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An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays.Friday, July 22, 2016
Manservisi F, Marquillas CB, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld EK, Belpoggi F,
Environmental health perspectives. 22-Jul-2016
This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances.
Rapid endoglin determination in serum samples using an amperometric magneto-actuated disposable immunosensing platform.Friday, July 22, 2016
Torrente-Rodríguez RM, Campuzano S, Ruiz-Valdepeñas-Montiel V, Pedrero M, Fernández-Aceñero MJ, Barderas R, Pingarrón JM,
Journal of pharmaceutical and biomedical analysis. 15-Jul-2016
A sensitive and rapid method for the determination of the clinically relevant biomarker human endoglin (CD105) in serum samples is presented, involving a magneto-actuated immunoassay and amperometric detection at disposable screen-printed carbon electrodes (SPCEs). Micro-sized magnetic particles were modified with a specific antibody to selectively capture the target protein which was further sandwiched with a secondary HRP-labeled antibody. The immunocomplexes attached to the magnetic carriers were amperometrically detected at SPCEs using the hydroquinone (HQ)/H2O2/HRP system. The magneto-actuated immunosensing platform was able to detect 5 pmoles of endoglin (in 25μL of sample, 0.2μM) in 30min providing statistically similar results to those obtained using a commercial ELISA kit for the determination of endogenous content of endoglin in human serum samples.
4.1N is involved in a flotillin-1/β-catenin/Wnt pathway and suppresses cell proliferation and migration in non-small cell lung cancer cell lines.Friday, July 22, 2016
Yang Q, Zhu M, Wang Z, Li H, Zhou W, Xiao X, Zhang B, Hu W, Liu J,
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 22-Jul-2016
The membrane-cytoskeletal protein 4.1N has recently been proposed as a tumor suppressor in a number of cancers of epithelial origin, including non-small-cell lung cancer (NSCLC). However, the molecular mechanism associated with 4.1N tumor suppression remains has not been thoroughly characterized. In this study, 4.1N was shown to directly interact with the lipid raft marker flotillin-1 through its FERM and U2 domains in several different NSCLC cell lines using immunoprecipitation, co-immunoprecipitation and pull-down assays. Moreover, 4.1N silencing/overexpression experiments in paired 95C/95D cells that are of homologous origin but varying endogenous 4.1N expression (high expression in 95C cells, low expression in 95D cells) indicated that 4.1N is involved in the suppression of cell proliferation and migration through a flotillin-1/β-catenin/Wnt pathway. Taken together, the findings of this study help to elucidate the novel tumor suppressor role of 4.1N in NSCLC.
Profiling of mRNA and long non-coding RNA of urothelial cancer in recipients after renal transplantation.Friday, July 22, 2016
Shang D, Zheng T, Zhang J, Tian Y, Liu Y,
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 22-Jul-2016
The molecular mechanism and signal transduction pathways involved in urothelial cancer (UC) after renal transplantation (RTx) remain unknown. In this study, we investigated the profiling of messenger RNA (mRNA) and long non-coding RNA (lncRNA) in RTx recipients with UC. The mRNA and lncRNA of six pairs of UC and corresponding normal urothelial tissues in RTx recipients were profiled using Arraystar Human lncRNA Microarray V3.0, which is designed for the global profiling of 26,109 coding transcripts and 30,586 lncRNAs. Quantitative real-time PCR (qRT-PCR) was used to validate the differentially expressed mRNAs and lncRNAs. Molecular function classification and biological process classification for the differentially expressed mRNAs were analyzed with Gene Ontology. The key pathways that were associated with UC after RTx were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Compared to normal urothelial tissues, 1597 mRNAs were upregulated and 1032 mRNAs were downregulated in UC; 2107 lncRNAs were upregulated and 1794 lncRNAs were downregulated (greater than twofold). Further qRT-PCR analysis of mRNA and lncRNA expression showed well consistency with the data of microarray analysis. The expression of matrix metalloprotease (MMP)-3, MMP-10, MMP-12, and MMP-13 was significantly increased, while the expression of CD36 was decreased in UC after RTx. Co-expression analysis of lncRNAs and their nearby coding genes showed that lncRNAs may play critical roles in regulating nearby genes in the carcinogenesis of UC. Our results also suggest that peroxisome proliferator-activated receptor (PPAR) signaling may be involved in UC after RTx. Moreover, several cytokines and their receptors were also significantly upregulated in UC after RTx, suggesting that cytokines might be modulated and participated in the carcinogenesis of UC after RTx. We analyzed the potential molecular mechanism and pathways involved in the UC of RTx recipients. Our results revealed that several key regulatory pathways and lncRNAs play critical roles in the carcinogenesis of UC, and suggest that UC in RTx recipients may be more likely to invade and metastasis. However, the detailed functional analysis of these mechanisms should be further performed in the future.
Development of a TaqMan Probe-Based Insulated Isothermal Polymerase Chain Reaction (iiPCR) Assay for Detection of Fusarium oxysporum f. sp. cubense Race 4.Friday, July 22, 2016
Lin YH, Lin YJ, Chang TD, Hong LL, Chen TY, Chang PL,
PloS one. 22-7-2016
This study developed a novel and inexpensive detection method based on a TaqMan probe-based insulated isothermal polymerase chain reaction (iiPCR) method for the rapid detection of Panama disease caused by Fusarium oxysporum f. sp. cubense (Foc) race 4, which is currently among the most serious fungal vascular diseases worldwide. By using the portable POCKIT™ device with the novel primer set iiFoc-1/iiFoc-2, the Foc race 4 iiPCR assay (including DNA amplification and signal monitoring) could be completed within one hour. The developed Foc race 4 iiPCR assay is thus a user-friendly and efficient platform designed specifically for the detection of Foc race 4. The detection limit of this optimized Foc iiPCR system was estimated to be 1 copy of the target standard DNA as well as 1 fg of the Foc genomic DNA. This approach can serve as a rapid detection method for in planta detection of Foc race 4 in field-infected banana. It was concluded that this molecular detection procedure based on iiPCR has good potential for use as an efficient detection method.
Post-Synthetic Defucosylation of AGP by Aspergillus nidulans α-1,2-Fucosidase Expressed in Arabidopsis Apoplast Induces Compensatory Upregulation of α-1,2-Fucosyltransferases.Friday, July 22, 2016
Pogorelko GV, Reem NT, Young ZT, Chambers L, Zabotina OA,
PloS one. 22-7-2016
Cell walls are essential components of plant cells which perform a variety of important functions for the different cell types, tissues and organs of a plant. Besides mechanical function providing cell shape, cell walls participate in intercellular communication, defense during plant-microbe interactions, and plant growth. The plant cell wall consists predominantly of polysaccharides with the addition of structural glycoproteins, phenolic esters, minerals, lignin, and associated enzymes. Alterations in the cell wall composition created through either changes in biosynthesis of specific constituents or their post-synthetic modifications in the apoplast compromise cell wall integrity and frequently induce plant compensatory responses as a result of these alterations. Here we report that post-synthetic removal of fucose residues specifically from arabinogalactan proteins in the Arabidopsis plant cell wall induces differential expression of fucosyltransferases and leads to the root and hypocotyl elongation changes. These results demonstrate that the post-synthetic modification of cell wall components presents a valuable approach to investigate the potential signaling pathways induced during plant responses to such modifications that usually occur during plant development and stress responses.
Quantitative PK/PD modeling of baclofen-mediated cardiovascular effects using blood pressure and heart rate in rats.Friday, July 22, 2016
Kamendi H, Barthlow H, Lengel D, Beaudoin ME, Snow D, Mettetal JT, Bialecki RA,
British journal of pharmacology. 22-Jul-2016
The systems pharmacology model developed fit baclofen-mediated changes in MAP and HR well. The findings correlate with known mechanisms of baclofen pharmacology and suggest that similar models using limited parameter sets may be useful to predict the cardiovascular effects of other pharmacologically active substances.
Effect of confounding factors on a phospho-flow assay of ribosomal S6 protein for therapeutic drug monitoring of the mTOR-inhibitor everolimus in heart transplanted patients.Friday, July 22, 2016
Dieterlen MT, John K, Haase S, Garbade J, Tarnok A, Mohr FW, Bittner HB, Barten MJ,
Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals. 22-Jul-2016
Evaluating the pS6RP-assay revealed that pS6RP is influenced by cyclosporine A (CsA) blood concentration, duration of ERL treatment, co-medication with thiazide diuretics and different metabolic parameters.
Metabolomic Profiling of Human Urine as a Screen for Multiple Inborn Errors of Metabolism.Friday, July 22, 2016
Kennedy AD, Miller MJ, Beebe K, Wulff JE, Evans AM, Miller LA, Sutton VR, Sun Q, Elsea SH,
Genetic testing and molecular biomarkers. 22-Jul-2016
A single urine sample analyzed with our integrated metabolomic platform can identify signatures of IEMs that are traditionally identified using many different assays and multiple sample types. Creatinine and osmolality-normalized data were robust to the detection of the disorders and samples tested here.
Fertile ground: human endometrial programming and lessons in health and disease.Friday, July 22, 2016
Evans J, Salamonsen LA, Winship A, Menkhorst E, Nie G, Gargett CE, Dimitriadis E,
Nature reviews. Endocrinology. 22-Jul-2016
The human endometrium is a highly dynamic tissue that is cyclically shed, repaired, regenerated and remodelled, primarily under the orchestration of oestrogen and progesterone, in preparation for embryo implantation. Humans are among the very few species that menstruate and that, consequently, are equipped with unique cellular and molecular mechanisms controlling these cyclic processes. Many reproductive pathologies are specific to menstruating species, and studies in animal models rarely translate to humans. Abnormal remodelling and regeneration of the human endometrium leads to a range of reproductive complications. Furthermore, the processes regulating endometrial remodelling and implantation, including those controlling hormonal impact, breakdown and repair, stem/progenitor cell activation, inflammation and cell invasion have broad applications to other fields. This Review presents current knowledge regarding the normal and abnormal function of the human endometrium. The development of biomarkers for prediction of uterine diseases and pregnancy disorders and future avenues of investigation to improve fertility and enhance endometrial function are also discussed.
Biomarkers: Mannose levels predict insulin resistance.Friday, July 22, 2016
Holmes D,
Nature reviews. Endocrinology. 22-Jul-2016
An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS.Sunday, July 24, 2016
Rickels R, Hu D, Collings CK, Woodfin AR, Piunti A, Mohan M, Herz HM, Kvon E, Shilatifard A,
Molecular cell. 21-Jul-2016
Polycomb response elements (PREs) are specific DNA sequences that stably maintain the developmental pattern of gene expression. Drosophila PREs are well characterized, whereas the existence of PREs in mammals remains debated. Accumulating evidence supports a model in which CpG islands recruit Polycomb group (PcG) complexes; however, which subset of CGIs is selected to serve as PREs is unclear. Trithorax (Trx) positively regulates gene expression in Drosophila and co-occupies PREs to antagonize Polycomb-dependent silencing. Here we demonstrate that Trx-dependent H3K4 dimethylation (H3K4me2) marks Drosophila PREs and maintains the developmental expression pattern of nearby genes. Similarly, the mammalian Trx homolog, MLL1, deposits H3K4me2 at CpG-dense regions that could serve as PREs. In the absence of MLL1 and H3K4me2, H3K27me3 levels, a mark of Polycomb repressive complex 2 (PRC2), increase at these loci. By inhibiting PRC2-dependent H3K27me3 in the absence of MLL1, we can rescue expression of these loci, demonstrating a functional balance between MLL1 and PRC2 activities at these sites. Thus, our study provides rules for identifying cell-type-specific functional mammalian PREs within the human genome.
Development of a sequential workflow based on LC-PRM for the verification of endometrial cancer protein biomarkers in uterine aspirate samples.Friday, July 22, 2016
Martinez-Garcia E, Lesur A, Devis L, Campos AR, Cabrera S, van Oostrum J, Matias-Guiu X, Gil-Moreno A, Reventos J, Colas E, Domon B,
Oncotarget. 16-Jul-2016
About 30% of endometrial cancer (EC) patients are diagnosed at an advanced stage of the disease, which is associated with a drastic decrease in the 5-year survival rate. The identification of biomarkers in uterine aspirate samples, which are collected by a minimally invasive procedure, would improve early diagnosis of EC. We present a sequential workflow to select from a list of potential EC biomarkers, those which are the most promising to enter a validation study. After the elimination of confounding contributions by residual blood proteins, 52 potential biomarkers were analyzed in uterine aspirates from 20 EC patients and 18 non-EC controls by a high-resolution accurate mass spectrometer operated in parallel reaction monitoring mode. The differential abundance of 26 biomarkers was observed, and among them ten proteins showed a high sensitivity and specificity (AUC > 0.9). The study demonstrates that uterine aspirates are valuable samples for EC protein biomarkers screening. It also illustrates the importance of a biomarker verification phase to fill the gap between discovery and validation studies and highlights the benefits of high resolution mass spectrometry for this purpose. The proteins verified in this study have an increased likelihood to become a clinical assay after a subsequent validation phase.
Prognostic value of a systemic inflammatory response index in metastatic renal cell carcinoma and construction of a predictive model.Friday, July 22, 2016
Gu L, Ma X, Wang L, Li H, Chen L, Li X, Zhang Y, Xie Y, Zhang X,
Oncotarget. 16-Jul-2016
Inflammation act as a crucial role in carcinogenesis and tumor progression. In this study, we aim to investigate the prognostic significance of systemic inflammatory biomarkers in metastatic renal cell carcinoma (mRCC) and develop a survival predictive model. One hundred and sixty-one mRCC patients who had undergone cytoreductive nephrectomy were enrolled from January 2006 to December 2013. We created a systemic inflammation response index (SIRI) basing on pretreatment hemoglobin and lymphocyte to monocyte ratio (LMR), and evaluated its associations with overall survival (OS) and clinicopathological features. Pretreatment hemoglobin and LMR both remained as independent factors adjusted for other markers of systemic inflammation responses and conventional clinicopathological parameters. A high SIRI seems to be an independent prognosis predictor of worse OS and was significantly correlated with aggressive tumor behaviors. Inclusion of the SIRI into a prognostic model including Fuhrman grade, histology, tumor necrosis and targeted therapy established a nomogram, which accurately predicted 1-year survival for mRCC patients. The SIRI seems to be a prognostic biomarker in mRCC patients. The proposed nomogram can be applied to predict OS of patients with mRCC after nephrectomy.
Serotonin transporter antagonists target tumor-initiating cells in a transgenic mouse model of breast cancer.Friday, July 22, 2016
Hallett RM, Girgis-Gabardo A, Gwynne WD, Giacomelli AO, Bisson JN, Jensen JE, Dvorkin-Gheva A, Hassell JA,
Oncotarget. 15-Jul-2016
Accumulating data suggests that the initiation and progression of human breast tumors is fueled by a rare subpopulation of tumor cells, termed breast tumor-initiating cells (BTIC), which resist radiotherapy and chemotherapy. Consequently, therapies that abrogate BTIC activity are needed to achieve durable cures for breast cancer patients. To identify such therapies we used a sensitive assay to complete a high-throughput screen of small molecules, including approved drugs, with BTIC-rich mouse mammary tumor cell populations. We found that inhibitors of the serotonin reuptake transporter (SERT) and serotonin receptors, which include approved drugs used to treat mood disorders, were potent inhibitors of mouse BTIC activity as determined by functional sphere-forming assays and the initiation of tumor formation by transplant of drug-exposed tumor cells into syngeneic mice. Moreover, sertraline (Zoloft), a selective serotonin reuptake inhibitor (SSRI), synergized with docetaxel (Taxotere) to shrink mouse breast tumors in vivo. Hence drugs targeting the serotonergic system might be repurposed to treat breast cancer patients to afford more durable breast cancer remissions.
Overexpression of NSUN2 by DNA hypomethylation is associated with metastatic progression in human breast cancer.Friday, July 22, 2016
Yi J, Gao R, Chen Y, Yang Z, Han P, Zhang H, Dou Y, Liu W, Wang W, Du G, Xu Y, Wang J,
Oncotarget. 15-Jul-2016
NSUN2 is a RNA methyltransferase that has been shown to be implicated in development of human cancer. However, the functional role of NSUN2, mechanism of NSUN2 overexpression and its correlation with clinicopathologic features in breast cancer remain unclear. To investigate alterations in the expression and functional role of NSUN2 in breast cancer, NSUN2 expression was assessed in breast cancer cells and tissues obtained from cancers at different American Joint Committee on Cancer (AJCC) stages, and its functions were investigated using breast cancer cells. NSUN2 expression was shown to be significantly higher in breast cancer cells and tissues than in normal breast epithelial cells and tissues, at both mRNA and protein levels. Overexpression of NSUN2 was shown to promote cell proliferation, migration, and invasion while NSUN2 knockdown inhibited these processes in vitro and in vivo. NSUN2 expression level was associated with the methylation level of its promoter. Our results demonstrated that the overall expression of NSUN2 significantly correlated with clinical stage (P=0.027), tumor classification (P=0.012), pathological differentiation (P=0.023), as well as with the expression levels of estrogen receptor (P<0.001), progesterone receptor (P=0.001), and Ki-67 (P<0.001). Our findings provide a unique insight into the roles and effects of NSUN2 overexpression in breast cancer cells, and highlight the necessity of the investigation of novel therapeutic targets, such as NSUN2, for the improvement of breast cancer treatments.
MicroRNA fingerprints in juvenile myelomonocytic leukemia (JMML) identified miR-150-5p as a tumor suppressor and potential target for treatment.Friday, July 22, 2016
Leoncini PP, Bertaina A, Papaioannou D, Flotho C, Masetti R, Bresolin S, Menna G, Santoro N, Zecca M, Basso G, Nigita G, Veneziano D, Pagotto S, D'Ovidio K, Rota R, Dorrance A, Croce CM, Niemeyer C, Locatelli F, Garzon R,
Oncotarget. 13-Jul-2016
Juvenile myelomonocytic leukemia (JMML) is an aggressive leukemia of early childhood characterized by aberrant proliferation of myelomonocytic cells and hypersensitivity to GM-CSF stimulation. Mutually exclusive mutations in the RAS/ERK pathway genes such as PTPN11, NRAS, KRAS, CBL, or NF1 are found in ~90% of the cases. These mutations give rise to disease at least in part by activating STAT5 through phosphorylation and by promoting cell growth. MicroRNAs (miRs) are small non-coding RNAs that regulate gene expression, which are often deregulated in leukemia. However, little is known about their role in JMML. Here, we report distinctive miR expression signatures associated with the molecular subgroups of JMML. Among the downregulated miRs in JMML, miR-150-5p was found to target STAT5b, a gene which is often over-activated in JMML, and contributes to the characteristic aberrant signaling of this disorder. Moreover, loss of miR-150-5p and upregulation of STAT5b expression were also identified in a murine model of JMML. Ectopic overexpression of miR-150-5p in mononuclear cells from three JMML patients significantly decreased cell proliferation. Altogether, our data indicate that miR expression is deregulated in JMML and may play a role in the pathogenesis of this disorder by modulating key effectors of cytokine receptor pathways.
miR-9 Acts as an OncomiR in Prostate Cancer through Multiple Pathways That Drive Tumour Progression and Metastasis.Friday, July 22, 2016
Seashols-Williams SJ, Budd W, Clark GC, Wu Q, Daniel R, Dragoescu E, Zehner ZE,
PloS one. 13-7-2016
Identification of dysregulated microRNAs (miRNAs) in prostate cancer is critical not only for diagnosis, but also differentiation between the aggressive and indolent forms of the disease. miR-9 was identified as an oncomiR through both miRNA panel RT-qPCR as well as high-throughput sequencing analysis of the human P69 prostate cell line as compared to its highly tumorigenic and metastatic subline M12, and found to be consistently upregulated in other prostate cell lines including DU-145 and PC3. While miR-9 has been characterized as dysregulated either as an oncomiR or tumour suppressor in a variety of other cancers including breast, ovarian, and nasopharyngeal carcinomas, it has not been previously evaluated and proven as an oncomiR in prostate cancer. miR-9 was confirmed an oncomiR when found to be overexpressed in tumour tissue as compared to adjacent benign glandular epithelium through laser-capture microdissection of radical prostatectomy biopsies. Inhibition of miR-9 resulted in reduced migratory and invasive potential of the M12 cell line, and reduced tumour growth and metastases in male athymic nude mice. Analysis showed that miR-9 targets e-cadherin and suppressor of cytokine signalling 5 (SOCS5), but not NF-ĸB mRNA. Expression of these proteins was shown to be affected by modulation in expression of miR-9.
Application of an NGS-based 28-gene panel in myeloproliferative neoplasms reveals distinct mutation patterns in essential thrombocythaemia, primary myelofibrosis and polycythaemia vera.Friday, July 22, 2016
Delic S, Rose D, Kern W, Nadarajah N, Haferlach C, Haferlach T, Meggendorfer M,
British journal of haematology. 22-Jul-2016
Molecular routine diagnostics for BCR-ABL1-negative myeloproliferative neoplasms (MPN) currently focusses on mutations in JAK2, CALR and MPL. In recent years, recurrent mutations in MPNs have been identified in several other genes. We here present the validation of a next generation sequencing (NGS)-based 28-gene panel and its use in MPN. We analysed the mutation status of 28 genes in 100 MPN patients [40 essential thrombocythaemia (ET), 30 primary myelofibrosis (PMF), 30 polycythaemia vera (PV)] and found two or more mutated genes in 53 patients. Moreover, significantly more mutated splicing genes (SF3B1, SRSF2 and U2AF1) were present in PMF (0·60 mutated genes/patient) compared to ET (0·15) while no mutations in splicing genes were found in PV. Additionally, chromatin modification genes (ASXL1 and EZH2) were frequently mutated in PMF patients (0·50) and, to a significantly lesser extent, in ET (0·13) and PV (0·07). Contrarily, DNA methylation genes (DNMT3A, IDH1, IDH2 and TET2) were mutated most often in PV (0·5) and less frequently in ET (0·23) and PMF (0·20), but without reaching statistical significance. Our results demonstrate the feasibility and utility of NGS-based panel diagnostics for MPN. With 53% of the patients bearing two or more mutated genes, their prognostic relevance needs further studies.
Osteosarcoma cells with genetic signatures of BRCAness are susceptible to the PARP inhibitor talazoparib alone or in combination with chemotherapeutics.Friday, July 22, 2016
Engert F, Kovac M, Baumhoer D, Nathrath M, Fulda S,
Oncotarget. 20-Jul-2016
We recently discovered mutation signatures reminiscent of BRCA deficiency in the vast majority of a set of primary osteosarcomas (OS). In the current study, we therefore investigated the sensitivity of a panel of OS cell lines to the poly(ADP)-ribose polymerase (PARP) inhibitor talazoparib alone and in combination with several chemotherapeutic drugs (i.e. temozolomide (TMZ), SN-38, doxorubicin, cisplatin, methotrexate (MTX), etoposide/carboplatin). Here, we identified an association between homologous recombination (HR) repair deficiency and the response of OS cell lines to talazoparib. All OS cell lines with molecular features characteristic of BRCA1/2 mutant tumors (so-called "BRCAness"), such as disruptive gains in PTEN or FANCD2 and/or losses of ATM, BAP1, BARD1 or CHEK2, were susceptible to talazoparib-induced reduction of cell viability (i.e. MG63, ZK-58,, SaOS-2 and MNNG-HOS). Consistent with their high sensitivity to talazoparib, MG63 and ZK-58 cells scored positive in a DNA-based measure of genomic instability (i.e. homologous recombination deficiency (HRD)-loss of heterozygosity (LOH) score). In contrast, U2OS cells that carry a heterozygous BRCA2 mutation and therefore most likely have one intact BRCA2 allele left proved to be resistant to talazoparib. Furthermore, we identified TMZ as the most potent chemotherapeutic drug together with talazoparib to synergistically reduce cell viability, as confirmed by calculation of combination index (CI) values, and to suppress long-term clonogenic survival. Mechanistically, talazoparib and TMZ cooperated to induce apoptotic cell death, as demonstrated by activation of BAX and BAK, loss of mitochondrial membrane potential (MMP), caspase activation, DNA fragmentation and caspase-dependent cell death. Genetic silencing of BAX and BAK or pharmacological inhibition of caspases by zVAD.fmk significantly rescued OS cells from talazoparib/TMZ-induced apoptosis. These findings have important implications for the development of novel treatment strategies using PARP inhibitors alone or together with chemotherapy in a subset of OS with features of BRCAness.
CTMP, a predictive biomarker for trastuzumab resistance in HER2-enriched breast cancer patient.Friday, July 22, 2016
Chen YC, Li HY, Liang JL, Ger LP, Hsiao M, Calkins MJ, Cheng HC, Chuang JH, Lu PJ,
Oncotarget. 20-Jul-2016
Trastuzumab is regarded as the primary therapy for patients with HER2-enriched breast cancer, but the pathological complete response for advanced cases is less than 30%. The underlying mechanism of trastuzumab resistance remains unclear and there are currently no conclusive biomarkers for patient response to trastuzumab. Identifying predictive biomarkers for trastuzumab response may allow treatments to be individually tailored and optimized multi-target therapies may be developed. CTMP activates AKT signaling in breast cancer and over-activation of AKT has been reported to contribute to trastuzumab resistance. In this study, we examined samples from 369 patients to investigate the correlation between CTMP expression level and patient outcome. Elevated CTMP expression was correlated with adverse outcomes in HER2-enriched patients including overall and disease-free survival as well as trastuzumab resistance. Ectopic expression of varying levels of CTMP in SkBR3 cells dose-dependently attenuated trastuzumab-mediated growth inhibition through AKT activation. In addition, inhibition of AKT signaling by AKT inhibitor IV and Rapamycin reversed CTMP-mediated trastuzumab resistance. In clinical samples, the high expression of CTMP was showed in trastuzumab non-responders and positively correlated with AKT activity. Taken together, we demonstrated that CTMP promotes AKT activation resulting in trastuzumab resistance in patients with HER2-enriched breast cancer. High CTMP expression not only predicted poor prognosis, but may also predict resistance to trastuzumab in HER2-enriched patients. Therefore, CTMP expression may be considered as a prognostic biomarker in HER2-enriched breast cancer and high expression may indicate a utility for AKT-inhibition in these patients.
Potential role of the N-MYC downstream-regulated gene family in reprogramming cancer metabolism under hypoxia.Friday, July 22, 2016
Lee GY, Chun YS, Shin HW, Park JW,
Oncotarget. 18-Jul-2016
Metabolic reprogramming toward aerobic glycolysis and lactate fermentation supplies cancer cells with intermediate metabolites, which are used as macromolecule precursors. The oncogene MYC contributes to such aerobic metabolism by activating the expression of numerous genes essential for glycolysis and mitochondrial biogenesis. However, to survive and evolve in a hypoxic tumor milieu, cancer cells must revise MYC-driven metabolism because the mitochondrial respiratory chain provides free electrons to generate oxygen free radicals with inefficient production of ATP due to oxygen depletion. Instead, hypoxia-inducible transcription factor hypoxia-inducible factor 1 (HIF-1) takes over the role of MYC in glycolysis, but suppresses mitochondrial biogenesis and activity to protect cells from such threats. Recently, the N-MYC downstream-regulated gene (NDRG) family has received attention as potential biomarkers of cancer prognosis. NDRGs are repressed MYC-dependently in various cancers, but induced under hypoxia because HIF-1 directly activates their promoters and indirectly de-represses them by antagonizing MYC. In this review, we summarize the current understanding of the reprogramming of cancer metabolism via the counterbalance between MYC and HIF-1, and discuss the proven and putative roles of the NDRG family in adjusting cancer metabolism according to the ambient oxygen level.
Prediction of recurrence free survival for esophageal cancer patients using a protein signature based risk model.Friday, July 22, 2016
Hasan R, Srivastava G, Alyass A, Sharma R, Saraya A, Chattopadhyay TK, DattaGupta S, Walfish PG, Chauhan SS, Ralhan R,
Oncotarget. 18-Jul-2016
Our comprehensive risk model predictive for recurrence allowed us to determine the robustness of our biomarker panel in stratification of ESCC patients at high or low risk of disease recurrence; high risk patients are stratified for more rigorous personalized treatment while the low risk patients may be spared from harmful side effects of toxic therapy.
Metabolomic and Genome-wide Association Studies Reveal Potential Endogenous Biomarkers for OATP1B1.Friday, July 22, 2016
Yee SW, Giacomini MM, Hsueh CH, Weitz D, Liang X, Goswami S, Kinchen JM, Coelho A, Zur AA, Mertsch K, Brian W, Kroetz DL, Giacomini KM,
Clinical pharmacology and therapeutics. 22-Jul-2016
Transporter-mediated drug-drug interactions (DDIs) are a major cause of drug toxicities. Using published genomewide association studies (GWAS) of the human metabolome, we identified 20 metabolites associated with genetic variants in OATP1B1 (p<5x10(-8) ). Of these, 12 metabolites were significantly higher in plasma samples from volunteers dosed with the OATP1B1 inhibitor, cyclosporine, CSA, versus placebo (q-value<0.2). Conjugated bile acids and fatty acid dicarboxylates were among the metabolites discovered using both GWAS and CSA administration. In vitro studies confirmed tetradecanedioate (TDA) and hexadecanedioate (HDA) were novel substrates of OATP1B1 as well as OAT1 and OAT3. This study highlights the use of multiple datasets for the discovery of endogenous metabolites that represent potential in vivo biomarkers for transporter-mediated DDIs. Future studies are needed to determine whether these metabolites can serve as qualified biomarkers for organic anion transporters. Quantitative relationships between metabolite levels and modulation of transporters should be established. This article is protected by copyright. All rights reserved.
Brain natriuretic peptide: Much more than a biomarker.Friday, July 22, 2016
Calzetta L, Orlandi A, Page C, Rogliani P, Rinaldi B, Rosano G, Cazzola M, Matera MG,
International journal of cardiology. 9-Jul-2016
Brain natriuretic peptide (BNP) modulates several biological processes by activating the natriuretic peptide receptor A (NPR-A). Atria and ventricles secrete BNP. BNP increases natriuresis, diuresis and vasodilatation, thus resulting in a decreased cardiac workload. BNP and NT-proBNP, which is the biologically inactive N-terminal portion of its pro-hormone, are fast and sensitive biomarkers for diagnosing heart failure. The plasma concentrations of both BNP and NT-proBNP also correlate with left ventricular function in patients with acute exacerbation of COPD, even without history of heart failure. Several studies have been conducted in vitro and in vivo, both in animals and in humans, in order to assess the potential role of the NPR-A activation as a novel therapeutic approach for treating obstructive pulmonary disorders. Unfortunately, these studies have yielded conflicting results. Nevertheless, further recent specific studies, performed in ex vivo models of asthma and COPD, have confirmed the bronchorelaxant effect of BNP and its protective role against bronchial hyperresponsiveness in human airways. These studies have also clarified the intimate mechanism of action of BNP, represented by an autocrine loop elicited by the activation of NPR-A, localized on bronchial epithelium, and the relaxant response of the surrounding ASM, which does not expresses NPR-A. This review explores the teleological activities and paradoxical effects of BNP with regard to chronic obstructive respiratory disorders, and provides an excursus on the main scientific findings that explain why BNP should be considered much more than a biomarker.
The mutational profile and infiltration pattern of murine MLH1-/- tumors - concurrences, disparities and cell line establishment for functional analysis.Friday, July 22, 2016
Maletzki C, Beyrich F, Hühns M, Klar E, Linnebacher M,
Oncotarget. 18-Jul-2016
Mice lines homozygous negative for one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, PMS2, MSH6) were generated as models for MMR deficient (MMR-D) diseases. Clinically, hereditary forms of MMR-D include Lynch syndrome (characterized by a germline MMR gene defect) and constitutional MMR-D, the biallelic form. MMR-D knockout mice may be representative for both diseases. Here, we aimed at characterizing the MLH1-/- model focusing on tumor-immune microenvironment and identification of coding microsatellite mutations in lymphomas and gastrointestinal tumors (GIT). All tumors showed microsatellite instability (MSI) in non-coding mononucleotide markers. Mutational profiling of 26 coding loci in MSI+ GIT and lymphomas revealed instability in half of the microsatellites, two of them (Rfc3 and Rasal2) shared between both entities. MLH1-/- tumors of both entities displayed a similar phenotype (high CD71, FasL, PD-L1 and CTLA-4 expression). Additional immunofluorescence verified the tumors' natural immunosuppressive character (marked CD11b/CD200R infiltration). Vice versa, CD3+ T cells as well as immune checkpoints molecules were detectable, indicative for an active immune microenvironment. For functional analysis, a permanent cell line from an MLH1-/- GIT was established. The newly developed MLH1-/- A7450 cells exhibit stable in vitro growth, strong invasive potential and heterogeneous drug response. Moreover, four additional MSI target genes (Nktr1, C8a, Taf1b, and Lig4) not recognized in the primary were identified in this cell line. Summing up, molecular and immunological mechanisms of MLH1-/- driven carcinogenesis correlate well with clinical features of MMR-D. MLH1-/- knockout mice combine characteristics of Lynch syndrome and constitutional MMR-D, making them suitable models for preclinical research aiming at MMR-D related diseases.
Muscular dystrophies and myopathies: the spectrum of mutated genes in the Czech Republic.Friday, July 22, 2016
Stehlíková K, Skálová D, Zídková J, Haberlová J, Voháňka S, Mazanec R, Mrázová L, Vondráček P, Ošlejšková H, Zámečník J, Honzík T, Zeman J, Magner M, Šišková D, Langová M, Gregor V, Godava M, Smolka V, Fajkusová L,
Clinical genetics. 22-Jul-2016
Inherited neuromuscular disorder (NMD) is a wide term covering different genetic disorders affecting muscles, nerves, and neuromuscular junctions. Genetic and clinical heterogeneity is the main drawback in a routine gene-by-gene diagnostics. We present Czech NMD patients with a genetic cause identified using targeted next-generation sequencing (NGS) and the spectrum of these causes. Overall 167 unrelated patients presenting NMD falling into categories of muscular dystrophies, congenital muscular dystrophies, congenital myopathies, distal myopathies, and other myopathies were tested by targeted NGS of 42 known NMD-related genes. Pathogenic or likely pathogenic sequence changes were identified in 79 patients (47.3%). In total, 37 novel and 51 known disease-causing variants were detected in 23 genes. Additionally, variants of uncertain significance were suspected in 7 cases (4.2%), and in 81 cases (48.5%) sequence changes associated with NMD were not found. Our results strongly indicate that for molecular diagnostics of heterogeneous disorders such as NMDs, targeted panel testing has a high clinical yield and should therefore be the preferred first-tier approach. Further, we show that in the genetic diagnostic practice of NMDs, it is necessary to take into account different types of inheritance including the occurrence of an autosomal recessive disorder in two generations of one family.
New Cyclotetrapeptides and a New Diketopiperzine Derivative from the Marine Sponge-Associated Fungus Neosartorya glabra KUFA 0702.Friday, July 22, 2016
May Zin WW, Buttachon S, Dethoup T, Fernandes C, Cravo S, Pinto MM, Gales L, Pereira JA, Silva AM, Sekeroglu N, Kijjoa A,
Marine drugs. 22-7-2016
Two new cyclotetrapeptides, sartoryglabramides A (5) and B (6), and a new analog of fellutanine A (8) were isolated, together with six known compounds including ergosta-4, 6, 8 (14), 22-tetraen-3-one, ergosterol 5, 8-endoperoxide, helvolic acid, aszonalenin (1), (3R)-3-(1H-indol-3-ylmethyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (2), takakiamide (3), (11aR)-2,3-dihydro-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione (4), and fellutanine A (7), from the ethyl acetate extract of the culture of the marine sponge-associated fungus Neosartorya glabra KUFA 0702. The structures of the new compounds were established based on extensive 1D and 2D spectral analysis. X-ray analysis was also used to confirm the relative configuration of the amino acid constituents of sartoryglabramide A (5), and the absolute stereochemistry of the amino acid constituents of sartoryglabramide A (5) and sartoryglabramides B (6) was determined by chiral HPLC analysis of their hydrolysates by co-injection with the d- and l- amino acids standards. Compounds 1-8 were tested for their antibacterial activity against Gram-positive (Escherichia coli ATCC 25922) and Gram-negative (Staphyllococus aureus ATCC 25923) bacteria, as well as for their antifungal activity against filamentous (Aspergillus fumigatus ATCC 46645), dermatophyte (Trichophyton rubrum ATCC FF5) and yeast (Candida albicans ATCC 10231). None of the tested compounds exhibited either antibacterial (MIC > 256 μg/mL) or antifungal activities (MIC > 512 μg/mL).
Current Stem Cell Biomarkers and Their Functional Mechanisms in Prostate Cancer.Friday, July 22, 2016
Zhang K, Zhou S, Wang L, Wang J, Zou Q, Zhao W, Fu Q, Fang X,
International journal of molecular sciences. 20-7-2016
Currently there is little effective treatment available for castration resistant prostate cancer, which is responsible for the majority of prostate cancer related deaths. Emerging evidence suggested that cancer stem cells might play an important role in resistance to traditional cancer therapies, and the studies of cancer stem cells (including specific isolation and targeting on those cells) might benefit the discovery of novel treatment of prostate cancer, especially castration resistant disease. In this review, we summarized major biomarkers for prostate cancer stem cells, as well as their functional mechanisms and potential application in clinical diagnosis and treatment of patients.
Tissue-Specific Effects of Vitamin E Supplementation.Friday, July 22, 2016
Jansen E, Viezeliene D, Beekhof P, Gremmer E, Ivanov L,
International journal of molecular sciences. 19-7-2016
A multivitamin and mineral supplementation study of 6 weeks was conducted with male and female mice. The control group received a standard dose of vitamins and minerals of 1× the Recommended Daily Intake (RDI), whereas a second group received 3× RDI. A third group received a high dose of vitamin E (25× RDI), close to the upper limit of toxicity (UL), but still recommended and considered to be harmless and beneficial. The high dose of vitamin E caused a number of beneficial, but also adverse effects. Different biomarkers of tissue toxicity, oxidative stress related processes and inflammation were determined. These biomarkers did not change in plasma and erythrocytes to a large extent. In the liver of male mice, some beneficial effects were observed by a lower concentration of several biomarkers of inflammation. However, in the kidney of male mice, a number of biomarkers increased substantially with the higher dose of vitamin E, indicating tissue toxicity and an increased level of inflammation. Since this dose of vitamin E, which is lower than the UL, cause some adverse effects, even after a short exposure period, further studies are required to reconsider the UL for vitamin E.
Long-term administration of ketamine induces erectile dysfunction by decreasing neuronal nitric oxide synthase on cavernous nerve and increasing corporal smooth muscle cell apoptosis in rats.Friday, July 22, 2016
Shang HS, Wu YN, Liao CH, Chiueh TS, Lin YF, Chiang HS,
Oncotarget. 20-Jul-2016
We investigated and evaluated the mechanisms of erectile dysfunction (ED) in a rat model of long-term ketamine administration.Adult male Sprague-Dawley rats (n = 32) were divided into four groups: namely the control group receiving intraperitoneal injection of saline, 1-month, 2-month and 3-month groups receiving daily intraperitoneal injection of ketamine (100 mg/kg/day) for 1, 2, and 3 month respectively. After treatment, animals underwent an erectile response protocol to assess intracavernosal pressure (ICP). Smooth muscle content was evaluated. Neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) expression were assessed using immunostaining assay. Ketamine-induced apoptosis was analyzed using TUNEL assay.Long-term ketamine administration caused significantly decreased erectile responses as measured by ICP. Smooth muscle content was significantly decreased in the ketamine-treated rats for 3 months. In the erectile tissue, ketamine administration significantly reduced nNOS expression and increased iNOS content compared with controls, whereas eNOS expression was not altered. Ketamine induced apoptosis in corpus cavernosum.The present study demonstrates that long-term ketamine administration led to erectile dysfunction in rat. The molecular mechanisms of ketamine-induced ED involved the increased apoptosis and up-regulated iNOS expression incorporating with loss of corporal smooth muscle content and reduced nNOS expression in cavernous nerve.
Oncogenic Ras triggers hyperproliferation and impairs polarized colonic morphogenesis by autocrine ErbB3 signaling.Friday, July 22, 2016
Möller Y, Morkel M, Schmid J, Beyes S, Hendrick J, Strotbek M, Riemer P, Schmid S, Schmitt LC, Kontermann R, Mürdter T, Schwab M, Sers C, Olayioye MA,
Oncotarget. 18-Jul-2016
Here we study the effects of inducible oncogenic K-Ras (G12V) expression on the polarized morphogenesis of colonic epithelial cells. We provide evidence that the autocrine production of heregulins, ligands for the ErbB3 receptor tyrosine kinase, is responsible for the hyperproliferation and aberrant 3D morphogenesis upon oncogenic K-Ras expression. This is in line with results obtained in primary intestinal organoid cultures, in which exogenous heregulin is shown to interfere with normal tissue architecture. Importantly, ErbB3 inhibition and heregulin gene silencing rescued K-RasG12V-induced features of cell transformation. Together with the increased ErbB3 positivity detected in human high-grade primary colorectal cancers, our findings provide support for an autocrine signaling loop engaged by oncogenic K-Ras involving ErbB3 that contributes to the dedifferentiation of the intestinal epithelium during tumor initiation and progression.
Cdkn2a suppresses metastasis in squamous cell carcinomas induced by the gain-of-function mutant p53(R172H).Friday, July 22, 2016
Li Z, Gonzalez CL, Wang B, Zhang Y, Mejia O, Katsonis P, Lichtarge O, Myers JN, El-Naggar AK, Caulin C,
The Journal of pathology. 22-Jul-2016
p53 (TP53) is the most frequently mutated gene in squamous cell carcinomas (SCCs) of the skin and head and neck. Certain p53 mutations are oncogenic and promote invasion and metastasis in SCCs. However, it is unclear how the oncogenic function of mutant p53 is modulated by other molecular alterations that co-exist in SCCs. Here, we show that deletion of the p53 gene and activation of an endogenous p53(R172H) gain-of-function mutation in the skin induces carcinomas with similar kinetics and penetrance. Deletion of p53 induced primarily well-differentiated SCCs. However, most of the tumours induced by p53(R172H) were poorly differentiated SCCs, the only metastatic tumours in this model. These tumours expressed higher levels of Cyclin D1 than the well differentiated SCCs and spindle carcinomas that developed in these mice. Unexpectedly, metastasis was not observed in mice that developed spindle carcinomas, which expressed high levels of the tumour suppressors p16(Ink4a) and p19(Arf) , encoded by Cdkn2a, a gene frequently deleted in human SCCs. Remarkably, deletion of the Cdkn2a gene in p53(R172H) -induced SCCs promoted a dramatic increase in metastasis rates and a shorter survival in mice that developed these tumours, compared with those observed in mice with tumours in which Cdkn2a was deleted in the presence of a p53 loss-of-function mutation or wild-type p53. Accordingly, the survival of patients with head and neck SCCs bearing co-occurring high-risk p53 mutations and CDKN2A homozygous deletions was much shorter than that of patients with tumours in which high-risk p53 mutations did not contain CDKN2A homozygous deletions, or that of patients with tumours in which homozygous CDKN2A deletions co-existed with either low-risk p53 mutations or potential loss-of-function mutations in p53. These findings genetically identify a population of SCC patients with worst outcomes and will help predict outcomes according to the p53 status and alterations in CDKN2A.
Combined oral contraceptive-induced hypertension is accompanied by endothelial dysfunction and upregulated intrarenal angiotensin II type 1 receptor gene expression.Friday, July 22, 2016
Olatunji LA, Seok YM, Igunnu A, Kang SH, Kim IK,
Naunyn-Schmiedeberg's archives of pharmacology. 22-Jul-2016
Combined oral contraceptive (COC) use is associated with increased risk of developing hypertension. Activation of the intrarenal renin-angiotensin system (RAS) and endothelial dysfunction play an important role in the development of hypertension. We tested the hypothesis that COC causes hypertension that is associated with endothelial dysfunction and upregulation of intrarenal angiotensin-converting enzyme 1 (Ace1) and angiotensin II type 1 receptor (At1r). Female Sprague-Dawley rats aged 12 weeks received (p.o.) olive oil (control) and a combination of 0.1 μg ethinylestradiol and 1.0 μg norgestrel (low COC) or 1.0 μg ethinylestradiol and 10.0 μg norgestrel (high COC) daily for 6 weeks. Blood pressure was recorded by tail cuff plethysmography. Expression of genes in kidney cortex was determined by quantitative real-time polymerase chain reaction. COC treatment led to increased blood pressure, circulating uric acid, C-reactive protein and plasminogen activator inhibitor-1, renal uric acid, and expression of renal Ace1 and At1r. COC treatment resulted in increased contractile responses to phenylephrine in endothelium-denuded aortic rings. Endothelium-dependent relaxation responses to acetylcholine, but not endothelium-independent relaxation responses to nitric oxide (NO) donation by sodium nitroprusside, were attenuated in COC-exposed rings. Impaired relaxation responses to acetylcholine were masked by the presence of NO synthase inhibitor (L-NAME) in the COC-exposed rings, whereas the responses to acetylcholine in the presence of selective cyclooxygenase-2 inhibitor (NS-398) were enhanced. These findings indicate that COC induces hypertension that is accompanied by endothelial dysfunction, upregulated intrarenal Ace1 and At1r expression, and elevated proinflammatory biomarkers.
A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild-Moderate Alzheimer's Disease.Friday, July 22, 2016
Malpas CB, Vivash L, Genc S, Saling MM, Desmond P, Steward C, Hicks RJ, Callahan J, Brodtmann A, Collins S, Macfarlane S, Corcoran NM, Hovens CM, Velakoulis D, O'Brien TJ,
Journal of Alzheimer's disease : JAD. 22-Jul-2016
Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks.
Performance Evaluation of an Automated ELISA System for Alzheimer's Disease Detection in Clinical Routine.Friday, July 22, 2016
Chiasserini D, Biscetti L, Farotti L, Eusebi P, Salvadori N, Lisetti V, Baschieri F, Chipi E, Frattini G, Stoops E, Vanderstichele H, Calabresi P, Parnetti L,
Journal of Alzheimer's disease : JAD. 22-Jul-2016
The variability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers undermines their full-fledged introduction into routine diagnostics and clinical trials. Automation may help to increase precision and decrease operator errors, eventually improving the diagnostic performance. Here we evaluated three new CSF immunoassays, EUROIMMUNtrademark amyloid-β 1-40 (Aβ1 - 40), amyloid-β 1-42 (Aβ1 - 42), and total tau (t-tau), in combination with automated analysis of the samples. The CSF biomarkers were measured in a cohort consisting of AD patients (n = 28), mild cognitive impairment (MCI, n = 77), and neurological controls (OND, n = 35). MCI patients were evaluated yearly and cognitive functions were assessed by Mini-Mental State Examination. The patients clinically diagnosed with AD and MCI were classified according to the CSF biomarkers profile following NIA-AA criteria and the Erlangen score. Technical evaluation of the immunoassays was performed together with the calculation of their diagnostic performance. Furthermore, the results for EUROIMMUN Aβ1 - 42 and t-tau were compared to standard immunoassay methods (INNOTESTtrademark). EUROIMMUN assays for Aβ1 - 42 and t-tau correlated with INNOTEST (r = 0.83, p < 0.001 for both) and allowed a similar interpretation of the CSF profiles. The Aβ1 - 42/Aβ1 - 40 ratio measured with EUROIMMUN was the best parameter for AD detection and improved the diagnostic accuracy of Aβ1 - 42 (area under the curve = 0.93). In MCI patients, the Aβ1 - 42/Aβ1 - 40 ratio was associated with cognitive decline and clinical progression to AD.The diagnostic performance of the EUROIMMUN assays with automation is comparable to other currently used methods. The variability of the method and the value of the Aβ1 - 42/Aβ1 - 40 ratio in AD diagnosis need to be validated in large multi-center studies.
Annexin A5 increases survival in murine sepsis model by inhibiting HMGB1-mediated pro-inflammation and coagulation.Friday, July 22, 2016
Park JH, Jang JH, Choi EJ, Kim YS, Lee EJ, Jung ID, Han HD, Wu TC, Hung CF, Kang TH, Park YM,
Molecular medicine (Cambridge, Mass.). 6-Jul-2016
The identification of HMGB1 as a late-mediator in sepsis has highlighted HMGB1 as a promising therapeutic target for sepsis treatment. Recent studies have revealed that annexin A5, a 35 kDa Ca(2+)-dependent phospholipid binding protein, exerts anti-inflammatory effect by inhibiting LPS binding to TLR4/MD2 complex. Annexin A5 administration has been shown to protect against endotoxin lethality even when the treatment was given after the early cytokine response, which prompted our group to suspect that annexin A5 may inhibit the binding of HMGB1, as well as endotoxin to TLR4. Here we suggest annexin A5 as a new inhibitor of HMGB1-mediated pro-inflammatory cytokine production and coagulation in sepsis. We first confirmed the inhibitory role of annexin A5 in LPS-induced production of pro-inflammatory cytokines both in vitro and in vivo. We observed that annexin A5 protects against tissue damage and organ dysfunction during endotoxemia in vivo. We then assessed the inhibiting role of annexin A5 in HMGB1/TLR4 interaction, and showed that annexin A5 treatment reduces HMGB1-mediated cytokines IL6 and TNFα both in vitro and in vivo. Finally, we confirmed that anticoagulant property of annexin A5 persists in various septic conditions including elevated HMGB1. Overall, we suggest annexin A5 as an alternative therapeutic approach for controlling HMGB1-mediated pro-inflammation and coagulation in patients with sepsis.
JOURNAL CLUB: Value of Quantitative FDG PET/CT Volumetric Biomarkers in Recurrent Colorectal Cancer Patient Survival.Sunday, July 24, 2016
Marcus C, Wray R, Taghipour M, Marashdeh W, Ahn SJ, Mena E, Subramaniam RM,
AJR. American journal of roentgenology. Aug-2016
SUVmax, MTVtotal, TLGtotal, and integrated score with FDG avidity and total tumor burden provide survival information for patients with biopsy-proven recurrent colorectal cancer.
The T Allele of MTHFR c.C677T and Its Synergism with G (Val 158) Allele of COMT c.G472A Polymorphism Are Associated with the Risk of Bipolar I Disorder.Friday, July 22, 2016
Rahimi Z, Kakabaraee K, Garavand A, Rahimi Z,
Genetic testing and molecular biomarkers. 22-Jul-2016
Our findings indicate that the presence of the lower activity allele of MTHFR (677T) increased the risk of BID. In addition, the concomitant presence of the MTHFR 677T allele with the COMT 472G allele was associated with increased susceptibility to BID in our population.
The NLRP3 Inflammasome Regulates Bronchial Epithelial Cell Injury and Pro-apoptosis After Exposure to Biomass Fuel Smoke.Friday, July 22, 2016
Li C, Zhihong H, Wenlong L, Xiaoyan L, Qing C, Wenzhi L, Siming X, Shengming L,
American journal of respiratory cell and molecular biology. 22-Jul-2016
The number of individuals in the population exposed to biomass fuel smoke (BS) is far greater than the number of cigarette smokers. About 20% of cigarette smokers develop chronic obstructive pulmonary disease (COPD) due to smoke caused irreversible damage and sustained inflammation of the airway epithelium. However, the role of BS in COPD pathogenesis remains to be elucidated. In this study, we investigated the expression of pyrin domain containing protein 3 (NLRP3) and caspase-1 in the bronchial epithelium from COPD patients, and further determined the specific role of the NLRP3 inflammasome in bronchial epithelium injury using two in vitro models (BS and cigarette smoke (CS)) in the human bronchial epithelial cell line (16HBE). After exposure to BS and CS, the release of damage-associated molecular patterns (DAMPs), the transcriptional and translational upregulation of NLRP3, and the activation of caspase-1 were observed in cells at different time points. Since IL-1β secretion was dependent on the NLRP3 inflammasome, we assessed CXCL-8 production in response to smoke.Using a transwell migration assay in which 16HBE cells and human alveolar macrophages (HAMs) were co-cultured, we showed that smoke-induced NLRP3 activation in 16HBE cells increased the migration of HAMs. When the NLRP3 expression was silenced, the average migration distance of 16HBE was increased in scratch assay, because the activation of NLRP3 induced apoptosis by the p53-Bax mitochondrial pathway in the smoke-induced action. These results demonstrated the importance of the NLRP3 inflammasome in mediating BS- and CS-induced HBE cell damage and proapoptosis.
Evaluation of the NanoCHIP® Gastrointestinal Panel (GIP) Test for Simultaneous Detection of Parasitic and Bacterial Enteric Pathogens in Fecal Specimens.Friday, July 22, 2016
Ken Dror S, Pavlotzky E, Barak M,
PloS one. 22-7-2016
Infectious gastroenteritis is a global health problem associated with high morbidity and mortality rates. Rapid and accurate diagnosis is crucial to allow appropriate and timely treatment. Current laboratory stool testing has a long turnaround time (TAT) and demands highly qualified personnel and multiple techniques. The need for high throughput and the number of possible enteric pathogens compels the implementation of a molecular approach which uses multiplex technology, without compromising performance requirements. In this work we evaluated the feasibility of the NanoCHIP® Gastrointestinal Panel (GIP) (Savyon Diagnostics, Ashdod, IL), a molecular microarray-based screening test, to be used in the routine workflow of our laboratory, a big outpatient microbiology laboratory. The NanoCHIP® GIP test provides simultaneous detection of nine major enteric bacteria and parasites: Campylobacter spp., Salmonella spp., Shigella spp., Giardia sp., Cryptosporidium spp., Entamoeba histolytica, Entamoeba dispar, Dientamoeba fragilis, and Blastocystis spp. The required high-throughput was obtained by the NanoCHIP® detection system together with the MagNA Pure 96 DNA purification system (Roche Diagnostics Ltd., Switzerland). This combined system has demonstrated a higher sensitivity and detection yield compared to the conventional methods in both, retrospective and prospective samples. The identification of multiple parasites and bacteria in a single test also enabled increased efficiency of detecting mixed infections, as well as reduced hands-on time and work load. In conclusion, the combination of these two automated systems is a proper response to the laboratory needs in terms of improving laboratory workflow, turn-around-time, minimizing human errors and can be efficiently integrated in the routine work of the laboratory.
Molecularly determined total tumour load in lymph nodes of stage I-II colon cancer patients correlates with high-risk factors. A multicentre prospective study.Friday, July 22, 2016
Aldecoa I, Atares B, Tarragona J, Bernet L, Sardon JD, Pereda T, Villar C, Mendez MC, Gonzalez-Obeso E, Elorriaga K, Alonso GL, Zamora J, Planell N, Palacios J, Castells A, Matias-Guiu X, Cuatrecasas M,
Virchows Archiv : an international journal of pathology. 22-Jul-2016
Stage I-II (pN0) colorectal cancer patients are surgically treated although up to 25 % will eventually die from disease recurrence. Lymph node (LN) status is an independent prognostic factor in colorectal cancer (CRC), and molecular tumour detection in LN of early-stage CRC patients is associated with an increased risk of disease recurrence and poor survival. This prospective multicentre study aimed to determine the relationship between LN molecular tumour burden and conventional high-risk factors in stage I-II colon cancer patients. A total of 1940 LN from 149 pathologically assessed pN0 colon cancer patients were analysed for the amount of tumour cytokeratin 19 (CK19) messenger RNA (mRNA) with the quantitative reverse transcription loop-mediated isothermal amplification molecular assay One-Step Nucleic Acid Amplification. Patient's total tumour load (TTL) resulted from the sum of all CK19 mRNA tumour copies/μL of each positive LN from the colectomy specimen. A median of 15 LN were procured per case (IQR 12;20). Molecular positivity correlated with high-grade (p < 0.01), mucinous/signet ring type (p = 0.017), male gender (p = 0.02), number of collected LN (p = 0.012) and total LN weight per case (p < 0.01). The TTL was related to pT stage (p = 0.01) and tumour size (p < 0.01) in low-grade tumours. Multivariate logistic regression showed independent correlation of molecular positivity with gender, tumour grade and number of fresh LN [AUC = 0.71 (95 % CI = 0.62-0.79)]. Our results show that lymph node CK19 mRNA detection correlates with classical high-risk factors in stage I-II colon cancer patients. Total tumour load is a quantitative and objective measure that may help to better stage early colon cancer patients.
Increased uptake of cervical screening by women with HIV infection in Auckland regardless of ethnicity, requirement for an interpreter or level of education.Sunday, July 24, 2016
Lowe M, Handy R, Ingram J, Nisbet M, Ritchie S, Thomas M, Briggs S,
The New Zealand medical journal. 2016
The proportion of women in this cohort who received a cervical smear in 2010 is comparable with other studies of women with HIV infection in New Zealand and overseas. We have not been able to identify barriers that prevent women with HIV infection in Auckland regularly receiving an annual cervical smear. We plan to encourage women who have not received a cervical smear in the previous 2-year period to have a cervical smear performed when they attend the Infectious Disease Clinic, and will continue to notify the National Cervical Screening Programme that all women who are newly diagnosed with HIV infection should have an annual recall code attached to future cervical smear reports. We expect that these interventions will further increase the proportion of women with HIV infection in Auckland who receive an annual cervical smear.
MYC and BCL2 evaluation in routine diagnostics of aggressive B-cell lymphomas - presentation of a work-flow and the experience with 248 cases.Friday, July 22, 2016
Menter T, Medani H, Ahmad R, Flora R, Trivedi P, Reid A, Naresh KN,
British journal of haematology. 22-Jul-2016
Lactobacillus rhamnosus induced epithelial cell apoptosis, ameliorates inflammation and prevents colon cancer development in an animal model.Friday, July 22, 2016
Gamallat Y, Meyiah A, Kuugbee ED, Hago AM, Chiwala G, Awadasseid A, Bamba D, Zhang X, Shang X, Luo F, Xin Y,
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 19-Jul-2016
LGG have a potential protection effect against colon carcinogenesis; inducing apoptosis and ameliorating inflammation, and may hold a promise as bio-therapeutic dietary agent.
Transplantation of Haploidentical TcRαβ-Depleted Hematopoietic Cells Allows for Optimal Timing and Sustained Correction of the Metabolic Defect in Children with Infantile Osteopetrosis.Friday, July 22, 2016
Pronk CJ, Turkiewicz D, Vult von Steyern K, Ehinger M, Dykes J, Toporski J,
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research. 22-Jul-2016
In osteopetrosis, osteoclast dysfunction can lead to deafness, blindness, bone marrow failure and death. Hematopoietic cell transplantation (HCT) is currently the only curative treatment, but outcome remains disappointing. Although a rapid progression towards HCT is detrimental to prevent further progress of disease manifestations, 70 percent of cases lack an HLA-matched sibling and require alternative stem cell sources. We present two cases of osteopetrosis that successfully received an HCT with haploidentical TcRαβ-depleted cells from one of the parents. These cases showed no further disease progression, had restoration of functional osteoclasts and illustrate this approach to enable prompt HCT with ready available parental donors and rapid and sustained hematological, including osteoclast, recovery. This article is protected by copyright. All rights reserved.
Phenotypes of California CF Newborn Screen-Positive Children with CFTR 5T Allele by TG Repeat Length.Friday, July 22, 2016
Salinas DB, Azen C, Young S, Keens TG, Kharrazi M, Parad RB,
Genetic testing and molecular biomarkers. 22-Jul-2016
CFTR (IVS8)-(TG)m-5T allele (TG) tract length determination provides valuable information in predicting the risk of developing a CF phenotype. Of the three types of 5T alleles evaluated, screen-positive children with genotype CF40mut/(TG)13-5T progressed from CRMS to CF at a high rate, while there was little evidence of clinical disease in those with CF40mut/(TG)11-5T. Additional data from longer follow-up intervals are needed to fully understand the natural history of individuals with a CF40mut/(TG)m-5T genotype.
Biomarkers for the prediction of venous thromboembolism in the community.Friday, July 22, 2016
Puurunen MK, Enserro D, Xanthakis V, Larson MG, Benjamin EJ, Tofler GH, Wollert KC, O'Donnell CJ, Vasan RS,
Thrombosis research. 14-Jul-2016
Venous and arterial thrombosis share common pathophysiology. Multiple biomarkers reflecting various biological pathways can predict arterial thrombosis. We studied whether this approach could identify persons at risk of first venous thromboembolism (VTE).
Seminal Fluid-Mediated Inflammation in Physiology and Pathology of the Female Reproductive Tract.Friday, July 22, 2016
Adefuye AO, Adeola HA, Sales KJ, Katz AA,
Journal of immunology research. 2016
Inflammation is a multifaceted process involving a host of resident and recruited immune cells that eliminate the insult or injury and initiate tissue repair. In the female reproductive tract (FMRT), inflammation-mediated alterations in epithelial, vascular, and immune functions are important components of complex physiological processes and many local and systemic pathologies. It is well established that intracoital and postcoital function of seminal fluid (SF) goes beyond nutritive support for the spermatozoa cells. SF, in particular, the inflammatory bioactive lipids, and prostaglandins present in vast quantities in SF, have a role in localized immune modulation and regulation of pathways that can exacerbate inflammation in the FMRT. In sexually active women SF-mediated inflammation has been implicated in physiologic processes such as ovulation, implantation, and parturition while also enhancing tumorigenesis and susceptibility to infection. This review highlights the molecular mechanism by which SF regulates inflammatory pathways in the FMRT and how alterations in these pathways contribute to physiology and pathology of the female reproductive function. In addition, based on findings from TaqMan® 96-Well Plate Arrays, on neoplastic cervical cells treated with SF, we discuss new findings on the role of SF as a potent driver of inflammatory and tumorigenic pathways in the cervix.
Biomarkers and Algorithms for the Diagnosis of Vitamin B12 Deficiency.Friday, July 22, 2016
Hannibal L, Lysne V, Bjørke-Monsen AL, Behringer S, Grünert SC, Spiekerkoetter U, Jacobsen DW, Blom HJ,
Frontiers in molecular biosciences. 2016
Vitamin B12 (cobalamin, Cbl, B12) is an indispensable water-soluble micronutrient that serves as a coenzyme for cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). Deficiency of Cbl, whether nutritional or due to inborn errors of Cbl metabolism, inactivate MS and MCM leading to the accumulation of homocysteine (Hcy) and methylmalonic acid (MMA), respectively. In conjunction with total B12 and its bioactive protein-bound form, holo-transcobalamin (holo-TC), Hcy, and MMA are the preferred serum biomarkers utilized to determine B12 status. Clinically, vitamin B12 deficiency leads to neurological deterioration and megaloblastic anemia, and, if left untreated, to death. Subclinical vitamin B12 deficiency (usually defined as a total serum B12 of <200 pmol/L) presents asymptomatically or with rather subtle generic symptoms that oftentimes are mistakenly ascribed to unrelated disorders. Numerous studies have now established that serum vitamin B12 has limited diagnostic value as a stand-alone marker. Low serum levels of vitamin B12 not always represent deficiency, and likewise, severe functional deficiency of the micronutrient has been documented in the presence of normal and even high levels of serum vitamin B12. This review discusses the usefulness and limitations of current biomarkers of B12 status in newborn screening, infant and adult diagnostics, the algorithms utilized to diagnose B12 deficiency and unusual findings of vitamin B12 status in various human disorders.
biosigner: A New Method for the Discovery of Significant Molecular Signatures from Omics Data.Friday, July 22, 2016
Rinaudo P, Boudah S, Junot C, Thévenot EA,
Frontiers in molecular biosciences. 2016
High-throughput technologies such as transcriptomics, proteomics, and metabolomics show great promise for the discovery of biomarkers for diagnosis and prognosis. Selection of the most promising candidates between the initial untargeted step and the subsequent validation phases is critical within the pipeline leading to clinical tests. Several statistical and data mining methods have been described for feature selection: in particular, wrapper approaches iteratively assess the performance of the classifier on distinct subsets of variables. Current wrappers, however, do not estimate the significance of the selected features. We therefore developed a new methodology to find the smallest feature subset which significantly contributes to the model performance, by using a combination of resampling, ranking of variable importance, significance assessment by permutation of the feature values in the test subsets, and half-interval search. We wrapped our biosigner algorithm around three reference binary classifiers (Partial Least Squares-Discriminant Analysis, Random Forest, and Support Vector Machines) which have been shown to achieve specific performances depending on the structure of the dataset. By using three real biological and clinical metabolomics and transcriptomics datasets (containing up to 7000 features), complementary signatures were obtained in a few minutes, generally providing higher prediction accuracies than the initial full model. Comparison with alternative feature selection approaches further indicated that our method provides signatures of restricted size and high stability. Finally, by using our methodology to seek metabolites discriminating type 1 from type 2 diabetic patients, several features were selected, including a fragment from the taurochenodeoxycholic bile acid. Our methodology, implemented in the biosigner R/Bioconductor package and Galaxy/Workflow4metabolomics module, should be of interest for both experimenters and statisticians to identify robust molecular signatures from large omics datasets in the process of developing new diagnostics.
Personalized Medicine in Cerebrovascular Neurosurgery: Precision Neurosurgical Management of Cerebral Aneurysms and Subarachnoid Hemorrhage.Friday, July 22, 2016
Achrol AS, Steinberg GK,
Frontiers in surgery. 2016
Cerebral aneurysms are common vascular lesions. Little is known about the pathogenesis of these lesions and the process by which they destabilize and progress to rupture. Treatment decisions are motivated by a desire to prevent rupture and the devastating morbidity and mortality associated with resulting subarachnoid hemorrhage (SAH). For patients presenting with SAH, urgent intervention is required to stabilize the lesion and prevent re-rupture. Those patients fortunate enough to survive a presenting SAH and subsequent securing of their aneurysm must still face a spectrum of secondary sequelae, which can include cerebral vasospasm, delayed ischemia, seizures, cerebral edema, hydrocephalus, and endocrinologic and catecholamine-induced systemic dysfunction in cardiac, pulmonary, and renal systems. Increased focus on understanding the pathophysiology and molecular characteristics of these secondary processes will enable the development of targeted therapeutics and novel diagnostics for improved patient selection in personalized medicine trials for SAH. In unruptured cerebral aneurysms, treatment decisions are less clear and currently based solely on treating larger lesions, using rigid aneurysm size cutoffs generalized from recent studies that are the subject of ongoing controversy. Further compounding this controversy is the fact that the vast majority of aneurysms that come to clinical attention at the time of a hemorrhagic presentation are of smaller size, suggesting that small aneurysms are indeed not benign lesions. As such, patient-specific biomarkers that better predict which aneurysms represent high-risk lesions that warrant clinical intervention are of vital importance. Recent advancements in genomic and proteomic technologies have enabled the identification of molecular characteristics that may prove useful in tracking aneurysm growth and progression and identifying targets for prophylactic therapeutic interventions. Novel quantitative neuroimaging technologies have also recently emerged, capable of non-invasive characterization of hemodynamic factors, inflammation, and structural changes in aneurysmal walls. The combined use of these quantitative neuroimaging and molecular-based approaches, called Radiogenomics, is a technique that holds great promise in better characterizing individual aneurysms. In the near future, these radiogenomic techniques may help improve quality of life and patient outcomes via patient-specific approaches to the treatment of unruptured cerebral aneurysms and personalized medical management of secondary processes following aneurysmal SAH.
p38MAPK and Chemotherapy: We Always Need to Hear Both Sides of the Story.Friday, July 22, 2016
García-Cano J, Roche O, Cimas FJ, Pascual-Serra R, Ortega-Muelas M, Fernández-Aroca DM, Sánchez-Prieto R,
Frontiers in cell and developmental biology. 2016
The p38MAPK signaling pathway was initially described as a stress response mechanism. In fact, during previous decades, it was considered a pathway with little interest in oncology especially in comparison with other MAPKs such as ERK1/2, known to be target of oncogenes like Ras. However, its involvement in apoptotic cell death phenomena makes this signaling pathway more attractive for many cancer research laboratories. This apoptotic role allows to establish a link between p38MAPK and regular chemotherapeutic agents such as Cisplatin or base analogs (Cytarabine, Gemcitabine or 5-Fluorouracil) which are currently used in hospitals across the world. In fact, and more recently, p38MAPK has also been connected with targeted therapies like tyrosine kinase inhibitors (vg. Imatinib, Sorafenib) and, to a lesser extent, with monoclonal antibodies. In addition, the oncogenic or tumor suppressor potential of this signaling pathway has aroused the interest of the scientific community in evaluating p38MAPK as a novel target for cancer therapy. In this review, we will summarize the role of p38MAPK in chemotherapy as well as the potential that p38MAPK inhibition can bring to cancer therapy. All the evidences suggest that p38MAPK could be a double-edged sword and that the search for the most appropriate candidate patients, depending on their pathology and treatment, will lead to a more rational use of this new therapeutic tool.
Study Protocol on Hormonal Mediation of Exercise on Cognition, Stress and Immunity (PRO-HMECSI): Effects of Different Exercise Programmes in Institutionalized Elders.Friday, July 22, 2016
Teixeira AM, Ferreira JP, Hogervorst E, Braga MF, Bandelow S, Rama L, Figueiredo A, Campos MJ, Furtado GE, Chupel MU, Pedrosa FM,
Frontiers in public health. 2016
Physical activity (PA) in elders has been shown to have positive effects on a plethora of chronic diseases and to improve immunity, mental health, and cognition. Chronic stress has also been shown to have immuno-suppressive effects and to accelerate immunosenescence. Exercise could be a significant factor in ameliorating the deleterious effects of chronic stress, but variables such as the type, intensity, and frequency of exercise that should be performed in order to effectively reduce the stress burden need to be defined clearly. PRO-HMECSI will allow us to investigate which hormonal and immunological parameters are able to mediate the effects of exercise on mucosal immunity, psychological/biological stress, and cognitive functioning in older people. Phase I consists of an observational cross-sectional study that compares elders groups (n = 223, >65 years) by functional fitness levels aiming to identify biomarkers involved in maintaining immune and mental health. Neuroendocrine and immune biomarkers of stress, psychological well-being related to mental health, neurocognitive function, functional fitness, and daily PA will be evaluated. Phase II consists of a 28-week intervention in elders with mild cognitive impairment (MCI) profile (n = 149, >65 years, divided in three groups of exercise and one control group), aiming to investigate whether the positive effect of three different types of chair-based exercise programs on physical and psychological health is mediated by an optimal endocrine environment. Primary outcomes are measures of cognitive function and global health. Secondary outcomes include the evaluation the other dimensions such as immune function, psychological health, and depression. Few studies addressed the effects of different types of exercise interventions in older population samples with MCI. We will also be able to determine which type of exercise is more effective in the immune and hormonal function of this population.
Pre-Adult MRI of Brain Cancer and Neurological Injury: Multivariate Analyses.Friday, July 22, 2016
Levman J, Takahashi E,
Frontiers in pediatrics. 2016
Brain cancer and neurological injuries, such as stroke, are life-threatening conditions for which further research is needed to overcome the many challenges associated with providing optimal patient care. Multivariate analysis (MVA) is a class of pattern recognition technique involving the processing of data that contains multiple measurements per sample. MVA can be used to address a wide variety of neuroimaging challenges, including identifying variables associated with patient outcomes; understanding an injury's etiology, development, and progression; creating diagnostic tests; assisting in treatment monitoring; and more. Compared to adults, imaging of the developing brain has attracted less attention from MVA researchers, however, remarkable MVA growth has occurred in recent years. This paper presents the results of a systematic review of the literature focusing on MVA technologies applied to brain injury and cancer in neurological fetal, neonatal, and pediatric magnetic resonance imaging (MRI). With a wide variety of MRI modalities providing physiologically meaningful biomarkers and new biomarker measurements constantly under development, MVA techniques hold enormous potential toward combining available measurements toward improving basic research and the creation of technologies that contribute to improving patient care.
Induction of Chronic Inflammation and Altered Levels of DNA Hydroxymethylation in Somatic and Germinal Tissues of CBA/CaJ Mice Exposed to (48)Ti Ions.Friday, July 22, 2016
Rithidech KN, Jangiam W, Tungjai M, Gordon C, Honikel L, Whorton EB,
Frontiers in oncology. 2016
Although the lung is one of the target organs at risk for cancer induction from exposure to heavy ions found in space, information is insufficient on cellular/molecular responses linked to increased cancer risk. Knowledge of such events may aid in the development of new preventive measures. Furthermore, although it is known that germinal cells are sensitive to X- or γ-rays, there is little information on the effects of heavy ions on germinal cells. Our goal was to investigate in vivo effects of 1 GeV/n (48)Ti ions (one of the important heavy ions found in the space environment) on somatic (lung) and germinal (testis) tissues collected at various times after a whole body irradiation of CBA/CaJ mice (0, 0.1, 0.25, or 0.5 Gy, delivered at 1 cGy/min). We hypothesized that (48)Ti-ion-exposure induced damage in both tissues. Lung tissue was collected from each mouse from each treatment group at 1 week, 1 month, and 6 months postirradiation. For the testis, we collected samples at 6 months postirradiation. Hence, only late-occurring effects of (48)Ti ions in the testis were studied. There were five mice per treatment group at each harvest time. We investigated inflammatory responses after exposure to (48)Ti ions by measuring the levels of activated nuclear factor kappa B and selected pro-inflammatory cytokines in both tissues of the same mouse. These measurements were coupled with the quantitation of the levels of global 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Our data clearly showed the induction of chronic inflammation in both tissues of exposed mice. A dose-dependent reduction in global 5hmC was found in the lung at all time-points and in testes collected at 6 months postirradiation. In contrast, significant increases in global 5mC were found only in lung and testes collected at 6 months postirradiation from mice exposed to 0.5 Gy of 1 GeV/n (48)Ti ions. Overall, our data showed that (48)Ti ions may create health risks in both lung and testicular tissues.
In vivo imaging of airway cilia and mucus clearance with micro-optical coherence tomography.Friday, July 22, 2016
Chu KK, Unglert C, Ford TN, Cui D, Carruth RW, Singh K, Liu L, Birket SE, Solomon GM, Rowe SM, Tearney GJ,
Biomedical optics express. 1-Jul-2016
We have designed and fabricated a 4 mm diameter rigid endoscopic probe to obtain high resolution micro-optical coherence tomography (µOCT) images from the tracheal epithelium of living swine. Our common-path fiber-optic probe used gradient-index focusing optics, a selectively coated prism reflector to implement a circular-obscuration apodization for depth-of-focus enhancement, and a common-path reference arm and an ultra-broadbrand supercontinuum laser to achieve high axial resolution. Benchtop characterization demonstrated lateral and axial resolutions of 3.4 μm and 1.7 μm, respectively (in tissue). Mechanical standoff rails flanking the imaging window allowed the epithelial surface to be maintained in focus without disrupting mucus flow. During in vivo imaging, relative motion was mitigated by inflating an airway balloon to hold the standoff rails on the epithelium. Software implemented image stabilization was also implemented during post-processing. The resulting image sequences yielded co-registered quantitative outputs of airway surface liquid and periciliary liquid layer thicknesses, ciliary beat frequency, and mucociliary transport rate, metrics that directly indicate airway epithelial function that have dominated in vitro research in diseases such as cystic fibrosis, but have not been available in vivo.
Erythrocyte-derived nano-probes functionalized with antibodies for targeted near infrared fluorescence imaging of cancer cells.Friday, July 22, 2016
Mac JT, Nuñez V, Burns JM, Guerrero YA, Vullev VI, Anvari B,
Biomedical optics express. 1-Apr-2016
Constructs derived from mammalian cells are emerging as a new generation of nano-scale platforms for clinical imaging applications. Herein, we report successful engineering of hybrid nano-structures composed of erythrocyte-derived membranes doped with FDA-approved near infrared (NIR) chromophore, indocyanine green (ICG), and surface-functionalized with antibodies to achieve molecular targeting. We demonstrate that these constructs can be used for targeted imaging of cancer cells in vitro. These erythrocyte-derived optical nano-probes may provide a potential platform for clinical translation, and enable molecular imaging of cancer biomarkers.
Terahertz otoscope and potential for diagnosing otitis media.Friday, July 22, 2016
Ji YB, Moon IS, Bark HS, Kim SH, Park DW, Noh SK, Huh YM, Suh JS, Oh SJ, Jeon TI,
Biomedical optics express. 1-Apr-2016
We designed and fabricated a novel terahertz (THz) otoscope to help physicians to diagnose otitis media (OM) with both THz diagnostics and conventional optical diagnostics. We verified the potential of this tool for diagnosing OM using mouse skin tissue and a human tympanic membrane samples prior to clinical application.
In vivo quantifying molecular specificity of Cy5.5-labeled cyclic 9-mer peptide probe with dynamic fluorescence imaging.Friday, July 22, 2016
Dai Y, Yin J, Huang Y, Chen X, Wang G, Liu Y, Zhang X, Nie Y, Wu K, Liang J,
Biomedical optics express. 1-Apr-2016
We quantified molecular specificity of Cy5.5-GX1 in vivo with dynamic fluorescence imaging to better understand its kinetic properties. According to whether or not free GX1 was injected and when it was injected, twelve of BGC-823 xenografted mice were randomly divided into three groups and underwent a 60 minute dynamic fluorescence scanning. Combined with a principal-component analysis, the binding potential (Bp) of the probe was determined by both Logan graphical analysis with reference tissue model (GARTM) and Lammertsma simplified reference tissue model (SRTM). The sum of the pharmacokinetic rate constants (SKRC) was quantified by the Gurfinkel exponential model (GEXPM). Cy5.5-GX1 specifically targeted tumor both in vitro and in vivo. We obtained similar quantification results of Bp (GARTM Bp = 0.582 ± 0.2655, SRTM Bp = 0.618 ± 0.2923), and obtained a good linear relation between the Bp value and the SKRC value. Our results indicate that the SKRC value is more suitable for an early-stage kinetic data analysis, and the Bp value depicts kinetic characteristics under the equilibrium state. Dynamic fluorescence imaging in conjunction with various kinetic models are optimal tools to quantify molecular specificity of the Cy5.5-GX1 probe in vivo.
Characterization of internodal collecting lymphatic vessel function after surgical removal of an axillary lymph node in mice.Friday, July 22, 2016
Kwon S, Price RE,
Biomedical optics express. 1-Apr-2016
Secondary lymphedema is an acquired lymphatic disorder, which occurs because of damage to the lymphatic system from surgery and/or radiation therapy for cancer treatment. However, it remains unknown how post-nodal collecting lymphatic vessels (CLVs) draining to the surgical wound area change in response to lymphadenectomy. We investigated functional and architectural changes of inguinal-to-axillary internodal CLVs (ICLVs) in mice after a single axillary LN (ALN) dissection using near-infrared fluorescence imaging. Our data showed no lymph flow in the ICLVs draining from the inguinal LN (ILN) at 2 days post-surgery. External compression enabled visualization of a small segment of contractile fluorescent ICLVs, but not all the way to the axillary region. At day 6, abnormal lymphatic drainage patterns, including lateral and retrograde lymph flow via vessels branching off the ICLVs were observed, which started to disappear beginning 9 days after surgery. The administration of vascular endothelial growth factor (VEGF)-C into the wound increased resolution of altered lymphatic drainage. Lymphatic drainage from the base of the tail to the ILN did not significantly change over time. These results demonstrate that lymph flow in the CLVs is dramatically affected by a LN dissection and long-term interruption of lymph flow might cause CLV dysfunction and thus contribute to chronic lymphatic disorders.
The Predictive Role of Inflammatory Biomarkers in Atrial Fibrillation as Seen through Neutrophil-Lymphocyte Ratio Mirror.Friday, July 22, 2016
Paquissi FC,
Journal of biomarkers. 2016
Atrial fibrillation (AF) is the most common arrhythmia and is responsible for significant disease burden worldwide. Current evidence has suggested that systemic inflammatory response plays a crucial role in the initiation, maintenance, and progression of AF. So, recent efforts have been directed in search of measurable inflammatory biomarkers as additional tools in severity and prognosis assessment of AF. A simple, and easily obtainable, inflammatory marker is the neutrophil-lymphocyte ratio (NLR), which has shown good performance in preliminary studies as a potential prognostic biomarker in patients with AF. In this work, we performed a thorough review of clinical studies that evaluated the role of C-reactive protein (CRP), interleukin-6 (IL-6), and NLR as predictors of outcomes in AF. We gave a particular emphasis on the NLR because it is a simpler, widely available, and inexpensive biomarker.
CXCL8, IL-1β and sCD200 are pro-inflammatory cytokines and their levels increase in the circulation of breast carcinoma patients.Friday, July 22, 2016
Celik B, Yalcin AD, Genc GE, Bulut T, Kuloglu Genc S, Gumuslu S,
Biomedical reports. Aug-2016
The influence of biomarkers on carcinogenesis has been investigated extensively. Whether they promote carcinogenesis or work against cancer development remains to be elucidated. To the best of our knowledge, the novel molecule cluster of differentiation 200 (CD200) has not been studied on human breast cancer subjects. The present study aimed to evaluate interleukin-1β (IL-1β), C-X-C motif chemokine ligand 8 (CXCL8), cancer antigen 15.3 (CA 15.3) and the soluble CD200 (sCD200) levels in the serum samples of breast carcinoma patients in order to predict their role in breast carcinoma. The subjects included individuals with early and advanced stage breast cancers, as well as healthy controls. Commercially available ELISA kits were used to measure the serum concentrations of sCD200, IL-1β, CXCL8, CA 15.3, C-reactive protein (CRP) and leukocyte count. A total of 130 subjects were recruited; 50 early stage cancer, 50 advanced stage and 30 control subjects. Serum sCD200, CXCL8, IL-1β and CRP levels were significantly higher in the early as well as the advanced stage breast cancer patients compared to the control group. The level of CA 15.3 was statistically different between early and advanced stage. There were significant positive correlations between IL-1β and CXCL8, and IL-1β and serum sCD200 levels in the control group. These correlations did not persist in the early or the advanced stage cancer groups except CRP and CA 15.3, but new correlations appeared between serum sCD200 level and leukocyte count for advanced stage breast cancer group. Multivariate regression correlation analysis revealed positive correlation between IL-1β and sCD200; and IL-1β and CXCL8. In conclusion, sCD200, CXCL8, CA 15.3 and IL-1β are proinflammatory molecules and their levels are influenced in breast cancer patients.
Identification of CD4(+)CD25(+)CD127(-) regulatory T cells and CD14(+)HLA(-)DR(-)/low myeloid-derived suppressor cells and their roles in the prognosis of breast cancer.Friday, July 22, 2016
Wang J, Yang J,
Biomedical reports. Aug-2016
The aim of the present study was to identify cluster of differentiation 4(+) (CD4(+))CD25(+)CD127(-) regulatory T cells (Tregs) and CD14(+) human leukocyte antigen-antigen D-related (HLA(-)DR(-))/low myeloid-derived suppressor cells (MDSCs) in patients with breast cancer of varying stages, and investigate their roles and the potential interactions in the prognosis of breast cancer. A total of 40 patients with breast cancer were included in the study. A total of 30 healthy individuals served as the healthy control. Flow cytometry was performed for the identification of biomarkers. Natural Tregs were characterized by the expression of CD4(+)CD25(+)CD127(-). The MDSC frequency was expressed as the percentage of CD33(+)CD11b(+)HLA(-)DR(-)lineage markers (Lin)(-). The absolute number of Tregs was higher in breast cancer patients compared to the healthy control. The absolute number of Tregs in the patients with stage III or IV breast cancer was higher than those of the stage I or II, respectively. The percentage showed a gradual increase in the patients with breast cancer compared with the normal control. No direct correlation was established between the number or percentage of Tregs and the patient survival. There was a higher percentage of circulating MDSCs in breast cancer patients compared with the normal individuals. A close correlation was established between clinical cancer stage and percentage and total number of circulating MDSCs. To be exact, a significant increase of MDSC percentage and total number was observed in patients with stage III-IV breast cancer compared with the other cancer patients (stage I-II) and the normal individuals. No statistical difference was observed in the 3- and 5-year survival rates in the breast cancer patients with enhanced expression of Tregs, compared with the normal individuals. In conclusion, enhanced expression of CD4(+)CD25(+)CD127(-) Tregs cells and CD33(+)CD11(+)HLA(-)DR(-)LIN(-) MDSCs were identified from patients with breast cancer. Patients with advanced stage breast cancer showed upregulation of such cells. However, these 2 types of cells showed no correlation with the prognosis of breast cancer.
Meta-analysis of microRNAs as biomarkers for muscle-invasive bladder cancer.Friday, July 22, 2016
Zheng LF, Sun WY,
Biomedical reports. Aug-2016
Bladder cancer is the most common cancer of the urinary tract. A quarter of bladder cancer patients presenting with muscle-invasive bladder cancer (MIBC) suffer significant morbidity and succumb to the disease. MicroRNA (miRNA) from tissue, urine or blood samples of MIBC patients have been demonstrated to differ from healthy individuals, and possibly have diagnostic value. The aim of the present meta-analysis was to access the overall diagnostic accuracy comprehensively and quantitatively. Systematic searching in PubMed, Web of Science, Embase and Chinese National Knowledge Infrastructure database was conducted. The pooled sensitivity, specificity, positive and negative likelihood ratios (PLR and NLR) and diagnostic odds ratio (DOR) were calculated via the random effects model to evaluate the overall test performance. Deeks' funnel plot asymmetry test was used to test the publication bias. A total of 10 studies were included in the meta-analysis, with a total of 577 patients and 412 controls. The pooled sensitivity and specificity were 0.78 [95% confidence interval (CI), 0.69-0.86] and 0.77 (95% CI, 0.72-0.81), respectively. The pooled PLR was 2.9 (95% CI, 2.1-3.8), the NLR was 0.31 (95% CI, 0.27-0.35), the DOR was 7 (95% CI, 4-13) and the pooled AUC was 0.80 (95% CI, 0.69-0.87). In conclusion, the current miRNA assays support their use as markers for MIBC diagnosis.
Metal-linked Immunosorbent Assay (MeLISA): the Enzyme-Free Alternative to ELISA for Biomarker Detection in Serum.Friday, July 22, 2016
Yu RJ, Ma W, Liu XY, Jin HY, Han HX, Wang HY, Tian H, Long YT,
Theranostics. 2016
Determination of disease biomarkers in clinical samples is of crucial significance for disease monitoring and public health. The dominating format is enzyme-linked immunosorbent assay (ELISA), which subtly exploits both the antigen-antibody reaction and biocatalytic property of enzymes. Although enzymes play an important role in this platform, they generally suffer from inferior stability and less tolerant of temperature, pH condition compared with general chemical product. Here, we demonstrate a metal-linked immunosorbent assay (MeLISA) based on a robust signal amplification mechanism that faithfully replaces the essential element of the enzyme. As an enzyme-free alternative to ELISA, this methodology works by the detection of α-fetoprotein (AFP), prostatic specific antigen (PSA) and C-reactive protein (CRP) at concentrations of 0.1 ng mL(-1), 0.1 ng mL(-1) and 1 ng mL(-1) respectively. It exhibits approximately two magnitudes higher sensitivity and is 4 times faster for chromogenic reaction than ELISA. The detection of AFP and PSA was further confirmed by over a hundred serum samples from hepatocellular carcinoma (HCC) and prostate cancer patients respectively.
Gastrin-releasing Peptide Receptor Imaging in Breast Cancer Using the Receptor Antagonist (68)Ga-RM2 And PET.Friday, July 22, 2016
Stoykow C, Erbes T, Maecke HR, Bulla S, Bartholomä M, Mayer S, Drendel V, Bronsert P, Werner M, Gitsch G, Weber WA, Stickeler E, Meyer PT,
Theranostics. 2016
Our study demonstrates that (68)Ga-RM2-PET/CT is a promising imaging method in ER-positive breast cancer. In vivo GRPR binding assessed by (68)Ga-RM2-PET/CT correlated with ER expression in primary tumors of untreated patients.
Holographic Assessment of Lymphoma Tissue (HALT) for Global Oncology Field Applications.Friday, July 22, 2016
Pathania D, Im H, Kilcoyne A, Sohani AR, Fexon L, Pivovarov M, Abramson JS, Randall TC, Chabner BA, Weissleder R, Lee H, Castro CM,
Theranostics. 2016
Low-cost, rapid and accurate detection technologies are key requisites to cope with the growing global cancer challenges. The need is particularly pronounced in resource-limited settings where treatment opportunities are often missed due to the absence of timely diagnoses. We herein describe a Holographic Assessment of Lymphoma Tissue (HALT) system that adopts a smartphone as the basis for molecular cancer diagnostics. The system detects malignant lymphoma cells labeled with marker-specific microbeads that produce unique holographic signatures. Importantly, we optimized HALT to detect lymphomas in fine-needle aspirates from superficial lymph nodes, procedures that align with the minimally invasive biopsy needs of resource-constrained regions. We equipped the platform to directly address the practical needs of employing novel technologies for "real world" use. The HALT assay generated readouts in <1.5 h and demonstrated good agreement with standard cytology and surgical pathology.
Simple, Sensitive and Accurate Multiplex Detection of Clinically Important Melanoma DNA Mutations in Circulating Tumour DNA with SERS Nanotags.Friday, July 22, 2016
Wee EJ, Wang Y, Tsao SC, Trau M,
Theranostics. 2016
Sensitive and accurate identification of specific DNA mutations can influence clinical decisions. However accurate diagnosis from limiting samples such as circulating tumour DNA (ctDNA) is challenging. Current approaches based on fluorescence such as quantitative PCR (qPCR) and more recently, droplet digital PCR (ddPCR) have limitations in multiplex detection, sensitivity and the need for expensive specialized equipment. Herein we describe an assay capitalizing on the multiplexing and sensitivity benefits of surface-enhanced Raman spectroscopy (SERS) with the simplicity of standard PCR to address the limitations of current approaches. This proof-of-concept method could reproducibly detect as few as 0.1% (10 copies, CV < 9%) of target sequences thus demonstrating the high sensitivity of the method. The method was then applied to specifically detect three important melanoma mutations in multiplex. Finally, the PCR/SERS assay was used to genotype cell lines and ctDNA from serum samples where results subsequently validated with ddPCR. With ddPCR-like sensitivity and accuracy yet at the convenience of standard PCR, we believe this multiplex PCR/SERS method could find wide applications in both diagnostics and research.
Effect of IL-6 and IL-8 on the expression of the complement activation inhibitors MAC-inhibitory protein and decay-accelerating factor in ovarian cancer A2780 cells.Friday, July 22, 2016
Kapka-Skrzypczak L, Popek S, Sawicki K, Wolińska E, Czajka M, Skrzypczak M,
Oncology letters. Aug-2016
The aim of the present study was to evaluate the role of interleukin (IL)-6 and IL-8 on the expression of the membrane-bound complement inhibitors membrane attack complex-inhibitory protein (CD59) and decay-accelerating factor (CD55), in the human ovarian carcinoma A2780 cell line, which is a non-producing IL-6 cell line that does exhibit IL-6 responsiveness, due to the presence of IL-6 receptors. Extracellular levels of complement system inhibitors were evaluated by western blotting and reverse transcription-quantitative polymerase chain reaction. Cellular localization of CD55 and CD59 in the ovarian cancer cells was assessed by immunofluorescence. The detection of a soluble form of CD55 and CD59 released by the A2780 cells following stimulation with IL-6 and IL-8 was detected by enzyme-linked immunosorbent assay. The present data revealed that A2780 cells express CD55 and CD59 at the mRNA and protein level, but do not secrete these proteins to the culture medium. Results of western blotting demonstrated that the protein level of CD59 was regulated by IL-6 and IL-8 in a dose-dependent manner. Immunofluorescence analysis revealed that the ovarian cancer A2780 cell line expresses the membrane bound form of CD55 protein. The present results indicate that CD55 and CD59 may affect the efficiency of complement-mediated immunotherapies.
Correlation between histological grade and positron emission tomography parameters in cervical carcinoma.Friday, July 22, 2016
Mocciaro V, Scollo P, Stefano A, Gieri S, Russo G, Scibilia G, Cosentino S, Murè G, Baldari S, Sabini MG, Fraggetta F, Gilardi MC, Ippolito M,
Oncology letters. Aug-2016
The aim of the present study was to evaluate the changes in cervical cancer glucose metabolism for different levels of cellular differentiation. The metabolic activity was measured by standardized uptake value (SUV), SUV normalized to lean body mass, metabolic tumor volume and total lesion glycolysis using fluorine-18 fluorodeoxyglucose positron emission tomography (PET). A correlation study of these values could be used to facilitate therapeutic choice and to improve clinical practice and outcome. This study considered 32 patients with diagnosed cervical cancers, at different International Federation of Gynecology and Obstetrics stages. Glucose metabolism was assessed by PET examination, and histological specimens were examined to determine their initial grade of differentiation. A correlation study of these values was evaluated. Histological examination showed that all cases were of squamous cell carcinoma. Regarding the differentiation of the tumor, 19 well- to moderately-differentiated tumors and 13 poorly-differentiated tumors were determined. Negative findings for correlations between metabolic parameters and initial grade of histological differentiation were found, and considering that histological grade has been shown to have no consistent prognostic value in cervical cancer treatment, PET imaging could play a significant role in cervical cancer prognosis.
Expression and localization of the immunophilin FKBP51 in colorectal carcinomas and primary metastases, and alterations following oxaliplatin-based chemotherapy.Friday, July 22, 2016
Rotoli D, Morales M, Del Carmen Maeso M, Del Pino García M, Morales A, Ávila J, Martín-Vasallo P,
Oncology letters. Aug-2016
The immunophilin FK506-binding protein 5 (FKBP51) is a scaffold protein that serves a pivotal role in the regulation of multiple signaling pathways, integrating external and internal stimuli into distinct signal outputs. In a previous study, we identified several genes that are significantly up- or downregulated in the peripheral white cells (PWCs) of colorectal adenocarcinoma (CRC) patients undergoing oxaliplatin-based chemotherapy. In our screening, FKBP51 gene expression was downregulated following chemotherapy. In order to determine whether this alteration in gene expression observed in PWCs may be detected at the protein level in tumors and metastases following the administration of adjuvant chemotherapy, an immunohistochemical analysis of FKBP51 in CRC and primary metastasis tissues was performed. The present study confirmed the downregulation of FKBP51 gene expression elicited by chemotherapy with folinic acid (leucovorin), fluorouracil and oxaliplatin in metastasized liver tissue that had been resected after the oxaliplatin-based chemotherapy, compared with tissue section samples of CRC from patients (prior to antineoplastic treatment). Furthermore, the results indicated that, in CRC tissue sections, the expression of FKBP51 protein is associated with an immature phenotype of stromal fibroblasts and with the epithelial-to-mesenchymal transition (EMT) phenotype, suggesting a role for this protein in the EMT process in CRC. Finally, the observation that only certain cells of the stroma express FKBP51 protein suggests a potential role for this immunophilin as a stroma cell subtype marker.
Attempt towards a novel classification of triple-negative breast cancer using immunohistochemical markers.Friday, July 22, 2016
Liu YX, Wang KR, Xing H, Zhai XJ, Wang LP, Wang W,
Oncology letters. Aug-2016
Significant efforts have been made to gain a better understanding of the heterogeneity of triple-negative breast cancers from the histological to the molecular and genomic levels. In this study, we attempted to bring forward gene expression subtypes of triple-negative breast cancer (TBNC) to the clinic, by translating gene stratification to clinically accessible immunohistochemical (IHC) classification. Using IHC analysis, we categorized 154 TBNC cases into three main subclasses. Differences in the frequencies of basic characteristics and clinicopathological parameters between the subtypes were examined using Chi-square tests. We defined three main groups among the 154 triple-negative cases. The basal-like (BL) group expressed cytokeratin (CK) 5/6 and/or CK14 (83 cases), the AR(+) group demonstrated positivity for androgen receptor (18 cases), and the final group exhibited a CD44+CD24-(/)low phenotype (39 cases). There were three overlapping cases between the BL subgroup and the CD44+CD24-/low phenotype subgroup, and 11 unclassified cases. In this new IHC classification, three subcategories exhibited a statistical difference with regard to age, tumor size, histological grade, tumor necrosis, Ki67 labeling index, relapse-free survival, breast cancer-specific survival and response to chemotherapy. According to our definition, the BL group and CD44+CD24-(/)low phenotype could be observed in tumors that were not triple-negative, and BL tumors that were triple-negative demonstrated almost undistinguishable clinicopathological characteristics compared with BL tumors that were not triple-negative. The same observation was made with CD44+CD24-/low tumors that were triple-negative vs. CD44+CD24-(/)low tumors that were not. The AR+ group demonstrated undistinguishable clinicopathological characteristics compared with the luminal subtype. We successfully distinguished three subtypes exhibiting diverse clinicopathological and prognostic characteristics with the minimum use of IHC markers.
Ikaros expression sensitizes leukemic cells to the chemotherapeutic drug doxorubicin.Friday, July 22, 2016
He L, Gao S, Zhu Z, Chen S, Gu H,
Oncology letters. Aug-2016
Ikaros is an important transcription factor involved in the development and differentiation of hematopoietic cells. However, its role in the treatment of hematopoietic malignancies such as leukemia is less well understood. In the present study, it was observed by data mining of the Oncomine database that high expression levels of full-length Ikaros (IK1) is correlated with increased sensitivity of cancer cells to treatments with chemotherapeutic drugs, including doxorubicin (DOX). To examine the functional significance of this observation, the expression of IK1 in a leukemia cell line was altered, and the response of leukemic cells to DOX treatment was analyzed. It was observed that overexpression of IK1 could enhance DOX-induced apoptosis, while knockdown of IK1 attenuated DOX-induced apoptosis in leukemic cells. Further experiments demonstrated that IK1 sensitized leukemic cells to DOX-induced apoptosis, probably through upregulation of caspase-9. These data suggest that high expression levels of IK1 may be a potential biomarker to predict responses of leukemia patients to treatment with chemotherapy.
FOXL2 molecular status in adult granulosa cell tumors of the ovary: A study of primary and metastatic cases.Friday, July 22, 2016
Zannoni GF, Improta G, Petrillo M, Pettinato A, Scambia G, Fraggetta F,
Oncology letters. Aug-2016
Granulosa cell tumors (GCTs) of the ovary are uncommon neoplasms, accounting for ~5% of all malignant ovarian tumors. GCTs are a relatively homogeneous group of tumors, categorized into two distinct subtypes, juvenile GCT and adult GCT (AGCT), likely arising from a limited set of molecular events usually involving the disruption of pathways that regulate granulosa cell proliferation. In the present study, the presence of forkheadbox L2 (FOXL2) c.402C>G mutation was investigated in a series of 42 samples of primary and metastatic AGCT of the ovary. The samples consisted of 37 primary and 5 metastatic ovarian AGCTs from 37 patients. FOXL2 mutational status was evaluated using a pyrosequencing approach on 2.5-µm sections of formalin-fixed paraffin-embedded tissue. FOXL2 c.402C>G mutation was found in 33/37 (89.2%) primary AGCTs and in 4/5 (80.0%) metastases, with the molecular status of the metastases recapitulating that of the primary tumors (4 mutated cases and 1 wild-type case). Overall, FOXL2 mutation is present in the majority of primary and metastatic AGCTs, and could be used as a valid tool in the diagnosis of the disease and in cases of metastatic lesions from an unknown primary origin. Moreover the concordance of FOXL2 molecular status in primary and associated metastases suggests its early appearance and genomic stability in AGCT tumorigenesis.
Expression levels of JNK associated with polymorphic lactotransferrin haplotypes in human nasopharyngeal carcinoma.Friday, July 22, 2016
Luo G, Zhou Y, Yi W, Yi H,
Oncology letters. Aug-2016
Lactotransferrin (LTF), a member of the transferrin family, serves a role in the innate immune response and is involved in anti-inflammatory, anti-microbial and anti-tumor activity. Alterations in the LTF gene are associated with an increased incidence of cancer. The LTF gene is polymorphic, and several common alleles may be observed in the general population. Our previous study identified a lower rate of occurrence of the 'A-G-G-T' haplotype (constructed with rs1126477, rs1126478, rs2073495 and rs9110) in nasopharyngeal carcinoma (NPC) patients compared with controls. In the present study, in order to elucidate a possible mechanism of LTF-mediated anti-tumor activity in NPC, the protein profiles of NPC and non-tumorous nasopharyngeal epithelium tissues with/without the 'A-G-G-T' haplotype were constructed using LTQ Orbitrap technology. The results revealed that c-Jun N-terminal kinase 2 (JNK2) was highly expressed in NPC tissues and non-tumor nasopharyngeal epithelium tissues without the 'A-G-G-T' haplotype. These results were confirmed by western blot analysis. Furthermore, microRNA (miRNA) microarray analysis was conducted to investigate the differential miRNA profiles of NPC and non-tumor nasopharyngeal epithelium tissues with/without the 'A-G-G-T' haplotype. It was observed that hsa-miR-1256 and hsa-miR-659, which are potentially targeted to the JNK2 gene, were downregulated in NPC tissues without the 'A-G-G-T' haplotype. Hsa-miR-298, another miRNA potentially targeted to the JNK2 gene, was downregulated in non-tumor nasopharyngeal epithelium tissues without the 'A-G-G-T' haplotype. In summary, these results suggested that the expression levels of JNK2 may be associated with polymorphic LTF haplotypes in human NPC.
miR-148a and miR-375 may serve as predictive biomarkers for early diagnosis of laryngeal carcinoma.Friday, July 22, 2016
Wu Y, Yu J, Ma Y, Wang F, Liu H,
Oncology letters. Aug-2016
The role of microRNAs (miRs) as possible biomarkers and therapy targets has been extensively investigated in a number of types of cancer. However, the aberrant expression of miRs in laryngeal squamous cell carcinoma (LSCC), particularly during the progression of the disease, is poorly understood. In the present study, the role of miRs as possible novel early pre-diagnostic biomarkers of LSCC was investigated. TaqMan probe stem-loop quantitative polymerase chain reaction was utilized to accurately measure the amount of miR-148a and miR-375 in clinical samples of mild dysplasia, moderate dysplasia, severe dysplasia, cancer in situ, laryngeal cancer and normal epithelial controls. The application of miR-148a and miR-375 as potential predictive biomarkers for early diagnosis of LSCC was analyzed. The results of the present study suggested that miR-148a and miR-375 were significantly upregulated in LSCC tissues, and increased expression of miR-375 was associated with a more aggressive phenotype of LSCC. Additional investigation revealed that miR-148a and miR-375 increased during different dysplasia stages of LSCC carcinogenesis, and high-level expression of miR-148a or miR-375 in patients with laryngeal dysplasia may predict subsequent malignant transformation. miR-148a and miR-375 were significantly upregulated during LSCC carcinogenesis and may serve as possible predictive biomarkers for early diagnosis of LSCC.
Ratio of microRNA-122/155 in isoniazid-induced acute liver injury in mice.Friday, July 22, 2016
Song L, Zhang Z, Zhang J, Zhu X, He L, Shi Z, Gao L, Feng F,
Experimental and therapeutic medicine. Aug-2016
Liver injury is a major hindrance to the treatment of tuberculosis (TB) patients due to the primary side effects associated with anti-TB drugs. Several investigations have identified sensitive biomarkers for the early diagnosis of anti-TB drug-induced liver injury (ADLI), including the use of microRNAs (miRNAs/miRs). However, the association between miR-122/155 and ADLI remains unknown. Thus, the present study used reverse transcription-quantitative polymerase chain reaction to observe changes in tissue miR-122/155 expression levels during the course of liver injury in mice. Liver injury was induced by the administration of isoniazid (INH), a first-line anti-TB drug. miR-122/155 expression levels were quantified at seven time points throughout 1 day (0.25, 0.75, 1.5, 6, 12, 18 and 24 h) based on the pharmacokinetics of INH in mice. Notably, over the timecourse of INH-induced liver injury, the tissue miR-122 expression level significantly decreased at 0.25 h, which is the peak concentration time of INH, compared with the control group (P<0.05). The change was more rapid than that of the serum aminotransferase and miR-155, which were significantly increased at 0.75 h. In addition, the pathological score correlated with the ratio of miR-122/miR-155 (r=-0.779; P<0.01). In conclusion, the miR-122/155 ratio may be utilized as a sensitive biomarker for ADLI, which could contribute to the early diagnosis of patients following anti-TB treatment.
Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker.Friday, July 22, 2016
Al-Kafaji G, Al-Mahroos G, Al-Muhtaresh HA, Skrypnyk C, Sabry MA, Ramadan AR,
Experimental and therapeutic medicine. Aug-2016
Circulating microRNAs (miRNAs) have been proposed as promising biomarkers for multiple diseases. miR-126 is reported to be associated with type 2 diabetes mellitus (T2D), diabetic nephropathy (DN) and end stage renal disease. The aim of this study was to investigate the expression of circulating miR-126 and to assess its potential as a blood-based biomarker for DN in T2D patients. In 52 patients with T2D without history of DN (with noromoalbuminuria), 50 patients with T2D and DN (29 with microalbuminuria and 21 with macroalbuminuria), and 50 non-diabetic healthy controls, the expression of circulating miR-126 in peripheral whole blood was evaluated by quantitative polymerase chain reaction. The expression levels of circulating miR-126 were significantly decreased in T2D patients and further decreased in DN patients compared with those in the controls. Multivariate logistic regression analysis confirmed the independent association of lower miR-126 levels with T2D [adjusted odds ratio (OR), 0.797; 95% confidence interval (CI), 0.613-0.960] and DN (adjusted OR, 0.513; 95% CI, 0.371-0.708). miR-126 levels were associated with the degree of albuminuria and showed significantly low expression in DN patients with microalbuminuria (adjusted OR, 0.781; 95% CI; 0.698-0.952) and further lower expression in DN patients with macroalbuminuria (adjusted OR, 0.433; 95% CI, 0.299-0.701), respectively compared with T2D patients with normoalbuminuria. miR-126 levels negatively correlated with albuminuria positively with glomerular filtration rate (P<0.05), and in addition, negatively correlated with fasting glucose, glycated hemoglobin, triglyceride and LDL (P<0.05). Stepwise multiple regression analysis identified albuminuria as a significant predictor of miR-126 (P<0.001). miR-126 in peripheral blood yielded area under the receiver operating characteristic curves of 0.854 (95% CI, 0.779-0.929) and 0.959 (95% CI, 0.916-1.000) in the differentiation of DN patients from T2D patients and DN patients from non-diabetic controls respectively. These data suggest that decreased expression of circulating miR-126 is associated with the development of DN in T2D patients, and may be a promising blood-based biomarker for DN risk estimation.
Clinical significance of elevated serum A-FABP and free fatty acid in neonates with hypoxic ischemic brain damage.Friday, July 22, 2016
Li M, Jiang L, Zhang H, Wang D, Zhang M, Zhang L,
Experimental and therapeutic medicine. Aug-2016
The main function of adipocyte fatty acid-binding protein (A-FABP) is to regulate fatty acid metabolism as its molecular chaperone. The clinical significance of A-FABP in hypoxic-ischemic brain damage (HIBD) neonates is not yet clear. Free fatty acid (FFA) in cerebral cortex increases along with hypoxia ischemia degree. Thus, we aimed to investigate whether FFA can induce A-FABP expression and elevate the serum A-FABP level in HIBD neonates. In the present study, 42 HIBD neonates were selected including 11 cases as mild, 16 cases as moderate and 15 cases as severe. The serum was collected from peripheral vein at 72 h after the first visit (acute stage) and 7 days after birth (recovery stage), and the serum from 10 normal neonates was used as the control. The serum level of A-FABP and FFA in 42 neonates with acute phase and recovery phase HIBD were detected using ELISA and copper colorimetric method. The overall serum A-FABP content in HIBD neonates at the acute stage was significantly higher compared to the normal neonates (P<0.05). The serum A-FABP level in severe HIBD neonates was significantly higher than that in mild HIBD, moderate HIBD and normal neonates (P<0.05). The serum FFA level in HIBD neonates at the acute stage was 1,521.57±605.63 µmol/l, which was significantly higher than that in the normal neonates 838.24±294.22 µmol/l. The serum FFA levels in mild, moderate and severe HIBD neonates were significantly higher than those in the normal neonates. The overall A-FABP level in HIBD neonates at the recovery stage was significantly lower compared to the acute stage, which was significant in severe HIBD neonates. A-FABP levels in mild and moderate HIBD neonates at recovery stage were decreased compared with the acute stage, although there was no statistical difference. There was a positive correlation between serum A-FABP and FFA in HIBD neonates at acute stage (r=0.369, P<0.05). In conclusion, serum A-FABP and FFA levels were signifcantly increased in HIBD neonates at acute stage, and were positively correlated. The serum A-FABP level in HIBD neonates at recovery stage was significantly lower than that in the acute stage. The results suggested that serum A-FABP and FFA levels at acute stage can reflect the severity of HIBD. The detection of serum A-FABP and FFA can be applied as indicators for the early diagnosis of HIBD, but also provides a basis for the clinical evaluation of HIBD treatment.
Myrrh attenuates oxidative and inflammatory processes in acetic acid-induced ulcerative colitis.Friday, July 22, 2016
Fatani AJ, Alrojayee FS, Parmar MY, Abuohashish HM, Ahmed MM, Al-Rejaie SS,
Experimental and therapeutic medicine. Aug-2016
The pathogenesis of ulcerative colitis (UC) has been associated with a weakened antioxidant capacity and increased inflammatory processes. Myrrh is traditionally used for the treatment of inflammatory diseases due to its antioxidant and anti-inflammatory properties. The present study aimed to evaluate the effects of myrrh on an experimental rat model of UC. UC was induced in rats using acetic acid (AA) after pre-treatment with myrrh (125, 250 or 500 mg/kg/day) or mesalazine (MES; 300 mg/kg/day) for 7 days. The levels of various inflammatory cytokines, prostaglandin E2 (PGE2) and nitric oxide (NO) in the rat colon tissues were assessed. In addition, the colonic levels of thiobarbituric acid reactive substances (TBARS) and non-protein sulfhydryl groups (NP-SH), as well as the activities of superoxide dismutase (SOD) and catalase (CAT), were estimated. Furthermore, total protein (TP) contents and the levels of DNA and RNA were measured, and histopathological changes in colonic tissues were analyzed. The results indicated that the levels of pro-inflammatory cytokines, PGE2, NO and TBARS were markedly increased. By contrast, the levels of interleukin-10, NP-SH, TP and nucleic acids, and the enzymatic activities of SOD and CAT were significantly decreased in the AA model group. In addition, pretreatment with myrrh and MES was able to attenuate the impaired oxidative stress response and upregulation of inflammatory biomarkers. Furthermore, the enzymatic activities of SOD and CAT were near to normal in the myrrh and MES pretreated groups. The ability of myrrh to protect against UC was further confirmed by histopathological analysis, and the high dose of myrrh exerted an effect comparable to MES. In conclusion, the results of the present study suggested that myrrh has potent therapeutic value in the amelioration of experimental colitis in laboratory animals by downregulating the expression of proinflammatory mediators and improving endogenous antioxidative activities.
Single Molecule Localization Microscopy of Mammalian Cell Nuclei on the Nanoscale.Friday, July 22, 2016
Szczurek A, Xing J, Birk UJ, Cremer C,
Frontiers in genetics. 2016
Nuclear texture analysis is a well-established method of cellular pathology. It is hampered, however, by the limits of conventional light microscopy (ca. 200 nm). These limits have been overcome by a variety of super-resolution approaches. An especially promising approach to chromatin texture analysis is single molecule localization microscopy (SMLM) as it provides the highest resolution using fluorescent based methods. At the present state of the art, using fixed whole cell samples and standard DNA dyes, a structural resolution of chromatin in the 50-100 nm range is obtained using SMLM. We highlight how the combination of localization microscopy with standard fluorophores opens the avenue to a plethora of studies including the spatial distribution of DNA and associated proteins in eukaryotic cell nuclei with the potential to elucidate the functional organization of chromatin. These views are based on our experience as well as on recently published research in this field.
Gibberellin-Stimulation of Rhizome Elongation and Differential GA-Responsive Proteomic Changes in Two Grass Species.Friday, July 22, 2016
Ma X, Huang B,
Frontiers in plant science. 2016
Rapid and extensive rhizome development is a desirable trait for perennial grass growth and adaptation to environmental stresses. The objective of this study was to determine proteomic changes and associated metabolic pathways of gibberellin (GA) -regulation of rhizome elongation in two perennial grass species differing in rhizome development. Plants of a short-rhizome bunch-type tall fescue (TF; Festuca arundinacea; 'BR') and an extensive rhizomatous Kentucky bluegrass (KB; Poa pratensis; 'Baron') were treated with 10 μM GA3 in hydroponic culture in growth chambers. The average rhizome length in KB was significantly longer than that in TF regardless of GA3 treatment, and increased significantly with GA3 treatment, to a greater extent than that in TF. Comparative proteomic analysis using two-dimensional electrophoresis and mass spectrometry was performed to further investigate proteins and associated metabolic pathways imparting increased rhizome elongation by GA. A total of 37 and 38 differentially expressed proteins in response to GA3 treatment were identified in TF and KB plants, respectively, which were mainly involved in photosynthesis, energy and amino acid metabolism, protein synthesis, defense and cell development processes. Accelerated rhizome elongation in KB by GA could be mainly associated with the increased abundance of proteins involved in energy metabolism (glyceraldehyde-3-phosphate dehydrogenase, fructose-bisphosphate aldolase, and ATP synthase), amino acid metabolism (S-adenosylmethionine and adenosylhomocysteinase), protein synthesis (HSP90, elongation factor Tu and eukaryotic translation initiation factor 5A), cell-wall development (cell dividion cycle protein, alpha tubulin-2A and actin), and signal transduction (calreticulin). These proteins could be used as candidate proteins for further analysis of molecular mechanisms controlling rhizome growth.
Does HIV Exploit the Inflammatory Milieu of the Male Genital Tract for Successful Infection?Friday, July 22, 2016
Esra RT, Olivier AJ, Passmore JA, Jaspan HB, Harryparsad R, Gray CM,
Frontiers in immunology. 2016
In many parts of the World, medical male circumcision (MMC) is used as standard prevention of care against HIV infection. This is based on seminal reports made over 10 years ago that removal of the foreskin provides up to 60% protection against HIV infection in males and seems currently the best antiretroviral-free prevention strategy yet against the global epidemic. We explore the potential mechanisms by which MMC protects against HIV-1 acquisition and that one of the oldest, albeit re-invented, rituals of removing a foreskin underscores the exploitative nature of HIV on the anatomy and tissue of the uncircumcised penis. Furthermore, foreskin removal also reveals how males acquire HIV, and in reality, the underlying mechanisms of MMC are not known. We argue that the normal sequelae of inflammation in the male genital tract (MGT) for protection from sexually transmitted infections (STI)-induced pathology represents a perfect immune and microbial ecosystem for HIV acquisition. The accumulation of HIV-1 target cells in foreskin tissue and within the urethra in response to STIs, both during and after resolution of infection, suggests that acquisition of HIV-1, through sexual contact, makes use of the natural immune milieu of the MGT. Understanding immunity in the MGT, the movement of HIV-1 target cells to the urethra and foreskin tissue upon encounter with microbial signals would provide more insight into viral acquisition and lay the foundation for further prevention strategies in males that would be critical to curb the epidemic in all sexual partners at risk of infection. The global female-centric focus of HIV-1 transmission and acquisition research has tended to leave gaps in our knowledge of what determines HIV-1 acquisition in men and such understanding would provide a more balanced and complete view of viral acquisition.
Tertiary Lymphoid Organs in Cancer Tissues.Friday, July 22, 2016
Hiraoka N, Ino Y, Yamazaki-Itoh R,
Frontiers in immunology. 2016
Tertiary lymphoid organs (TLOs) are induced postnatally in non-lymphoid tissues such as those affected by chronic infections, autoimmune diseases, and chronic allograft rejection, and also in cancer tissues. TLOs are thought to provide important lymphocytic functional environments for both cellular and humoral immunity, similar to lymph nodes or Peyer's patches. TLOs have a structure similar to that of lymph nodes or Peyer's patches, including T cell zones, B cell follicles, and high endothelial venules (HEV) without encapsulation. Here, we review recent advances in our knowledge of TLOs in human solid cancers, including their location, structure, methods of evaluation, and clinicopathological impact. We also discuss the formation and/or maintenance of TLOs in cancer tissues in association with the tumor immune microenvironment, cancer invasion, and the tissue structure of the cancer stroma.
An Analysis of the Effects of Vancomycin and/or Vancomycin-Resistant Citrobacter freundii Exposure on the Microbial Community Structure in Soil.Friday, July 22, 2016
Cycoń M, Borymski S, Orlewska K, Wąsik TJ, Piotrowska-Seget Z,
Frontiers in microbiology. 2016
The occurrence of antibiotics and antibiotic resistance genes in the environment has become a subject of growing concern. The extensive use of vancomycin and other pharmaceuticals may alter the biodiversity of soil microbial communities and select antibiotic-resistant bacteria. Therefore, the purpose of the study was to evaluate the impact of vancomycin and/or vancomycin-resistant Citrobacter freundii on soil microbial communities using the denaturing gradient gel electrophoresis (DGGE) and the phospholipid fatty acid (PLFA) approaches. The experiment had a completely randomized block design with the following treatments: control soil (C), soil with vancomycin (1 mg/kg soil-VA1), soil with vancomycin (10 mg/kg soil-VA10), soil with C. freundii (Cit), soil with vancomycin (1 mg/kg soil) and C. freundii (VA1+Cit), and soil with vancomycin (10 mg/kg soil) and C. freundii (VA10+Cit). A bacterial strain resistant to vancomycin was isolated from raw sewage collected from the municipal sewage treatment plant. The obtained results indicated that the antibiotic and/or the bacterial strain exerted a selective pressure that resulted in qualitative and quantitative changes in the population of soil microorganisms. However, a multivariate analysis showed that the genetic and structural diversity of the soil microbial community was primarily affected by the incubation time and to a lesser extent by the antibiotic and introduced bacteria. DGGE analysis clearly showed that certain species within the bacterial community were sensitive to vancomycin as was evidenced by a decrease in the values of S (richness) and H (Shannon-Wiener) indices. Moreover, a PLFA method-based analysis revealed alterations in the structure of the soil microbial community as indicated by changes in the biomass of the PLFA biomarkers specific for Gram-positive and Gram-negative bacteria as well as fungi. The changes observed in the community of soil microorganisms may decrease the rate of microbial-mediated processes, which can lead to a disturbance in the ecological balance of the soil ecosystem.
Sterol Synthesis in Diverse Bacteria.Friday, July 22, 2016
Wei JH, Yin X, Welander PV,
Frontiers in microbiology. 2016
Sterols are essential components of eukaryotic cells whose biosynthesis and function has been studied extensively. Sterols are also recognized as the diagenetic precursors of steranes preserved in sedimentary rocks where they can function as geological proxies for eukaryotic organisms and/or aerobic metabolisms and environments. However, production of these lipids is not restricted to the eukaryotic domain as a few bacterial species also synthesize sterols. Phylogenomic studies have identified genes encoding homologs of sterol biosynthesis proteins in the genomes of several additional species, indicating that sterol production may be more widespread in the bacterial domain than previously thought. Although the occurrence of sterol synthesis genes in a genome indicates the potential for sterol production, it provides neither conclusive evidence of sterol synthesis nor information about the composition and abundance of basic and modified sterols that are actually being produced. Here, we coupled bioinformatics with lipid analyses to investigate the scope of bacterial sterol production. We identified oxidosqualene cyclase (Osc), which catalyzes the initial cyclization of oxidosqualene to the basic sterol structure, in 34 bacterial genomes from five phyla (Bacteroidetes, Cyanobacteria, Planctomycetes, Proteobacteria, and Verrucomicrobia) and in 176 metagenomes. Our data indicate that bacterial sterol synthesis likely occurs in diverse organisms and environments and also provides evidence that there are as yet uncultured groups of bacterial sterol producers. Phylogenetic analysis of bacterial and eukaryotic Osc sequences confirmed a complex evolutionary history of sterol synthesis in this domain. Finally, we characterized the lipids produced by Osc-containing bacteria and found that we could generally predict the ability to synthesize sterols. However, predicting the final modified sterol based on our current knowledge of sterol synthesis was difficult. Some bacteria produced demethylated and saturated sterol products even though they lacked homologs of the eukaryotic proteins required for these modifications emphasizing that several aspects of bacterial sterol synthesis are still completely unknown.
Whole Genome Sequencing for Genomics-Guided Investigations of Escherichia coli O157:H7 Outbreaks.Friday, July 22, 2016
Rusconi B, Sanjar F, Koenig SS, Mammel MK, Tarr PI, Eppinger M,
Frontiers in microbiology. 2016
Multi isolate whole genome sequencing (WGS) and typing for outbreak investigations has become a reality in the post-genomics era. We applied this technology to strains from Escherichia coli O157:H7 outbreaks. These include isolates from seven North America outbreaks, as well as multiple isolates from the same patient and from different infected individuals in the same household. Customized high-resolution bioinformatics sequence typing strategies were developed to assess the core genome and mobilome plasticity. Sequence typing was performed using an in-house single nucleotide polymorphism (SNP) discovery and validation pipeline. Discriminatory power becomes of particular importance for the investigation of isolates from outbreaks in which macrogenomic techniques such as pulse-field gel electrophoresis or multiple locus variable number tandem repeat analysis do not differentiate closely related organisms. We also characterized differences in the phage inventory, allowing us to identify plasticity among outbreak strains that is not detectable at the core genome level. Our comprehensive analysis of the mobilome identified multiple plasmids that have not previously been associated with this lineage. Applied phylogenomics approaches provide strong molecular evidence for exceptionally little heterogeneity of strains within outbreaks and demonstrate the value of intra-cluster comparisons, rather than basing the analysis on archetypal reference strains. Next generation sequencing and whole genome typing strategies provide the technological foundation for genomic epidemiology outbreak investigation utilizing its significantly higher sample throughput, cost efficiency, and phylogenetic relatedness accuracy. These phylogenomics approaches have major public health relevance in translating information from the sequence-based survey to support timely and informed countermeasures. Polymorphisms identified in this work offer robust phylogenetic signals that index both short- and long-term evolution and can complement currently employed typing schemes for outbreak ex- and inclusion, diagnostics, surveillance, and forensic studies.
Transhydrogenase and Growth Substrate Influence Lipid Hydrogen Isotope Ratios in Desulfovibrio alaskensis G20.Friday, July 22, 2016
Leavitt WD, Flynn TM, Suess MK, Bradley AS,
Frontiers in microbiology. 2016
Microbial fatty acids preserve metabolic and environmental information in their hydrogen isotope ratios ((2)H/(1)H). This ratio is influenced by parameters that include the (2)H/(1)H of water in the microbial growth environment, and biosynthetic fractionations between water and lipid. In some microbes, this biosynthetic fractionation has been shown to vary systematically with central energy metabolism, and controls on fatty acid (2)H/(1)H may be linked to the intracellular production of NADPH. We examined the apparent fractionation between media water and the fatty acids produced by Desulfovibrio alaskensis G20. Growth was in batch culture with malate as an electron donor for sulfate respiration, and with pyruvate and fumarate as substrates for fermentation and for sulfate respiration. A larger fractionation was observed as a consequence of respiratory or fermentative growth on pyruvate than growth on fumarate or malate. This difference correlates with opposite apparent flows of electrons through the electron bifurcating/confurcating transhydrogenase NfnAB. When grown on malate or fumarate, mutant strains of D. alaskensis G20 containing transposon disruptions in a copy of nfnAB show different fractionations than the wild type strain. This phenotype is muted during fermentative growth on pyruvate, and it is absent when pyruvate is a substrate for sulfate reduction. All strains and conditions produced similar fatty acid profiles, and the (2)H/(1)H of individual lipids changed in concert with the mass-weighted average. Unsaturated fatty acids were generally depleted in (2)H relative to their saturated homologs, and anteiso-branched fatty acids were generally depleted in (2)H relative to straight-chain fatty acids. Fractionation correlated with growth rate, a pattern that has also been observed in the fractionation of sulfur isotopes during dissimilatory sulfate reduction by sulfate-reducing bacteria.
Current Knowledge and Future Research Directions on Fecal Bacterial Patterns and Their Association with Asthma.Friday, July 22, 2016
Claassen-Weitz S, Wiysonge CS, Machingaidze S, Thabane L, Horsnell WG, Zar HJ, Nicol MP, Kaba M,
Frontiers in microbiology. 2016
Comparison between Variable and Conventional Volume-Controlled Ventilation on Cardiorespiratory Parameters in Experimental Emphysema.Friday, July 22, 2016
Henriques I, Padilha GA, Huhle R, Wierzchon C, Miranda PJ, Ramos IP, Rocha N, Cruz FF, Santos RS, de Oliveira MV, Souza SA, Goldenberg RC, Luiz RR, Pelosi P, de Abreu MG, Silva PL, Rocco PR,
Frontiers in physiology. 2016
Emphysema is characterized by loss of lung tissue elasticity and destruction of structures supporting alveoli and capillaries. The impact of mechanical ventilation strategies on ventilator-induced lung injury (VILI) in emphysema is poorly defined. New ventilator strategies should be developed to minimize VILI in emphysema. The present study was divided into two protocols: (1) characterization of an elastase-induced emphysema model in rats and identification of the time point of greatest cardiorespiratory impairment, defined as a high specific lung elastance associated with large right ventricular end-diastolic area; and (2) comparison between variable (VV) and conventional volume-controlled ventilation (VCV) on lung mechanics and morphometry, biological markers, and cardiac function at that time point. In the first protocol, Wistar rats (n = 62) received saline (SAL) or porcine pancreatic elastase (ELA) intratracheally once weekly for 4 weeks, respectively. Evaluations were performed 1, 3, 5, or 8 weeks after the last intratracheal instillation of saline or elastase. After identifying the time point of greatest cardiorespiratory impairment, an additional 32 Wistar rats were randomized into the SAL and ELA groups and then ventilated with VV or VCV (n = 8/group) [tidal volume (VT) = 6 mL/kg, positive end-expiratory pressure (PEEP) = 3 cmH2O, fraction of inspired oxygen (FiO2) = 0.4] for 2 h. VV was applied on a breath-to-breath basis as a sequence of randomly generated VT values (mean VT = 6 mL/kg), with a 30% coefficient of variation. Non-ventilated (NV) SAL and ELA animals were used for molecular biology analysis. The time point of greatest cardiorespiratory impairment, was observed 5 weeks after the last elastase instillation. At this time point, interleukin (IL)-6, cytokine-induced neutrophil chemoattractant (CINC)-1, amphiregulin, angiopoietin (Ang)-2, and vascular endothelial growth factor (VEGF) mRNA levels were higher in ELA compared to SAL. In ELA animals, VV reduced respiratory system elastance, alveolar collapse, and hyperinflation compared to VCV, without significant differences in gas exchange, but increased right ventricular diastolic area. Interleukin-6 mRNA expression was higher in VCV and VV than NV, while surfactant protein-D was increased in VV compared to NV. In conclusion, VV improved lung function and morphology and reduced VILI, but impaired right cardiac function in this model of elastase induced-emphysema.
Systemic Low-Frequency Oscillations in BOLD Signal Vary with Tissue Type.Friday, July 22, 2016
Tong Y, Hocke LM, Lindsey KP, Erdoğan SB, Vitaliano G, Caine CE, Frederick Bd,
Frontiers in neuroscience. 2016
Blood-oxygen-level dependent (BOLD) signals are widely used in functional magnetic resonance imaging (fMRI) as a proxy measure of brain activation. However, because these signals are blood-related, they are also influenced by other physiological processes. This is especially true in resting state fMRI, during which no experimental stimulation occurs. Previous studies have found that the amplitude of resting state BOLD is closely related to regional vascular density. In this study, we investigated how some of the temporal fluctuations of the BOLD signal also possibly relate to regional vascular density. We began by identifying the blood-bound systemic low-frequency oscillation (sLFO). We then assessed the distribution of all voxels based on their correlations with this sLFO. We found that sLFO signals are widely present in resting state BOLD signals and that the proportion of these sLFOs in each voxel correlates with different tissue types, which vary significantly in underlying vascular density. These results deepen our understanding of the BOLD signal and suggest new imaging biomarkers based on fMRI data, such as amplitude of low-frequency fluctuation (ALFF) and sLFO, a combination of both, for assessing vascular density.
One-Class Support Vector Machines Identify the Language and Default Mode Regions As Common Patterns of Structural Alterations in Young Children with Autism Spectrum Disorders.Friday, July 22, 2016
Retico A, Gori I, Giuliano A, Muratori F, Calderoni S,
Frontiers in neuroscience. 2016
The identification of reliable brain endophenotypes of autism spectrum disorders (ASD) has been hampered to date by the heterogeneity in the neuroanatomical abnormalities detected in this condition. To handle the complexity of neuroimaging data and to convert brain images in informative biomarkers of pathology, multivariate analysis techniques based on Support Vector Machines (SVM) have been widely used in several disease conditions. They are usually trained to distinguish patients from healthy control subjects by making a binary classification. Here, we propose the use of the One-Class Classification (OCC) or Data Description method that, in contrast to two-class classification, is based on a description of one class of objects only. This approach, by defining a multivariate normative rule on one class of subjects, allows recognizing examples from a different category as outliers. We applied the OCC to 314 regional features extracted from brain structural Magnetic Resonance Imaging (MRI) scans of young children with ASD (21 males and 20 females) and control subjects (20 males and 20 females), matched on age [range: 22-72 months of age; mean = 49 months] and non-verbal intelligence quotient (NVIQ) [range: 31-123; mean = 73]. We demonstrated that a common pattern of features characterize the ASD population. The OCC SVM trained on the group of ASD subjects showed the following performances in the ASD vs. controls separation: the area under the receiver operating characteristic curve (AUC) was 0.74 for the male and 0.68 for the female population, respectively. Notably, the ASD vs. controls discrimination results were maximized when evaluated on the subsamples of subjects with NVIQ ≥ 70, leading to AUC = 0.81 for the male and AUC = 0.72 for the female populations, respectively. Language regions and regions from the default mode network-posterior cingulate cortex, pars opercularis and pars triangularis of the inferior frontal gyrus, and transverse temporal gyrus-contributed most to distinguishing individuals with ASD from controls, arguing for the crucial role of these areas in the ASD pathophysiology. The observed brain patterns associate preschoolers with ASD independently of their age, gender and NVIQ and therefore they are expected to constitute part of the ASD brain endophenotype.
Early Bronchus-Associated Lymphoid Tissue Lymphoma Diagnosed with Immunoglobulin Heavy Chain Molecular Testing.Friday, July 22, 2016
Li P, Cheung L, Chiu B,
Canadian respiratory journal. 2016
When extranodal marginal zone B-cell lymphoma of mucosa associated lymphoid tissue (MALT), a low grade B-cell lymphoma, arises in the lung it is referred to as bronchus-associated lymphoid tissue (BALT) lymphoma. We describe a patient with a history of Sjögren's syndrome and rheumatoid arthritis with dyspnea and imaging consistent with lymphoid interstitial pneumonia (LIP). However, while histology and immunohistochemistry lacked definitive features of a lymphoma, immunoglobulin heavy chain (IgH) polymerase chain reaction testing demonstrated B-cell monoclonality, consistent with an early BALT lymphoma.
New developments in the treatment of chemotherapy-induced neutropenia: focus on balugrastim.Friday, July 22, 2016
Ghidini M, Hahne JC, Trevisani F, Panni S, Ratti M, Toppo L, Tomasello G,
Therapeutics and clinical risk management. 2016
Neutropenia and febrile neutropenia are two major complications of chemotherapy. Dose reductions, delays in treatment administration, and the use of granulocyte colony-stimulating factors are equally recommended options to preserve absolute neutrophil count in case of chemotherapy regimens bringing a risk of febrile neutropenia of 20% or higher. Recombinant granulocyte colony-stimulating factors, such as filgrastim and lenograstim, have a short elimination half-life (t1/2) and need to be used daily, while others, like pegfilgrastim and lipegfilgrastim, are characterized by a long t1/2 requiring only a single administration per cycle. Balugrastim is a novel long-acting recombinant granulocyte colony-stimulating factor obtained by means of a genetic fusion between recombinant human serum albumin and granulocyte colony-stimulating factor. Albumin binding increases the molecular weight and determines a high plasmatic stability leading to a t1/2 of ~19 days. Balugrastim's efficacy, safety, and tolerability have been assessed in four different clinical trials involving breast cancer patients treated with doxorubicin and docetaxel. Pegfilgrastim was chosen as a comparator. Balugrastim was noninferior to pegfilgrastim with regard to the reduction of mean duration of severe neutropenia during cycle 1. Moreover, both treatments were comparable in terms of efficacy and safety profile. Balugrastim was well tolerated, with the only related adverse event being mild to moderate bone pain. The aim of this review is to summarize the currently available literature data on balugrastim.
Disease Biomarkers in Gastrointestinal Malignancies.Friday, July 22, 2016
Moaven O, Raziee H, Bowne W, Abbaszadegan MR, Fuchs BC,
Disease markers. 2016
Proteomic-Based Approaches for the Study of Cytokines in Lung Cancer.Friday, July 22, 2016
Marrugal Á, Ojeda L, Paz-Ares L, Molina-Pinelo S, Ferrer I,
Disease markers. 2016
Proteomic techniques are currently used to understand the biology of different human diseases, including studies of the cell signaling pathways implicated in cancer progression, which is important in knowing the roles of different proteins in tumor development. Due to its poor prognosis, proteomic approaches are focused on the identification of new biomarkers for the early diagnosis, prognosis, and targeted treatment of lung cancer. Cytokines are proteins involved in inflammatory processes and have been proposed as lung cancer biomarkers and therapeutic targets because it has been reported that some cytokines play important roles in tumor development, invasion, and metastasis. In this review, we aim to summarize the different proteomic techniques used to discover new lung cancer biomarkers and therapeutic targets. Several cytokines have been identified as important players in lung cancer using these techniques. We underline the most important cytokines that are useful as biomarkers and therapeutic targets. We also summarize some of the therapeutic strategies targeted for these cytokines in lung cancer.
Genome Sequence of the K139-Like Phage VcP032 Originating from the Vibrio cholerae O1 El Tor Ogawa Serotype.Friday, July 22, 2016
Jäckel C, Strauch E, Hammerl JA,
Genome announcements. 2016
Vibrio cholerae is the cause of large cholera outbreaks, especially in endemic regions with high poverty and inadequate sanitation. Here, we announce the complete genome sequence of the virulence-associated broad host range V. cholerae phage VcP032, including a brief summary of its genotypic and phenotypic features.
Draft Genome Sequence and Complete Plasmid Sequence of Acinetobacter lwoffii F78, an Isolate with Strong Allergy-Protective Properties.Friday, July 22, 2016
Fritzenwanker M, Hain T, Kesper DA, Harb H, Renz H, Domann E,
Genome announcements. 2016
The hygiene hypothesis states that the tremendous increase in atopic diseases correlates significantly with less contact to microbes in childhood. Here, we report the draft genome sequence of Acinetobacter lwoffii F78, a rural cowshed isolate with strong allergy-protective properties that contains an 8,579-bp plasmid.
Genome Sequence of Fusarium Isolate MYA-4552 from the Midgut of Anoplophora glabripennis, an Invasive, Wood-Boring Beetle.Friday, July 22, 2016
Herr JR, Scully ED, Geib SM, Hoover K, Carlson JE, Geiser DM,
Genome announcements. 2016
The Fusarium solani species complex (FSSC) is a clade of environmentally ubiquitous fungi that includes plant, animal, and insect associates. Here, we report the draft genome sequence of the undescribed species FSSC 6 (isolate MYA-4552), housed in the gut of the wood-boring cerambycid beetle Anoplophora glabripennis.
Source: NCBI - Disclaimer and Copyright notice
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