Corporate Banner
Satellite Banner
Molecular & Clinical Diagnostics
Scientific Community
Become a Member | Sign in
Home>Resources>Latest Publications
  Latest Publications
Advanced Search


Showing 100 Latest Publications
TitleDate Created
TGFBI Gene Mutation Analysis in Chinese Families with Corneal Dystrophies.Monday, June 27, 2016
Cai J, Zhu L, Zha Y, Kang Q,
Genetic testing and molecular biomarkers. 27-Jun-2016
TGFBI gene mutations were present in all three Chinese families with corneal dystrophy, and our study further verified the relationship between phenotype and genotype of corneal dystrophy.
Angiotensin II-Receptor Inhibition With Candesartan to Prevent Trastuzumab-Related Cardiotoxic Effects in Patients With Early Breast Cancer: A Randomized Clinical Trial.Monday, June 27, 2016
Boekhout AH, Gietema JA, Milojkovic Kerklaan B, van Werkhoven ED, Altena R, Honkoop A, Los M, Smit WM, Nieboer P, Smorenburg CH, Mandigers CM, van der Wouw AJ, Kessels L, van der Velden AW, Ottevanger PB, Smilde T, de Boer J, van Veldhuisen DJ, Kema IP, de Vries EG, Schellens JH,
JAMA oncology. 23-Jun-2016 Identifier: NCT00459771.
Metabolomic Quality Assessment of EDTA Plasma and Serum Samples.Monday, June 27, 2016
Malm L, Tybring G, Moritz T, Landin B, Galli J,
Biopreservation and biobanking. 27-Jun-2016
Handling and processing of blood can significantly alter the molecular composition and consistency of biobank samples and can have a major impact on the identification of biomarkers. It is thus crucial to identify tools to determine the quality of samples to be used in biomarker discovery studies. In this study, a non-targeted gas chromatography/time-of-flight mass spectrometry (GC-TOFMS) metabolomic strategy was used with the aim of identifying quality markers for serum and plasma biobank collections lacking proper documentation of preanalytical handling. The effect of postcentrifugation delay was examined in serum stored in tubes with gel separation plugs and ethylenediaminetetraacetic acid (EDTA) plasma in tubes with or without gel separation plugs. The change in metabolic pattern was negligible in all sample types processed within 3 hours after centrifugation regardless of whether the samples were kept at 4°C or 22°C. After 8 and 24 hours postcentrifugation delay before aliquoting, there was a pronounced increase in the number of affected metabolites, as well as in the magnitude of the observed changes. No protective effect on the metabolites was observed in gel-separated EDTA plasma samples. In a separate series of experiments, lactate and glucose levels were determined in plasma to estimate the effect of precentrifugation delay. This separate experiment indicates that the lactate to glucose ratio may serve as a marker to identify samples with delayed time to centrifugation. Although our data from the untargeted GC-TOFMS analysis did not identify any specific markers, we conclude that plasma and serum metabolic profiles remain quite stable when plasma and serum are centrifuged and separated from the blood cells within 3 hours.
Peripheral Motor and Sensory Nerve Conduction following Transplantation of Undifferentiated Autologous Adipose Tissue-Derived Stem Cells in a Biodegradable U.S. Food and Drug Administration-Approved Nerve Conduit.Tuesday, June 28, 2016
Klein SM, Vykoukal J, Li DP, Pan HL, Zeitler K, Alt E, Geis S, Felthaus O, Prantl L,
Plastic and reconstructive surgery. Jul-2016
Therapeutic, V.
Automated measurement of estrogen receptor in breast cancer: a comparison of fluorescent and chromogenic methods of measurement.Monday, June 27, 2016
Zarrella ER, Coulter M, Welsh AW, Carvajal DE, Schalper KA, Harigopal M, L Rimm D, M Neumeister V,
Laboratory investigation; a journal of technical methods and pathology. 27-Jun-2016
Whereas FDA-approved methods of assessment of estrogen receptor (ER) are 'fit for purpose', they represent a 30-year-old technology. New quantitative methods, both chromogenic and fluorescent, have been developed and studies have shown that these methods increase the accuracy of assessment of ER. Here, we compare three methods of ER detection and assessment on two retrospective tissue microarray (TMA) cohorts of breast cancer patients: estimates of percent nuclei positive by pathologists and by Aperio's nuclear algorithm (standard chromogenic immunostaining), and immunofluorescence as quantified with the automated quantitative analysis (AQUA) method of quantitative immunofluorescence (QIF). Reproducibility was excellent (R(2)>0.95) between users for both automated analysis methods, and the Aperio and QIF scoring results were also highly correlated, despite the different detection systems. The subjective readings show lower levels of reproducibility and a discontinuous, bimodal distribution of scores not seen by either mechanized method. Kaplan-Meier analysis of 10-year disease-free survival was significant for each method (Pathologist, P=0.0019; Aperio, P=0.0053, AQUA, P=0.0026); however, there were discrepancies in patient classification in 19 out of 233 cases analyzed. Out of these, 11 were visually positive by both chromogenic and fluorescent detection. In 10 cases, the Aperio nuclear algorithm labeled the nuclei as negative; in 1 case, the AQUA score was just under the cutoff for positivity (determined by an Index TMA). In contrast, 8 out of 19 discrepant cases had clear nuclear positivity by fluorescence that was unable to be visualized by chromogenic detection, perhaps because of low positivity masked by the hematoxylin counterstain. These results demonstrate that automated systems enable objective, precise quantification of ER. Furthermore, immunofluorescence detection offers the additional advantage of a signal that cannot be masked by a counterstaining agent. These data support the usage of automated methods for measurement of this and other biomarkers that may be used in companion diagnostic tests.Laboratory Investigation advance online publication, 27 June 2016; doi:10.1038/labinvest.2016.73.
The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity.Monday, June 27, 2016
Wang W, Wang L, Lu J, Siedlak SL, Fujioka H, Liang J, Jiang S, Ma X, Jiang Z, da Rocha EL, Sheng M, Choi H, Lerou PH, Li H, Wang X,
Nature medicine. 27-Jun-2016
Genetic mutations in TAR DNA-binding protein 43 (TARDBP, also known as TDP-43) cause amyotrophic lateral sclerosis (ALS), and an increase in the presence of TDP-43 (encoded by TARDBP) in the cytoplasm is a prominent histopathological feature of degenerating neurons in various neurodegenerative diseases. However, the molecular mechanisms by which TDP-43 contributes to ALS pathophysiology remain elusive. Here we have found that TDP-43 accumulates in the mitochondria of neurons in subjects with ALS or frontotemporal dementia (FTD). Disease-associated mutations increase TDP-43 mitochondrial localization. In mitochondria, wild-type (WT) and mutant TDP-43 preferentially bind mitochondria-transcribed messenger RNAs (mRNAs) encoding respiratory complex I subunits ND3 and ND6, impair their expression and specifically cause complex I disassembly. The suppression of TDP-43 mitochondrial localization abolishes WT and mutant TDP-43-induced mitochondrial dysfunction and neuronal loss, and improves phenotypes of transgenic mutant TDP-43 mice. Thus, our studies link TDP-43 toxicity directly to mitochondrial bioenergetics and propose the targeting of TDP-43 mitochondrial localization as a promising therapeutic approach for neurodegeneration.
Positive Affect, Social Connectedness, and Healthy Biomarkers in Japan and the U.S.Monday, June 27, 2016
Yoo J, Miyamoto Y, Ryff CD,
Emotion (Washington, D.C.). 27-Jun-2016
Previous studies have shown that positive affect (PA) and social connectedness predict better health in the United States (U.S.). However, the relevance of such findings for other cultural contexts has been largely ignored. The present study investigated the interplay of PA, social connectedness, and health using large probability samples of Japanese and U.S. adults. Health was measured objectively with biomarkers that represent well-functioning physiological systems: HDL (high-density lipoprotein) and DHEA-S (dehydroepiandrosterone-sulfate). Lower levels of both biomarkers (i.e., less healthy biomarker profile) were found among those in Japan who reported high PA in combination with low social connectedness. In the U.S, the general pattern was that those with greater PA showed healthier HDL levels regardless of social connectedness. The findings highlight cultural variations in the health implications of how PA and social connectedness come together. (PsycINFO Database Record
Biomarkers in pancreas transplant.Monday, June 27, 2016
Burke GW, Chen LJ, Ciancio G, Pugliese A,
Current opinion in organ transplantation. 24-Jun-2016
The monitoring of pancreas transplant biomarkers, particularly those associated with autoimmunity, has led to new insights into the pathogenesis of T1D. Progress in the elucidation of mechanisms of autoimmunity may lead to novel therapeutic approaches to both T1D recurrence of the pancreas transplant and perhaps also new onset T1D.
Application of ambient ionization high resolution mass spectrometry to determination of the botanical provenance of the constituents of psychoactive drug mixtures.Monday, June 27, 2016
Lesiak AD, Musah RA,
Forensic science international. 14-Jun-2016
A continuing challenge in analytical chemistry is species-level determination of the constituents of mixtures that are made of a combination of plant species. There is an added urgency to identify components in botanical mixtures that have mind altering properties, due to the increasing global abuse of combinations of such plants. Here we demonstrate the proof of principle that ambient ionization mass spectrometry, namely direct analysis in real time-high resolution mass spectrometry (DART-HRMS), and statistical analysis tools can be used to rapidly determine the individual components within a psychoactive brew (Ayahuasca) made from a mixture of botanicals. Five plant species used in Ayahuasca preparations were subjected to DART-HRMS analysis. The chemical fingerprint of each was reproducible but unique, thus enabling discrimination between them. The presence of important biomarkers, including N,N-dimethyltryptamine, harmaline and harmine, was confirmed using in-source collision-induced dissociation (CID). Six Ayahuasca brews made from combinations of various plant species were shown to possess a high level of similarity, despite having been made from different constituents. Nevertheless, the application of principal component analysis (PCA) was useful in distinguishing between each of the brews based on the botanical species used in the preparations. From a training set based on 900 individual analyses, three principal components covered 86.38% of the variance, and the leave-one-out cross validation was 98.88%. This is the first report of ambient ionization MS being successfully used for determination of the individual components of plant mixtures.
Integrated multidisciplinary care for the management of chronic conditions in adults: an overview of reviews and an example of using indirect evidence to inform clinical practice recommendations in the field of rare diseases.Tuesday, June 28, 2016
Yeung CH, Santesso N, Zeraatkar D, Wang A, Pai M, Sholzberg M, Schünemann HJ, Iorio A,
Haemophilia : the official journal of the World Federation of Hemophilia. Jul-2016
This overview provides the most up to date evidence on integrated multidisciplinary care for chronic conditions in adults, and an example of how it can be used for guidelines in rare diseases.
Care models in the management of haemophilia: a systematic review.Tuesday, June 28, 2016
Yeung CH, Santesso N, Pai M, Kessler C, Key NS, Makris M, Navarro-Ruan T, Soucie JM, Schünemann HJ, Iorio A,
Haemophilia : the official journal of the World Federation of Hemophilia. Jul-2016
Our comprehensive review found low- to very low-quality evidence from a limited number of non-randomized studies assessing the impact of haemophilia care models on some patient-important outcomes. While the available evidence suggests that adoption of the integrated care model may provide benefit to PWH, further high-quality research in the field is needed.
Understanding stakeholder important outcomes and perceptions of equity, acceptability and feasibility of a care model for haemophilia management in the US: a qualitative study.Tuesday, June 28, 2016
Lane SJ, Sholapur NS, Yeung CH, Iorio A, Heddle NM, Sholzberg M, Pai M,
Haemophilia : the official journal of the World Federation of Hemophilia. Jul-2016
Twenty-nine interviews were conducted with participants representing 18 US states. Participants in the study sample had experience receiving or providing care predominantly within an HTC setting. Integrated care at HTCs was highly acceptable to participants, who appreciated the value of specialized, expert care in a multidisciplinary team setting. Equity and feasibility issues were primarily related to health insurance and funding limitations. Additional research is required to document the impact of care on health and psychosocial outcomes and identify effective ways to facilitate equitable access to haemophilia treatment and care.
Methodology for the development of the NHF-McMaster Guideline on Care Models for Haemophilia Management.Tuesday, June 28, 2016
Pai M, Santesso N, Yeung CH, Lane SJ, Schünemann HJ, Iorio A,
Haemophilia : the official journal of the World Federation of Hemophilia. Jul-2016
Despite the paucity of high-quality evidence typical of a rare condition such as haemophilia, we successfully applied a rigorous and transparent methodology based on GRADE to develop an evidence-based clinical practice guideline.
NHF-McMaster Guideline on Care Models for Haemophilia Management.Tuesday, June 28, 2016
Pai M, Key NS, Skinner M, Curtis R, Feinstein M, Kessler C, Lane SJ, Makris M, Riker E, Santesso N, Soucie JM, Yeung CH, Iorio A, Schünemann HJ,
Haemophilia : the official journal of the World Federation of Hemophilia. Jul-2016
This guideline was developed to identify evidence-based best practices in haemophilia care delivery, and discuss the range of care providers and services that are most important to optimize outcomes for persons with haemophilia (PWH) across the United States. The guideline was developed following specific methods described in detail in this supplement and based on the GRADE (Grading of Recommendations, Assessment, Development and Evaluation approach). Direct evidence from published literature and the haemophilia community, as well as indirect evidence from other chronic diseases, were reviewed, synthesized and applied to create evidence-based recommendations. The Guideline panel suggests that the integrated care model be used over non-integrated care models for PWH (conditional recommendation, moderate certainty in the evidence). For PWH with inhibitors and those at high risk for inhibitor development, the same recommendation was graded as strong, with moderate certainty in the evidence. The panel suggests that a haematologist, a specialized haemophilia nurse, a physical therapist, a social worker and round-the-clock access to a specialized coagulation laboratory be part of the integrated care team, over an integrated care team that does not include all of these components (conditional recommendation, very low certainty in the evidence). Based on available evidence, the integrated model of care in its current structure, is suggested for optimal care of PWH. There is a need for further appropriately designed studies that address unanswered questions about specific outcomes and the optimal structure of the integrated care delivery model in haemophilia.
Genomic analyses of dominant US clonal lineages of Phytophthora infestans reveals a shared common ancestry for clonal lineages US11 and US18 and a lack of recently shared ancestry among all other US lineages.Monday, June 27, 2016
Knaus BJ, Tabima J, Davis C, Judelson H, Grünwald NJ,
Phytopathology. 27-Jun-2016
Populations of the potato and tomato late blight pathogen, Phytophthora infestans, are well known for emerging as novel clonal lineages. These successions of dominant clones have historically been named US1 through US24, in order of appearance, since their first characterization using molecular markers. Hypothetically, these lineages can emerge through divergence from other US lineages, recombination among lineages or as novel, independent lineages originating outside the US. We tested for the presence of phylogenetic relationships among US lineages using a population of 31 whole genome sequences including dominant US clonal lineages as well as available samples from global populations. We analyzed ancestry of the whole mitochondrial genome and samples of nuclear loci including supercontigs 1.1 and 1.5 as well as several previously characterized coding regions. We found support for a shared ancestry among lineages US11 and US18 from the mitochondrial genome as well as from one nuclear haplotype on each supercontig analyzed. The other nuclear haplotype from each sample assorted independently indicating an independent ancestry. We found no support for emergence of any other of the US lineages from a common ancestor shared with the other US lineages. Each of the US clonal lineages fit a model where populations of new clonal lineages emerge via migration from a source population that is sexual in nature and potentially located in central Mexico or elsewhere. This work provides novel insights into patterns of emergence of clonal lineages in plant pathogen genomes.
Methods for Doping Detection.Tuesday, June 28, 2016
Ponzetto F, Giraud S, Leuenberger N, Boccard J, Nicoli R, Baume N, Rudaz S, Saugy M,
Frontiers of hormone research. 27-6-2016
Over the past few years, the World Anti-Doping Agency (WADA) has focused its efforts on detecting not only small prohibited molecules, but also larger endogenous molecules such as hormones, in the view of implementing an endocrinological module in the Athlete Biological Passport (ABP). In this chapter, the detection of two major types of hormones used for doping, growth hormone (GH) and endogenous anabolic androgenic steroids (EAASs), will be discussed: a brief historical background followed by a description of state-of-the-art methods applied by accredited anti-doping laboratories will be provided and then current research trends outlined. In addition, microRNAs (miRNAs) will also be presented as a new class of biomarkers for doping detection.
The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis.Monday, June 27, 2016
Gibson WJ, Hoivik EA, Halle MK, Taylor-Weiner A, Cherniack AD, Berg A, Holst F, Zack TI, Werner HM, Staby KM, Rosenberg M, Stefansson IM, Kusonmano K, Chevalier A, Mauland KK, Trovik J, Krakstad C, Giannakis M, Hodis E, Woie K, Bjorge L, Vintermyr OK, Wala JA, Lawrence MS, Getz G, Carter SL, Beroukhim R, Salvesen HB,
Nature genetics. 27-Jun-2016
Recent studies have detailed the genomic landscape of primary endometrial cancers, but the evolution of these cancers into metastases has not been characterized. We performed whole-exome sequencing of 98 tumor biopsies including complex atypical hyperplasias, primary tumors and paired abdominopelvic metastases to survey the evolutionary landscape of endometrial cancer. We expanded and reanalyzed The Cancer Genome Atlas (TCGA) data, identifying new recurrent alterations in primary tumors, including mutations in the estrogen receptor cofactor gene NRIP1 in 12% of patients. We found that likely driver events were present in both primary and metastatic tissue samples, with notable exceptions such as ARID1A mutations. Phylogenetic analyses indicated that the sampled metastases typically arose from a common ancestral subclone that was not detected in the primary tumor biopsy. These data demonstrate extensive genetic heterogeneity in endometrial cancers and relative homogeneity across metastatic sites.
An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis.Tuesday, June 28, 2016
Sivaprakasam S, Gurav A, Paschall AV, Coe GL, Chaudhary K, Cai Y, Kolhe R, Martin P, Browning D, Huang L, Shi H, Sifuentes H, Vijay-Kumar M, Thompson SA, Munn DH, Mellor A, McGaha TL, Shiao P, Cutler CW, Liu K, Ganapathy V, Li H, Singh N,
Oncogenesis. 2016
Composition of the gut microbiota has profound effects on intestinal carcinogenesis. Diet and host genetics play critical roles in shaping the composition of gut microbiota. Whether diet and host genes interact with each other to bring specific changes in gut microbiota that affect intestinal carcinogenesis is unknown. Ability of dietary fibre to specifically increase beneficial gut microbiota at the expense of pathogenic bacteria in vivo via unknown mechanism is an important process that suppresses intestinal inflammation and carcinogenesis. Free fatty acid receptor 2 (FFAR2 or GPR43) is a receptor for short-chain fatty acids (acetate, propionate and butyrate), metabolites of dietary fibre fermentation by gut microbiota. Here, we show FFAR2 is down modulated in human colon cancers than matched adjacent healthy tissue. Consistent with this, Ffar2(-/-) mice are hypersusceptible to development of intestinal carcinogenesis. Dietary fibre suppressed colon carcinogenesis in an Ffar2-dependent manner. Ffar2 played an essential role in dietary fibre-mediated promotion of beneficial gut microbiota, Bifidobacterium species (spp) and suppression of Helicobacter hepaticus and Prevotellaceae. Moreover, numbers of Bifidobacterium is reduced, whereas those of Prevotellaceae are increased in human colon cancers than matched adjacent normal tissue. Administration of Bifidobacterium mitigated intestinal inflammation and carcinogenesis in Ffar2(-/-) mice. Taken together, these findings suggest that interplay between dietary fibre and Ffar2 play a key role in promoting healthy composition of gut microbiota that stimulates intestinal health.
HMGB1 Is a Potential Biomarker for Severe Viral Hemorrhagic Fevers.Tuesday, June 28, 2016
Resman Rus K, Fajs L, Korva M, Avšič-Županc T,
PLoS neglected tropical diseases. Jun-2016
Hemorrhagic fever with renal syndrome (HFRS) and Crimean-Congo hemorrhagic fever (CCHF) are common representatives of viral hemorrhagic fevers still often neglected in some parts of the world. Infection with Dobrava or Puumala virus (HFRS) and Crimean-Congo hemorrhagic fever virus (CCHFV) can result in a mild, nonspecific febrile illness or as a severe disease with hemorrhaging and high fatality rate. An important factor in optimizing survival rate in patients with VHF is instant recognition of the severe form of the disease for which significant biomarkers need to be elucidated. To determine the prognostic value of High Mobility Group Box 1 (HMGB1) as a biomarker for disease severity, we tested acute serum samples of patients with HFRS or CCHF. Our results showed that HMGB1 levels are increased in patients with CCHFV, DOBV or PUUV infection. Above that, concentration of HMGB1 is higher in patients with severe disease progression when compared to the mild clinical course of the disease. Our results indicate that HMGB1 could be a useful prognostic biomarker for disease severity in PUUV and CCHFV infection, where the difference between the mild and severe patients group was highly significant. Even in patients with severe DOBV infection concentrations of HMGB1 were 2.8-times higher than in the mild group, but the difference was not statistically significant. Our results indicated HMGB1 as a potential biomarker for severe hemorrhagic fevers.
Beisenayeva A, Muldaeva G, Azizov I, Kalbekov Z, Kim N, Litvinova E, Ibysheva A,
Georgian medical news. May-2016
patients ranging in age from18 to 44, verified diagnosis - acute tonsillopharyngitis. It was found that in all cases antimicrobial agents have been prescribed speculatively, without previous bacteriological study or method of express diagnostics of Group A beta-hemolytic streptococcus (GABHS). In a majority of cases β-lactams were prescribed. Flemoxin Solutab was the most commonly prescribed β-lactam in Polyclinic №1; Amoxicillin was the most commonly prescribed β-lactam at Polyclinic №2; it associated with personal experience of administration of these agents rather than data of evidentiary medicine. Study of actual medicine administration showed that in half of the cases dosage regimen, rout of administration, dosage and treatment session duration have not been followed. For the development of clinical guidelines for rational treatment of acute tonsillopharyngitis is necessary to study the local spectrum of the major pathogens and their antimicribial resistance.
Zhumaliyeva V, Cialkowska-Rysz A, Sirota V, Kulishov V, Omarova I,
Georgian medical news. May-2016
The aim of the study was to analyze the primary prevalence of chronic neuropathic pain syndrome in oncology patients of Karaganda (Kazakhstan), to estimate the structure of pain syndrome in randomly chosen patients, to assess the effectiveness of analgesic therapy in oncology patients. All the patients with confirmed cancer admitted to hospital in Karaganda regional oncologic dispensary were studied. The study period was limited to 60 consecutive days. The results were statistically processed using 6.0 «STATISTICA» program. In 11,2±1,6% of the cases, oncology patients that got combined modality treatment suffered from the chronic neuropathic pain syndrome; 66,7±7,3% patients of them had the III cancer stage. 2. While studying the chronic neuropathic pain structure it was revealed that: 52,4±7,7% of the patients suffered from a mild pain, from average - 38,1±7,5% of the patients, from severe pain - 9,5±4,5%. Neuropathic pain syndrome in the form of numbness occurred in 47,6±7,7% of the respondents, tingling - in 38,1±7,5% of the patients and 14,3±5,4% of the respondents described it as «electric shock». 52,4±7,7% of the patients described temperature changes of the skin, 28,6±7,0% of them told about allodynia. The given pain can be correctly diagnosed on rare occasions. It brings about the low efficiency of currently prescribed standard pain treatment. It was 20%-effective only for ¼ of the patients. In sum, it can be brought into focus that each 10th oncology patient of the II clinical group in Kazakhstan may potentially suffer from the chronic neuropathic pain syndrome. The given syndrome in cancer patients requires selective differential diagnostics and constant management of the pain treatment regimen because of occurrence of standard regimens incapacity, progression of tolerance to the actual pain treatment and significant deterioration of oncology patients' life quality.
Assessing zinc in humans.Monday, June 27, 2016
Lowe NM,
Current opinion in clinical nutrition and metabolic care. 24-Jun-2016
The most recent data on the potentially useful biomarkers support the further investigation of hair Zn concentration and indices of neurological function, particularly those assessing memory and attention. Of the emerging biomarkers, the measurement of DNA integrity and the expression of zinc transport proteins look promising.
Mitochondrial Encephalopathy and Optic Neuropathy Due to m.10158 MT-ND3 Complex I Mutation Presenting in an Adult Patient: Case Report and Review of the Literature.Tuesday, June 28, 2016
Vodopivec I, Cho TA, Rizzo JF, Frosch MP, Sims KB,
The neurologist. Jul-2016
ND3 disease due to m.10158T>C mutation was previously described only in patients with Leigh or Leigh-like syndrome. Our findings thus indicate that ND3 disease can manifest with atypical phenotype in adults. The diagnosis of mitochondrial disease caused by other than typical MELAS-associated mutations in adults with stroke-like episodes, headaches, and seizures should be considered. An analysis of tissue other than blood, which is more likely to harbor a tissue-specific mitochondrial DNA mutation at a measurable level, may be necessary for diagnosis.
Mechanisms of Zika Virus Infection and Neuropathogenesis.Monday, June 27, 2016
Olagnier D, Muscolini M, Coyne CB, Diamond MS, Hiscott J,
DNA and cell biology. 27-Jun-2016
A spotlight has been focused on the mosquito-borne Zika virus (ZIKV) because of its epidemic outbreak in Brazil and Latin America, as well as the severe neurological manifestations of microcephaly and Guillain-Barré syndrome associated with infection. In this review, we discuss the recent literature on ZIKV-host interactions, including new mechanistic insight concerning the basis of ZIKV-induced neuropathogenesis.
The dependency on neighboring amino acids for reactivity of anti-citrullinated protein antibodies to citrullinated proteins.Monday, June 27, 2016
Dam CE, Houen G, Trier NH,
Scandinavian journal of clinical and laboratory investigation. 27-Jun-2016
Rheumatoid arthritis (RA) is an autoimmune connective tissue disease, associated with the presence of anti-citrullinated protein antibodies (ACPA). These antibodies have been found in approximately 70% of patients suffering from RA and they are currently used for diagnosis of RA. Although they exhibit an absolute need for citrulline for antibody reactivity, no precise cognate antigen for these antibodies has been determined. In this study, we analyzed the reactivity of ACPA to various citrullinated peptides by modified enzyme-linked immunosorbent assays, in order to determine the dependency of specific amino acids for antibody reactivity. A non-human protein (ovalbumin) and antigens directly related to RA were used as templates for synthesis of non-modified and citrullinated peptides, becoming potential target epitopes. Mainly peptides containing a Cit-Gly motif were recognized by ACPAs, while no particular amino acids N-terminal of citrulline were found to be essential for antibody reactivity. Moreover, ACPA reactivity was not restricted to antigens known to be associated with ACPA-positive RA alone, but also to proteins without relation to RA, primarily illustrating that any protein in theory can be turned into an RA autoantigen, by introducing Cit-Gly motifs. Knowledge about the interaction between ACPAs and their citrullinated targets is important for understanding autoimmune ACPA responses in RA, which are known to contribute to the pathophysiology.
Regulation of Skeletal Muscle by microRNAs.Tuesday, June 28, 2016
Diniz GP, Wang DZ,
Comprehensive Physiology. 2016
MicroRNAs (miRNAs) are a class of small noncoding RNAs highly conserved across species. miRNAs regulate gene expression posttranscriptionally by base pairing to complementary sequences mainly in the 3'-untranslated region of their target mRNAs to induce mRNA cleavage and translational repression. Thousands of miRNAs have been identified in human and their function has been linked to the regulation of both physiological and pathological processes. The skeletal muscle is the largest human organ responsible for locomotion, posture, and body metabolism. Several conditions such as aging, immobilization, exercise, and diet are associated with alterations in skeletal muscle structure and function. The genetic and molecular pathways that regulate muscle development, function, and regeneration as well as muscular disease have been well established in past decades. In recent years, numerous studies have underlined the importance of miRNAs in the control of skeletal muscle development and function, through its effects on several biological pathways critical for skeletal muscle homeostasis. Furthermore, it has become clear that alteration of the expression of many miRNAs or genetic mutations of miRNA genes is associated with changes on myogenesis and on progression of several skeletal muscle diseases. The present review provides an overview of the current studies and recent progress in elucidating the complex role exerted by miRNAs on skeletal muscle physiology and pathology. © 2016 American Physiological Society. Compr Physiol 6:1279-1294, 2016.
Genetic Resistance Determinants for Cefixime and Molecular Analysis of Gonococci Isolated in Italy.Monday, June 27, 2016
Carannante A, Vacca P, Ghisetti V, Latino MA, Cusini M, Matteelli A, Vocale C, Prignano G, Leli C, Ober P, Antonetti R, Poletti F, Stefanelli P,
Microbial drug resistance (Larchmont, N.Y.). 27-Jun-2016
A strictly defined subset of gonococci (n = 65) isolated in Italy from 2011 to 2014 was characterized by antimicrobial susceptibility for cefixime (CFM) and ceftriaxone (CRO) and by sequencing of resistance determinant genes (penA, mtrR, porB1b, ponA) for extended-spectrum cephalosporins and Neisseria gonorrhoeae multiantigen sequence typing (NG-MAST). The penA mosaic alleles XXXIV and XXXV were found in all resistant (R) and decreased susceptibility (DS) gonococci to CFM, except for one. They were associated with an adenine deletion in the mtrR promoter plus amino acid substitutions, H105Y or G45D, in the coding region and ponA L421P. The penA mosaic allele XXXIV, and one variant, was found exclusively among genogroup (G) 1407 and its closely related sequence types (STs), as in CFM-DS as well as in CFM-R isolates. Single or combined mutation patterns in penA, mtrR, porB1b, and ponA genes were associated with different CFM susceptibility patterns and NG-MAST STs. Genotyping and antimicrobial resistance (AMR) determinant analyses can be valuable to enhance the gonococcal AMR surveillance.
Impact of Afirma gene expression classifier on cytopathology diagnosis and rate of thyroidectomy.Monday, June 27, 2016
Sacks WL, Bose S, Zumsteg ZS, Wong R, Shiao SL, Braunstein GD, Ho AS,
Cancer cytopathology. 27-Jun-2016
The incidence of indeterminate FNA diagnoses significantly increased after Afirma became routinely available, whereas the incidence of benign diagnoses significantly decreased. These data suggest that Afirma may shift FNA interpretation toward Bethesda III/IV, in which molecular testing is used. Moreover, the institutional rates of surgery and malignancy did not appear to change, raising uncertainty regarding the benefits of molecular assay risk stratification. Afirma may produce unintended collateral effects, increasing the number of indeterminate FNA diagnoses while not affecting the institutional thyroidectomy rate or malignancy yield. Cancer Cytopathol 2016. © 2016 American Cancer Society.
Genome-wide specificities of CRISPR-Cas Cpf1 nucleases in human cells.Monday, June 27, 2016
Kleinstiver BP, Tsai SQ, Prew MS, Nguyen NT, Welch MM, Lopez JM, McCaw ZR, Aryee MJ, Joung JK,
Nature biotechnology. 27-Jun-2016
The activities and genome-wide specificities of CRISPR-Cas Cpf1 nucleases are not well defined. We show that two Cpf1 nucleases from Acidaminococcus sp. BV3L6 and Lachnospiraceae bacterium ND2006 (AsCpf1 and LbCpf1, respectively) have on-target efficiencies in human cells comparable with those of the widely used Streptococcus pyogenes Cas9 (SpCas9). We also report that four to six bases at the 3' end of the short CRISPR RNA (crRNA) used to program Cpf1 nucleases are insensitive to single base mismatches, but that many of the other bases in this region of the crRNA are highly sensitive to single or double substitutions. Using GUIDE-seq and targeted deep sequencing analyses performed with both Cpf1 nucleases, we were unable to detect off-target cleavage for more than half of 20 different crRNAs. Our results suggest that AsCpf1 and LbCpf1 are highly specific in human cells.
Quantitative comparison of DNA methylation assays for biomarker development and clinical applications.Monday, June 27, 2016
Nature biotechnology. 27-Jun-2016
DNA methylation patterns are altered in numerous diseases and often correlate with clinically relevant information such as disease subtypes, prognosis and drug response. With suitable assays and after validation in large cohorts, such associations can be exploited for clinical diagnostics and personalized treatment decisions. Here we describe the results of a community-wide benchmarking study comparing the performance of all widely used methods for DNA methylation analysis that are compatible with routine clinical use. We shipped 32 reference samples to 18 laboratories in seven different countries. Researchers in those laboratories collectively contributed 21 locus-specific assays for an average of 27 predefined genomic regions, as well as six global assays. We evaluated assay sensitivity on low-input samples and assessed the assays' ability to discriminate between cell types. Good agreement was observed across all tested methods, with amplicon bisulfite sequencing and bisulfite pyrosequencing showing the best all-round performance. Our technology comparison can inform the selection, optimization and use of DNA methylation assays in large-scale validation studies, biomarker development and clinical diagnostics.
Metabolomics analysis of urine from rats administered with long-term, low-dose acrylamide by ultra-performance liquid chromatography-mass spectrometry.Monday, June 27, 2016
Shi H, Hu L, Chen S, Bao W, Yang S, Zhao X, Sun C,
Xenobiotica; the fate of foreign compounds in biological systems. 27-Jun-2016
1. To study the toxic effect of chronic exposure to acrylamide (AA) at low-dose levels, we applied metabolomics approach based on ultra-performance liquid chromatography/mass spectrometry (UPLC-MS). A total of 40 male Wistar rats were randomly assigned to different groups: control, low-dose AA (0.2 mg/, middle-dose AA (1 mg/ and high-dose AA (5 mg/ The rats continuously received AA via drinking water for 16 weeks. Rat urine samples were collected at different time points for measurement of metabolomic profiles. 2. Thirteen metabolites, including the biomarkers of AA exposure (AAMA, GAMA and iso-GAMA), were identified from the metabolomic profiles of rat urine. Compared with the control group, the treated groups showed significantly increased intensities of GAMA, AAMA, iso-GAMA, vinylacetylglycine, 1-salicylate glucuronide, PE (20:1(11Z)/14:0), cysteic acid, L-cysteine, p-cresol sulfate and 7-ketodeoxycholic acid, as well as decreased intensities of 3-acetamidobutanal, 2-indolecarboxylic acid and kynurenic acid in rat urine. Notably, three new candidate biomarkers (p-cresol sulfate, 7-ketodeoxycholic acid and 1-salicylate glucuronide) in rat urine exposed to AA have been found in this study. 3. The results indicate exposure to AA disrupts the metabolism of lipids and amino acids, induces oxidative stress.
Circulating long noncoding RNAs as novel biomarkers of human diseases.Monday, June 27, 2016
Jiang X, Lei R, Ning Q,
Biomarkers in medicine. 27-Jun-2016
Long noncoding RNAs (lncRNAs) are a kind of noncoding RNAs which are longer than ˜200 nucleotides, lacking of protein-encoding capacity and are implicated in the pathogenesis of various diseases. Recently, it was demonstrated that lncRNAs could be released into the circulation and be stable in blood. Circulating lncRNAs have been reported to have potential in distinguishing patients from healthy individuals. Therefore, the detection of circulating lncRNAs may be valuable for improving the diagnosis and prognosis of various diseases. This review summarized the current understanding of circulating lncRNAs as novel biomarkers of various human diseases, such as cancer, cardiovascular diseases, nervous system diseases and other diseases, which highlighted the significance of circulating lncRNAs as novel diagnostic and prognostic biomarkers of human diseases.
A Novel One-Tube-One-Step Real-Time Methodology for Rapid Transcriptomic Biomarker Detection: Signal Amplification by Ternary Initiation Complexes.Monday, June 27, 2016
Fujita H, Kataoka Y, Tobita S, Kuwahara M, Sugimoto N,
Analytical chemistry. 27-Jun-2016
We have developed a novel RNA detection method, termed signal amplification by ternary initiation complexes (SATIC), in which an analyte sample is simply mixed with the relevant reagents and allowed to stand for a short time under isothermal conditions (37°C). The advantage of the technique is that there is no requirement for (i) heat annealing, (ii) thermal cycling during the reaction, (iii) a reverse transcription step, or (iv) enzymatic or mechanical fragmentation of the target RNA. SATIC involves the formation of a ternary initiation complex between the target RNA, a circular DNA template, and a DNA primer, followed by rolling circle amplification (RCA) to generate multiple copies of G-quadruplex (G4) on a long DNA strand like beads on a string. The G4s can be specifically fluorescence-stained with N3-hydroxyethyl thioflavin T (ThT-HE), which emits weakly with single- and double-stranded RNA/DNA but strongly with parallel G4s. An improved dual SATIC system, which involves the formation of two different ternary initiation complexes in the RCA process, exhibited a wide quantitative detection range of 1 to 5,000 pM. Furthermore, this enabled visual observation-based RNA detection, which is more rapid and convenient than conventional isothermal methods, such as reverse transcription-loop-mediated isothermal amplification, signal mediated amplification of RNA technology, and RNA-primed rolling circle amplification. Thus, SATIC methodology may serve as an on-site and/or real-time measurement technique for transcriptomic biomarkers for various diseases.
Etiology of Diarrhea, Nutritional Outcomes and Novel Intestinal Biomarkers in Tanzanian Infants: A Preliminary Study.Monday, June 27, 2016
Gosselin KB, Aboud S, McDonald CM, Moyo S, Khavari N, Manji K, Kisenge R, Fawzi W, Kellogg M, Tran HQ, Kibiki G, Gratz J, Liu J, Gewirtz A, Houpt E, Duggan C,
Journal of pediatric gastroenterology and nutrition. 24-Jun-2016
This quantitative PCR method may allow identification of enteropathogens that place children at higher risk for suboptimal growth. IgA anti-LPS and flagellin antibodies hold promise as emerging intestinal biomarkers.
Stress, COMT Polymorphisms, and Depressive Symptoms in Older Australian Women: An Exploratory Study.Monday, June 27, 2016
Seib C, Whiteside E, Voisey J, Lee K, Alexander K, Humphreys J, Chopin L, Anderson D,
Genetic testing and molecular biomarkers. 27-Jun-2016
Our research suggests that women with polymorphisms in COMT were less susceptible to depressive symptoms but these polymorphisms do not appear to influence susceptibility to depression in those exposed to life stressors. Further research should consider other genetic variants in catecholamine pathways and their potential impact on women's mental health.
Weak cation exchange magnetic beads coupled with matrix-assisted laser desorption ionization-time of flight-mass spectrometry in screening serum protein markers in osteopenia.Monday, June 27, 2016
He WT, Liang BC, Shi ZY, Li XY, Li CW, Shi XL,
SpringerPlus. 2016
The present study aimed at investigating the weak cation magnetic separation technology and matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) in screening serum protein markers of osteopenia from ten postmenopausal women and ten postmenopausal women without osteopenia as control group, to find a new method for screening biomarkers and establishing a diagnostic model for primary type I osteoporosis. Serum samples were collected from postmenopausal women with osteopenia and postmenopausal women with normal bone mass. Proteins were extracted from serum samples by weak cation exchange magnetic beads technology, and mass spectra acquisition was done by MALDI-TOF-MS. The visualization and comparison of data sets, statistical peak evaluation, model recognition, and discovery of biomarker candidates were handled by the proteinchip data analysis system software(ZJU-PDAS). The diagnostic models were established using genetic arithmetic based support vector machine (SVM). The SVM result with the highest Youden Index was selected as the model. Combinatorial Peaks having the highest accuracy in distinguishing different samples were selected as potential biomarker. From the two group serum samples, a total of 133 differential features were selected. Ten features with significant intensity differences were screened. In the pair-wise comparisons, processing of MALDI-TOF spectra resulted in the identification of ten differential features between postmenopausal women with osteopenia and postmenopausal women with normal bone mass. The difference of features by Youden index showed that the highest features had a mass to charge ratio of 1699 and 3038 Da. A diagnosis model was established with these two peaks as the candidate marker, and the specificity of the model is 100 %, the sensitivity was 90 % by leave-one-out cross validation test. The two groups of specimens in SVM results on the scatter plot could be clearly distinguished. The peak with m/z 3038 in the SVM model was suggested as Secretin by TagIdent tool. To provide further validation, the secretin levels in serum were analyzed using enzyme-linked immunosorbent assays that is a competitive inhibition enzyme immunoassay technique for the in vitro quantitative measurement of secretin in human serum.
The prognosis of MYC translocation positive diffuse large B-cell lymphoma depends on the second hit.Monday, June 27, 2016
Clipson A, Barrans S, Zeng N, Crouch S, Grigoropoulos NF, Liu H, Kocialkowski S, Wang M, Huang Y, Worrillow L, Goodlad J, Buxton J, Neat M, Fields P, Wilkins B, Grant JW, Wright P, Ei-Daly H, Follows GA, Roman E, Watkins AJ, Johnson PW, Jack A, Du MQ,
The journal of pathology. Clinical research. Jul-2015
A proportion of MYC translocation positive diffuse large B-cell lymphomas (DLBCL) harbour a BCL2 and/or BCL6 translocation, known as double-hit DLBCL, and are clinically aggressive. It is unknown whether there are other genetic abnormalities that cooperate with MYC translocation and form double-hit DLBCL, and whether there is a difference in clinical outcome between the double-hit DLBCL and those with an isolated MYC translocation. We investigated TP53 gene mutations along with BCL2 and BCL6 translocations in a total of 234 cases of DLBCL, including 81 with MYC translocation. TP53 mutations were investigated by PCR and sequencing, while BCL2 and BCL6 translocation was studied by interphase fluorescence in situ hybridization. The majority of MYC translocation positive DLBCLs (60/81 = 74%) had at least one additional genetic hit. In MYC translocation positive DLBCL treated by R-CHOP (n = 67), TP53 mutation and BCL2, but not BCL6 translocation had an adverse effect on patient overall survival. In comparison with DLBCL with an isolated MYC translocation, cases with MYC/TP53 double-hits had the worst overall survival, followed by those with MYC/BCL2 double-hits. In MYC translocation negative DLBCL treated by R-CHOP (n = 101), TP53 mutation, BCL2 and BCL6 translocation had no impact on patient survival. The prognosis of MYC translocation positive DLBCL critically depends on the second hit, with TP53 mutations and BCL2 translocation contributing to an adverse prognosis. It is pivotal to investigate both TP53 mutations and BCL2 translocations in MYC translocation positive DLBCL, and to distinguish double-hit DLBCLs from those with an isolated MYC translocation.
Morphological remodeling of C. elegans neurons during aging is modified by compromised protein homeostasis.Monday, June 27, 2016
Vayndorf EM, Scerbak C, Hunter S, Neuswanger JR, Toth M, Parker JA, Neri C, Driscoll M, Taylor BE,
NPJ aging and mechanisms of disease. 30-3-2015
Understanding cellular outcomes, such as neuronal remodeling, that are common to both healthy and diseased aging brains is essential to the development of successful brain aging strategies. Here, we used Caenorhabdits elegans to investigate how the expression of proteotoxic triggers, such as polyglutamine (polyQ)-expanded huntingtin and silencing of proteostasis regulators, such as the ubiquitin-proteasome system (UPS) and protein clearance components, may impact the morphological remodeling of individual neurons as animals age. We examined the effects of disrupted proteostasis on the integrity of neuronal cytoarchitecture by imaging a transgenic C. elegans strain in which touch receptor neurons express the first 57 amino acids of the human huntingtin (Htt) gene with expanded polyQs (128Q) and by using neuron-targeted RNA interference in adult wild-type neurons to knockdown genes encoding proteins involved in proteostasis. We found that proteostatic challenges conferred by polyQ-expanded Htt and knockdown of specific genes involved in protein homeostasis can lead to morphological changes that are restricted to specific domains of specific neurons. The age-associated branching of PLM neurons is suppressed by N-ter polyQ-expanded Htt expression, whereas ALM neurons with polyQ-expanded Htt accumulate extended outgrowths and other soma abnormalities. Furthermore, knockdown of genes important for ubiquitin-mediated degradation, lysosomal function, and autophagy modulated these age-related morphological changes in otherwise normal neurons. Our results show that the expression of misfolded proteins in neurodegenerative disease such as Huntington's disease modifies the morphological remodeling that is normally associated with neuronal aging. Our results also show that morphological remodeling of healthy neurons during aging can be regulated by the UPS and other proteostasis pathways. Collectively, our data highlight a model in which morphological remodeling during neuronal aging is strongly affected by disrupted proteostasis and expression of disease-associated, misfolded proteins such as human polyQ-Htt species.
Correlation analysis between four serum biomarkers of liver fibrosis and liver function in infants with cholestasis.Monday, June 27, 2016
Tang N, Zhang Y, Liu Z, Fu T, Liang Q, Ai X,
Biomedical reports. Jul-2016
The aim of the present study was to investigate the correlation between four serum biomarkers of liver fibrosis and liver function in infants with cholestasis. A total of 30 infants with cholestasis and 20 healthy infants were included in the study. Biochemical assays based on the initial rate method and colorimetric assays were conducted to determine the levels of liver function markers in the serum [such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), γ-glutamyl transferase (γ-GT), cholinesterase (CHE) and total bile acids (TBA)] and four serum biomarkers of liver fibrosis were measured using radioimmunoassays [hyaluronic acid (HA), procollagen type III (PCIII), laminin (LN) and collagen type IV (cIV)]. The serum levels of ALT, AST, TBIL, DBIL, IBIL, γ-GT and TBA in the infants with cholestasis were significantly higher compared to the healthy infants (P<0.01); the serum levels of CHE in the infants with cholestasis were significantly lower compared to the healthy infants (P<0.01). The serum levels of HA, PCIII, and cIV in the infants with cholestasis were significantly higher compared to the healthy infants (P<0.01). Correlation analyses between liver function and the four biomarkers of liver fibrosis showed that HA was positively correlated with AST and γ-GT (P<0.05) and negatively correlated with ALT, CHE and TBA (P<0.05). cIV was positively correlated with γ-GT (P<0.05) and negatively correlated with CHE (P<0.05). In conclusion, statistically significant differences were identified for the liver function markers (ALT, AST, TBIL, DBIL, IBIL, γ-GT and TBA) and the biomarkers HA, PCIII and cIV of liver fibrosis between infants with cholestasis and healthy infants. Thus, the serum levels of HA, cIV, γ-GT and CHE are sensitive markers for cholestatic liver fibrosis in infants.
Urinary volatile organic compounds as potential biomarkers for renal cell carcinoma.Monday, June 27, 2016
Wang D, Wang C, Pi X, Guo L, Wang Y, Li M, Feng Y, Lin Z, Hou W, Li E,
Biomedical reports. Jul-2016
Currently, there is no adequate, sensitive, reproducible, specific and noninvasive biomarker that can reliably be used to detect renal cell carcinoma (RCC). Previous studies have elucidated the urinary non-volatile metabolic profile of RCC. However, whether urinary volatile organic compound (VOC) profiles are able to identify RCC remains to be elucidated. In the present study, urine was collected from 22 patients with RCC and 25 healthy subjects. Principal component analysis and orthogonal partial least square discriminant analysis were used to compare the data of patients and healthy subjects, and preoperative and postoperative patients undergoing radical nephrectomy. In total, 11 VOC biomarkers were elevated in the RCC patients compared to the healthy subjects, which were phenol; decanal; 1,6-dioxacyclododecane-7,12-dione; 1-bromo-1-(3-methyl-1-pentenylidene)-2,2,3,3-tetramethyl-cyclopropane; nonanal; 3-ethyl-3-methylheptane; isolongifolene-5-ol; 2,5-cyclohexadiene-1,4-dione, 2,6-bis(1,1-dimethylethyl); tetradecane; aniline; and 2,6,10,14-tetramethyl-pentadecane. Three biomarkers were decreased in RCC patients: styrene, 4-heptanone and dimethylsilanediol. In preoperative patients, 2-ethyl-1-hexanol and cyclohexanone were elevated, while 6-t-butyl-2,2,9,9-tetramethyl-3,5-decadien-7-yne were decreased when compared to postoperative patients. Compared with the healthy subjects, RCC has a unique VOC profile, suggesting that VOC profiles may be a useful diagnostic assay for RCC.
Proteomic analysis of cerebrospinal fluid for relapsing-remitting multiple sclerosis and clinically isolated syndrome.Monday, June 27, 2016
Pavelek Z, Vyšata O, Tambor V, Pimková K, Vu DL, Kuča K, Šťourač P, Vališ M,
Biomedical reports. Jul-2016
Early diagnosis and treatment of multiple sclerosis (MS) in the initial stages of the disease can significantly retard its progression. The aim of the present study was to identify changes in the cerebrospinal fluid proteome in patients with relapsing-remitting MS and clinically isolated MS syndrome who are at high risk of developing MS (case group) compared to healthy population (control) in order to identify potential new markers, which could ultimately aid in early diagnosis of MS. The protein concentrations of each of the 11 case and 15 control samples were determined using a bicinchoninic acid assay. Nanoscale liquid chromatography coupled with tandem mass spectrometry was used for protein identification. Proteomics data were processed using the Perseus software suite and R. The results were filtered using the Benjamini-Hochberg procedure for the false discovery rate (FDR) correction (FDR<0.05). The results showed that, 26 proteins were significantly dysregulated in case samples compared to the controls. Nine proteins were found to be significantly less abundant in case samples, while the abundance of 17 proteins was significantly increased in case samples compared to controls. Three of the proteins were previously linked to RR MS, including immunoglobulin (Ig) γ-1 chain C region, Ig heavy chain V-III region BRO and Ig κ chain C region. Three proteins that were uniquely expressed in patients with RR MS were identified and these proteins may serve as prognostic biomarkers for identifying patients with a high risk of developing RR MS.
Circulating low IL-23: IL-35 cytokine ratio promotes progression associated with poor prognosisin breast cancer.Monday, June 27, 2016
Chen G, Liang Y, Guan X, Chen H, Liu Q, Lin B, Chen C, Huang M, Chen J, Wu W, Liang Y, Zhou K, Zeng J,
American journal of translational research. 2016
The interleukin (IL)-12 family, composed of heterodimeric cytokines including IL-12 (formed by IL-12p35 and IL-12p40 subunits), IL-23 (formed by IL-23p19 and IL-12p40 subunits), IL-27 (formed by IL-27p28 and EBI3 subunits) and IL-35 (formed by IL-12p35 and EBI3 subunits), establishes a link between innate and adaptive immunity that involves different immune effector cells and cytokines to tumors. However, the role of IL-12 family in breast cancer (BC) progression and prognosis remains unclear. In the present study, we demonstrated evidence indicating that EBI3, IL-12p35 and IL-12p40 but not IL-23p19 or IL-27p28 were highly expressed in BC tissues, suggested that tumor derived EBI3, IL-12p35 and IL-12p40 were associated with tumor progression. Circulating IL-12 and IL-23 low expressed, but IL-27 and IL-35 high expressed in BC patients, especially circulating IL-23 associated with IL-35 to mediate BC tumor resection. Ki-67, p53 and EGFR expression on BC tissues, as well as CA125, CA153 and CA199 levels on BC bloods increased when circulating IL-23: IL-35 ratio decreased. Together, for the first time, our data suggest that circulating IL-23: IL-35 ratio may be an important indicator association with BC progression and prognosis. However, further research should be carried out to assess the implications of circulating IL-23: IL-35 ratio in a larger sample size.
OTUB1 promotes tumor invasion and predicts a poor prognosis in gastric adenocarcinoma.Monday, June 27, 2016
Weng W, Zhang Q, Xu M, Wu Y, Zhang M, Shen C, Chen X, Wang Y, Sheng W,
American journal of translational research. 2016
OTUB1 contributes to gastric cancer development by enhancing tumor invasiveness. Targeting OTUB1 should be considered in future molecular therapies.
Targeting TGF-β1 inhibits invasion of anaplastic thyroid carcinoma cell through SMAD2-dependent S100A4-MMP-2/9 signalling.Monday, June 27, 2016
Zhang K, Liu X, Hao F, Dong A, Chen D,
American journal of translational research. 2016
Therapies targeting the TGF-β1 inhibits invasion of ATC cells by impeding the SMAD2-dependent S100A4-MMP-2/9 signalling in vitro.
Protein expression of nucleophosmin, annexin A3 and nm23-H1 correlates with human nasopharyngeal carcinoma radioresistance in vivo.Monday, June 27, 2016
Qu S, Li XY, Liang ZG, Li L, Huang ST, Li JQ, Li DR, Zhu XD,
Oncology letters. Jul-2016
Radioresistance is a significant obstacle in the treatment of endemic nasopharyngeal carcinoma (NPC). The present study aimed to identify proteins associated with radioresistance in NPC in vitro and in vivo. Proteomics analyses were conducted to screen for differentially-expressed proteins (DEPs) in parental CNE-2 cells and CNE-2R cells. Using proteomics approaches, 16 DEPs were identified. Of these DEPs, nucleophosmin (NPM1), annexin A3 and nm23-H1, were verified using western blot analyses. The tumorigenicity was investigated using mouse xenograft tumorigenicity assays, and tumor growth curves were generated. The protein expression of NPM1, annexin A3 and nm23-H1 was examined by immunohistochemically staining tumor tissues. NPM1 and annexin A3 protein levels were downregulated in the CNE-2R cells, whereas nm23-H1 expression was upregulated. In vivo tests showed that compared with the CNE-2 tumors, CNE-2R tumor growth was significantly retarded (P<0.05). CNE-2 tumor progression was inhibited by irradiation, but CNE-2R tumor progression was not, indicating that the CNE-2R cells were also radioresistant in vivo. NPM1 and annexin A3 expression was significantly lower in non-irradiated (NIR)-CNE-2R tumors compared with NIR-CNE-2 tumors (P<0.01). However, Nm23-H1 protein levels were significantly higher (P<0.05). Overall, the present study established comparable radioresistant and radiosensitive tumor models of human NPC, and identified candidate biomarkers that may correlate with radioresistance. The data showed that dysregulation of NPM1, annexin A3 and nm23-H1 expression correlated with the cellular and tumor radioresponse. These proteins are involved in the regulation of intracellular functions, including stress responses, cell proliferation and DNA repair. However, further clinical evaluations are required.
Shift in prevalence of HPV types in cervical cytology specimens in the era of HPV vaccination.Monday, June 27, 2016
Fischer S, Bettstetter M, Becher A, Lessel M, Bank C, Krams M, Becker I, Hartmann A, Jagla W, Gaumann A,
Oncology letters. Jul-2016
The aim of the present population-based cohort study was to analyze the association between the prevalence of 32 types of human papilloma virus (HPV) in 615 female patients with abnormal cervical cytopathology findings. In total, 32 HPV types were screened by DNA array technology. HPV infection was detected in 470 women (76.42%), 419 of whom (89.15%) were infected with ≥1 high-risk (HR)-HPV type. HPV16, which is recognized as the main HR-HPV type responsible for the development of cervical cancer, was observed in 32.98% of HPV(+) participants, followed by HPV42 (18.09%), HPV31 (17.66%), HPV51 (13.83%), HPV56 (10.00%), HPV53 (8.72%) and HPV66 (8.72%). The prevalence of HR-HPV types, which may be suppressed directly (in the case of HPV16 and 18), or possibly via cross-protection (in the case of HPV31) following vaccination, was considerably lower in participants ≤22 years of age (HPV16, 28.57%; HPV18, 2.04%; HPV31, 6.12%), compared with participants 23-29 years of age (HPV16, 45.71%; HPV18, 7.86%; HPV31, 22.86%), who were less likely to be vaccinated. Consequently, the present study hypothesizes that there may be a continuous shift in the prevalence of HPV types as a result of vaccination. Furthermore, the percentage of non-vaccine HR-HPV types was higher than expected, considering that eight HPV types formerly classified as 'low-risk' or 'probably high-risk' are in fact HR-HPV types. Therefore, it may be important to monitor non-vaccine HPV types in future studies, and an investigation concerning several HR-HPV types as risk factors for the development of cervical cancer is required.
Investigation of potential molecular biomarkers and small molecule drugs for hepatocellular carcinoma transformed from cirrhosis.Monday, June 27, 2016
Xie F, Zhu F, Lu Z, Liu Z, Wang H,
Oncology letters. Jul-2016
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China and the third leading cause of cancer-associated morality. The aim of the present study was to investigate and analyze differentially-expressed genes (DEGs) between cirrhosis and HCC, in order to screen the key genes involved in the transformation from cirrhosis to HCC and provide novel targets for the diagnosis and treatment of HCC in patients with cirrhosis. The gene expression profile, GSE17548, was obtained from Gene Expression Omnibus database and the DEGs were identified by LIMMA package in R language. Kyoto Encyclopedia of Genes and Genomes and gene ontology biology process analysis were performed for the DEGs. Differential co-expression network (DEN) analysis was conducted and the network was visualized using Cytoscape. Small molecule drugs were also screened from the Comparative Toxicogenomics Database for higher degree DEGs. A total of 95 DEGs were obtained, including 46 upregulated and 49 downregulated genes. The upregulated DEGs were primarily involved in biological processes and pathways associated with the cell cycle, while the downregulated DEGs were primarily involved in immune-associated biological processes. A total of 22 key DEGs were identified by DEN analysis, which distinguished HCC from cirrhosis samples. Furthermore, estradiol, benzo(a)pyrene, acetaminophen, copper sulfate and bisphenol A were identified as the five most associated chemicals to these 22 DEGs. In conclusion, the hub genes and chemicals identified by the present study may provide a theoretical basis for additional research on diagnosis and treatment of HCC transformed from cirrhosis.
miR-10b promotes invasion by targeting HOXD10 in colorectal cancer.Monday, June 27, 2016
Wang Y, Li Z, Zhao X, Zuo X, Peng Z,
Oncology letters. Jul-2016
Studies have shown that homeobox D10 (HOXD10) is the target gene of microRNA-10b (miR-10b) and is closely associated with the inhibition of cell migration and invasion. Ras homolog family member C (RhoC) has been reported to promote tumor metastasis in various types of cancer. The effect of miR-10b on colorectal cancer (CRC) metastasis and the associated molecular mechanisms remain elusive. The present study aimed to investigate whether miR-10b could promote invasion by targeting HOXD10 in CRC by exploring the association between miR-10b and HOXD10 expression in CRC patients. The findings revealed that miR-10b levels were elevated in the CRC specimens and significantly correlated with advanced clinical stage and lymph node metastasis. In addition, HOXD10 was a direct target of miR-10b, and the increased expression of RhoC and downregulation of HOXD10 correlated with the increased expression level of miR-10b. HOXD10 protein level was also markedly attenuated in lymph node metastasis-positive tumor tissues compared with lymph node metastasis-free tumor tissues. These findings suggest that miR-10b may stimulate the upregulation of RhoC through targeting HOXD10, thus promoting the invasion and migration in CRC tumor.
Late recurrence of a malignant hypoglycemia-inducing pelvic solitary fibrous tumor secreting high-molecular-weight insulin-like growth factor-II: A case report with protein analysis.Monday, June 27, 2016
Ishihara H, Omae K, Iizuka J, Kobayashi H, Fukuda I, Kondo T, Hizuka N, Nagashima Y, Tanabe K,
Oncology letters. Jul-2016
The present study reports a case of recurrent malignant pelvic solitary fibrous tumor (SFT) that induced non-islet cell tumor hypoglycemia via high-molecular-weight insulin-like growth factor-II in a 72-year-old male patient. The tumor recurred ~12 years after the complete resection of the original mass. The recurrent tumor, which had directly invaded the left ureter and perirectal fat tissue, could not be completely excised due to its fragility and adhesiveness. At 13 days post-surgery, the patient presented with rectal perforation, and an urgent rectal resection and colostomy was performed. Neither recurrence of the tumor nor hypoglycemic symptoms were observed 9 months after the surgery. High molecular weight insulin-like growth factor-II was detected in the serum and tumor specimens by western blot analysis and immunohistochemistry. The present case report suggests that certain SFTs can relapse even ≥10 years after a presumed complete resection of the primary tumor, and that performing a safe and complete resection of these tumors can be challenging, due to their adhesiveness or physical presentation; therefore, the indications for surgery should be considered with caution.
Interleukin-33 in human gliomas: Expression and prognostic significance.Monday, June 27, 2016
Gramatzki D, Frei K, Cathomas G, Moch H, Weller M, Mertz KD,
Oncology letters. Jul-2016
Interleukin-33 (IL-33) is a nuclear and pleiotropic cytokine with regard to its cellular sources and its actions. IL-33 is involved in the pathogenesis of brain diseases. Several factors account for the tumorigenicity of human gliomas, including cytokines and their receptors. The present study assessed the expression and prognostic significance of IL-33 in human astroglial brain tumors. Protein levels of IL-33 were determined by immunohistochemistry using a tissue microarray containing 95 human gliomas. mRNA expression data of IL-33, as well as of its receptors, IL-1 receptor-like 1 protein and IL-1 receptor accessory protein (IL1RAcP), were obtained from The Cancer Genome Atlas database. IL-33 protein was expressed heterogeneously in tumor tissue, but was, however, not detected in normal brain tissue. There was no differential IL-33 protein expression by tumor grade, while IL-33 protein expression was associated with inferior survival in patients with recurrent glioblastomas. Interrogations of the TCGA database indicated that mRNA expression of IL-33 and the IL-33 receptors was heterogeneous, and that IL-33 and IL1RAcP mRNA levels were correlated with the tumor grade. Elevated IL-33 mRNA levels were associated with the inferior survival of glioblastoma patients. Therefore, IL-33 may play an important role in the pathogenesis and prognosis of human gliomas.
Serum expression levels of microRNA-382-3p, -598-3p, -1246 and -184 in breast cancer patients.Monday, June 27, 2016
Fu L, Li Z, Zhu J, Wang P, Fan G, Dai Y, Zheng Z, Liu Y,
Oncology letters. Jul-2016
The purpose of the present study was to investigate the serum levels of microRNA (miRNA/miR)-382-3p, -598-3p, -1246 and -184 in breast cancer patients and to assess their feasibility as biomarkers for breast cancer screening. Serum samples were obtained from 100 breast cancer patients and 40 age-matched healthy control subjects in Taizhou Central Hospital (Taizhou, Zhejiang, China) between January 2013 and September 2014. The serum expression levels of miR-382-3p, -598-3p, -1246 and -184 were determined by stem-loop reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic curves were drawn to evaluate the sensitivity and specificity of the serum miRNA expression levels for the screening of breast cancer. miR-382-3p and -1246 were significantly upregulated in the serum of the breast cancer patients, while miR-598-3p and -184 were significantly downregulated. The sensitivity and specificity to detect breast cancer were as follows: miR-382-3p, 52.0 and 92.5%; miR-598-3p, 95.0 and 85.0%; miR-1246, 93.0 and 75.0%; and miR-184, 87.5 and 71.0%, respectively. The expression levels of the four serum miRNAs were not correlated with the patients' clinical stage. In summary, miR-382-3p, -598-3p, -1246 and -184 are all involved in the development of breast cancer, and are promising biomarkers for breast cancer detection.
Effect of therapy-related acute myeloid leukemia on the outcome of patients with acute myeloid leukemia.Monday, June 27, 2016
ESPíRITO Santo AE, Chacim S, Ferreira I, Leite L, Moreira C, Pereira D, Dantas Brito MD, Nunes M, Domingues N, Oliveira I, Moreira I, Martins A, Viterbo L, Mariz JM, Medeiros R,
Oncology letters. Jul-2016
Therapy-related acute myeloid leukemia (t-AML) is a rare and almost always fatal late side effect of antineoplastic treatment involving chemotherapy, radiotherapy or the two combined. The present retrospective study intended to characterize t-AML patients that were diagnosed and treated in a single referral to an oncological institution in North Portugal. Over the past 10 years, 231 cases of AML were diagnosed and treated at the Portuguese Institute of Oncology of Porto, of which 38 t-AML cases were identified. Data regarding the patient demographics, primary diagnosis and treatment, age at onset of therapy-related myeloid neoplasm, latency time of the neoplasm, cytogenetic characteristics, AML therapy and outcome were collected from medical records. A previous diagnosis with solid tumors was present in 28 patients, and 10 patients possessed a history of hematological conditions, all a lymphoproliferative disorder. Breast cancer was the most frequent solid tumor identified (39.5% of all solid tumors diagnosed). The mean latency time was 3 years. In the present study, t-AML patients were older (P<0.001) and more frequently carried cytogenetic abnormalities (P=0.009) compared with de novo AML patients. The overall survival time was observed to be significantly poorer among individuals with t-AML (P<0.001). However, in younger patients (age, <50 years) there was no difference between the overall survival time of patients with t-AML and those with de novo AML (P=0.983). Additionally, patients with promyelocytic leukemia possess a good prognosis, even when AML occurs as a secondary event (P=0.98). To the best of our knowledge, the present study is the first to evaluate t-AML in Portugal and the results are consistent with the data published previously in other populations. The present study concludes that although t-AML demonstrates a poor prognosis, this is not observed among younger patients or promyelocytic leukemia patients.
Cytokeratin and protein expression patterns in squamous cell carcinoma of the oral cavity provide evidence for two distinct pathogenetic pathways.Monday, June 27, 2016
Frohwitter G, Buerger H, VAN Diest PJ, Korsching E, Kleinheinz J, Fillies T,
Oncology letters. Jul-2016
Squamous cell carcinoma (SCC) of the oral cavity is a morphological heterogeneous disease. Various cytokeratin (CK) expression patterns with different prognostic values have been described, but little is known concerning the underlying biological cell mechanisms. Therefore, the present study investigated 193 cases of oral SCCs using immunohistochemistry for α/β/γ-catenin, glucose transporter 1, caspase-3, X-linked inhibitor of apoptosis protein, hypoxia inducible factor-1α, carbonic anhydrase 9, heat shock protein (hsp) 70, mast/stem cell growth factor receptor, p21, p27, p16, p53, B-cell lymphoma 6, epidermal growth factor receptor, cyclin D1 and CK1, 5/6, 8/18, 10, 14 and 19. Expression patterns were analyzed with biomathematical permutation analysis. The present results revealed a significant association between the expression of low-molecular weight CK8/18 and 19 and a high-tumor grade, β and γ-catenin expression, deregulated cell cycle proteins and a predominant localization of the tumor on the floor of the mouth. By contrast, expression of high-molecular weight CK1, 5/6, 10 and 14 was significantly associated with the expression of p21 and hsp70. In conclusion, the current study presents evidence for the existence of two parallel pathogenetic pathways in oral SCCs, characterized by the expression of low- and high-molecular weight CKs. Additional studies are required to demonstrate the extent that these results may be used to improve therapeutic regimens.
Identification of genes associated with renal cell carcinoma using gene expression profiling analysis.Monday, June 27, 2016
Yao T, Wang Q, Zhang W, Bian A, Zhang J,
Oncology letters. Jul-2016
Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and accounts for ~80% of all kidney cancer cases. However, the pathogenesis of RCC has not yet been fully elucidated. To interpret the pathogenesis of RCC at the molecular level, gene expression data and bio-informatics methods were used to identify RCC associated genes. Gene expression data was downloaded from Gene Expression Omnibus (GEO) database and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in RCC patients compared with controls. In addition, a regulatory network was constructed using the known regulatory data between transcription factors (TFs) and target genes in the University of California Santa Cruz (UCSC) Genome Browser ( and the regulatory impact factor of each TF was calculated. A total of 258,0427 pairs of DCGs were identified. The regulatory network contained 1,525 pairs of regulatory associations between 126 TFs and 1,259 target genes and these genes were mainly enriched in cancer pathways, ErbB and MAPK. In the regulatory network, the 10 most strongly associated TFs were FOXC1, GATA3, ESR1, FOXL1, PATZ1, MYB, STAT5A, EGR2, EGR3 and PELP1. GATA3, ERG and MYB serve important roles in RCC while FOXC1, ESR1, FOXL1, PATZ1, STAT5A and PELP1 may be potential genes associated with RCC. In conclusion, the present study constructed a regulatory network and screened out several TFs that may be used as molecular biomarkers of RCC. However, future studies are needed to confirm the findings of the present study.
Applications of nanoparticle drug delivery systems for the reversal of multidrug resistance in cancer.Monday, June 27, 2016
Huang Y, Cole SP, Cai T, Cai YU,
Oncology letters. Jul-2016
Multidrug resistance (MDR) to chemotherapy presents a major obstacle in the treatment of cancer patients, which directly affects the clinical success rate of cancer therapy. Current research aims to improve the efficiency of chemotherapy, whilst reducing toxicity to prolong the lives of cancer patients. As with good biocompatibility, high stability and drug release targeting properties, nanodrug delivery systems alter the mechanism by which drugs function to reverse MDR, via passive or active targeting, increasing drug accumulation in the tumor tissue or reducing drug elimination. Given the potential role of nanodrug delivery systems used in multidrug resistance, the present study summarizes the current knowledge on the properties of liposomes, lipid nanoparticles, polymeric micelles and mesoporous silica nanoparticles, together with their underlying mechanisms. The current review aims to provide a reliable basis and useful information for the development of new treatment strategies of multidrug resistance reversal using nanodrug delivery systems.
Identification of novel biomarkers for preeclampsia on the basis of differential expression network analysis.Monday, June 27, 2016
Wu Y, Fu X, Wang L,
Experimental and therapeutic medicine. Jul-2016
Preeclampsia (PE) is a severe pregnancy complication, which is a leading cause of maternal and fetal mortality. The present study aimed to screen potential biomarkers for the diagnosis and prediction of PE and to investigate the underlying mechanisms of PE development based on the differential expression network (DEN). The microarray datasets E-GEOD-6573 and E-GEOD-48424 were downloaded from the European Bioinformatics Institute database. Differentially expressed genes (DEGs) between the PE and normal groups were screened by Significant Analysis of Microarrays with the cutoff value of a |log2 fold change| of >2, and a false discovery rate of <0.05. The DEN was constructed based on the differential and non-differential interactions observed. In addition, genes with higher connectivity degrees in the DEN were identified on the basis of centrality analysis, while disease genes were also extracted from the DEN. In order to understand the functional roles of genes in DEN, Gene Ontology (GO) and pathway enrichment analyses were performed. The present results indicated that a total of 225 genes were considered as DEGs in the PE group, while 466 nodes and 314 gene interactions were involved in the DEN. Among these 466 nodes, 4 nodes with higher degrees were identified, including ubiquitin C (UBC), small ubiquitin-like modifier 1 (SUMO1), SUMO2 and RAD21 homolog (S. pombe) (RAD21). Notably, UBC was also found to be a disease gene. UBC, RAD21, SUMO2 and SUMO1 were markedly enriched in the regulation of programmed cell death, as well as in the regulation of apoptosis, cell cycle and chromosomal part. In conclusion, based on these results, we suggest that UBC, RAD21, SUMO2 and SUMO1 may be reliable biomarkers for the prediction of the development and progression of PE.
Interference of M-protein on prothrombin time test - case report.Monday, June 27, 2016
Margetić S, Ćelap I, Dukić L, Vukasović I, Virović-Jukić L,
Biochemia medica. 2016
The aim of this report was to present a case of interference on prothrombin time (PT) test that directed further laboratory diagnostics and resulted with final detection of monoclonal gammopathy in an 88-year old man. Routine coagulation testing during medical examination at Emergency Department revealed unmeasurable PT (< 7% activity) and activated partial thromboplastin time (aPTT) within reference range. After repeated sampling for coagulation testing, PT was unmeasurable again, as well as fibrinogen level (< 0.8 g/L), thrombin time (TT) was significantly prolonged (107 seconds) and aPTT was within reference range. In both plasma samples refrigerated at 4 ˚C overnight, white gelatinous precipitate was visible between the cell and plasma layers and the presence of monoclonal protein (M-protein) was suggested in our patient. Further laboratory diagnostics revealed total serum proteins at concentration of 123 g/L and the presence of M-protein IgG lambda (λ) at concentration of 47.1 g/L. These results suggested monoclonal gammopathy as an underlying pathophysiological condition in our patient. Activities of coagulation factors II, V, VII and X were within reference ranges or increased. These results and correction of unmeasurable PT result to 67% in mixing test with commercial normal plasma suggest in vitro rather than in vivo interference of M-protein on PT result. In contrast, significantly prolonged TT results in all analysed samples suggest impact of M-protein on this global coagulation test due to possible effect on fibrin polymerization.
Additional technician tasks and turnaround time in the clinical Stat laboratory.Monday, June 27, 2016
Salinas M, López-Garrigós M, Flores E, Leiva-Salinas M, Lillo R, Leiva-Salinas C,
Biochemia medica. 2016
The technicians accomplished a significant number of additional tasks, and the workload kept increasing over the period of 10 years. That did not affect the TAT results.
Identification of authors without surnames: is ORCID the right way forward?Monday, June 27, 2016
Supak-Smolcic V, Simundic AM, Lundberg GD,
Biochemia medica. 2016
The Melanoma MAICare Framework: A Microsimulation Model for the Assessment of Individualized Cancer Care.Monday, June 27, 2016
van der Meijde E, van den Eertwegh AJ, Linn SC, Meijer GA, Fijneman RJ, Coupé VM,
Cancer informatics. 2016
Recently, new but expensive treatments have become available for metastatic melanoma. These improve survival, but in view of the limited funds available, cost-effectiveness needs to be evaluated. Most cancer cost-effectiveness models are based on the observed clinical events such as recurrence- free and overall survival. Times at which events are recorded depend not only on the effectiveness of treatment but also on the timing of examinations and the types of tests performed. Our objective was to construct a microsimulation model framework that describes the melanoma disease process using a description of underlying tumor growth as well as its interaction with diagnostics, treatments, and surveillance. The framework should allow for exploration of the impact of simultaneously altering curative treatment approaches in different phases of the disease as well as altering diagnostics. The developed framework consists of two components, namely, the disease model and the clinical management module. The disease model consists of a tumor level, describing growth and metastasis of the tumor, and a patient level, describing clinically observed states, such as recurrence and death. The clinical management module consists of the care patients receive. This module interacts with the disease process, influencing the rate of transition between tumor growth states at the tumor level and the rate of detecting a recurrence at the patient level. We describe the framework as the required input and the model output. Furthermore, we illustrate model calibration using registry data and data from the literature.
Imaging Glycosylation In Vivo by Metabolic Labeling and Magnetic Resonance Imaging.Monday, June 27, 2016
Neves AA, Wainman YA, Wright A, Kettunen MI, Rodrigues TB, McGuire S, Hu DE, Bulat F, Geninatti Crich S, Stöckmann H, Leeper FJ, Brindle KM,
Angewandte Chemie (Weinheim an der Bergstrasse, Germany). 22-Jan-2016
Glycosylation is a ubiquitous post-translational modification, present in over 50 % of the proteins in the human genome,1 with important roles in cell-cell communication and migration. Interest in glycome profiling has increased with the realization that glycans can be used as biomarkers of many diseases,2 including cancer.3 We report here the first tomographic imaging of glycosylated tissues in live mice by using metabolic labeling and a gadolinium-based bioorthogonal MRI probe. Significant N-azidoacetylgalactosamine dependent T 1 contrast was observed in vivo two hours after probe administration. Tumor, kidney, and liver showed significant contrast, and several other tissues, including the pancreas, spleen, heart, and intestines, showed a very high contrast (>10-fold). This approach has the potential to enable the rapid and non-invasive magnetic resonance imaging of glycosylated tissues in vivo in preclinical models of disease.
Linking DNA adduct formation and human cancer risk in chemical carcinogenesis.Monday, June 27, 2016
Poirier MC,
Environmental and molecular mutagenesis. 27-Jun-2016
Over two centuries ago, Sir Percival Pott, a London surgeon, published a pioneering treatise showing that soot exposure was the cause of high incidences of scrotal cancers occurring in young men who worked as chimney sweeps. Practicing at a time when cellular pathology was not yet recognized, Sir Percival nonetheless observed that the high incidence and short latency of the chimney sweep cancers, was fundamentally different from the rare scrotal cancers typically found in elderly men. Furthermore, his diagnosis that the etiology of these cancers was related to chimney soot exposure, was absolutely accurate, conceptually novel, and initiated the field of "occupational cancer epidemiology." After many intervening years of research focused on mechanisms of chemical carcinogenesis, briefly described here, it is clear that DNA damage, or DNA adduct formation, is "necessary but not sufficient" for tumor induction, and that many additional factors contribute to carcinogenesis. This review includes a synopsis of carcinogen-induced DNA adduct formation in experimental models and in the human population, with particular attention paid to molecular dosimetry and molecular cancer epidemiology. Environ. Mol. Mutagen., 2016. © 2016 Wiley Periodicals, Inc.
Acute inhalation toxicity of carbon monoxide and hydrogen cyanide revisited: Comparison of models to disentangle the concentration × time conundrum of lethality and incapacitation.Monday, June 27, 2016
Pauluhn J,
Regulatory toxicology and pharmacology : RTP. 23-Jun-2016
Contemporary emergency response planning guidelines are stratified to consider the threshold for serious toxicity and/or impairment of escape, relative to the potentially lethal level above this threshold and the lower level at which individuals should not experience or develop effects more serious than mild irritation. While harmonized testing guidelines and risk assessment paradigms are available for the quantification of thresholds for lethality or establishing no adverse effect levels, the quantification of 'impairment of escape' appears to be a more elusive goal. Approaches were explored in context with CO and HCN in past experimental combustion toxicology studies to estimate the time available for escape. This point of departure (POD) was compared with the non-lethal threshold (LC01) and one third thereof from published recent acute inhalation studies in rats examining the Cxt-matrix of both CO and HCN. The findings from this analysis suggest that the rat delivers the most consistent data. However, it remains challenging yet to bridge the behavioral variables of human behavior typical of escape to any surrogate animal model. For the asphyxiant gases examined, the PODs characterizing 'impairment of escape' were difficult to distinguish from those indicative of impending death. No specific modeled carboxyhemoglobin (COHb) level could be linked to onset of incapacitation. In summary, the higher ventilation of rats (kg body weight adjusted) renders this species even more susceptible than heavy breathing humans. LCt01 × 1/3 values derived from the comprehensive Cxt matrix of rat inhalation studies are considered to be most suitable and robust to estimate the human equivalent threshold (POD) of 'impairment of escape'.
Serum miRNA-499 and miRNA-210: A potential role in early diagnosis of acute coronary syndrome.Monday, June 27, 2016
Shalaby SM, El-Shal AS, Shoukry A, Khedr MH, Abdelraheim N,
IUBMB life. 27-Jun-2016
In clinical practice, there is still a need for novel biomarkers, which can reliably rule in or rule out acute coronary syndrome (ACS) immediately on admission. This is of particular interest in patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI) in whom diagnostic uncertainty is high. The aim of the present study is to evaluate the potential role of miRNA-499 and miRNA-210 as novel molecular biomarkers for early diagnosis of UA and NSTEMI suspected patients presented at the emergency unit. A total of 110 patients presenting to the intensive care unit (ICU) within 24 h of onset of chest pain suggestive of ACS were enrolled in the study. They included 37 UA, 48 NSTEMI and 25 noncardiac chest pain (NCCP) patients. Immediately at enrollment, blood samples were taken for estimation of serum miRNA-499 and miRNA-210 expression levels by real time PCR. miRNA-499 and miRNA-210 expression levels were significantly increased in UA and NSTEMI patients compared with NCCP patients (P < 0.001). Receiver operating characteristic (ROC) curve analysis revealed that the area under curve (AUC) of miR-499 for the diagnosis of UA and NSTEMI was 0.98 and 0.97, respectively; while the AUC of miRNA-210 was 0.84 and 0.90, respectively. The important finding of our study was that the AUC of miRNA-499 for the diagnosis of ACS patients with symptoms onset <3 h was 0.89, while the AUC of miRNA-210 was 0.86. Interestingly, combining miRNA-499 and miRNA-210 significantly improved the diagnostic value by increasing the AUC to 0.96, P < 0.001. In conclusion, serum miRNA-499 and miRNA-210 are associated with UA and NSTEMI and with those presenting within 3 h of symptom onset. Both miRNAs might be potentially novel biomarkers for accelerating the diagnosis of ACS patients in emergency unit. © 2016 IUBMB Life, 2016.
MGMT-Methylated Alleles Are Distributed Heterogeneously Within Glioma Samples Irrespective of IDH Status and Chromosome 10q Deletion.Monday, June 27, 2016
Fontana L, Tabano S, Bonaparte E, Marfia G, Pesenti C, Falcone R, Augello C, Carlessi N, Silipigni R, Guerneri S, Campanella R, Caroli M, Maria Sirchia S, Bosari S, Miozzo M,
Journal of neuropathology and experimental neurology. 26-Jun-2016
Several molecular markers drive diagnostic classification, prognostic stratification, and/or prediction of response to therapy in patients with gliomas. Among them, IDH gene mutations are valuable markers for defining subtypes and are strongly associated with epigenetic silencing of the methylguanine DNA methyltransferase (MGMT) gene. However, little is known about the percentage of MGMT-methylated alleles in IDH-mutated cells or the potential association between MGMT methylation and deletion of chromosome 10q, which encompasses the MGMT locus. Here, we quantitatively assessed MGMT methylation and IDH1 mutation in 208 primary glioma samples to explore possible differences associated with the IDH genotype. We also explored a potential association between MGMT methylation and loss of chromosome 10q. We observed that MGMT methylation was heterogeneously distributed within glioma samples irrespective of IDH status suggesting an incomplete overlap between IDH1-mutated and MGMT-methylated alleles and indicating a partial association between these two events. Moreover, loss of one MGMT allele did not affect the methylation level of the remaining allele. MGMT was methylated in about half of gliomas harboring a 10q deletion; in those cases, loss of heterozygosity might be considered a second hit leading to complete inactivation of MGMT and further contributing to tumor progression.
Associations of urinary 5-methyl-2'-deoxycytidine and 5-hydroxymethyl-2'-deoxycytidine with phthalate exposure and semen quality in 562 Chinese adult men.Monday, June 27, 2016
Pan Y, Jing J, Yeung LW, Sheng N, Zhang H, Yao B, Dai J,
Environment international. 23-Jun-2016
5-methyl-2'-deoxycytidine (5mdC) and 5-hydroxymethyl-2'-deoxycytidine (5hmdC), products of DNA methylation and hydroxymethylation processes, have been detected previously in human urine, but their associations with environmental chemicals or healthy outcomes are unclear. The present investigation explored the associations between urinary 5mdC and 5hmdC with phthalate exposure and semen quality. We assessed semen parameters including sperm concentration, motility, and morphology, before measuring urinary 5mdC, 5hmdC and 13 phthalate metabolites among 562 subfertile men from Nanjing, China. Urinary 5mdC and 5hmdC were positively associated with the levels of low molecular weight phthalate metabolites (Low-MWP), high molecular weight phthalate metabolites (High-MWP), and the sum of all phthalate metabolites (ΣPAEs), respectively. Urinary 5mdC was associated with below-reference sperm concentration (odds ratios for increasing quartiles=1.0, 2.2, 3.0, 2.0; p for trend =0.02), sperm motility (1.0, 1.1, 1.9, 1.3; p for trend =0.05), and sperm morphology (1.0, 1.4, 2.3, 1.5; p for trend =0.05). Sperm concentration was associated with the highest quartile of urinary 5hmdC [odds ratio=1.9 (95% CI: 1.1, 3.6)]. Our findings showed significant associations between urinary 5mdC and 5hmdC with phthalate metabolites and semen parameters, which suggested urinary 5mdC and 5hmdC may be promising biomarkers in future epidemiological studies.
Assessment of cadmium bioaccessibility to predict its bioavailability in contaminated soils.Monday, June 27, 2016
Li SW, Sun HJ, Li HB, Luo J, Ma LQ,
Environment international. 23-Jun-2016
In vitro assays have been developed to determine metal bioaccessibility in contaminated soils; however, their application to Cd is limited. To assess their suitability to determine Cd relative bioavailability (RBA), Cd-RBA in 12 contaminated soils containing 3.00-296mgkg(-1) Cd were determined using a mouse model and compared with Cd bioaccessibility data based on four assays including the UBM, SBRC, IVG, and PBET. After being administered feed amended with soil or CdCl2 for 10-day, the Cd concentrations in the mouse liver and/or kidneys were used as biomarkers to estimate Cd-RBA. Cd-RBA was comparable at 34-90% and 40-78% based on mouse liver and kidneys with RSD of 7.10-8.99%, and 37-84% based on mouse liver plus kidneys with lower RSD of 5.8%. Cadmium bioaccessibility in soils varied with assays, with 61-99, 59-103, 54-107, and 35-97% in the gastric phase and 20-56, 38-77, 42-88, and 19-64% in the intestinal phase of the UBM, SBRC, IVG and PBET assays. Based on the combined biomarker of liver plus kidneys, better correlation was observed for PBET (r(2)=0.61-0.70) than those for IVG, UBM and SBRC assays (0.12-0.52). The monthly Cd intake in children was 0.24-23.9μgkg(-1) using total Cd concentration in soils, which was reduced by 43% to 0.18-12.3μgkg(-1) using bioavailable Cd. Our data suggest it is important to consider Cd-RBA to assess risk associated with contaminated soils and the PBET may have potential to predict Cd-RBA in contaminated soils.
Parasites as bioindicators of environmental degradation in Latin America: A meta-analysis.Monday, June 27, 2016
Vidal-Martínez VM, Wunderlich AC,
Journal of helminthology. 27-Jun-2016
Unregulated economic growth in Latin America has resulted in environmental degradation, including the release of toxic compounds into the environment. One strategy to understand and prevent the outcomes of this harmful environmental degradation is the use of bioindicators. These are free-living or parasite species that respond to habitat alterations with changes in their numbers, physiology or chemical composition. The aim of this review was to determine whether there is evidence of a significant parasite response to environmental damage in Latin America. We collected 26 papers published between 2003 and 2015 and conducted a meta-analysis to test the null hypothesis that there is no significant overall effect of environmental insults on parasites. The meta-analysis showed a low but still significant negative mean overall effect (Hedges' g = -0.221; 95% CI: -0.241 to -0.200; P < 0.0001). However, the magnitudes and directions of the significant effects varied widely. These results suggest that different groups of parasites have distinct responses to various environmental insults and that the groups should be separately analysed after the accumulation of a sufficient number of studies. For future studies on this topic in Latin America, we suggest: (1) using field and experimental approaches to determine the response of parasites to environmental degradation; (2) using an interdisciplinary approach, including different types of biomarkers in both parasites and individual hosts to generate long-term datasets in polluted and reference areas; (3) conducting studies on parasites as accumulation bioindicators.
Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.Monday, June 27, 2016
Tajuddin SM, Schick UM, Eicher JD, Chami N, Giri A, Brody JA, Hill WD, Kacprowski T, Li J, Lyytikäinen LP, Manichaikul A, Mihailov E, O'Donoghue ML, Pankratz N, Pazoki R, Polfus LM, Smith AV, Schurmann C, Vacchi-Suzzi C, Waterworth DM, Evangelou E, Yanek LR, Burt A, Chen MH, van Rooij FJ, Floyd JS, Greinacher A, Harris TB, Highland HM, Lange LA, Liu Y, Mägi R, Nalls MA, Mathias RA, Nickerson DA, Nikus K, Starr JM, Tardif JC, Tzoulaki I, Velez Edwards DR, Wallentin L, Bartz TM, Becker LC, Denny JC, Raffield LM, Rioux JD, Friedrich N, Fornage M, Gao H, Hirschhorn JN, Liewald DC, Rich SS, Uitterlinden A, Bastarache L, Becker DM, Boerwinkle E, de Denus S, Bottinger EP, Hayward C, Hofman A, Homuth G, Lange E, Launer LJ, Lehtimäki T, Lu Y, Metspalu A, O'Donnell CJ, Quarells RC, Richard M, Torstenson ES, Taylor KD, Vergnaud AC, Zonderman AB, Crosslin DR, Deary IJ, Dörr M, Elliott P, Evans MK, Gudnason V, Kähönen M, Psaty BM, Rotter JI, Slater AJ, Dehghan A, White HD, Ganesh SK, Loos RJ, Esko T, Faraday N, Wilson JG, Cushman M, Johnson AD, Edwards TL, Zakai NA, Lettre G, Reiner AP, Auer PL,
American journal of human genetics. 21-Jun-2016
White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of ∼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.
Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.Monday, June 27, 2016
Eicher JD, Chami N, Kacprowski T, Nomura A, Chen MH, Yanek LR, Tajuddin SM, Schick UM, Slater AJ, Pankratz N, Polfus L, Schurmann C, Giri A, Brody JA, Lange LA, Manichaikul A, Hill WD, Pazoki R, Elliot P, Evangelou E, Tzoulaki I, Gao H, Vergnaud AC, Mathias RA, Becker DM, Becker LC, Burt A, Crosslin DR, Lyytikäinen LP, Nikus K, Hernesniemi J, Kähönen M, Raitoharju E, Mononen N, Raitakari OT, Lehtimäki T, Cushman M, Zakai NA, Nickerson DA, Raffield LM, Quarells R, Willer CJ, Peloso GM, Abecasis GR, Liu DJ, Deloukas P, Samani NJ, Schunkert H, Erdmann J, Fornage M, Richard M, Tardif JC, Rioux JD, Dube MP, de Denus S, Lu Y, Bottinger EP, Loos RJ, Smith AV, Harris TB, Launer LJ, Gudnason V, Velez Edwards DR, Torstenson ES, Liu Y, Tracy RP, Rotter JI, Rich SS, Highland HM, Boerwinkle E, Li J, Lange E, Wilson JG, Mihailov E, Mägi R, Hirschhorn J, Metspalu A, Esko T, Vacchi-Suzzi C, Nalls MA, Zonderman AB, Evans MK, Engström G, Orho-Melander M, Melander O, O'Donoghue ML, Waterworth DM, Wallentin L, White HD, Floyd JS, Bartz TM, Rice KM, Psaty BM, Starr JM, Liewald DC, Hayward C, Deary IJ, Greinacher A, Völker U, Thiele T, Völzke H, van Rooij FJ, Uitterlinden AG, Franco OH, Dehghan A, Edwards TL, Ganesh SK, Kathiresan S, Faraday N, Auer PL, Reiner AP, Lettre G, Johnson AD,
American journal of human genetics. 21-Jun-2016
Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.
Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.Monday, June 27, 2016
Chami N, Chen MH, Slater AJ, Eicher JD, Evangelou E, Tajuddin SM, Love-Gregory L, Kacprowski T, Schick UM, Nomura A, Giri A, Lessard S, Brody JA, Schurmann C, Pankratz N, Yanek LR, Manichaikul A, Pazoki R, Mihailov E, Hill WD, Raffield LM, Burt A, Bartz TM, Becker DM, Becker LC, Boerwinkle E, Bork-Jensen J, Bottinger EP, O'Donoghue ML, Crosslin DR, de Denus S, Dubé MP, Elliott P, Engström G, Evans MK, Floyd JS, Fornage M, Gao H, Greinacher A, Gudnason V, Hansen T, Harris TB, Hayward C, Hernesniemi J, Highland HM, Hirschhorn JN, Hofman A, Irvin MR, Kähönen M, Lange E, Launer LJ, Lehtimäki T, Li J, Liewald DC, Linneberg A, Liu Y, Lu Y, Lyytikäinen LP, Mägi R, Mathias RA, Melander O, Metspalu A, Mononen N, Nalls MA, Nickerson DA, Nikus K, O'Donnell CJ, Orho-Melander M, Pedersen O, Petersmann A, Polfus L, Psaty BM, Raitakari OT, Raitoharju E, Richard M, Rice KM, Rivadeneira F, Rotter JI, Schmidt F, Smith AV, Starr JM, Taylor KD, Teumer A, Thuesen BH, Torstenson ES, Tracy RP, Tzoulaki I, Zakai NA, Vacchi-Suzzi C, van Duijn CM, van Rooij FJ, Cushman M, Deary IJ, Velez Edwards DR, Vergnaud AC, Wallentin L, Waterworth DM, White HD, Wilson JG, Zonderman AB, Kathiresan S, Grarup N, Esko T, Loos RJ, Lange LA, Faraday N, Abumrad NA, Edwards TL, Ganesh SK, Auer PL, Johnson AD, Reiner AP, Lettre G,
American journal of human genetics. 21-Jun-2016
Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.
Stepwise Application of Transient Elastography and Routine Biomarkers Optimizes Hepatitis B Cirrhosis Detection.Monday, June 27, 2016
Liang XE, Zhong C, Huang L, Yang S, Zhu Y, Chen Y, Hou J,
Journal of gastroenterology and hepatology. 26-Jun-2016
By transient elastography based stepwise combination with readily available serum markers, performance of detecting compensated CHB cirrhosis could be significantly improved in terms of diagnosis accuracy and proportion of obviating liver biopsy.
Polycyclic Aromatic Hydrocarbons: Part II, Urine Markers.Monday, June 27, 2016
Ifegwu OC, Anyakora C,
Advances in clinical chemistry. 2016
There has been increasing demand for simple, rapid, highly sensitive, inexpensive yet reliable method for detecting predisposition to cancer. Human biomonitoring of exposure to the largest class of chemical carcinogen, polycyclic aromatic hydrocarbons (PAHs) that are rapidly transformed into detectable metabolites (eg, 1-hydroxypyrene), can serve as strong pointers to early detection of predisposition to cancer. Given that any exposure to PAH is assumed to pose a certain risk of cancer, several biomarkers have been employed in biomonitoring these ninth most threatening ranked compounds. They include metabolites in urine, urinary thioethers, urinary mutagenicity, genetoxic end points in lymphocytes, hemoglobin adducts of benzo(a)pyrene, PAH-protein adducts, and PAH-DNA adducts among others. In this chapter, the main focus will be on the urine metabolites since urine samples are easily collected and there is a robust analytical instrument for the determination of their metabolites.
Transferrin Saturation: A Body Iron Biomarker.Monday, June 27, 2016
Elsayed ME, Sharif MU, Stack AG,
Advances in clinical chemistry. 2016
Iron is an essential element for several metabolic pathways and physiological processes. The maintenance of iron homeostasis within the human body requires a dynamic and highly sophisticated interplay of several proteins, as states of iron deficiency or excess are both potentially deleterious to health. Among these is plasma transferrin, which is central to iron metabolism not only through iron transport between body tissues in a soluble nontoxic form but also through its protective scavenger role in sequestering free toxic iron. The transferrin saturation (TSAT), an index that takes into account both plasma iron and its main transport protein, is considered an important biochemical marker of body iron status. Its increasing use in many health systems is due to the increased availability of measurement methods, such as calorimetry, turbidimetry, nephelometry, and immunochemistry to estimate its value. However, despite its frequent use in clinical practice to detect states of iron deficiency or iron overload, careful attention should be paid to the inherent limitations of the test especially in certain settings such as inflammation in order to avoid misinterpretation and erroneous conclusions. Beyond its usual clinical use, an emerging body of evidence has linked TSAT levels to major clinical outcomes such as cardiovascular mortality. This has the potential to extend the utility of TSAT index to risk stratification and prognostication. However, most of the current evidence is mainly driven by observational studies where the risk of residual confounding cannot be fully eliminated. Indeed, future efforts are required to fully explore this capability in well-designed clinical trials or prospective large-scale cohorts.
Circulating Tumor Cell Isolation and Analysis.Monday, June 27, 2016
Zhang J, Chen K, Fan ZH,
Advances in clinical chemistry. 2016
Isolation and analysis of cancer cells from body fluids have significant implications in diagnosis and therapeutic treatment of cancers. Circulating tumor cells (CTCs) are cancer cells circulating in the peripheral blood or spreading iatrogenically into blood vessels, which is an early step in the cascade of events leading to cancer metastasis. Therefore, CTCs can be used for diagnosing for therapeutic treatment, prognosing a given anticancer intervention, and estimating the risk of metastatic relapse. However, isolation of CTCs is a significant technological challenge due to their rarity and low recovery rate using traditional purification techniques. Recently microfluidic devices represent a promising platform for isolating cancer cells with high efficiency in processing complex cellular fluids, with simplicity, sensitivity, and throughput. This review summarizes recent methods of CTC isolation and analysis, as well as their applications in clinical studies.
High Frequency of KRAS Mutation in Early Onset Colorectal Adenocarcinoma: Implications for Pathogenesis.Monday, June 27, 2016
Watson R, Liu TC, Ruzinova MB,
Human pathology. 23-Jun-2016
While the incidence of sporadic early onset (defined here as ≤40 years of age) colorectal cancer is increasing, its molecular pathogenesis remains unclear. In particular, previous studies have suggested that the genetic initiating events in these patients may be distinct from those observed in older colorectal cancer patients. We aimed to study clinical, histopathological, and molecular features of early onset colorectal cancer. We identified 68 consecutive sporadic early onset colorectal cancer cases with available molecular data treated in our institution between 2007 and 2014. Consistent with previous reports, the majority of sporadic early onset colorectal cancer patients had left-sided tumors, which were predominantly of low histologic grade, but advanced clinical stage. A subset of tumors (< 40%) contained mucinous or signet ring cell features. DNA mismatch repair pathway, commonly associated with Lynch syndrome, was abnormal only in a minor subset of cases. In contrast to the low prevalence (< 30%) of KRAS mutations reported by previous studies, we found that a significantly higher proportion (54%) of early onset colorectal cancer cases harbored KRAS mutations, a finding that was independent of tumor stage. The high prevalence of KRAS mutation in early onset colorectal cancer suggests that it shares common genetic initiating events with colorectal cancer in older patients.
Cortical sensorimotor alterations classify clinical phenotype and putative genotype of spasmodic dysphonia.Monday, June 27, 2016
Battistella G, Fuertinger S, Fleysher L, Ozelius LJ, Simonyan K,
European journal of neurology. 27-Jun-2016
Our findings present the first effort to identify and categorize isolated focal dystonia based on its brain functional connectivity profile, which may have a potential impact on the future development of biomarkers for this rare disorder.
miR-145 modulates lncRNA-ROR and Sox2 expression to maintain human amniotic epithelial stem cell pluripotency and β islet-like cell differentiation efficiency.Monday, June 27, 2016
Zou G, Liu T, Guo L, Huang Y, Feng Y, Huang Q, Duan T,
Gene. 23-Jun-2016
In this study, we observed a great reduction in the expression of the endogenous long noncoding RNA ROR (lncRNA-ROR) and the stem cell transcription factor Sox2, in contrast to a marked increase in miR-145 expression, during the course of in vitro induced differentiation of human amniotic epithelial stem cells (HuAECs). Bioinformatics analysis and the luciferase reporter assay revealed binding of miR-145 to specific sites in lncRNA-ROR and Sox2, silencing their expression. Overexpression of a lncRNA-ROR-specific siRNA effectively downregulated the expression levels of Sox2 and other stem cell markers in HuAECs while weakening the efficiency of HuAEC differentiation into β islet-like cells. Moreover, the in vitro response of HuAEC-derived β islet-like cells to extracellular stimuli and C-peptide release by these cells were markedly weakened in the siRNA-ROR transfection group. Furthermore, the in vivo expression of β islet-like cell biomarkers was substantially reduced in HuAECs in the siRNA-ROR transfection group, and their in vivo β islet-like cell differentiation and insulin release capacities were reduced in a streptozocin-induced diabetic rat model. The experimental results indicate that lncRNA-ROR effectively maintains Sox2 gene expression through competitive binding to miR-145, achieving pluripotency maintenance in HuAECs and regulation of their directed β islet-like cell differentiation efficiency.
Primate liver tissue as an alternative substrate for endomysium antibody immunofluorescence testing in diagnostics of paediatric coeliac disease.Monday, June 27, 2016
Wolf J, Jahnke A, Fechner K, Richter T, Laass MW, Hauer A, Stern M, de Laffolie J, Flemming G, Mothes T,
Clinica chimica acta; international journal of clinical chemistry. 23-Jun-2016
Primate liver can be used as alternative, equally well functioning substrate for IgA-EmA testing.
Long-term effects of angiotensin II blockade with irbesartan on inflammatory markers in hemodialysis patients: A randomized double blind placebo controlled trial (SAFIR study).Monday, June 27, 2016
Peters CD, Kjaergaard KD, Nielsen CH, Christensen KL, Bibby BM, Jensen JD, Jespersen B,
Hemodialysis international. International Symposium on Home Hemodialysis. 27-Jun-2016
Introduction Low-grade chronic inflammation is common in hemodialysis (HD) patients. Previous studies suggest an anti-inflammatory effect of angiotensin II receptor blocker (ARB) treatment. The aim of this study was to compare the effect of ARB vs. placebo on plasma concentrations of inflammatory markers in HD patients. Methods Adult HD patients were randomized for double-blind treatment with the ARB irbesartan 150-300 mg/day or placebo. At baseline, 1 week, 3, 6, 9, and 12 months plasma high sensitivity C-reactive protein (hsCRP), interleukin (IL)-1β, IL-6, IL-8, IL-18, and transforming growth factor-β (TGF-β) were measured using Luminex and enzyme-linked immunosorbent assay (ELISA) technology. Findings Eighty-two patients were randomized (placebo/ARB: 41/41). The groups did not differ in initial levels of any of the inflammatory markers (placebo/ARB median(range)): hsCRP 3.3(0.2-23.4)/2.7(0.2-29.6) μg/mL; IL-1β 1.1(0.0-45.9)/1.1(0.0-7.2) pg/mL; IL-6 10(1-90)/12(1-84) pg/mL; IL-8 31(9-134)/34(5-192) pg/mL; IL-18 364(188-1343)/377(213-832) pg/mL; TGF-β 3.2(0.8-13.9)/3.6(1.3-3.8) ng/mL. Overall, there was no significant difference in hsCRP, IL-6, IL-8, and TGF-β between placebo and ARB-treated patients during the study period, and hsCRP, IL-6, IL-8, and TGF-β were relatively stable during the study period (P ≥ 0.18 in all tests for parallel curves, equal levels, and constant levels). The IL-1β level was slightly different in the two groups over time, but not significantly (P = 0.09 in test for parallel curves) and it was also relatively stable during the study period (P ≥ 0.49 in tests for equal levels and constant level). IL-18 was the only inflammatory marker which was not constant during the study period (P = 0.001 in test for constant level), but there was no significant difference between placebo and ARB-treated (P ≥ 0.51 in tests for parallel curves and equal levels). Discussion Inflammatory biomarkers were neither acutely, nor in the long-term significantly affected by the ARB irbesartan. Our findings suggest that ARB treatment in HD patients does not offer protective anti-inflammatory effects.
Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks.Monday, June 27, 2016
Rendeiro AF, Schmidl C, Strefford JC, Walewska R, Davis Z, Farlik M, Oscier D, Bock C,
Nature communications. 2016
Chronic lymphocytic leukaemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, here we present genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients measured by the ATAC-seq assay. We also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting data set, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status-which distinguishes the two major subtypes of CLL-was accurately predicted by the chromatin profiles and gene regulatory networks inferred for IGHV-mutated versus IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukaemia and demonstrated the feasibility of large-scale chromatin accessibility mapping in cancer cohorts and clinical research.
MEIS2 Is an Oncogenic Partner in AML1-ETO-Positive AML.Monday, June 27, 2016
Vegi NM, Klappacher J, Oswald F, Mulaw MA, Mandoli A, Thiel VN, Bamezai S, Feder K, Martens JH, Rawat VP, Mandal T, Quintanilla-Martinez L, Spiekermann K, Hiddemann W, Döhner K, Döhner H, Stunnenberg HG, Feuring-Buske M, Buske C,
Cell reports. 22-Jun-2016
Homeobox genes are known to be key factors in leukemogenesis. Although the TALE family homeodomain factor Meis1 has been linked to malignancy, a role for MEIS2 is less clear. Here, we demonstrate that MEIS2 is expressed at high levels in patients with AML1-ETO-positive acute myeloid leukemia and that growth of AML1-ETO-positive leukemia depends on MEIS2 expression. In mice, MEIS2 collaborates with AML1-ETO to induce acute myeloid leukemia. MEIS2 binds strongly to the Runt domain of AML1-ETO, indicating a direct interaction between these transcription factors. High expression of MEIS2 impairs repressive DNA binding of AML1-ETO, inducing increased expression of genes such as the druggable proto-oncogene YES1. Collectively, these data describe a pivotal role for MEIS2 in AML1-ETO-induced leukemia.
Oncogenic EGFR Represses the TET1 DNA Demethylase to Induce Silencing of Tumor Suppressors in Cancer Cells.Monday, June 27, 2016
Forloni M, Gupta R, Nagarajan A, Sun LS, Dong Y, Pirazzoli V, Toki M, Wurtz A, Melnick MA, Kobayashi S, Homer RJ, Rimm DL, Gettinger SJ, Politi K, Dogra SK, Wajapeyee N,
Cell reports. 21-Jun-2016
Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis are not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting the DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression through active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in the majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors that may have therapeutic benefits for oncogenic EGFR-mediated lung cancers and glioblastomas.
Glutamine Metabolism Regulates the Pluripotency Transcription Factor OCT4.Monday, June 27, 2016
Marsboom G, Zhang GF, Pohl-Avila N, Zhang Y, Yuan Y, Kang H, Hao B, Brunengraber H, Malik AB, Rehman J,
Cell reports. 21-Jun-2016
The molecular mechanisms underlying the regulation of pluripotency by cellular metabolism in human embryonic stem cells (hESCs) are not fully understood. We found that high levels of glutamine metabolism are essential to prevent degradation of OCT4, a key transcription factor regulating hESC pluripotency. Glutamine withdrawal depletes the endogenous antioxidant glutathione (GSH), which results in the oxidation of OCT4 cysteine residues required for its DNA binding and enhanced OCT4 degradation. The emergence of the OCT4(lo) cell population following glutamine withdrawal did not result in greater propensity for cell death. Instead, glutamine withdrawal during vascular differentiation of hESCs generated cells with greater angiogenic capacity, thus indicating that modulating glutamine metabolism enhances the differentiation and functional maturation of cells. These findings demonstrate that the pluripotency transcription factor OCT4 can serve as a metabolic-redox sensor in hESCs and that metabolic cues can act in concert with growth factor signaling to orchestrate stem cell differentiation.
Better colonisation of newly emerged Bordetella pertussis in the co-infection mouse model study.Monday, June 27, 2016
Safarchi A, Octavia S, Luu LD, Tay CY, Sintchenko V, Wood N, Marshall H, McIntyre P, Lan R,
Vaccine. 23-Jun-2016
Molecular epidemiological data indicates that the resurgence of pertussis (whooping cough) in populations with high vaccine coverage is associated with genomic adaptation of Bordetella pertussis, the causative agent of the disease, to vaccine selection pressure. We have previously shown that in the period after the introduction of acellular pertussis vaccine (ACV), the majority of circulating strains in Australia switched to single nucleotide polymorphism (SNP) cluster I (carrying ptxP3/prn2), replacing SNP cluster II (carrying ptxP1/prn3). In this study, we carried out an in vivo competition assay using a mouse model infected with SNP cluster I and II B. pertussis strains from Australia. We found that the SNP cluster I strain colonised better than the SNP cluster II strain, in both naïve and immunised mice, suggesting that SNP cluster I strains had better fitness regardless of immunisation status of the host, consistent with SNP cluster I strains replacing SNP cluster II. Nevertheless, we found that ACV enhanced clearance of both SNP cluster I and II strains from the mouse respiratory tract.
A single-centre cohort study of National Early Warning Score (NEWS) and near patient testing in acute medical admissions.Monday, June 27, 2016
Abbott TE, Torrance HD, Cron N, Vaid N, Emmanuel J,
European journal of internal medicine. 23-Jun-2016
Admission NEWS is more strongly associated with death or critical care unit admission within 2days of hospital admission, compared to combinations of NEWS and blood-gas derived biomarkers.
Development and Validation of Liquid Chromatography/Tandem Mass Spectrometry Analysis for Therapeutic Drug Monitoring of Risperidone and 9-Hydroxyrisperidone in Pediatric Patients with Autism Spectrum Disorders.Monday, June 27, 2016
Vanwong N, Prommas S, Puangpetch A, Hongkaew Y, Nuntamool N, Nakorn CN, Ngamsamut N, Limsila P, Sukasem C,
Journal of clinical laboratory analysis. 26-Jun-2016
The determination of RIS in individual patients might be clinically useful for monitoring and prediction of treatment response.
Derivation of HVR1, HVR2 and HVR3 human embryonic stem cell lines from IVF embryos after preimplantation genetic diagnosis (PGD) for monogenic disorder.Monday, June 27, 2016
Hmadcha A, Aguilera Y, Lozano-Arana MD, Mellado N, Sánchez J, Moya C, Sánchez-Palazón L, Palacios J, Antiñolo G, Soria B,
Stem cell research. May-2016
From 106 human blastocyts donate for research after in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) for monogenetic disorder, 3 human embryonic stem cells (hESCs) HVR1, HVR2 and HVR3 were successfully derived. HVR1 was assumed to be genetically normal, HVR2 carrying Becker muscular dystrophy and HVR3 Hemophilia B. Despite the translocation t(9;15)(q34.3;q14) detected in HVR2, all the 3 cell lines were characterised in vitro and in vivo as normal hESCs lines and were registered in the Spanish Stem Cell Bank.
Assessment of the role of serum ischemia-modified albumin in obstructive sleep apnea in comparison with interleukin-6.Monday, June 27, 2016
Dogan D, Ocal N, Aydogan M, Tasci C, Arslan Y, Tapan S, Yetkin S, Bilgic H,
Postgraduate medicine. 26-Jun-2016
Serum IMA may be a valuable oxidative stress indicator for OSA and could act as a better biomarker than IL-6 for reflecting the presence and the severity of OSA.
[Research progress regarding the clinical evaluation on recombinant human papillomavirus vaccines].Monday, June 27, 2016
He WG, Zhao J, Huang SJ, Wu T,
Zhonghua liu xing bing xue za zhi = Zhonghua liuxingbingxue zazhi. 10-Jun-2016
Human papillomavirus (HPV) is the main cause for cervical cancer, anogenital cancers and genital warts. Three HPV vaccines have been licensed abroad. Data from clinical trials showed high efficacy of the HPV vaccines in young women with 90%-100% vaccine-related HPV diseases prevented. Though efficacy of the vaccine appears lower in older women, this population can still benefit from vaccination. Immunobriging trials show that the two-dose schedule in 9-14 years old girls elicits non-inferior immune response than the three-dose one in young adults. In addition, HPV vaccines can reduce the recurrent rates in CIN2+ patients after therapeutic surgery and the vaccines have cross-protection aganist diseases caused by non-vaccine type HPV. Safety data on HPV vaccines are assuring. Thus HPV vaccine should be widely used in adolescent girls and women of appropriate age groups.
Generation of human control iPS cell line CHOPWT10 from healthy adult peripheral blood mononuclear cells.Monday, June 27, 2016
Maguire JA, Gagne AL, Jobaliya CD, Gandre-Babbe S, Gadue P, French DL,
Stem cell research. Mar-2016
The CHOPWT10 iPS cell line was generated to be used as a control for applications such as in differentiation analyses to the three germ layers and derivative tissues. Peripheral blood mononuclear cells (PBMCs) obtained from a healthy adult male were reprogrammed using the non-integrating Sendai virus expressing Oct3/4, Sox2, c-Myc, and Klf4.
Generation of Hermansky Pudlak syndrome type 2 (HPS2) induced pluripotent stem cells (iPSCs).Monday, June 27, 2016
Maguire JA, Lu L, Mills JA, Sullivan LM, Gadue P, French DL,
Stem cell research. Mar-2016
Hermansky-Pudlak syndrome type 2 (HPS2) is a rare autosomal recessive disorder resulting from functional mutations in the adaptor-related protein complex 3, beta 1 subunit (AP3B1) gene. This gene plays a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Here we describe the generation of an HPS2 iPS cell line (CHOPHPS2) using a Cre-excisable polycistronic STEMCCA lentivirus. This line was derived from human fibroblasts isolated from a patient carrying two mutations in the AP3B1 gene. The patient presented with severe neutropenia, ocular albinism, interstitial pulmonary fibrosis, hemorrhagic diathesis, and an absence of platelet-dense granules.
Generation of Hermansky-Pudlak Syndrome Type 1 (HPS1) induced pluripotent stem cells (iPSCs).Monday, June 27, 2016
Maguire JA, Lu L, Mills JA, Sullivan LM, Gagne A, Gadue P, French DL,
Stem cell research. Mar-2016
Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by deficiencies in lysosome-related organelles such as melanosomes and platelet-dense granules. The disorder is classified into nine different subtypes (HPS1-HPS9) based on genetic mutations in 9 unique genes. Here we describe the generation of an HPS1 iPSC line (CHOPHPS1) using a Cre-excisable polycistronic STEMCCA lentivirus. This line was derived from human fibroblasts isolated from a patient carrying a duplicative mutation in the HPS1 gene. The patient presented with oculocutaneous albinism, early pulmonary fibrosis, and hemorrhagic diathesis.
Hypothermia for neonatal hypoxic-ischemic encephalopathy: NICHD Neonatal Research Network contribution to the field.Monday, June 27, 2016
Shankaran S, Natarajan G, Chalak L, Pappas A, McDonald SA, Laptook AR,
Seminars in perinatology. 23-Jun-2016
In this article, we summarize the NICHD Neonatal Research Network (NRN) trial of whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy in relation to other randomized controlled trials (RCTs) of hypothermia neuroprotection. We describe the NRN secondary studies that have been published in the past 10 years evaluating clinical, genetic, biochemical, and imaging biomarkers of outcome.
Haralick textural features on T2 -weighted MRI are associated with biochemical recurrence following radiotherapy for peripheral zone prostate cancer.Monday, June 27, 2016
Gnep K, Fargeas A, Gutiérrez-Carvajal RE, Commandeur F, Mathieu R, Ospina JD, Rolland Y, Rohou T, Vincendeau S, Hatt M, Acosta O, de Crevoisier R,
Journal of magnetic resonance imaging : JMRI. 27-Jun-2016
T2 -w Haralick features appear to be strongly associated with biochemical recurrence following prostate cancer radiotherapy. J. Magn. Reson. Imaging 2016.
Red Blood Cell Antigen Genotyping for Sickle Cell Disease, Thalassemia, and Other Transfusion Complications.Monday, June 27, 2016
Fasano RM, Chou ST,
Transfusion medicine reviews. 28-May-2016
Since the discovery of the ABO blood group in the early 20th century, more than 300 blood group antigens have been categorized among 35 blood group systems. The molecular basis for most blood group antigens has been determined and demonstrates tremendous genetic diversity, particularly in the ABO and Rh systems. Several blood group genotyping assays have been developed, and 1 platform has been approved by the Food and Drug Administration as a "test of record," such that no phenotype confirmation with antisera is required. DNA-based red blood cell (RBC) phenotyping can overcome certain limitations of hemagglutination assays and is beneficial in many transfusion settings. Genotyping can be used to determine RBC antigen phenotypes in patients recently transfused or with interfering allo- or autoantibodies, to resolve discrepant serologic typing, and/or when typing antisera are not readily available. Molecular RBC antigen typing can facilitate complex antibody evaluations and guide RBC selection for patients with sickle cell disease (SCD), thalassemia, and autoimmune hemolytic anemia. High-resolution RH genotyping can identify variant RHD and RHCE in patients with SCD, which have been associated with alloimmunization. In the future, broader access to cost-efficient, high-resolution RBC genotyping technology for both patient and donor populations may be transformative for the field of transfusion medicine.
Generation of induced pluripotent stem cells (iPSCs) from an Alzheimer's disease patient carrying a L150P mutation in PSEN-1.Monday, June 27, 2016
Tubsuwan A, Pires C, Rasmussen MA, Schmid B, Nielsen JE, Hjermind LE, Hall V, Nielsen TT, Waldemar G, Hyttel P, Clausen C, Kitiyanant N, Freude KK, Holst B,
Stem cell research. Jan-2016
Induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts isolated from a 58-year old male with a L150P mutation in the presenilin 1 (PSEN-1) gene, which is responsible for the majority of familial cases of Alzheimer's disease (AD). The iPSCs were established by co-electroporation with episomal plasmids containing hOCT4, hSOX2, hL-MYC, hKLF4, hNANOG, hLIN28, and short hairpin RNA against TP53. The iPSCs contained the specific heterozygous mutation c.449C>T, had normal karyotype, expressed the expected pluripotency genes and displayed in vitro differentiation potential to the three germ layers. The iPSCs may be useful for studying familial AD pathology in vitro.
Induced pluripotent stem cells (iPSCs) derived from a pre-symptomatic carrier of a R406W mutation in microtubule-associated protein tau (MAPT) causing frontotemporal dementia.Monday, June 27, 2016
Rasmussen MA, Hjermind LE, Hasholt LF, Waldemar G, Nielsen JE, Clausen C, Hyttel P, Holst B,
Stem cell research. Jan-2016
Skin fibroblasts were obtained from a 28-year-old pre-symptomatic woman carrying a R406W mutation in microtubule-associated protein tau (MAPT), known to cause frontotemporal dementia. Induced pluripotent stem cell (iPSCs) were established by electroporation with episomal plasmids containing hOCT4, hSOX2, hKLF2, hL-MYC, hLIN-28 and shP53. iPSCs were free of genomically integrated reprogramming genes, contained the expected c.1216C>T substitution in exon 13 of the MAPT gene, expressed the expected pluripotency markers, displayed in vitro differentiation potential to the three germ layers and had normal karyotype. The iPSC line may be useful for studying hereditary frontotemporal dementia and TAU pathology in vitro.
Induced pluripotent stem cells (iPSCs) derived from a patient with frontotemporal dementia caused by a R406W mutation in microtubule-associated protein tau (MAPT).Monday, June 27, 2016
Rasmussen MA, Hjermind LE, Hasholt LF, Waldemar G, Nielsen JE, Clausen C, Hyttel P, Holst B,
Stem cell research. Jan-2016
Skin fibroblasts were obtained from a 59-year-old woman diagnosed with frontotemporal dementia. The disease is caused by a R406W mutation in microtubule-associated protein tau (MAPT). Induced pluripotent stem cells (iPSCs) were established by electroporation with episomal plasmids containing hOCT4, hSOX2, hKLF2, hL-MYC, hLIN-28 and shP53. iPSCs were free of genomically integrated reprogramming genes, contained the expected c.1216C>T substitution in exon 13 of the MAPT gene, expressed the expected pluripotency markers, displayed in vitro differentiation potential to the three germ layers and had normal karyotype. The iPSC line may be useful for studying hereditary frontotemporal dementia and TAU pathology in vitro.
Induced pluripotent stem cells (iPSCs) derived from a patient with frontotemporal dementia caused by a P301L mutation in microtubule-associated protein tau (MAPT).Monday, June 27, 2016
Rasmussen MA, Hjermind LE, Hasholt LF, Waldemar G, Nielsen JE, Clausen C, Hyttel P, Holst B,
Stem cell research. Jan-2016
Skin fibroblasts were obtained from a 57-year-old woman diagnosed with frontotemporal dementia. The disease is caused by a P301L mutation in microtubule-associated protein tau (MAPT). Induced pluripotent stem cells (iPSCs) were established by electroporation with episomal plasmids containing hOCT4, hSOX2, hKLF2, hL-MYC, hLIN-28 and shP53. iPSCs were free of genomically integrated reprogramming genes, contained the expected c.902C>T substitution in exon 10 of the MAPT gene, expressed the expected pluripotency markers, displayed in vitro differentiation potential to the three germ layers and had normal karyotype. The iPSC line may be useful for studying hereditary frontotemporal dementia and TAU pathology in vitro.
Source: NCBI - Disclaimer and Copyright notice

SELECTBIO Market Reports
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
3,200+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,700+ scientific videos