the expected heritable fraction. This discrepancy is known as "missing heritability", and its underlying factors and molecular mechanisms are not established. Epigenetic programs may account for a significant fraction of the "missing heritability." Epigenetic modifications, such as DNA methylation and chromatin assembly states, reflect the high plasticity of the genome and contribute to stably alter gene expression without modifying genomic DNA sequences. Consistent components of complex traits, such as those linked to human stature/height, fertility, and food metabolism or to hereditary defects, have been shown to respond to environmental or nutritional condition and to be epigenetically inherited. The knowledge acquired from epigenetic genome reprogramming during development, stem cell differentiation/de-differentiation, and model organisms is today shedding light on the mechanisms of (a) mitotic inheritance of epigenetic traits from cell to cell, (b) meiotic epigenetic inheritance from generation to generation, and (c) true transgenerational inheritance. Such mechanisms have been shown to include incomplete erasure of DNA methylation, parental effects, transmission of distinct RNA types (mRNA, non-coding RNA, miRNA, siRNA, piRNA), and persistence of subsets of histone marks.
The impact of sleep on age-related sarcopenia: possible connections and clinical implications.Tuesday, July 28, 2015
Piovezan RD, Abucham J, Dos Santos RV, Mello MT, Tufik S, Poyares D,
Ageing research reviews. 24-Jul-2015
Sarcopenia is a geriatric condition that comprises declined skeletal muscle mass, strength and function, leading to the risk of multiple adverse outcomes, including death. Its pathophysiology involves neuroendocrine and inflammatory factors, unfavorable nutritional habits and low physical activity. Sleep may play a role in muscle protein metabolism, although this hypothesis has not been studied extensively. Reductions in duration and quality of sleep and increases in prevalence of circadian rhythm and sleep disorders with age favor proteolysis, modify body composition and increase the risk of insulin resistance, all of which have been associated with sarcopenia. Data on the effects of age-related slow-wave sleep decline, circadian rhythm disruptions and obstructive sleep apnea (OSA) on hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-gonadal (HPG), somatotropic axes, and glucose metabolism indicate that sleep disorder interventions may affect muscle loss. OSA parameters and recent research associating the risk of conditions closely related to the sarcopenia process, such as frailty and sleep quality impairment, indirectly suggest that sleep can influence skeletal muscle decline in the elderly. Several protein synthesis and degradation pathways are mediated by growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, cortisol and insulin, which act on the cellular and molecular levels to increase or reestablish muscle fiber, strength and function. Age-related sleep problems potentially interfere intracellularly by inhibiting anabolic hormone cascades and enhancing catabolic pathways in the skeletal muscle. Nutritional recommendations and specific physical exercises are the current treatment options for sarcopenia. Clinical studies testing exogenous administration of anabolic hormones have not yielded adequate safety profiles. Therapeutic approaches targeting sleep disturbances to normalize circadian rhythms and sleep homeostasis may represent a novel strategy to preserve or recover muscle health in older adults. Promising research results regarding the associations between sleep variables and sarcopenia biomarkers and clinical parameters are required to confirm this hypothesis.
Genotype-phenotype correlations in 5-fluorouracil metabolism: a candidate DPYD haplotype to improve toxicity prediction.Tuesday, July 28, 2015
Gentile G, Botticelli A, Lionetto L, Mazzuca F, Simmaco M, Marchetti P, Borro M,
The pharmacogenomics journal. 28-Jul-2015
5-Fluorouracil is among the most widely used anticancer drug, but a fraction of treated patients develop severe toxicity, with potentially lethal injuries. The predictive power of the available pretreatment assays, used to identify patients at risk of severe toxicity, needs improvements. This study aimed to correlate a phenotypic marker of 5-fluorouracil metabolism (the individual degradation rate of 5-fluorouracil-5-FUDR) with 15 functional polymorphisms in the dihydropyrimidine dehydrogenase gene (DPYD). Single SNP (single-nucleotide polymorphism) analysis revealed that the SNPs rs1801160, rs1801265, rs2297595 and rs3918290 (splice site variant IVS14+1G>A) were significantly associated with a decreased value of 5-FUDR, and the rs3918290 causing the larger decrease. Multi-SNP analysis showed that a three-SNP haplotype (Hap7) involving rs1801160, rs1801265 and rs2297595 causes a marked decrease in 5-FUDR, comparable to that caused by the splice site variant rs3918290, which is the main pharmacogenetic marker associated with severe fluorouracil toxicity. The similar effect played by Hap7 and by the splice site variant rs3918290 upon individual 5-FUDR suggests that Hap7 could also represent a similar determinant of fluorouracil toxicity. Haplotype assessment could improve the predictive value of DPYD genetic markers aimed at the pre-emptive identification of patients at risk of severe 5-fluorouracil toxicity.The Pharmacogenomics Journal advance online publication, 28 July 2015; doi:10.1038/tpj.2015.56.
Oral lichen planus: salival biomarkers cortisol, immunoglobulin A, adiponectin.Tuesday, July 28, 2015
Lopez-Jornet P, Cayuela CA, Tvarijonaviciute A, Parra-Perez F, Escribano D, Ceron J,
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 27-Jul-2015
OLP patients presented worse psychological profiles and sleep disturbances, as well as higher values for IgA, cortisol, and total proteins than control subjects.
Interobserver agreement in dysplasia grading: toward an enhanced gold standard for clinical pathology trials.Tuesday, July 28, 2015
Speight PM, Abram TJ, Floriano PN, James R, Vick J, Thornhill MH, Murdoch C, Freeman C, Hegarty AM, D'Apice K, Kerr AR, Phelan J, Corby P, Khouly I, Vigneswaran N, Bouquot J, Demian NM, Weinstock YE, Redding SW, Rowan S, Yeh CK, McGuff HS, Miller FR, McDevitt JT,
Oral surgery, oral medicine, oral pathology and oral radiology. 17-Jun-2015
The use of the defined protocol resulted in a substantial increase (30%) in diagnostic agreement and has the potential to improve the level of agreement for establishing gold standards for studies based on histopathologic diagnosis.
Identification of somatic gene mutations in penile squamous cell carcinoma.Tuesday, July 28, 2015
Ferrándiz-Pulido C, Hernández-Losa J, Masferrer E, Vivancos A, Somoza R, Marés R, Valverde C, Salvador C, Placer J, Morote J, Pujol RM, Ramon S, Cajal Y, de Torres I, Toll A, García-Patos V,
Genes, chromosomes & cancer. 27-Jul-2015
There is a lack of studies on somatic gene mutations and cell signaling driving penile carcinogenesis. Our objective was to analyze somatic mutations in genes downstream of EGFR in penile squamous cell carcinomas, especially the mTOR and RAS/MAPK pathways. We retrospectively analyzed somatic mutations in 10 in situ and 65 invasive penile squamous cell carcinomas by using Sequenom's Mass Spectrometry iPlex Technology and Oncocarta v1.0 Panel. The DNA was extracted from FFPE blocks and we identified somatic missense mutations in three in situ tumors and in 19 invasive tumors, mostly in PIK3CA, KRAS, HRAS, NRAS, and PDGFA genes. Somatic mutations in the PIK3CA gene or RAS family genes were neither associated with tumor grade, stage or outcome, and were equally often identified in hrHPV positive and in hrHPV negative tumors that showed no p53 expression. Mutations in PIK3CA, KRAS, and HRAS are frequent in penile squamous cell carcinoma and likely play a role in the development of p53-negative tumors. Although the presence of these mutations does not seem to correlate with tumoral behavior or outcome, they could be biomarkers of treatment failure with anti-EGFR mAb in patients with penile squamous cell carcinoma. © 2015 Wiley Periodicals, Inc.
Human Islets Have Fewer Blood Vessels than Mouse Islets and the Density of Islet Vascular Structures Is Increased in Type 2 Diabetes.Tuesday, July 28, 2015
Brissova M, Shostak A, Fligner CL, Revetta FL, Washington MK, Powers AC, Hull RL,
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. Aug-2015
Human and rodent islets differ substantially in several features, including architecture, cell composition, gene expression and some aspects of insulin secretion. Mouse pancreatic islets are highly vascularized with interactions between islet endothelial and endocrine cells being important for islet cell differentiation and function. To determine whether human islets have a similar high degree of vascularization and whether this is altered with diabetes, we examined the vascularization of islets from normal human subjects, subjects with type 2 diabetes (T2D), and normal mice. Using an integrated morphometry approach to quantify intra-islet capillary density in human and mouse pancreatic sections, we found that human islets have five-fold fewer vessels per islet area than mouse islets. Islets in pancreatic sections from T2D subjects showed capillary thickening, some capillary fragmentation and had increased vessel density as compared with non-diabetic controls. These changes in islet vasculature in T2D islets appeared to be associated with amyloid deposition, which was noted in islets from 8/9 T2D subjects (and occupied 14% ± 4% of islet area), especially around the intra-islet capillaries. The physiological implications of the differences in the angioarchitecture of mouse and human islets are not known. Islet vascular changes in T2D may exacerbate β cell/islet dysfunction and β cell loss.
Hyaluronan: A Mediator of Islet Dysfunction and Destruction in Diabetes?Tuesday, July 28, 2015
Hull RL, Bogdani M, Nagy N, Johnson PY, Wight TN,
The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. Aug-2015
Hyaluronan (HA) is an extracellular matrix (ECM) component that is present in mouse and human islet ECM. HA is localized in peri-islet and intra-islet regions adjacent to microvessels. HA normally exists in a high molecular weight form, which is anti-inflammatory. However, under inflammatory conditions, HA is degraded into fragments that are proinflammatory. HA accumulates in islets of human subjects with recent onset type 1 diabetes (T1D), and is associated with myeloid and lymphocytic islet infiltration, suggesting a possible role for HA in insulitis. A similar accumulation of HA, in amount and location, occurs in non-obese diabetic (NOD) and DORmO mouse models of T1D. Furthermore, HA accumulates in follicular germinal centers and in T-cell areas in lymph nodes and spleen in both human and mouse models of T1D, as compared with control tissues. Whether HA accumulates in islets in type 2 diabetes (T2D) or models thereof has not been previously described. Here we show evidence that HA accumulates in a mouse model of islet amyloid deposition, a well-known component of islet pathology in T2D. In summary, islet HA accumulation is a feature of both T1D and a model of T2D, and may represent a novel inflammatory mediator of islet pathology.
Evaluating the Atrial Myopathy Underlying Atrial Fibrillation: Identifying the Arrhythmogenic and Thrombogenic Substrate.Tuesday, July 28, 2015
Goldberger JJ, Arora R, Green D, Greenland P, Lee DC, Lloyd-Jones DM, Markl M, Ng J, Shah SJ,
Circulation. 28-Jul-2015
Atrial disease or myopathy forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. Current diagnostic approaches in patients with AF focus on identifying clinical predictors with the evaluation of left atrial size by echocardiography serving as the sole measure specifically evaluating the atrium. Although the atrial substrate underlying AF is likely developing for years before the onset of AF, there is no current evaluation to identify the preclinical atrial myopathy. Atrial fibrosis is 1 component of the atrial substrate that has garnered recent attention based on newer MRI techniques that have been applied to visualize atrial fibrosis in humans with prognostic implications regarding the success of treatment. Advanced ECG signal processing, echocardiographic techniques, and MRI imaging of fibrosis and flow provide up-to-date approaches to evaluate the atrial myopathy underlying AF. Although thromboembolic risk is currently defined by clinical scores, their predictive value is mediocre. Evaluation of stasis via imaging and biomarkers associated with thrombogenesis may provide enhanced approaches to assess risk for stroke in patients with AF. Better delineation of the atrial myopathy that serves as the substrate for AF and thromboembolic complications might improve treatment outcomes. Furthermore, better delineation of the pathophysiologic mechanisms underlying the development of the atrial substrate for AF, particularly in its earlier stages, could help identify blood and imaging biomarkers that could be useful to assess risk for developing new-onset AF and suggest specific pathways that could be targeted for prevention.
State of the art in germ cell tumor imaging.Tuesday, July 28, 2015
Secil M, Altay C, Basara I,
Urologic oncology. 24-Jul-2015
Germ cell tumors (GCTs) are the most common tumors of the testis and arise from germinal epithelium cells in the seminiferous tubules. All GCTs show malignant behavior and frequently metastasize. The diagnosis of GCTs depends on the clinical manifestations, laboratory parameters, preoperative imaging features, and tissue biomarkers. Ultrasonography and Doppler ultrasonography are the primary imaging modalities used to evaluate testicular masses. Sonoelastography is a diagnostic tool that can measure the stiffness of tissue and may differentiate between benign and malignant tumors of testis. Magnetic resonance imaging of the scrotum may be used as an additional tool, which may provide additional information owing to its high soft tissue contrast discrimination capability. Computed tomography of the thorax and abdomen and positron emission tomography/computed tomography are used for staging of the disease and for follow-up after treatment.
microRNA-150: a promising novel biomarker for hepatitis B virus-related hepatocellular carcinoma.Tuesday, July 28, 2015
Yu F, Lu Z, Chen B, Dong P, Zheng J,
Diagnostic pathology. 2015
Serum miR-150 can serve as a non-invasive biomarker for the diagnosis and prognosis of HCC patients.
Protein prenylation in islet β-cell function in health and diabetes: Putting the pieces of the puzzle together.Tuesday, July 28, 2015
Kowluru A, Kowluru RA,
Biochemical pharmacology. 24-Jul-2015
Post-translational prenylation involves incorporation of 15- [farnesyl] or 20- [geranylgeranyl] carbon derivatives of mevalonic acid into highly conserved C-terminal cysteines of proteins. The farnesyl transferase [FTase] and the geranylgeranyl transferase [GGTase] mediate incorporation of farnesyl and geranylgeranyl groups, respectively. At least 300 proteins are prenylated in the human genome; the majority of these are implicated in cellular processes including growth, differentiation, cytoskeletal function and vesicle trafficking. From a functional standpoint, isoprenylation is requisite for targeting of modified proteins to relevant cellular compartments for regulation of effector proteins. Pharmacological and molecular biological studies have provided compelling evidence for key roles of this signaling pathway in physiological insulin secretion in normal rodent and human islets. Recent evidence indicates that inhibition of prenylation results in mislocalization of unprenylated proteins, and surprisingly, they remain in active [GTP-bound] conformation. Sustained activation of G proteins has been reported in mice lacking GGTase, suggesting alternate mechanisms for the activation of non-prenylated G proteins. These findings further raise an interesting question if mislocalized, non-prenylated and functionally active G proteins cause cellular pathology since aberrant protein prenylation has been implicated in the onset of cardiovascular disease and diabetes. Herein, we overview the existing evidence to implicate prenylation in islet function and potential defects in this signaling pathways in the diabetic β-cell. We will also identify critical knowledge gaps that need to be addressed for the development of therapeutics to halt defects in these signaling steps in β cells in models of impaired insulin secretion, metabolic stress and diabetes.
Penetration depth of corneal cross-linking with riboflavin and UV-A (CXL) in horses and rabbits.Tuesday, July 28, 2015
Gallhoefer NS, Spiess BM, Guscetti F, Hilbe M, Hartnack S, Hafezi F, Pot SA,
Veterinary ophthalmology. 27-Jul-2015
CXL penetration depth, as determined by a novel ex vivo fluorescent assay, shows clear differences between species. A distinct effect was observed following epithelium-off CXL treatment in the anterior stroma of rabbits, but no different effect was observed in horses in comparison with nontreated controls. Different protocols need to be established to effectively treat equine patients with infectious corneal disease.
Morphology in the Digital Age: Integrating High-Resolution Description of Structural Alterations With Phenotypes and Genotypes.Tuesday, July 28, 2015
Nast CC, Lemley KV, Hodgin JB, Bagnasco S, Avila-Casado C, Hewitt SM, Barisoni L,
Seminars in nephrology. May-2015
Conventional light microscopy has been used to characterize and classify renal diseases, evaluate histopathology in studies and trials, and educate renal pathologists and nephrologists. The advent of digital pathology, in which a glass slide can be scanned to create whole slide images (WSIs) for viewing and manipulating on a computer monitor, provides real and potential advantages compared with conventional light microscopy. Software tools such as annotation, morphometry, and image analysis can be applied to WSIs for studies or educational purposes, and the digital images are available globally to clinicians, pathologists, and investigators. New ways of assessing renal pathology with observational data collection may allow better morphologic correlations and integration with molecular and genetic signatures, refinements of classification schema, and understanding of disease pathogenesis. In multicenter studies, WSIs, which require additional quality assurance steps, provide efficiency by reducing slide shipping and consensus conference costs, and they allow slide viewing anytime and anywhere. Although validation studies for the routine diagnostic use of digital pathology still are needed, this is a powerful tool currently available for translational research, clinical trials, and education in renal pathology.
Matching Kidneys and Urines: Establishing Noninvasive Surrogates of Intrarenal Events in Primary Glomerulonephritis.Tuesday, July 28, 2015
Reich HN, Sabelnykova VY, Boutros PC,
Seminars in nephrology. May-2015
Kidney biopsy is the gold standard procedure for providing diagnostic and prognostic information for patients with glomerular-based diseases, however, the utility of this procedure for assessing longitudinal disease activity is limited. The intense search for noninvasive biomarkers of kidney disease activity and injury is driven in large part by the inherent risks of the kidney biopsy procedure and limited information derived from the morphologic description of biopsy findings. Furthermore, gaps in our understanding of the core intrarenal molecular processes underlying the development and progression of glomerular-based diseases has limited the development of effective targeted therapy. In this review, we discuss the potential utility of molecular analysis of the urine to provide a dynamic window into intrarenal molecular and morphologic responses. We focus on molecular analysis of the urine to identify noninvasive surrogate markers of kidney responses, with the goal of using these biomarkers as more sensitive indicators of progression and tissue-level responses to therapeutic interventions in patients with primary glomerulonephritis.
APOL1 Kidney Disease Risk Variants: An Evolving Landscape.Tuesday, July 28, 2015
Dummer PD, Limou S, Rosenberg AZ, Heymann J, Nelson G, Winkler CA, Kopp JB,
Seminars in nephrology. May-2015
Apolipoprotein L1 (APOL1) genetic variants account for much of the excess risk of chronic and end-stage kidney disease, which results in a significant global health disparity for persons of African ancestry. We estimate the lifetime risk of kidney disease in APOL1 dual-risk allele individuals to be at least 15%. Experimental evidence suggests a direct role of APOL1 in pore formation, cellular injury, and programmed cell death in renal injury. The APOL1 BH3 motif, often associated with cell death, is unlikely to play a role in APOL1-induced cytotoxicity because it is not conserved within the APOL family and is dispensable for cell death in vitro. We discuss two models for APOL1 trypanolytic activity: one involving lysosome permeabilization and another involving colloid-osmotic swelling of the cell body, as well as their relevance to human pathophysiology. Experimental evidence from human cell culture models suggests that both mechanisms may be operative. A systems biology approach whereby APOL1-associated perturbations in gene and protein expression in affected individuals are correlated with molecular pathways may be productive to elucidate APOL1 function in vivo.
Improved diagnostics targeting c-MET in non-small cell lung cancer: expression, amplification and activation?Tuesday, July 28, 2015
Watermann I, Schmitt B, Stellmacher F, Müller J, Gaber R, Kugler Ch, Reinmuth N, Huber RM, Thomas M, Zabel P, Rabe KF, Jonigk D, Warth A, Vollmer E, Reck M, Goldmann T,
Diagnostic pathology. 2015
Our data indicate, that neither expression of c-MET nor the gene amplification status might be the best way to select patients for MET targeting therapies, since no correlation with the activation status of MET was observed. We propose to take into account analyzing the phosphorylation status of MET by IHC to select patients for MET targeting therapies. Signaling of the receptor and the activation of downstream molecules might be more crucial for the benefit of therapeutics targeting MET receptor tyrosine kinases than expression levels alone.
A randomized clinical trial of ascorbic acid in open abdominal aortic aneurysm repair.Tuesday, July 28, 2015
Duffy MJ, O'Kane CM, Stevenson M, Young IS, Harkin DW, Mullan BA, McAuley DF,
Intensive care medicine experimental. Dec-2015
Localization of Bovine Papillomavirus Nucleic Acid in Equine Sarcoids.Tuesday, July 28, 2015
Gaynor AM, Zhu KW, Cruz FN, Affolter VK, Pesavento PA,
Veterinary pathology. 27-Jul-2015
Bovine papillomaviruses (BPV1/BPV2) have long been associated with equine sarcoids; deciphering their contribution has been difficult due to their ubiquitous presence on skin and in the environment, as well as the lack of decent techniques to interrogate their role in pathogenesis. We have developed and characterized an in situ hybridization (ISH) assay that uses a pool of probes complementary to portions of the E5, E6, and E7 genes. This assay is highly sensitive for direct visualization of viral transcript and nucleic acid in routinely processed histopathologic samples. We demonstrate here the visualization of BPV nucleic acid in 18 of 18 equine sarcoids, whereas no detectable viral DNA was present in 15 of 15 nonsarcoid controls by this technique. In nearly 90% (16/18) of the sarcoids, 50% or more of the fibroblastic cell nuclei distributed throughout the neoplasm had detectable hybridization. In the remaining 2 cases, fewer than half of the fibroblastic cells contained detectable hybridization, but viral nucleic acid was also detected in epithelial cells of the sebaceous glands, hair follicles and epidermis. A sensitive ISH assay is an indispensable addition to the molecular methods used to detect viral nucleic acid in tissue. We have used this technique to determine the specific cellular localization and distribution of BPV in a subset of equine sarcoids.
Transmembrane protein 106a activates mouse peritoneal macrophages via the MAPK and NF-κB signaling pathways.Tuesday, July 28, 2015
Dai H, Xu D, Su J, Jang J, Chen Y,
Scientific reports. 2015
The M1 and M2 states of macrophage are the two extremes of a physiologic/phenotypic continuum that is dynamically influenced by environmental signals. Molecular mechanism analysis indicated that they gain M1 and M2-related functions after encountering specific ligands in the tissue environment. Here, we first characterized the previously unknown immunobiological functions of mouse Tmem106a. This protein is abundantly expressed on the surface of mouse macrophages. Activation of Tmem106a by stimulation with anti-Tmem106a upregulated the expression of CD80, CD86, CD69 and MHC II on macrophage, and induced the release of TNF-α, IL-1β, IL-6, CCL2 and NO, but not IL-10. These effects were largely abrogated by pretreatment with siRNA against Tmem106a. Notably, anti-Tmem106a significantly increased iNOS production and phosphorylation of STAT1, and had no effect on the ARGINASE-1 or p-STAT6 level, indicating that anti-Tmem106a activated macrophages and polarized them into M1-like macrophages. Further analysis found that anti-Tmem106a stimulation increased phosphorylation of ERK-1/2, JNK, p38 MAPK, NF-κB p65 and IKKα/β, and promoted nuclear translocation of the cytosolic NF-κB p65 subunit. Collectively, these data suggest that mouse Tmem106a might be a new trigger of macrophage activation and have some influence toward the M1 state through the activation of the MAPKs and NF-κB pathway.
Serum biomarkers for the early diagnosis of TIA: The MIND-TIA study protocol.Tuesday, July 28, 2015
Dolmans LS, Rutten FH, El Bartelink ML, Seppenwoolde G, van Delft S, Kappelle LJ, Hoes AW,
BMC neurology. 2015 Identifier NCT01954329.
The significance of NTR1 expression and its correlation with β-catenin and EGFR in gastric cancer.Tuesday, July 28, 2015
Zhou Z, Xie J, Cai Y, Yang S, Chen Y, Wu H,
Diagnostic pathology. 2015
By immunohistochemistry, we found that a high expression of NTR1 in GC specimens, which showed a bad prognosis, besides, NTR1 expression was related to invasion and migration of GC. These findings provide new and important information on the progression of GC. This study indicated that NTR1 may play an important role in tumor progression of GC and have its potential to be a predictive biomarker or a therapeutic molecular target in GC. The interaction between NTR1 and β-catenin may participate in the development of GC. However, the relationship between NTR1 and EGFR needs to be further investigated.
Neutrophil extracellular traps in the host defense against sepsis induced by Burkholderia pseudomallei (melioidosis).Tuesday, July 28, 2015
de Jong HK, Koh GC, Achouiti A, van der Meer AJ, Bulder I, Stephan F, Roelofs JJ, Day NP, Peacock SJ, Zeerleder S, Wiersinga WJ,
Intensive care medicine experimental. Dec-2014
B. pseudomallei is a potent inducer of NETosis which was reflected by greatly increased levels of NET-related components in melioidosis patients. Although NETs exhibited antibacterial activity against B. pseudomallei, NET formation did not protect against bacterial dissemination and inflammation during B. pseudomallei-induced sepsis.
Survival of patients with structurally-grouped TP53 mutations in ovarian and breast cancers.Tuesday, July 28, 2015
Seagle BL, Eng KH, Dandapani M, Yeh JY, Odunsi K, Shahabi S,
Oncotarget. 22-Jun-2015
The objective of this study was to determine if ovarian cancer patients with a TP53 mutation grouped by location of the mutation within the p53 protein structure exhibit differential survival outcomes. Data from patients with high grade serous ovarian cancer (HGS OvCa) (N = 316) or breast cancer (BrCa) (N = 981) sequenced by The Cancer Genome Atlas (TCGA) was studied by Kaplan-Meier and Cox proportional hazards survival analysis. A TP53 DNA binding domain (BD) missense mutation (MM) occurred in 58.5% (185/316) of HGS OvCas and 16.8% (165/981) of BrCas. Patients with a TP53 DNA BD MM grouped by structural location had significantly different overall survival (OS) and progression free survival (PFS). Median OS (months) of HGS OvCa patients by structural group were: Sheet-loop-helix stabilizers, 31.1; DNA minor groove residue R248, 33.6; Wild-type, 34.2; all other MMs, 44.5; DNA major groove residues, 84.1, and zinc ion coordinating residues, 87.0 (log-rank p = 0.006). PFS of DNA major groove MM cases was longer than TP53 wild-type cases (19.1 versus 10.1 months, log-rank p = 0.038). HGS OvCa and BrCa patients with structurally-grouped TP53 DNA BD MMs have different survival outcomes.
Risk of disability pension in patients following rectal cancer treatment and surgery.Tuesday, July 28, 2015
Chen L, Glimelius I, Neovius M, Eloranta S, Ekberg S, Martling A, Smedby KE,
The British journal of surgery. 27-Jul-2015
Relapse-free patients with rectal cancer of working age are at risk of disability pension.
The pseudokinase SgK223 promotes invasion of pancreatic ductal epithelial cells through JAK1/Stat3 signaling.Tuesday, July 28, 2015
Tactacan CM, Phua YW, Liu L, Zhang L, Humphrey ES, Cowley M, Pinese M, Biankin AV, Daly RJ,
Molecular cancer. 2015
Increased expression of SgK223 occurs in PDAC, and overexpression of SgK223 in pancreatic ductal epithelial cells promotes acquisition of a migratory and invasive phenotype through enhanced JAK1/Stat3 signaling. This represents the first association of SgK223 with a particular human cancer, and links SgK223 with a major signaling pathway strongly implicated in PDAC progression.
On Molecular Classification of Bladder Cancer: Out of One, Many.Tuesday, July 28, 2015
Aine M, Eriksson P, Liedberg F, Höglund M, Sjödahl G,
European urology. 24-Jul-2015
Comparative analysis showed that bladder cancer classification systems identify overlapping subtypes but at different levels. Muscle-invasive bladder cancer shows remarkable heterogeneity, and six subtypes were identified that differ in transcriptional networks, marker profiles, and expression of actionable targets.
Source: NCBI - Disclaimer and Copyright notice
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