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Showing 99 Latest Publications
TitleDate Created
Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26.Thursday, May 26, 2016
Chiu DK, Xu IM, Lai RK, Tse AP, Wei LL, Koh HY, Li LL, Lee D, Lo RC, Wong CM, Ng IO, Wong CC,
Hepatology (Baltimore, Md.). 26-May-2016
A population of stromal cells, myeloid-derived suppressor cells (MDSCs), are present in tumors. Though studies have gradually revealed the pro-tumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers whose growth often exceeds growth of the functional blood vessels. Here, using hepatocellular carcinoma (HCC) as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observe that MDSCs preferentially infiltrate into hypoxic regions in human HCC tissues and hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors (HIFs). We further find that HIFs activate the transcription of chemokine (C-C motif) ligand 26 (CCL26) in cancer cells to recruit chemokine (C-X3-C motif) receptor 1 (CX3 CR1)-expressing MDSCs to the primary tumor. Knockdown of CCL26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of CCL26 production in cancer cells by HIF inhibitor, digoxin, or blockade of CX3 CR1 in MDSCs by CX3 CR1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth. In conclusion, this study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSCs homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. This article is protected by copyright. All rights reserved.
Multidrug-resistant organisms in liver transplant - mitigating risk and managing infections.Thursday, May 26, 2016
Hand J, Patel G,
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 26-May-2016
Liver transplant recipients are vulnerable to infections with multidrug-resistant pathogens. Risk factors for colonization and infection with resistant bacteria are ubiquitous and unavoidable in transplantation. During the past decade, progress in transplantation and infection prevention has contributed to the decreased incidence of infections with methicillin-resistant Staphylococcus aureus. However, even in the face of potentially effective antibiotics, vancomycin-resistant enterococci continue to plague liver transplantation. Gram-negative bacilli prove to be more problematic and are responsible for high rates of both morbidity and mortality. Despite the licensure of novel antibiotics, there is no universal agent available to safely and effectively treat infections with multidrug-resistant Gram-negative organisms. Currently, efforts dedicated toward prevention and treatment require involvement of multiple disciplines including transplant providers, specialists in infectious diseases and infection prevention, and researchers dedicated to the development of rapid diagnostics and safe and effective antibiotics with novel mechanisms of action. This article is protected by copyright. All rights reserved.
Role of SEP15 Gene Polymorphisms in the Time of Progression to AIDS.Thursday, May 26, 2016
Benelli JL, de Medeiros RM, Matte MC, de Melo MG, Almeida SE, Fiegenbaum M,
Genetic testing and molecular biomarkers. 26-May-2016
These findings show the importance of genetic analysis of the SEP15 gene in individual patients with regard to predicting time of progression to AIDS.
Fetal Alcohol Syndrome and Maternal Alcohol Biomarkers in Sera: A Register-Based Case-Control Study.Thursday, May 26, 2016
Niemelä S, Niemelä O, Ritvanen A, Gissler M, Bloigu A, Werler M, Surcel HM,
Alcoholism, clinical and experimental research. 26-May-2016
In this explorative case-control study, we demonstrate that the FMC biobank can be used to screen alcohol biomarkers for epidemiological research purposes. According to our results, the use of alcohol biomarkers during the first trimester may help to identify the high-risk pregnancies for FAS. A more systematic use of alcohol biomarkers at maternity care may open new possibilities for screening and intervention of alcohol use among pregnant mothers.
Long-term exercise training prevents mammary tumorigenesis-induced muscle wasting in rats through the regulation of TWEAK signalling.Thursday, May 26, 2016
Padrão AI, Figueira AC, Rocha-Faustino A, Gama A, Loureiro MM, Neuparth MJ, Moreira-Gonçalves D, Vitorino R, Amado F, Santos LL, Oliveira PA, Duarte JA, Ferreira R,
Acta physiologica (Oxford, England). 26-May-2016
Data supports the benefits of an active lifestyle for the prevention of muscle wasting secondary to breast cancer, highlighting TWEAK/NF- κB signalling as a potential therapeutic target for the preservation of muscle mass. This article is protected by copyright. All rights reserved.
Navigating highly homologous genes in a molecular diagnostic setting: a resource for clinical next-generation sequencing.Thursday, May 26, 2016
Mandelker D, Schmidt RJ, Ankala A, McDonald Gibson K, Bowser M, Sharma H, Duffy E, Hegde M, Santani A, Lebo M, Funke B,
Genetics in medicine : official journal of the American College of Medical Genetics. 26-May-2016
This resource can help guide clinical test design, supplemental assay implementation, and results interpretation in the context of high homology.Genet Med advance online publication 26 May 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.58.
Glial biomarkers in human central nervous system disease.Thursday, May 26, 2016
Garden GA, Campbell BM,
Glia. 26-May-2016
There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments. GLIA 2016.
Comparative Proteomic Analysis of Whole-Gut Lavage Fluid and Pancreatic Juice Reveals a Less Invasive Method of Sampling Pancreatic Secretions.Thursday, May 26, 2016
Rocker JM, Tan MC, Thompson LW, Contreras CM, DiPalma JA, Pannell LK,
Clinical and translational gastroenterology. 26-5-2016
WGLF and pancreatic juice appear to have similar proteomic profiles. This supports the notion that WGLF is a non-invasive, surrogate bio-fluid for pancreatic juice. Further studies are required to further elucidate its role in the diagnosis of pancreatic cancer.
AXIN2 Polymorphisms and Its Association with Colorectal Cancer in Mexican Patients.Thursday, May 26, 2016
Rosales-Reynoso MA, Arredondo-Valdez AR, Wence-Chávez LI, Barros-Núñez P, Gallegos-Arreola MP, Flores-Martínez SE, Sánchez-Corona J,
Genetic testing and molecular biomarkers. 26-May-2016
Our results indicate the possibility that variations in the AXIN2 gene may play a significant role in promoting or preventing the CRC development.
BCOR-CCNB3-Positive Soft Tissue Sarcoma with Round and Spindle Histology: A Series of 4 Cases Highlighting the Pitfall of Mimicking Poorly Differentiated Synovial Sarcoma.Thursday, May 26, 2016
Li WS, Liao IC, Wen MC, Lan HH, Yu SC, Huang HY,
Histopathology. 26-May-2016
BCOR-CCNB3-positive sarcomas may primarily occur in soft tissues of adults and display PDSS-mimicking round and spindle cell histology with aggressive behaviour. Cyclin B3 is useful to select candidates for BCOR-CCNB3 molecular testing. This article is protected by copyright. All rights reserved.
A Tetra-Primer Amplification Refractory System Technique for the Cost-Effective and Novel Genotyping of Eight Single-Nucleotide Polymorphisms of the Catechol-O-Methyltransferase Gene.Thursday, May 26, 2016
Wang CK, Aleksic A, Xu MS, Procyshyn RM, Ross CJ, Vila-Rodriguez F, Ramos-Miguel A, Yan R, Honer WG, Barr AM,
Genetic testing and molecular biomarkers. 26-May-2016
Compared to traditional low-throughput methods that require post-PCR modification or high-throughput technologies that require sophisticated equipment, T-ARMS is a cost-effective and efficient assay that can be easily adapted by any standard molecular laboratory. This T-ARMS assay provides a practical and robust method for COMT SNP detection.
Quantitative MRI to understand Alzheimer's disease pathophysiology.Thursday, May 26, 2016
Bozzali M, Serra L, Cercignani M,
Current opinion in neurology. 25-May-2016
White matter abnormalities occur early in Alzheimer's disease, and might actively contribute to the progression of the disease. Functional and structural gray matter abnormalities parallel the white matter changes, and successful biomarkers are likely to be multiparametric.
A circulating miRNA assay as a first-line test for prostate cancer screening.Thursday, May 26, 2016
Sharova E, Grassi A, Marcer A, Ruggero K, Pinto F, Bassi P, Zanovello P, Zattoni F, D'Agostino DM, Iafrate M, Ciminale V,
British journal of cancer. 26-May-2016
Testing for circulating miR-106a/miR-130b and miR-106a/miR-223 ratios may reduce the costs and morbidity of unnecessary biopsies and is feasible for large-scale screening, as it requires measuring only three miRNAs.British Journal of Cancer advance online publication, 26 May 2016; doi:10.1038/bjc.2016.151 www.bjcancer.com.
Maxillary Implant-Supported Fixed Prosthesis: A Survey of Reviews and Key Variables for Treatment Planning.Thursday, May 26, 2016
Gallucci GO, Avrampou M, Taylor JC, Elpers J, Thalji G, Cooper LF,
The International journal of oral & maxillofacial implants. 26-5-2016
The existing literature demonstrated that maxillary edentulism may be treated successfully using alternative approaches involving four, six, or more implants. The procedural diagnostics, treatment, and maintenance for these different approaches all require advanced knowledge and careful communication among the therapeutic team. The prosthetic therapeutic success requires maintenance, repair, and possible multiple replacements within the patient's lifetime.
XPG Gene Polymorphisms and the Risk of Gastric Cardiac Adenocarcinoma.Thursday, May 26, 2016
Zhou RM, Niu CX, Wang N, Liu L, Huang X, Chen ZF, Huo XR, Hao YL, Li Y,
Genetic testing and molecular biomarkers. 26-May-2016
Our findings indicate that carriers of the T/T genotype should receive periodic upper gastrointestinal fiber tests to facilitate the early detection and early treatment of GCA.
Association of Polymorphisms in IL1β -511C>T, IL1RN 86 bp VNTR, and IL6 -174G>C Genes with Clinical Dengue Signs and Symptoms in Brazilian Dengue Patients.Thursday, May 26, 2016
Cansanção IF, Carmo AP, Leite RD, Rabenhorst SH,
Viral immunology. 26-May-2016
Dengue is an important infectious disease that has high morbidity and mortality rates in most tropical and subtropical areas of the world. The diversity of the clinical manifestations involved in the outcome of dengue virus infection is affected by the relationship between serotype/genotype of the virus, host immune status, host genetic background, and environmental factors. Polymorphisms in interleukin (IL) genes have been associated with risk of developing symptomatic dengue. This study aimed to determine the association of the single-nucleotide polymorphisms of IL1β -511C>T, IL1RN 86 bp VNTR, and IL6 -174G>C genes with the clinical features of 198 individuals admitted to the São José Infectious Diseases Hospital with suspected dengue infection. Dengue was confirmed in 118 of the patients. The control group consisted of 80 other individuals who had symptoms similar to dengue, but negative for that. A higher frequency of increased hematocrit (p = 0.009), leukopenia (p = 0.000007), neutropenia (p = 0.0004), lymphocytosis (p = 0.00001), monocytosis (p = 0.004), atypical lymphocytes (p = 0.03), and thrombocytopenia (p = 0.0000009) was observed in the dengue patients. Among the polymorphisms studied, only IL1β (-511C>T) was associated with dizziness, (p = 0.01), suggesting that IL1β may be related to hypotensive episodes and increased vascular permeability. These results pointed out the importance of the IL1β (-511C>T) polymorphism in the development of clinical symptoms of dengue symptomology.
Further understanding of the pathology of glioma: implications for the clinic.Thursday, May 26, 2016
Camelo-Piragua S, Kesari S,
Expert review of neurotherapeutics. 26-May-2016
In this paper we will review the major molecular changes associated with gliomas and their implications in diagnosis, prognosis, and opportunities in therapeutics. Expert Commentary: Based on current understanding, adult diffuse infiltrating gliomas can be molecularly divided into three to five major subgroups with different clinical outcomes. Pediatric gliomas harbor mutations for H3F3A, ATRX and DAXX but not IDH. Circumscribed low-grade gliomas tend to have BRAF alterations. Clinical behavior of ependymomas correlates more with location than WHO grading. Posterior fossa ependymomas tend to behave worse than their cerebral or spinal cord counterparts. However, with the posterior fossa ependymomas, two distinct subtypes have emerged molecularly.
Alkaline phosphatase activity in airway fluid obtained by tracheal wash from adult horses.Thursday, May 26, 2016
Viscardi V, Jorge ML, Silva KM, Sad EP, Fonseca AB, Alencar NX, Lessa DA,
Veterinary clinical pathology / American Society for Veterinary Clinical Pathology. 26-May-2016
Determining tracheal wash ALP activity is a simple, inexpensive and safe technique that can be used to facilitate the early diagnosis of equine respiratory disease, since it is higher in asymptomatic adult horses with a TW cytology profile consistent with LRT inflammation than in healthy adult horses with a normal TW cytology profile.
Novel oral anticoagulants in the management of coronary artery disease.Thursday, May 26, 2016
McMahon SR, Brummel-Ziedins K, Schneider DJ,
Coronary artery disease. 25-May-2016
Despite advances in interventional and pharmacologic therapy, survivors of myocardial infarction remain at an increased risk of subsequent cardiovascular events. Initial pharmacological management includes both platelet inhibition and parenteral anticoagulation, whereas long-term pharmacological therapy relies on antiplatelet therapy for prevention of thrombotic complications. Biomarkers showing ongoing thrombin generation after acute coronary syndromes suggest that anticoagulants may provide additional benefit in reducing cardiovascular events. We review the pharmacokinetics of novel anticoagulants, clinical trial results, the role of monitoring, and future directions for the use of novel oral anticoagulants in the treatment of coronary artery disease. Clinical trials have shown that long-term use of oral anticoagulants decreases the risk of cardiovascular events, but they do so at a cost of an increased risk of bleeding. Future studies will need to identify optimal treatment combinations for selected patients and conditions that address both the appropriate combination of therapy and the appropriate dosage of each agent when used in combination.
Whole Exome Sequencing Analysis Identifies Mutations in LRP5 in Indian Families with Familial Exudative Vitreoretinopathy.Thursday, May 26, 2016
Zhang L, Yang Y, Li S, Tai Z, Huang L, Liu Y, Zhu X, Di Y, Qu C, Jiang Z, Li Y, Zhang G, Kim R, Sundaresan P, Yang Z, Zhu X,
Genetic testing and molecular biomarkers. 26-May-2016
Our findings expand the mutational spectrum of FEVR in the Indian population and provide some guidelines in clinical diagnosis.
Threonine 89 Is an Important Residue of Profilin-1 That Is Phosphorylatable by Protein Kinase A.Thursday, May 26, 2016
Gau D, Veon W, Zeng X, Yates N, Shroff SG, Koes DR, Roy P,
PloS one. 26-5-2016
We identified several PKA phosphorylation sites of Pfn1 including Threonine 89 (T89), a novel site. Consistent with PKA's ability to phosphorylate Pfn1 in vitro, FSK stimulation increased the pool of the most negatively charged form of Pfn1 in HEK-293 cells which can be attenuated by PKA inhibitor H89. MDS predicted that T89 phosphorylation destabilizes an intramolecular interaction of Pfn1, potentially increasing its affinity for actin. The T89D phosphomimetic mutation of Pfn1 elicits several changes that are hallmarks of proteins folded into alternative three-dimensional conformations including detergent insolubility, protein aggregation and accelerated proteolysis, suggesting that T89 is a structurally important residue of Pfn1. Expression of T89D-Pfn1 induces actin:T89D-Pfn1 co-clusters and dramatically reduces overall actin polymerization in cells, indicating an actin-sequestering action of T89D-Pfn1. Finally, rendering T89 non-phosphorylatable causes a positive charge shift in the isoelectric profile of Pfn1 in a 2D gel electrophoresis analysis of cell extracts, a finding that is consistent with phosphorylation of a certain pool of intracellular Pfn1 on the T89 residue. In summary, we propose that T89 phosphorylation could have major functional consequences on Pfn1. This study paves the way for further investigation of the potential role of Pfn1 phosphorylation in PKA-mediated regulation of actin-dependent biological processes.
Temporal Expression of Peripheral Blood Leukocyte Biomarkers in a Macaca fascicularis Infection Model of Tuberculosis; Comparison with Human Datasets and Analysis with Parametric/Non-parametric Tools for Improved Diagnostic Biomarker Identification.Thursday, May 26, 2016
Javed S, Marsay L, Wareham A, Lewandowski KS, Williams A, Dennis MJ, Sharpe S, Vipond R, Silman N, Ball G, Kempsell KE,
PloS one. 26-5-2016
A temporal study of gene expression in peripheral blood leukocytes (PBLs) from a Mycobacterium tuberculosis primary, pulmonary challenge model Macaca fascicularis has been conducted. PBL samples were taken prior to challenge and at one, two, four and six weeks post-challenge and labelled, purified RNAs hybridised to Operon Human Genome AROS V4.0 slides. Data analyses revealed a large number of differentially regulated gene entities, which exhibited temporal profiles of expression across the time course study. Further data refinements identified groups of key markers showing group-specific expression patterns, with a substantial reprogramming event evident at the four to six week interval. Selected statistically-significant gene entities from this study and other immune and apoptotic markers were validated using qPCR, which confirmed many of the results obtained using microarray hybridisation. These showed evidence of a step-change in gene expression from an 'early' FOS-associated response, to a 'late' predominantly type I interferon-driven response, with coincident reduction of expression of other markers. Loss of T-cell-associate marker expression was observed in responsive animals, with concordant elevation of markers which may be associated with a myeloid suppressor cell phenotype e.g. CD163. The animals in the study were of different lineages and these Chinese and Mauritian cynomolgous macaque lines showed clear evidence of differing susceptibilities to Tuberculosis challenge. We determined a number of key differences in response profiles between the groups, particularly in expression of T-cell and apoptotic makers, amongst others. These have provided interesting insights into innate susceptibility related to different host `phenotypes. Using a combination of parametric and non-parametric artificial neural network analyses we have identified key genes and regulatory pathways which may be important in early and adaptive responses to TB. Using comparisons between data outputs of each analytical pipeline and comparisons with previously published Human TB datasets, we have delineated a subset of gene entities which may be of use for biomarker diagnostic test development.
Implementation of a High-Resolution Single-Nucleotide Polymorphism Array in Analyzing the Products of Conception.Thursday, May 26, 2016
Zhang H, Liu W, Chen M, Li Z, Sun X, Wang C,
Genetic testing and molecular biomarkers. 26-May-2016
This whole-genome high-resolution SNP array not only provides copy number information but also identifies the heterozygosity status, which facilitates the discovery of the novel genetic alterations associated with pregnancy failure and improves the management of subsequent pregnancies.
Association of MSX1 c.*6C > T Variant with Nonsyndromic Cleft Lip With or Without Cleft Palate in Turkish Patients.Thursday, May 26, 2016
Aslar Oner D, Tastan H,
Genetic testing and molecular biomarkers. 26-May-2016
Our identification of the c.*6C > T variant appears to be the first reported result associating variants of the MSX1 gene with nsCL/P patients.
Clinicopathological Features Associated With the Prognosis of Patients With Adrenal Cortical Carcinoma: Usefulness of the Ki-67 Index.Thursday, May 26, 2016
Choi YM, Kwon H, Jeon MJ, Sung TY, Hong SJ, Kim TY, Kim WB, Shong YK, Lee JL, Song DE, Kim WG,
Medicine. May-2016
Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Identification of clinicopathological features and molecular prognostic markers is important for the treatment of ACC. The aim of this study was to evaluate the clinical and histopathological features of ACC for prognostic prediction.This retrospective cohort study included 86 patients pathologically confirmed with ACC in a single center. Ki-67 index was evaluated by immunohistochemical staining of paraffin-embedded samples.The median age of the 86 (46 male and 40 female) patients with ACC was 49 years old (range 21-78), and the mean primary tumor size was 12.2 ± 5.2 cm. ACCs were incidentally found in 29 patients (34%). Three patients (3%) had bilateral ACC, and 59 patients (69%) had distant metastasis (37 synchronous and 22 metachronous). Twenty-four patients (28%) had symptoms from hormone excess or mass effects, and 25 patients (29%) had nonspecific symptoms. The 5-year survival rate for ACC was 28%. Sixty patients underwent surgical treatment, including 37 patients with an R0 resection. Tumor size, Ki-67 index, stage, and resection status were independently associated with overall survival by multivariate analysis. In patients with R0 resection, recurrence was significantly associated with larger tumor size and functional tumor.Tumor size, Ki-67 index, stage, and resection status are important prognostic indicators of survival in ACC patients.
Relaxin Level in Patients With Atrial Fibrillation and Association with Heart Failure Occurrence: A STROBE Compliant Article.Thursday, May 26, 2016
Zhou H, Qu X, Gao Z, Zheng G, Lin J, Su L, Huang Z, Li H, Huang W,
Medicine. May-2016
Atrial fibrillation (AF) is the most common arrhythmia requiring medical treatment and has been associated with enhanced atrial fibrosis and heart failure (HF). Relaxin (RLX), an antifibrosis and antiinflammatory peptide hormone, may be used to evaluate atrial fibrosis and is associated with HF occurrence in AF. We aimed to clarify the clinical significance of RLX level in patients with AF.We measured circulating levels of RLX and other fibrosis-related factors in 311 patients with sinus rhythm (SR; n = 116) or AF (n = 195). All discharged AF patients were followed up for the occurrence of HF for a mean of 6 months.Circulating levels of RLX were significantly different in patients with AF as compared with SR (P < 0.001), and in the subgroup analysis of AF. RLX level was correlated with left atrial diameter (LAD; R = 0.358, P < 0.001). Among followed up AF patients, on Kaplan-Meier curve analysis, patients with the third RLX tertile (T3) had a significantly higher HF rate than those with the 1st tertile (T1) (P = 0.002) and the cut-off value was 294.8 ng/L (area under the ROC curve [AUC] = 0.723). On multivariable analysis, HF occurrence with AF was associated with increased tertile of serum RLX level (odds ratio [OR] 2.659; confidence interval [95% CI] 1.434-4.930; P = 0.002).RLX is associated with fibrosis-related biomarkers and significantly elevated in AF. RLX was related to the HF occurrence in patients with AF.
Variants of the CDH1 (E-Cadherin) Gene Associated with Oral Clefts in the Thai Population.Thursday, May 26, 2016
Ittiwut R, Ittiwut C, Siriwan P, Chichareon V, Suphapeetiporn K, Shotelersuk V,
Genetic testing and molecular biomarkers. 26-May-2016
We found that nonsynonymous variants of CDH1 were associated with oral clefts in the Thai population.
MR Imaging Biomarkers to Monitor Early Response to Hypoxia-Activated Prodrug TH-302 in Pancreatic Cancer Xenografts.Thursday, May 26, 2016
Zhang X, Wojtkowiak JW, Martinez GV, Cornnell HH, Hart CP, Baker AF, Gillies R,
PloS one. 26-5-2016
TH-302 is a hypoxia-activated prodrug known to activate selectively under the hypoxic conditions commonly found in solid tumors. It is currently being evaluated in clinical trials, including two trials in Pancreatic Ductal Adenocarcinomas (PDAC). The current study was undertaken to evaluate imaging biomarkers for prediction and response monitoring of TH-302 efficacy in xenograft models of PDAC. Dynamic contrast-enhanced (DCE) and diffusion weighted (DW) magnetic resonance imaging (MRI) were used to monitor acute effects on tumor vasculature and cellularity, respectively. Three human PDAC xenografts with known differential responses to TH-302 were imaged prior to, and at 24 h and 48 hours following a single dose of TH-302 or vehicle to determine if imaging changes presaged changes in tumor volumes. DW-MRI was performed at five b-values to generate apparent diffusion coefficient of water (ADC) maps. For DCE-MRI, a standard clinically available contrast reagent, Gd-DTPA, was used to determine blood flow into the tumor region of interest. TH-302 induced a dramatic decrease in the DCE transfer constant (Ktrans) within 48 hours after treatment in the sensitive tumors, Hs766t and Mia PaCa-2, whereas TH-302 had no effect on the perfusion behavior of resistant SU.86.86 tumors. Tumor cellularity, estimated from ADC, was significantly increased 24 and 48 hours after treatment in Hs766t, but was not observed in the Mia PaCa-2 and SU.86.86 groups. Notably, growth inhibition of Hs766t was observed immediately (day 3) following initiation of treatment, but was not observed in MiaPaCa-2 tumors until 8 days after initiation of treatment. Based on these preclinical findings, DCE-MRI measures of vascular perfusion dynamics and ADC measures of cell density are suggested as potential TH-302 response biomarkers in clinical trials.
Debunking the Myth of the Genetic Superman.Thursday, May 26, 2016
Ehrlich GD,
Genetic testing and molecular biomarkers. 26-May-2016
Neuroendocrine liver metastases: Value of apparent diffusion coefficient and enhancement ratios for characterization of histopathologic grade.Thursday, May 26, 2016
Besa C, Ward S, Cui Y, Jajamovich G, Kim M, Taouli B,
Journal of magnetic resonance imaging : JMRI. 26-May-2016
ADC is a promising marker for characterization of histopathologic grade of NETLM. These results should be confirmed in a prospective study. J. Magn. Reson. Imaging 2016.
Hyperglycemic memory in metabolism and cancer.Thursday, May 26, 2016
Lee C, An D, Park J,
Hormone molecular biology and clinical investigation. 26-May-2016
Hyperglycemia is a hallmark of both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Recent evidence strongly suggests that prolonged exposure to hyperglycemia can epigenetically modify gene expression profiles in human cells and that this effect is sustained even after hyperglycemic control is therapeutically achieved; this phenomenon is called hyperglycemic memory. This metabolic memory effect contributes substantially to the pathology of various diabetic complications, such as diabetic retinopathy, hypertension, and diabetic nephropathy. Due to the metabolic memory in cells, diabetic patients suffer from various complications, even after hyperglycemia is controlled. With regard to this strong association between diabetes and cancer risk, cancer cells have emerged as key target cells of hyperglycemic memory in diabetic cancer patients. In this review, we will discuss the recent understandings of the molecular mechanisms underlying hyperglycemic memory in metabolism and cancer.
Steroidogenic Factor 1, Pit-1, and Adrenocorticotropic Hormone: A Rational Starting Place for the Immunohistochemical Characterization of Pituitary Adenoma.Thursday, May 26, 2016
McDonald WC, Banerji N, McDonald KN, Ho B, Macias V, Kajdacsy-Balla A,
Archives of pathology & laboratory medicine. 26-May-2016
-Comparison between diagnoses generated by our algorithm and the gold standard diagnoses showed excellent agreement. When compared with a commonly used panel using 6 IHC for anterior pituitary hormones plus IHC for a low-molecular-weight cytokeratin in certain tumors, our algorithm uses approximately one-third fewer IHC stains and detects gonadotroph adenomas with greater sensitivity.
Seventeen Novel Mutations in PCCA and PCCB Genes in Indian Propionic Acidemia Patients, and Their Outcomes.Thursday, May 26, 2016
Gupta D, Bijarnia-Mahay S, Kohli S, Saxena R, Puri RD, Shigematsu Y, Yamaguchi S, Sakamoto O, Gupta N, Kabra M, Thakur S, Deb R, Verma IC,
Genetic testing and molecular biomarkers. 26-May-2016
The spectrum of mutations in the PCCA and PCCB genes among Indians is distinct from other populations. The absence of a common mutation signifies the heterogeneity and admixture of various subpopulations. These findings also suggest that individuals of Indian origin may not benefit from the mutation-based "carrier screening panels" offered by many genetic laboratories.
Colony-stimulating factor 1 should be considered when studying the miR-28-5p-IL-34-macrophage feedback loop in hepatocellular carcinoma.Thursday, May 26, 2016
Zou Y, Li G, Wang L,
Hepatology (Baltimore, Md.). 26-May-2016
Rapid Classification and Identification of Microcystis aeruginosa Strains Using MALDI-TOF MS and Polygenetic Analysis.Thursday, May 26, 2016
Sun LW, Jiang WJ, Sato H, Kawachi M, Lu XW,
PloS one. 26-5-2016
Matrix-assisted laser desorption-ionization-time-of-flight mass spectrometry (MALDI-TOF MS) was used to establish a rapid, simple, and accurate method to differentiate among strains of Microcystis aeruginosa, one of the most prevalent types of bloom-forming cyanobacteria. M. aeruginosa NIES-843, for which a complete genome has been sequenced, was used to characterize ribosomal proteins as biomarkers and to optimize conditions for observing ribosomal proteins as major peaks in a given mass spectrum. Thirty-one of 52 ribosomal subunit proteins were detected and identified along the mass spectrum. Fifty-five strains of M. aeruginosa from different habitats were analyzed using MALDI-TOF MS; among these samples, different ribosomal protein types were observed. A polygenetic analysis was performed using an unweighted pair-group method with arithmetic means and different ribosomal protein types to classify the strains into five major clades. Two clades primarily contained toxic strains, and the other three clades contained exclusively non-toxic strains. This is the first study to differentiate cyanobacterial strains using MALDI-TOF MS.
Effect of ATM-111 (G>A) Polymorphism on Cancer Risk: A Meta-Analysis.Thursday, May 26, 2016
Huang S, Zhang Y, Zeng T,
Genetic testing and molecular biomarkers. 26-May-2016
This meta-analysis suggests that AA genotype of the ATM-111 gene (G>A) may be a risk factor for breast cancer and lung cancer, especially among nonsmokers, within the Chinese population.
Protein induced by vitamin K absence or antagonist-II (PIVKA-II) specifically increased in Italian hepatocellular carcinoma patients.Thursday, May 26, 2016
Viggiani V, Palombi S, Gennarini G, D'Ettorre G, De Vito C, Angeloni A, Frati L, Anastasi E,
Scandinavian journal of gastroenterology. 26-May-2016
The combination of the two biomarkers, evaluated by the ROC analysis, improved the specificity compared to a single marker. These data suggest that the combined analysis of the two markers could be a useful tool in clinical practice.
T1ρ and T2 -based characterization of regional variations in intervertebral discs to detect early degenerative changes.Thursday, May 26, 2016
Pandit P, Talbott JF, Pedoia V, Dillon W, Majumdar S,
Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 26-May-2016
Lower back pain is one of the main contributors to morbidity and chronic disability in the United States. Despite the significance of the problem, it is still not well understood. There is a clear need for objective, non-invasive biomarkers to localize specific pain generators and identify early stage changes to enable reliable diagnosis and treatment. In this study we focus on intervertebral disc degeneration as a source of lower back pain. Quantitative imaging markers T1ρ and T2 have been shown to be promising techniques for in vivo diagnosis of biochemical degeneration in discs due to their sensitivity to macromolecular changes in proteoglycan content and collagen integrity. We describe a semi-automated technique for quantifying T1ρ and T2 relaxation time maps in the nucleus pulposus (NP) and the annulus fibrosus (AF) of the lumbar intervertebral discs. Compositional changes within the NP and AF associated with degeneration occur much earlier than the visually observable structural changes. The proposed technique rigorously quantifies these biochemical changes taking into account subtle regional variations to allow interpretation of early degenerative changes that are difficult to interpret with traditional MRI techniques and clinical subjective grading scores. T1ρ and T2 relaxation times in the NP decrease with degenerative severity in the disc. Moreover, standard deviation and texture measurements of these values show sharper and more significant changes during early degeneration compared to later degenerative stages. Our results suggest that future prospective studies should include automated T1ρ and T2 metrics as early biomarkers for disc degeneration-induced lower back pain. This article is protected by copyright. All rights reserved.
Elevated Levels of Protein Disulfide Isomerase and Binding Immunoglobulin Protein Implicated in Spinal Cord Injury Paraplegia Patients with Pressure Ulcers.Thursday, May 26, 2016
Chen W, Liu J, Zhao L, Wang C, Li Z, Liu T,
Genetic testing and molecular biomarkers. 26-May-2016
ER stress proteins may be involved in the process of PU formation and healing; moreover, the levels of PDI and BIP were also associated with the severity of the PUs. Finally, we found that the PUSH scores can be used as a reference to evaluate PU severity and healing.
Interactions of Pri-miRNA-34b/c and TP53 Polymorphisms on the Risk of Osteoporosis.Thursday, May 26, 2016
Jia F, Sun R, Li J, Li Q, Chen G, Fu W,
Genetic testing and molecular biomarkers. 26-May-2016
The present findings indicate that pri-miR-34b/c rs4938723 and TP53 Arg72Pro polymorphisms may contribute to the risk of OP.
Old player, new partner: EGFRvIII and cytokine receptor signaling in glioblastoma.Thursday, May 26, 2016
Villa GR, Mischel PS,
Nature neuroscience. 26-May-2016
Serum Salusin-β Levels Are Correlated with Slow Coronary Flow.Thursday, May 26, 2016
Wang T, Dong AH, Cao HY,
Genetic testing and molecular biomarkers. 26-May-2016
Serum salusin-β levels were independently associated with SCF. Therefore, our findings implicate a potential role of salusin-β in the pathophysiology of SCF and provide insights on both risk stratification and modification in this patient population.
Diagnosis and Treatment of the Febrile ChildTuesday, April 05, 2016
Black RE, Laxminarayan R, Temmerman M, Walker N,
Herlihy JM, D’Acremont V, Hay Burgess DC, Hamer DH, Ho C, Cimon K, Weeks L, Mierzwinski-Urban M, Dunfield L, Soril L, Clement F, Jabr M,
Fever is one of the most common presenting symptoms of pediatric illnesses. Fever in children under age five years signifies systemic inflammation, typically in response to a viral, bacterial, parasitic, or less commonly, a noninfectious etiology. Patients’ ages and geographic settings can help direct the appropriate diagnostic approach and treatment, if local epidemiology is well understood. The combined proportion of deaths due to AIDS, diarrheal diseases, pertussis, tetanus, measles, meningitis/encephalitis, malaria, pneumonia and sepsis was 58.5 percent for children ages 1–59 months in 2015; it was 23.4 percent for neonates (Liu and others 2016, chapter 4 of this volume). Evidence regarding fever incidence is variable, with country-specific reports from cross-sectional surveys or weekly active case detection ranging from two to nine febrile episodes per child under age five years per year, a mean of 5.88 fever episodes per child under age five years per year (Gething and others 2010). National survey data from 42 Sub-Saharan African countries (excluding Botswana, Cabo Verde, Eritrea, and South Africa) were collected and analyzed for an estimated 655.6 million under-five fever episodes in 2007; 32 percent of these episodes occurred in 11 outpatient units in the Democratic Republic of Congo, Ethiopia, and Nigeria (Gething and others 2010). At the health facility and community levels, fever is by far the most common pediatric presenting symptom. Multiple studies summarized in table 8.1 highlight the most common presenting symptoms at the facility and community levels. Before the availability of affordable and accurate malaria rapid diagnostic tests (RDTs), most health care providers in malaria-endemic countries presumed that malaria was the cause of fever; the proportion of fevers due to malaria was very high in the early 1990s, and the priority was to reduce malaria mortality by any means. The 1997 World Health Organization’s (WHO’s) initial Integrated Management of Childhood Illness (IMCI) guidelines recommended the use of injectable antimalarials and antibiotics in children in malaria- endemic areas who were suspected of having severe disease with the presence of danger signs (Gove 1997; Communicable Disease Surveillance and Response Vaccines and Biologicals 1997). Until 2010, the first edition of the WHO guidelines for the treatment of malaria recommended empiric, oral, antimalarial therapy for fever without other source in children under age five years living in malaria-endemic areas (WHO 2006). The decline of malaria incidence; rise of antimicrobial resistance; and availability of accurate, low-cost, point-of-care diagnostics have challenged the effectiveness of the presumptive treatment of febrile illnesses and reopened the discussion of the most accurate and cost-effective approaches for fever diagnosis and treatment. There are settings with very high malaria transmission and limited availability of diagnostic test where presumptive treatment would be most practical and cost-effective (DCP3 volume 6, Babigumira, forthcoming). In 2009, experts debated whether sufficient information was available to abandon presumptive treatment guidelines and move to an emphasis on diagnosis before treatment (D’Acremont, Lengeler, and Genton 2007; D’Acremont and others 2009; English and others 2009). Mounting evidence demonstrated the decline of Plasmodium falciparum infections in response to intense national and multinational initiatives to control malaria. In 2012 more than US$2.5 billion was invested from global partners, including the Global Fund to Fight AIDS, Tuberculosis and Malaria; the World Bank Malaria Booster Program; the U.S. President’s Malaria Initiative; the Bill & Melinda Gates Foundation’s Malaria Control and Evaluation Partnership in Africa; and the Roll Back Malaria Partnership (D’Acremont, Lengeler, and Genton 2010; Feachem and others 2010; Leslie and others 2012; WHO 2013a). Countries with previously defined high-transmission regions are reporting decreasing malaria incidence, making the management of nonmalarial fevers critically important (Feachem and others 2010; WHO 2013a; Hertz and others 2013; Ishengoma and others 2011). In 2010, the WHO revised its fever treatment guidelines to recommend antimalarial treatment only for those with a positive malaria test result, either point-of-care or microscopy (WHO 2010a). This new strategy is being implemented in the public sector in most Sub-Saharan African countries (Bastiaens and others 2011). However, many patients first present for care in the informal private sector, and more research is needed to better understand treatment decision making in this context and how to reduce overuse of antimicrobials and ensure appropriate care. The epidemiology of pediatric febrile illness is undoubtedly shifting; understanding the etiology of nonmalarial fevers in each context is the logical next step to improve pediatric clinical outcomes of other treatable serious febrile illnesses, such as pneumonia, sepsis, bacterial meningitis, enteric fever, rickettsioses, and influenza. Given rampant and expanding antimicrobial drug resistance globally, care must be taken to use antibiotics only when indicated and to develop careful guidelines when resources are limited. Present guidelines are based on clinical features that are unfortunately poorly predictive of the diseases causing fever. Low-cost, accurate, point-of-care diagnostics are needed to determine which children can benefit from antibacterial therapies to guide the most effective use of antibiotics. This chapter discusses the evidence that informs current etiologies of fever, stratified by regional geography. It presents the clinical presentation, diagnosis, and treatment of the most common diseases, with special considerations for certain age groups, the burden of disease for different conditions, classification and treatment strategies, and a review of available diagnostic tests. In addition, different health systems approaches to diagnosis and treatment of the febrile child at the community and health-facility levels are discussed, as is the evidence base for WHO-sponsored approaches such as IMCI and Integrated Community Case Management (iCCM). Fever in adults and RDT use for malaria are discussed further in volume 6 (Holmes, Bertozzi, Bloom, Jha, and Nugent, forthcoming).
Endoscopic ablation is a cost-effective cancer preventative therapy in patients with Barrett's esophagus who have elevated genomic instability.Thursday, May 26, 2016
Das A, Callenberg KM, Styn MA, Jackson SA,
Endoscopy international open. May-2016
The use of ML to stratify patients with NDBE by risk was the most cost-effective strategy for preventive EAC treatment. Targeting ablation toward patients with high ML presents an opportunity for a paradigm shift in the management of NDBE.
High intensity interval training in the heat enhances exercise-induced lipid peroxidation, but prevents protein oxidation in physically active men.Thursday, May 26, 2016
Souza-Silva AA, Moreira E, de Melo-Marins D, Schöler CM, de Bittencourt PI, Laitano O,
Temperature (Austin, Tex.). 15-04-2016
Aim. The purpose of this study was to determine the response of circulating markers of lipid and protein oxidation following an incremental test to exhaustion before and after 4 weeks of high-intensity interval training performed in the heat. Methods. To address this question, 16 physically active men (age = 23 ± 2 years; body mass = 73 ± 12 kg; height = 173 ± 6 cm; % body fat = 12.5 ± 6 %; body mass index = 24 ± 4 kg/m(2)) were allocated into 2 groups: control group (n = 8) performing high-intensity interval training at 22°C, 55% relative humidity and heat group (n = 8) training under 35°C, 55% relative humidity. Both groups performed high-intensity interval training 3 times per week for 4 consecutive weeks, accumulating a total of 12 training sessions. Before and after the completion of 4 weeks of high-intensity interval training, participants performed an incremental cycling test until exhaustion under temperate environment (22°C, 55% relative humidity) where blood samples were collected after the test for determination of exercise-induced changes in oxidative damage biomarkers (thiobarbituric acid reactive species and protein carbonyls). Results. When high-intensity interval training was performed under control conditions, there was an increase in protein carbonyls (p < 0.05) following the incremental test to exhaustion with no changes in thiobarbituric acid reactive species. Conversely, high-intensity interval training performed in high environmental temperature enhanced the incremental exercise-induced increases in thiobarbituric acid reactive species (p < 0.05) with no changes in protein carbonyls. Conclusion. In conclusion, 4 weeks of high-intensity interval training performed in the heat enhances exercise-induced lipid peroxidation, but prevents protein oxidation following a maximal incremental exercise in healthy active men.
Temperature and toxic Tau in Alzheimer's disease: new insights.Thursday, May 26, 2016
Carrettiero DC, Santiago FE, Motzko-Soares AC, Almeida MC,
Temperature (Austin, Tex.). 29-12-2015
Alzheimer's disease (AD), the most common dementia in the elderly, is characterized by cognitive impairment and severe autonomic symptoms such as disturbance in core body temperature (Tc), which may be predictors or early events in AD onset. Inclusions of phosphorylated Tau (p-Tau) are a hallmark of AD and other neurodegenerative disorders called "Tauopathies." Animal and human studies show that anesthesia augments p-Tau levels through reduction of Tc, with implications for AD. Additionally, hypothermia impairs memory and cognitive function. The molecular networks related to Tc that are associated with AD remain poorly characterized. Under physiological conditions, Tau binds microtubules, promoting their assembly and stability. The dynamically regulated Tau-microtubule interaction plays an important role in structural remodeling of the cytoskeleton, having important functions in neuronal plasticity and memory in the hippocampus. Hypothermia-induced increases in p-Tau levels are significant, with an 80% increase for each degree Celsius below normothermic conditions. Although the effects of temperature on Tau phosphorylation are evident, its effects on p-Tau degradation remain poorly understoodWe review information concerning the mechanisms of Tau regulation of neuron plasticity via its effects on microtubule dynamics, with focus on pathways regulating the abundance of phosphorylated Tau species.  We highlight the effects of temperature on molecular mechanisms influencing the development of Tau-related diseases. Specifically, we argue that cold might preferentially affects central nervous system structures that are highly reliant upon plasticity, such as the hippocampus, and that the effect of cold on Tau phosphorylation may constitute a pathology-initiating trigger leading to neurodegeneration.
Feeling hot, feeling cold: TRP channels-a great story unfolds.Thursday, May 26, 2016
Vetter I, Kym PR, Szallasi A,
Temperature (Austin, Tex.). 19-10-2015
This editorial is about the roles that TRP channels play in heat and cold sensation and body temperature regulation. These roles may be exploited for therapeutic purposes (indeed, drugs targeting TRPV1, TRPA1 and TRPM8 channels are currently undergoing clinical trials for indications that range from pain through chronic cough and overactive bladder to cancer) or, conversely, may limit drug development (for example, several TRPV1 antagonists were withdrawn from clinical trials due to the hyperthermic reaction that they caused). In the future, modulation of thermosensitive TRP channels may ultimately find application in the treatment not only of pain, but also itch, stroke, asthma, and metabolic disorders. Of the multitude of targets involved in temperature sensation and body temperature regulation, why TRP channels? And why now?
Screening for Anti-Cancer Compounds in Marine Organisms in Oman.Thursday, May 26, 2016
Dobretsov S, Tamimi Y, Al-Kindi MA, Burney I,
Sultan Qaboos University medical journal. May-2016
Some Omani marine organisms showed high anti-cancer potential. The efficacy, specificity and molecular mechanisms of anti-cancer compounds from Omani marine organisms on various cancer models should be investigated in future in vitro and in vivo studies.
Hepatitis E Virus Circulation in Italy: Phylogenetic and Evolutionary Analysis.Thursday, May 26, 2016
Montesano C, Giovanetti M, Ciotti M, Cella E, Lo Presti A, Grifoni A, Zehender G, Angeletti S, Ciccozzi M,
Hepatitis monthly. Mar-2016
This study provides support for the hypothesis that humans are probably infected after contact with swine sources. The findings emphasize the importance of checking the country of origin of swine and of improving sanitary control measures from the veterinary standpoint to prevent the spread of HEV infection in Italy.
Perspectives for Monocyte/Macrophage-Based Diagnostics of Chronic Inflammation.Thursday, May 26, 2016
Kzhyshkowska J, Gudima A, Moganti K, Gratchev A, Orekhov A,
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur̈ Transfusionsmedizin und Immunham̈atologie. Mar-2016
Low-grade chronic inflammation underlies the development of the most dangerous cardiometabolic disorders including type 2 diabetes and its vascular complications. In contrast to acute inflammation induced by bacteria and viruses, chronic inflammation can be driven by abnormal reaction to endogenous factors, including Th2 cytokines, metabolic factors like advanced glycation end products (AGEs), modified lipoproteins, or hyperglycemia. The key innate immune cells that recognize these factors in blood circulation are monocytes. Inflammatory programming of monocytes which migrate into tissues can, in turn, result into generation of tissue macrophages with pathological functions. Therefore, determination of the molecular and functional phenotype of circulating monocytes is a very promising diagnostic tool for the identification of hidden inflammation, which can precede the development of the pathology. Here we propose a new test system for the identification of inflammatory programming of monocytes: surface biomarkers and ex vivo functional system. We summarize the current knowledge about surface biomarkers for monocyte subsets, including CD16, CCR2, CX3CR1, CD64, stabilin-1 and CD36, and their association with inflammatory human disorders. Furthermore, we present the design of an ex vivo monocyte-based test system with minimal set of parameters as a potential diagnostic tool for the identification of personalized inflammatory responses.
Innate Immune System for Diagnostics and Therapy: Progress in Fundamental Knowledge and Clinical Application.Thursday, May 26, 2016
Kzhyshkowska J, Bugert P,
Transfusion medicine and hemotherapy : offizielles Organ der Deutschen Gesellschaft fur̈ Transfusionsmedizin und Immunham̈atologie. Mar-2016
Screening for Fabry Disease by Urinary Globotriaosylceramide Isoforms Measurement in Patients with Left Ventricular Hypertrophy.Thursday, May 26, 2016
Gaggl M, Lajic N, Heinze G, Voigtländer T, Sunder-Plassmann R, Paschke E, Fauler G, Sunder-Plassmann G, Mundigler G,
International journal of medical sciences. 2016
Measurement of urinary Gb3 isoforms in a non-selected cohort with LVH was unable to identify new cases of FD. False positive results may be prevented by more restricted inclusion criteria and may improve diagnostic accuracy of this method.
Secretion of N- and O-linked Glycoproteins from 4T1 Murine Mammary Carcinoma Cells.Thursday, May 26, 2016
Phang WM, Tan AA, Gopinath SC, Hashim OH, Kiew LV, Chen Y,
International journal of medical sciences. 2016
Breast cancer is one of the most common cancers that affect women globally and accounts for ~23% of all cancers diagnosed in women. Breast cancer is also one of the leading causes of death primarily due to late stage diagnoses and a lack of effective treatments. Therefore, discovering protein expression biomarkers is mandatory for early detection and thus, critical for successful therapy. Two-dimensional electrophoresis (2D-E) coupled with lectin-based analysis followed by mass spectrometry were applied to identify potential biomarkers in the secretions of a murine mammary carcinoma cell line. Comparisons of the protein profiles of the murine 4T1 mammary carcinoma cell line and a normal murine MM3MG mammary cell line indicated that cadherin-1 (CDH), collagenase 3 (MMP-13), Viral envelope protein G7e (VEP), Gag protein (GAG) and Hypothetical protein LOC433182 (LOC) were uniquely expressed by the 4T1 cells, and pigment epithelium-derived factor (PEDF) was exclusively secreted by the MM3MG cells. Further analysis by a lectin-based study revealed that aberrant O-glycosylated CDH, N-glycosylated MMP-13 and LOC were present in the 4T1 medium. These differentially expressed N- and O-linked glycoprotein candidates, which were identified by combining lectin-based analysis with 2D-E, could serve as potential diagnostic and prognostic markers for breast cancer.
Targeted Radionuclide Therapy: Practical Applications and Future Prospects.Thursday, May 26, 2016
Zukotynski K, Jadvar H, Capala J, Fahey F,
Biomarkers in cancer. 2016
In recent years, there has been a proliferation in the development of targeted radionuclide cancer therapy. It is now possible to use baseline clinical and imaging assessments to determine the most effective therapy and to tailor this therapy during the course of treatment based on radiation dosimetry and tumor response. Although this personalized approach to medicine has the advantage of maximizing therapeutic effect while limiting toxicity, it can be challenging to implement and expensive. Further, in order to use targeted radionuclide therapy effectively, there is a need for multidisciplinary awareness, education, and collaboration across the scientific, industrial, and medical communities. Even more important, there is a growing understanding that combining radiopharmaceuticals with conventional treatment such as chemotherapy and external beam radiotherapy may limit patient morbidity while improving survival. Developments in radiopharmaceuticals as biomarkers capable of predicting therapeutic response and targeting disease are playing a central role in medical research. Adoption of a practical approach to manufacturing and delivering radiopharmaceuticals, assessing patient eligibility, optimizing post-therapy follow-up, and addressing reimbursement issues will be essential for their success.
miR-125b inhibited epithelial-mesenchymal transition of triple-negative breast cancer by targeting MAP2K7.Thursday, May 26, 2016
Hong L, Pan F, Jiang H, Zhang L, Liu Y, Cai C, Hua C, Luo X, Sun J, Chen Z,
OncoTargets and therapy. 2016
MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis and tumor progression. Among the differentially expressed miRNAs in breast cancer, miR-125b was revealed to be deregulated and associated with poor prognosis and chemoresistance in triple-negative breast cancer (TNBC), but the mechanism is still unknown. In our study, we showed downregulated expression of miR-125b in TNBC tissues and decreased migration and invasion in miR-125b-expressing Hs578T cells. MAP2K7 was then detected to be a novel target of miR-125b, and downregulation of MAP2K7 by miR-125b was similar to transient knockdown of MAP2K7 which hindered epithelial-mesenchymal transition (EMT) of Hs578T cells. Upregulation of MAP2K7 in miR-125b-overexpressing Hs578T cells partly rescued the migration and invasion suppression of miR-125b. Furthermore, MAP2K7 was overexpressed in TNBC samples compared with normal tissues and negatively correlated with miR-125b expression. In light of these findings, miR-125b emerged as a tumor suppressor in TNBC by targeting MAP2K7 to inhibit EMT.
Oncolytic viruses as immunotherapy: progress and remaining challenges.Thursday, May 26, 2016
Aurelian L,
OncoTargets and therapy. 2016
Oncolytic viruses (OVs) comprise an emerging cancer therapeutic modality whose activity involves both direct tumor cell lysis and the induction of immunogenic cell death (ICD). Cellular proteins released from the OV-lysed tumor cells, known as damage-associated molecular patterns and tumor-associated antigens, activate dendritic cells and elicit adaptive antitumor immunity. Interaction with the innate immune system and the development of long-lasting immune memory also contribute to OV-induced cell death. The degree to which the ICD component contributes to the clinical efficacy of OV therapy is still unclear. Modulation of a range of immune interactions may be beneficial or detrimental in nature and the interactions depend on the specific tumor, the site and extent of the disease, the immunosuppressive tumor microenvironment, the OV platform, the dose, time, and delivery conditions, as well as individual patient responses. To enhance the contribution of ICD, OVs have been engineered to express immunostimulatory genes and strategies have been developed to combine OV therapy with chemo- and immune-based therapeutic regimens. However, these approaches carry the risk that they may also be tolerogenic depending on their levels and the presence of other cytokines, their direct antiviral effects, and the timing and conditions of their expression. The contribution of autophagy to adaptive immunity, the ability of the OVs to kill cancer stem cells, and the patient's baseline immune status are additional considerations. This review focuses on the complex and as yet poorly understood balancing act that dictates the outcome of OV therapy. We summarize current understanding of the OVs' function in eliciting antitumor immunity and its relationship to therapeutic efficacy. Also discussed are the criteria involved in restraining antiviral immune responses and minimizing pathology while promoting antitumor immunity to override immune tolerance.
Multigene Testing in Localized Prostate Cancer.Thursday, May 26, 2016
Ross AE,
Journal of the National Comprehensive Cancer Network : JNCCN. May-2016
Currently, there are several commercially available multigene tests for risk stratification in prostate cancer. These tests have been validated retrospectively; however, prospective studies are needed to fully establish their clinical roles. In some cases, molecular studies may add value, and updated NCCN Guidelines recommend "consideration" of molecular tests under certain circumstances, such as to help ascertain the likelihood of death from conservative management, of biochemical progression after radical prostatectomy or external-beam therapy, and of developing metastasis after radical prostatectomy or salvage radiotherapy.
Histological outcomes and predictive value of faecal markers in moderately to severely active Ulcerative Colitis patients receiving infliximab.Thursday, May 26, 2016
Magro F, Lopes SI, Lopes J, Portela F, Cotter J, Lopes S, Moreira MJ, Lago P, Peixe P, Albuquerque A, Rodrigues S, Silva MR, Monteiro P, Lopes C, Monteiro L, Macedo G, Veloso L, Camila C, Afonso J, Geboes K, Carneiro F,
Journal of Crohn's & colitis. 25-May-2016
Infliximab was able to induce histological remission. There was a good agreement between histology and faecal biomarkers. Faecal calprotectin and lactoferrin were good predictors of histological remission. Our data support inclusion of histology as a treatment target complementary to endoscopy in clinical trials when evaluating therapeutic response in UC.Clinicaltrials.gov Identifier: NCT01408810.
Stage-specific proteomes from Onchocerca ochengi, sister species of the human river blindness parasite, uncover adaptations to a nodular lifestyle.Thursday, May 26, 2016
Armstrong SD, Xia D, Bah GS, Krishna R, Ngangyung HF, LaCourse EJ, McSorley HJ, Kengne-Ouafo JA, Chounna-Ndongmo PW, Wanji S, Enyong PA, Taylor DW, Blaxter ML, Wastling JM, Tanya VN, Makepeace BL,
Molecular & cellular proteomics : MCP. 25-May-2016
In spite of 40 years of control efforts, onchocerciasis (river blindness) remains one of the most important neglected tropical diseases, with 17 million people affected. The aetiological agent, Onchocerca volvulus, is a filarial nematode with a complex lifecycle involving several distinct stages in the definitive host and blackfly vector. The challenges of obtaining sufficient material have prevented high-throughput studies and the development of novel strategies for disease control and diagnosis. Here, we utilise the closest relative of O. volvulus, the bovine parasite Onchocerca ochengi, to compare stage-specific proteomes and host-parasite interactions within the secretome. We identified a total of 4,260 unique O. ochengi proteins from adult males and females, infective larvae, intrauterine microfilariae, and fluid from intradermal nodules. In addition, 135 proteins were detected from the obligate Wolbachia symbiont. Observed protein families that were enriched in all whole body extracts relative to the complete search database included immunoglobulin-domain proteins, whereas redox and detoxification enzymes and proteins involved in intracellular transport displayed stage-specific overrepresentation. Unexpectedly, the larval stages exhibited enrichment for several mitochondrial-related protein families, including members of peptidase family M16 and proteins which mediate mitochondrial fission and fusion. Quantification of proteins across the lifecycle using the Hi-3 approach supported these qualitative analyses. In nodule fluid, we identified 94 O. ochengi secreted proteins, including homologs of transforming growth factor-β and a second member of a novel 6-ShK toxin-domain family, which was originally identified from a model filarial nematode (Litomosoides sigmodontis). Strikingly, the 498 bovine proteins identified in nodule fluid were strongly dominated by antimicrobial proteins, especially cathelicidins. This first high-throughput analysis of an Onchocerca spp. proteome across the lifecycle highlights its profound complexity and emphasises the extremely close relationship between O. ochengi and O. volvulus The insights provided here provide new candidates for vaccine development, drug targeting and diagnostic biomarkers.
Release of infectious hepatitis C virus from Huh7 cells occurs via a trans-Golgi network to endosome pathway independent of VLDL.Thursday, May 26, 2016
Mankouri J, Walter C, Stewart H, Bentham M, Park WS, Heo WD, Fukuda M, Griffin S, Harris M,
Journal of virology. 25-May-2016
The mechanisms by which infectious hepatitis C virus particles are assembled and released from the cell are poorly understood. We show that the virus subverts host cell trafficking pathways to effect the release of virus particles and disrupts the structure of the Golgi apparatus, a key cellular organelle involved in secretion. In addition we demonstrate that the mechanisms used by the virus to exit the cell are distinct from those used by the cell to release lipoproteins, suggesting that the virus effects an unique modification to cellular trafficking pathways.
MAVS expressed by hematopoietic cells is critical for control of West Nile virus infection and pathogenesis.Thursday, May 26, 2016
Zhao J, Vijay R, Zhao J, Gale M, Diamond MS, Perlman S,
Journal of virology. 25-May-2016
West Nile virus (WNV) is the most important cause of mosquito-transmitted encephalitis in the United States. The innate immune response is known to be critical for protection in infected mice. Here, we show that expression of MAVS, a key adaptor molecule in the RIG-I-like receptor RNA sensing pathway, in hematopoietic cells is critical for protection from lethal WNV infection. In the absence of MAVS, there is a massive infiltration of myeloid cells and virus-specific T cells into the brain and over-exuberant production of pro-inflammatory cytokines. These results demonstrate the important role that MAVS expression in hematopoietic cells has in regulating the inflammatory response in the WNV-infected brain.
The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm.Thursday, May 26, 2016
Alvau A, Battistone MA, Gervasi MG, Navarrete FA, Xu X, Sánchez-Cárdenas C, De la Vega-Beltran JL, Da Ros VG, Greer P, Darszon A, Krapf D, Salicioni AM, Cuasnicu P, Visconti PE,
Development (Cambridge, England). 25-May-2016
Sperm capacitation is required for fertilization. At the molecular level, this process is associated with a fast activation of protein kinase A. Downstream of this event, capacitating conditions lead to an increase in tyrosine phosphorylation. The identity of the tyrosine kinase(s) mediating this process has not been conclusively demonstrated. Recent experiments using stallion and human sperm have suggested a role for PYK2 based on the use of small molecule inhibitors directed against this kinase. However, critical loss-of-function experiments have not been reported. Here, we used both pharmacological inhibitors and genetically modified mice models to investigate the identity of the tyrosine kinase(s) mediating the increase in tyrosine phosphorylation in mouse sperm. Similar to stallion and human, PF431396 blocks the capacitation-associated increase in tyrosine phosphorylation. Yet, sperm from Pyk2(-/-) mice displayed normal increase in tyrosine phosphorylation, implying that PYK2 is not responsible for this phosphorylation process. Here we show that PF431396 can also inhibit FER, a tyrosine kinase known to be present in sperm. Sperm from mice targeted with a kinase inactivating mutation in Fer failed to undergo capacitation-associated increases in tyrosine phosphorylation. While these mice are fertile, their sperm displayed a reduced ability to fertilize metaphase-II arrested eggs in vitro.
Differences in iron and manganese concentration may confound the measurement of myelin from R1 and R2 relaxation rates in studies of dysmyelination.Thursday, May 26, 2016
Desmond KL, Al-Ebraheem A, Janik R, Oakden W, Kwiecien JM, Dabrowski W, Rola R, Geraki K, Farquharson MJ, Stanisz GJ, Bock NA,
NMR in biomedicine. 26-May-2016
A model of dysmyelination, the Long Evans Shaker (les) rat, was used to study the contribution of myelin to MR tissue properties in white matter. A large region of white matter was identified in the deep cerebellum and was used for measurements of the MR relaxation rate constants, R1  = 1/T1 and R2  = 1/T2 , at 7 T. In this study, R1 of the les deep cerebellar white matter was found to be 0.55 ± 0.08 s (-1) and R2 was found to be 15 ± 1 s(-1) , revealing significantly lower R1 and R2 in les white matter relative to wild-type (wt: R1  = 0.69 ± 0.05 s(-1) and R2  = 18 ± 1 s(-1) ). These deviated from the expected ΔR1 and ΔR2 values, given a complete lack of myelin in the les white matter, derived from the literature using values of myelin relaxivity, and we suspect that metals could play a significant role. The absolute concentrations of the paramagnetic transition metals iron (Fe) and manganese (Mn) were measured by a micro-synchrotron radiation X-ray fluorescence (μSRXRF) technique, with significantly greater Fe and Mn in les white matter than in wt (in units of μg [metal]/g [wet weight tissue]: les: Fe concentration,19 ± 1; Mn concentration, 0.71 ± 0.04; wt: Fe concentration,10 ± 1; Mn concentration, 0.47 ± 0.04). These changes in Fe and Mn could explain the deviations in R1 and R2 from the expected values in white matter. Although it was found that the influence of myelin still dominates R1 and R2 in wt rats, there were non-negligible changes in the contribution of the metals to relaxation. Although there are already problems with the estimation of myelin from R1 and R2 changes in disease models with pathology that also affects the relaxation rate constants, this study points to a specific pitfall in the estimation of changes in myelin in diseases or models with disrupted concentrations of paramagnetic transition metals. Copyright © 2016 John Wiley & Sons, Ltd.
Validation of a method for noninvasive prenatal testing for fetal aneuploidies risk and considerations for its introduction in the Public Health System.Thursday, May 26, 2016
Gerundino F, Giachini C, Contini E, Benelli M, Marseglia G, Giuliani C, Marin F, Nannetti G, Lisi E, Sbernini F, Periti E, Cordisco A, Colosi E, D'ambrosio V, Mazzi M, Rossi M, Staderini L, Minuti B, Pelo E, Cicatiello R, Maruotti GM, Sglavo G, Conti A, Frusconi S, Pescucci C, Torricelli F,
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians. 26-May-2016
The overall test accuracy allowed us introducing NIPT for T21, T18 and T13 as a clinical service for pregnant women after 10 + 4 weeks of gestation. Sex chromosome aneuploidy assessment needs further validation due to the limited number of aneuploid cases in this study.
Evaluation of the methods to identify patients who may benefit from PARP inhibitor use.Thursday, May 26, 2016
Lim D, Ngeow J,
Endocrine-related cancer. 25-May-2016
The effectiveness of Poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germline and/or somatic) as part of the selection criteria. Mounting evidence however, suggest that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway. Advances in molecular profiling techniques together with increased research efforts have led to a better understanding of the molecular aberrations underlying this BRCA-like phenotype and helped broaden the concept of BRCAness. Hence, it is likely that the list of predictive biomarkers for PARPi therapy will increase in future. There is currently no gold standard method of testing for PARPi response and no universal guidelines are in place on how to incorporate biomarker testing into routine clinical diagnostics. In this review, we explore the concept of BRCAness and highlight the different methods that have been used to identify patients who may benefit from the use of these anticancer agents. The identification of predictive biomarkers is crucial in improving patient selection and expanding the clinical applications of PARPi therapy.
Continuous Cardiac Monitoring Around Atrial Fibrillation Ablation: Insights on Clinical Classifications and Endpoints.Thursday, May 26, 2016
Dekker LR, Pokushalov E, Sanders P, Lindborg KA, Maus B, Pürerfellner H,
Pacing and clinical electrophysiology : PACE. 26-May-2016
ICM monitoring to determine AF burden pre- and post-AF ablation may have clinical utility for management of ablation candidates through more accurate AF classification and guiding treatment decisions. This article is protected by copyright. All rights reserved.
Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentration and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone.Thursday, May 26, 2016
Adamczyk-Sowa M, Sowa P, Adamczyk J, Niedziela N, Misiolek H, Owczarek M, Zwirska-Korczala K,
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. Apr-2016
In all MS patient groups melatonin application resulted in significant decrease in plasma LHP concentrations. Plasma homocysteine concentration was similar in healthy people, RRMS-pretreated, RRMS-INF-beta and SP/PP-MS-mitoxantrone groups. However, in the RRMS-relapse group plasma levels of homocysteine were significantly higher compared to the RRMS-pretreated group. There were no significant differences in plasma homocysteine concentration in the studied groups before and after melatonin application. The fatigue score was significantly lower in RRMS pretreated group compared to RRMS-INF-beta and SP/PP MS-mitoxantrone treated patients. Plasma lipid hydroxyperoxides could be potential biochemical chronic fatigue syndrome biomarker in MS patients and homocysteine could be a potential marker of acute phase of MS. Melatonin exerts beneficial effects in MS patients based on its' proved antioxidative properties.
A Multiplex Electrochemical Biosensor for Bloodstream Infection Diagnosis.Thursday, May 26, 2016
Gao J, Jeffries L, Mach KE, Craft DW, Thomas NJ, Gau V, Liao JC, Wong PK,
Journal of laboratory automation. 25-May-2016
Accurate and timely detection of bacterial pathogens will improve the clinical management of infections. Herein, we demonstrate an electrochemical biosensor that directly detects bacteria in human blood samples, resulting in the rapid diagnosis of a bloodstream infection. The multiplex biosensor detects the species-specific sequences of the 16S ribosomal RNA of bacteria for pathogen identification in physiological samples without preamplification. The analytical performance characteristics of the biosensor, including the limit of detection and probe cross-reactivity, are evaluated systematically. The feasibility of the biosensor for a diagnosis of a bloodstream infection is demonstrated by identifying bacterial clinical isolates spiked in whole blood and blood culture samples that were tested positive for bacteria. The electrochemical biosensor correctly identifies all the species in the samples with 100% concordance to microbiological analysis.
Comparison of Cystatin C and NGAL in Early Diagnosis of Acute Kidney Injury After Heart Transplantation.Thursday, May 26, 2016
Hošková L, Franekova J, Málek I, Kautzner J, Szárszoi O, Jabor A, Pinďák M, Viklický O, Melenovský V,
Annals of transplantation. 2016
BACKGROUND Acute kidney injury (AKI) is a risk factor for adverse hospital outcomes in recipients of a heart transplantation (HTx). Timely recognition of AKI is crucial for the initiation of proper treatment. We hypothesized that serum or urine biomarkers can predict AKI. MATERIAL AND METHODS In this prospective study we evaluated 117 consecutive patients after HTx. AKI was defined as an increase of the serum creatinine level by ≥50% or a worsening of the renal function requiring renal replacement therapy during the first post-HTx week. We serially sampled serum cystatin C (S-cystatin C) as a marker of glomerular filtration and urinary neutrophil gelatinase-associated lipocalin (U-NGAL) as a marker of tubular damage. RESULTS A cohort of 30 patients (25.6%) fulfilled the criteria of AKI. S-cystatin C allowed the earliest separation between the AKI and non-AKI groups, with a significant difference present as soon as 3 h after surgery and it persisted on days 7, 10, and 30. The increase in S-cystatin C preceded the serum creatinine elevation by 4 days. In a multivariate analysis, S-cystatin C >1.6 mg/L at 3 h after HTx predicted AKI with OR 4.3 (95% CI: 1.6-11.5). U-NGAL was significantly higher at day 3 in the AKI group (p=0.003) and elevated S-cystatin C (≥2.54 mg/L on day 7) could predict 1-year mortality in these HTx recipients. CONCLUSIONS Our study showed that the measurement of S-cystatin C at 3 h after surgery may help to identify patients with high risk for renal complications. A persistent elevation of S-cystatin C also predicts 1-year mortality.
Clinical Value and Practical Worth of Repeated Measurements of Vascular Biomarkers in End-Stage Renal Disease.Thursday, May 26, 2016
Husmann M, Schlager O,
Journal of clinical hypertension (Greenwich, Conn.). 25-May-2016
The time-of-day of myocardial infarction onset affects healing through oscillations in cardiac neutrophil recruitment.Thursday, May 26, 2016
Schloss MJ, Horckmans M, Nitz K, Duchene J, Drechsler M, Bidzhekov K, Scheiermann C, Weber C, Soehnlein O, Steffens S,
EMBO molecular medicine. 25-May-2016
Myocardial infarction (MI) is the leading cause of death in Western countries. Epidemiological studies show acute MI to be more prevalent in the morning and to be associated with a poorer outcome in terms of mortality and recovery. The mechanisms behind this association are not fully understood. Here, we report that circadian oscillations of neutrophil recruitment to the heart determine infarct size, healing, and cardiac function after MI Preferential cardiac neutrophil recruitment during the active phase (Zeitgeber time, ZT13) was paralleled by enhanced myeloid progenitor production, increased circulating numbers of CXCR2(hi) neutrophils as well as upregulated cardiac adhesion molecule and chemokine expression. MI at ZT13 resulted in significantly higher cardiac neutrophil infiltration compared to ZT5, which was inhibited by CXCR2 antagonism or neutrophil-specific CXCR2 knockout. Limiting exaggerated neutrophilic inflammation at this time point significantly reduced the infarct size and improved cardiac function.
Effects of subchronic extremely low-frequency electromagnetic field exposure on biochemical parameters in rats.Thursday, May 26, 2016
Luo X, Ma L, Gao P, Zhang Y,
Toxicology and industrial health. 25-May-2016
The objective of the present study was to systematically determine the effects of 50 Hertz (Hz) magnetic fields (MFs) on biochemical parameters in rats. Sixty-four adult (5 weeks old, 140-165 g) male Sprague-Dawley rats were randomly divided into four groups: sham, 20 µTesla (µT), 100 µT, and 500 µT 50 Hz MF (n = 16 in each group). The rats in the MF groups were exposed for 2 h daily for up to 4 weeks. Under these experimental conditions, body weight, organ coefficients, biochemical parameters (blood lipids, myocardial enzymes, liver function, and renal function) were measured. We found that 50 Hz MFs had no significant effects on growth or on the majority of blood biochemical parameters, with the exception of creatinine and cholesterol. However, the changes in creatinine and cholesterol were relatively small and unlikely to be clinically relevant.
Evaluation of Systemic Inflammatory Response Biomarkers in Patients Receiving Chemotherapy for Unresectable and Recurrent Advanced Gastric Cancer.Thursday, May 26, 2016
Namikawa T, Munekage E, Munekage M, Maeda H, Yatabe T, Kitagawa H, Kobayashi M, Hanazaki K,
Oncology. 26-May-2016
NLR and histological type are independent prognostic factors for patients receiving chemotherapy for unresectable and recurrent gastric cancer.
Pattern Genes Suggest Functional Connectivity of Organs.Thursday, May 26, 2016
Qin Y, Pan J, Cai M, Yao L, Ji Z,
Scientific reports. 2016
Human organ, as the basic structural and functional unit in human body, is made of a large community of different cell types that organically bound together. Each organ usually exerts highly specified physiological function; while several related organs work smartly together to perform complicated body functions. In this study, we present a computational effort to understand the roles of genes in building functional connection between organs. More specifically, we mined multiple transcriptome datasets sampled from 36 human organs and tissues, and quantitatively identified 3,149 genes whose expressions showed consensus modularly patterns: specific to one organ/tissue, selectively expressed in several functionally related tissues and ubiquitously expressed. These pattern genes imply intrinsic connections between organs. According to the expression abundance of the 766 selective genes, we consistently cluster the 36 human organs/tissues into seven functional groups: adipose &gland, brain, muscle, immune, metabolism, mucoid and nerve conduction. The organs and tissues in each group either work together to form organ systems or coordinate to perform particular body functions. The particular roles of specific genes and selective genes suggest that they could not only be used to mechanistically explore organ functions, but also be designed for selective biomarkers and therapeutic targets.
Challenges, priorities and novel therapies for hypoxemic respiratory failure and pulmonary hypertension in the neonate.Thursday, May 26, 2016
Aschner JL, Gien J, Ambalavanan N, Kinsella JP, Konduri GG, Lakshminrusimha S, Saugstad OD, Steinhorn RH,
Journal of perinatology : official journal of the California Perinatal Association. Jun-2016
Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.
Management of hypoxemic respiratory failure and pulmonary hypertension in preterm infants.Thursday, May 26, 2016
Ambalavanan N, Aschner JL,
Journal of perinatology : official journal of the California Perinatal Association. Jun-2016
While diagnoses of hypoxemic respiratory failure (HRF) and pulmonary hypertension (PH) in preterm infants may be based on criteria similar to those in term infants, management approaches often differ. In preterm infants, HRF can be classified as 'early' or 'late' based on an arbitrary threshold of 28 postnatal days. Among preterm infants with late HRF, the pulmonary vascular abnormalities associated with bronchopulmonary dysplasia (BPD) represent a therapeutic challenge for clinicians. Surfactant, inhaled nitric oxide (iNO), sildenafil, prostacyclin and endothelin receptor blockers have been used to manage infants with both early and late HRF. However, evidence is lacking for most therapies currently in use. Chronic oral sildenafil therapy for BPD-associated PH has demonstrated some preliminary efficacy. A favorable response to iNO has been documented in some preterm infants with early PH following premature prolonged rupture of membranes and oligohydramnios. Management is complicated by a lack of clear demarcation between interventions designed to manage respiratory distress syndrome, prevent BPD and treat HRF. Heterogeneity in clinical phenotype, pathobiology and genomic underpinnings of BPD pose challenges for evidence-based management recommendations. Greater insight into the spectrum of disease phenotypes represented by BPD can optimize existing therapies and promote development of new treatments. In addition, better understanding of an individual's phenotype, genotype and biomarkers may suggest targeted personalized interventions. Initiatives such as the Prematurity and Respiratory Outcomes Program provide a framework to address these challenges using genetic, environmental, physiological and clinical data as well as large repositories of patient samples.
Potential role of heat-shock protein 70 and interleukin-15 in the pathogenesis of threatened spontaneous abortions.Thursday, May 26, 2016
Gulic T, Laskarin G, Dominovic M, Glavan Gacanin L, Babarovic E, Haller H, Rukavina D,
American journal of reproductive immunology (New York, N.Y. : 1989). 26-May-2016
Downregulation of Hsc70, Hsp70, and IL-15 expression at gene and/or protein levels might support the retention of fertilization products in cases of missed abortion and blighted ovum.
MicroRNAs and liver disease.Thursday, May 26, 2016
Otsuka M, Kishikawa T, Yoshikawa T, Yamagami M, Ohno M, Takata A, Shibata C, Ishibashi R, Koike K,
Journal of human genetics. 26-May-2016
The biological roles of microRNAs (miRNAs) have been extensively studied. miRNA122 represents more than half of the miRNAs expressed in the liver and has various physiological and pathological functions, which include enhancing hepatitis virus replication, regulating lipid metabolism and suppressing hepatocellular carcinoma. miRNAs, whether globally or individually, have been linked with hepatocarcinogenesis. Furthermore, some miRNAs have been shown to be involved in the pathogenesis of nonalcoholic steatohepatitis. Using nucleotide-based strategies, these miRNAs may be developed as potential therapeutic targets. Because changes in miRNA expression can be measured in sera, they may be used as non-invasive biomarkers if they correctly reflect the pathological state of the liver. In this review, we show the biological roles of representative miRNAs in liver disease and discuss the current issues that remain to be clarified for future clinical applications.Journal of Human Genetics advance online publication, 26 May 2016; doi:10.1038/jhg.2016.53.
Clinical and prognostic utility of cardiovascular magnetic resonance imaging in myeloma patients with suspected cardiac amyloidosis.Thursday, May 26, 2016
Bhatti S, Watts E, Syed F, Vallurupalli S, Pandey T, Jambekar K, Mazur W, Hakeem A,
European heart journal cardiovascular Imaging. 25-May-2016
CMR is a clinically useful tool for diagnosis and prognostication in myeloma patients with suspected CA.
Synapse Formation in Monosynaptic Sensory-Motor Connections Is Regulated by Presynaptic Rho GTPase Cdc42.Thursday, May 26, 2016
Imai F, Ladle DR, Leslie JR, Duan X, Rizvi TA, Ciraolo GM, Zheng Y, Yoshida Y,
The Journal of neuroscience : the official journal of the Society for Neuroscience. 25-May-2016
Group Ia proprioceptive sensory neurons form direct synapses with motor neurons, but the molecular mechanisms underlying synapse formation in these monosynaptic sensory-motor connections are unknown. We show that deleting Cdc42 in sensory neurons does not affect proprioceptive sensory axon targeting because axons reach the ventral spinal cord appropriately, but these neurons form significantly fewer presynaptic terminals on motor neurons. Electrophysiological analysis further shows that EPSPs are decreased in these mice. Finally, we demonstrate that Cdc42 is involved in neuroligin-dependent presynaptic differentiation of proprioceptive sensory neurons in vitro These data suggest that Cdc42 in presynaptic sensory neurons is essential for proper synapse formation in the development of monosynaptic sensory-motor circuits.
The distribution pattern of ERα expression, ESR1 genetic variation and expression of growth factor receptors: association with breast cancer prognosis in Russian patients treated with adjuvant tamoxifen.Thursday, May 26, 2016
Babyshkina N, Vtorushin S, Zavyalova M, Patalyak S, Dronova T, Litviakov N, Slonimskaya E, Kzhyshkowska J, Cherdyntseva N, Choynzonov E,
Clinical and experimental medicine. 25-May-2016
Identification of additional biomarkers associated with ER genomic and nongenomic pathways could be very useful to distinguish patients who will benefit from tamoxifen treatment. The aim of this study was to analyze the prognostic significance of the distribution pattern of ERα expression, ESR1 gene single-nucleotide polymorphisms and expression levels of growth factor receptors in Russian hormone receptor-positive breast cancer patients treated with adjuvant tamoxifen. Formalin-fixed paraffin-embedded tumor tissue samples from 97 patients were examined for the distribution pattern of ERα expression, as well as for EGFR and TGF-βR1 expression by immunohistochemistry. Genotypes for ESR1 +30T>C (rs2077647) and ESR1 2014G>A (rs2228480) were analyzed using a TaqMan assay. Progression-free survival (PFS) was used as an endpoint for the survival analyses. We found that patients with the heterogeneous distribution of ERα expression had poor prognosis on tamoxifen treatment (P = 0.021). We identified a high EGFR expression in patients who developed distant metastasis or recurrence during tamoxifen treatment (a tamoxifen-resistant group-TR) in contrast to the distant metastasis-free patients (a tamoxifen-sensitive group-TS) (80.0 vs. 41.9 %, respectively, P = 0.009). Carriers of the ESR12014A mutant allele were more prevalent among the TR patients compared to the TS patients (26.3 vs. 8.0 %, respectively, P = 0.009). EGFR expression and the distribution pattern of ERα expression were associated with the response to tamoxifen by both univariate and multivariate logistic regression analyses. The presence of these markers either alone or in combination was correlated with the worse PFS for all patients. Analysis of the distribution pattern of ERα expression and the EGFR status in tumor tissue may be valuable for patient selection for tamoxifen adjuvant therapy.
The Role of Scoring Systems and Urine Dipstick in Prediction of Rhabdomyolysis-induced Acute Kidney Injury: a Systematic Review.Thursday, May 26, 2016
Safari S, Yousefifard M, Hashemi B, Baratloo A, Forouzanfar MM, Rahmati F, Motamedi M, Najafi I,
Iranian journal of kidney diseases. May-2016
The findings of this systematic review showed that based on the available resources, using the prediction rules and urine dipstick could be considered as valuable screening tools for detection of patients at risk for AKI following rhabdomyolysis. Yet, the external validity of the mentioned tools should be assessed before their general application in routine practice.
EGFR Mutations and ALK Rearrangements Are Associated with Low Response Rates to PD-1 Pathway Blockade in Non-Small Cell Lung Cancer (NSCLC): A Retrospective Analysis.Thursday, May 26, 2016
Gainor JF, Shaw AT, Sequist LV, Fu X, Azzoli CG, Piotrowska Z, Huynh TG, Zhao L, Fulton L, Schultz K, Howe E, Farago AF, Sullivan RJ, Stone JR, Digumarthy S, Moran T, Hata AN, Yagi Y, Yeap BY, Engelman JA, Mino-Kenudson M,
Clinical cancer research : an official journal of the American Association for Cancer Research. 25-May-2016
NSCLCs harboring EGFR mutations or ALK rearrangements are associated with low ORRs to PD-1/PD-L1 inhibitors. Low rates of concurrent PD-L1 expression and CD8+ TILs within the tumor microenvironment may underlie these clinical observations.
Trends in vital signs and routine biomarkers in patients with sepsis during resuscitation in the emergency department: a prospective observational pilot study.Thursday, May 26, 2016
Quinten VM, van Meurs M, Ter Maaten JC, Ligtenberg JJ,
BMJ open. 2016
Vital signs and biomarker levels showed descending trends during resuscitation, except for parameters directly affected by treatment modalities. Despite these trends, most patients improved clinically. Trends in vital signs and routine biomarkers might be helpful in predicting clinical course and response to treatment in patients with sepsis during early resuscitation.
Myeloid-derived suppressor cells as intruders and targets: clinical implications in cancer therapy.Thursday, May 26, 2016
Baniyash M,
Cancer immunology, immunotherapy : CII. 25-May-2016
Chronic inflammation, typical of various diseases including cancer, is a "silent bomb within the body," leading to complications that are only evident in most cases upon their appearance, when disease is already deteriorated. Chronic inflammation is associated with accumulation of myeloid-derived suppressor cells (MDSCs), which lead to immunosuppression. MDSCs have numerous harmful effects as they support tumor initiation, tumor growth and spreading, which in turn, perpetuate the inflammatory and suppressive conditions, thus preventing anticancer responses. As the concept of the immune system combating many types of tumors was revived in recent years, immunotherapy has dramatically changed the view of cancer treatment, and numerous novel therapies have been developed and approved by the FDA. However, cumulative clinical data point at very limited success rates. It is most likely that the developing chronic inflammation and MDSC-induced immunosuppression interfere with responses to such treatments and hence are major obstacles in achieving higher response rates to immune-based therapies. Moreover, chemotherapies were shown to have adverse immunoregulatory effects, enhancing or decreasing MDSC levels and activity, thus affecting treatment success. Therefore, therapeutic manipulations of chronic inflammation and MDSCs during cancer development are likely to enhance efficacy of immune- and chemo-based treatments, switching chronic pro-cancer inflammatory environments to an anticancerous milieu. Based on the functional relevance of immune networking in tumors, it is critical to merge monitoring immune system biomarkers into the traditional patient's categorization and treatment regimens. This will provide new tools for clinical practice, allowing appropriate management of cancer patients toward a better-personalized medicine.
Gene and microRNA Expression Are Predictive of Tumor Response in Rectal Adenocarcinoma Patients Treated with Preoperative Chemoradiotherapy.Thursday, May 26, 2016
Millino C, Maretto I, Pacchioni B, Digito M, De Paoli A, Canzonieri V, D'Angelo E, Agostini M, Rizzolio F, Giordano A, Barina A, Rajendran S, Esposito G, Lanfranchi G, Nitti D, Pucciarelli S,
Journal of cellular physiology. 25-May-2016
Preoperative chemoradiotherapy (pCRT) followed by surgery is the standard treatment for locally advanced rectal cancer (LARC). However, tumor response to pCRT is not uniform, and there are no effective predictive methods. This study investigated whether specific gene and miRNA expression are associated with tumor response to pCRT. Tissue biopsies were obtained from patients before pCRT and resection. Gene and miRNA expression were analyzed using a one-color microarray technique that compares signatures between responders (R) and non-responders (NR), as measured based on tumor regression grade. Two groups composed of 38 "exploration cohort" and 21 "validation cohort" LARC patients were considered for a total of 32 NR and 27 R patients. In the first cohort, using SAM Two Class analysis, 256 genes and 29 miRNAs that were differentially expressed between the NR and R patients were identified. The anti-correlation analysis showed that the same 8 miRNA interacted with different networks of transcripts. The miR-630 appeared only with the NR patients and was anti-correlated with a single transcript: RAB5B. After PAM, the following 8 transcripts were strong predictors of tumor response: TMEM188, ITGA2, NRG, TRAM1, BCL2L13, MYO1B, KLF7 and GTSE1. Using this gene set, an unsupervised cluster analysis was applied to the validation cohort and correctly assigned the patients to the NR or R group with 85.7% accuracy, 90% sensitivity and 82% specificity. All three parameters reached 100% when both cohorts were considered together. In conclusion, gene and miRNA expression profiles may be helpful for predicting response to pCRT in LARC patients. This article is protected by copyright. All rights reserved.
Chair/bedside diagnosis of oral and respiratory tract infections, and identification of antibiotic resistances for personalised monitoring and treatment.Thursday, May 26, 2016
Mitsakakis K, Stumpf F, Strohmeier O, Klein V, Mark D, Von Stetten F, Peham JR, Herz C, Tawakoli PN, Wegehaupt F, Attin T, Bostanci N, Bao K, Belibasakis GN, Hays JP, Elshout G, Huisman RC, Klein S, Stubbs AP, Doms L, Wolf A, Rusu V, Goethel S, Binsl T, Michie A, Jancovicova J, Kolar V, Kostka M, Smutny J, Karpisek M, Estephan C, Cocaud C, Zengerle R,
Studies in health technology and informatics. 2016
Global healthcare systems are struggling with the enormous burden associated with infectious diseases, as well as the incessant rise of antimicrobial resistance. In order to adequately address these issues, there is an urgent need for rapid and accurate infectious disease diagnostics. The H2020 project DIAGORAS aims at diagnosing oral and respiratory tract infections using a fully integrated, automated and user-friendly platform for physicians' offices, schools, elderly care units, community settings, etc. Oral diseases (periodontitis, dental caries) will be detected via multiplexed, quantitative analysis of salivary markers (bacterial DNA and host response proteins) for early prevention and personalised monitoring. Respiratory Tract Infections will be diagnosed by means of DNA/RNA differentiation so as to identify their bacterial or viral nature. Together with antibiotic resistance screening on the same platform, a more efficient treatment management is expected at the point-of-care. At the heart of DIAGORAS lies a centrifugal microfluidic platform (LabDisk and associated processing device) integrating all components and assays for a fully automated analysis. The project involves an interface with a clinical algorithm for the comprehensive presentation of results to end-users, thereby increasing the platform's clinical utility. DIAGORAS' performance will be validated at clinical settings and compared with gold standards.
Automated innovative diagnostic, data management and communication tool, for improving malaria vector control in endemic settings.Thursday, May 26, 2016
Vontas J, Mitsakakis K, Zengerle R, Yewhalaw D, Sikaala CH, Etang J, Fallani M, Carman B, Müller P, Chouaïbou M, Coleman M, Coleman M,
Studies in health technology and informatics. 2016
Malaria is a life-threatening disease that caused more than 400,000 deaths in sub-Saharan Africa in 2015. Mass prevention of the disease is best achieved by vector control which heavily relies on the use of insecticides. Monitoring mosquito vector populations is an integral component of control programs and a prerequisite for effective interventions. Several individual methods are used for this task; however, there are obstacles to their uptake, as well as challenges in organizing, interpreting and communicating vector population data. The Horizon 2020 project "DMC-MALVEC" consortium will develop a fully integrated and automated multiplex vector-diagnostic platform (LabDisk) for characterizing mosquito populations in terms of species composition, Plasmodium infections and biochemical insecticide resistance markers. The LabDisk will be interfaced with a Disease Data Management System (DDMS), a custom made data management software which will collate and manage data from routine entomological monitoring activities providing information in a timely fashion based on user needs and in a standardized way. The ResistanceSim, a serious game, a modern ICT platform that uses interactive ways of communicating guidelines and exemplifying good practices of optimal use of interventions in the health sector will also be a key element. The use of the tool will teach operational end users the value of quality data (relevant, timely and accurate) to make informed decisions. The integrated system (LabDisk, DDMS & ResistanceSim) will be evaluated in four malaria endemic countries, representative of the vector control challenges in sub-Saharan Africa, (Cameroon, Ivory Coast, Ethiopia and Zambia), highly representative of malaria settings with different levels of endemicity and vector control challenges, to support informed decision-making in vector control and disease management.
18-kDa translocator protein ligand (18)F-FEMPA: Biodistribution and uptake into atherosclerotic plaques in mice.Thursday, May 26, 2016
Hellberg S, Silvola JM, Kiugel M, Liljenbäck H, Savisto N, Li XG, Thiele A, Lehmann L, Heinrich T, Vollmer S, Hakovirta H, Laine VJ, Ylä-Herttuala S, Knuuti J, Roivainen A, Saraste A,
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 25-May-2016
(18)F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.
Effects of Dietary Exposure to Sulfamethazine on the Hematological Parameters and Hepatic Oxidative Stress Biomarkers in Nile Tilapia (Oreochromis niloticus).Thursday, May 26, 2016
Sampaio FG, Carra ML, Jonsson CM, Gonçalves VT, Dal'Bo G, Nunes KS, Valim JH, Dallago BS, do Nascimento de Queiroz SC, Reyes FG,
Bulletin of environmental contamination and toxicology. 25-May-2016
Sulfamethazine (SMZ) is one of the most commonly used sulfonamide compounds in fish farming, and its physiological effects on fish are unknown. SMZ was administered to juvenile Nile tilapia (Oreochromis niloticus) at a dose level of 422 mg kg(-1) body weight, for a period of 11 days, via medicated feed. Fish were divided into two groups, the control group (CG) and the group fed with SMZ in feed. The administration of SMZ did not alter the erythrograms and leukograms of the Nile tilapia. The SMZ-fed group showed the same hepatic lipid peroxidation (LPO) concentration as the CG. Nonetheless, the oral administration of SMZ raised the hepatic catalase (CAT) and glutathione S-transferase (GST) activities, the increase probably being sufficient to prevent hepatic LPO production. The oral administration of SMZ affects the hepatic GST and CAT activities of Nile tilapia.
Biopharmaceutical Evaluation of Novel Cyclosporine A Nano-matrix Particles for Inhalation.Thursday, May 26, 2016
Sato H, Suzuki H, Yakushiji K, Wong J, Seto Y, Prud'homme RK, Chan HK, Onoue S,
Pharmaceutical research. 25-May-2016
Upon these findings, nCsAm prepared with the flash nano-precipitation technique could be a novel dosage form of CsA for inhalation therapy of airway inflammation with a better safety margin.
Systemic Besnoitiosis in a Juvenile Roe Deer (Capreolus capreolus).Thursday, May 26, 2016
Arnal MC, Gutiérrez-Expósito D, Martínez-Durán D, Regidor-Cerrillo J, Revilla M, Fernández de Luco D, Jiménez-Meléndez A, Ortega-Mora LM, Álvarez-García G,
Transboundary and emerging diseases. 26-May-2016
Herein, we report the first incidence of systemic besnoitiosis in a male juvenile roe deer Capreolus capreolus. The animal was found dead in an area where bovine besnoitiosis is endemic and showed cachexia and multiple skin erosions in the metacarpal and metatarsal areas. Moreover, round and elevated white structures suggestive of Besnoitia spp. tissue cysts were also present. Twenty-eight tissue samples from different anatomical locations were collected for microscopic lesion and parasite detection through histopathology and PCR. Immunohistochemistry was performed to confirm Besnoitia-positive reaction in the tissue cysts. In addition, the identity of Besnoitia spp. in PCR-positive tissue samples was also investigated using microsatellite (MS) markers, and the comparison of protein disulphide isomerase gene sequences (BbPDI) of B. besnoiti and B. tarandi isolated from cattle and reindeer, respectively. Besnoitia cysts were detected in the skin (several parts), respiratory and upper digestive tracts, eyes, kidney, liver, testicle, cardiac muscle and lymphoid tissue. Remarkably, the presence of tissue cysts in the brain confirmed the capacity of Besnoitia spp. to form tissue cysts in the central nervous system (CNS). Finally, the Besnoitia species detected showed the same MS genotype as B. besnoiti, and BbPDI sequences from roe deer and two B. besnoiti isolates were genetically identical throughout multiple sequence alignment. Thus, for the first time, there is evidence that roe deer might act as an intermediate host of B. besnoiti. Further molecular analyses and parasite isolations are needed to corroborate these findings.
Serum caffeine and paraxanthine concentrations and menstrual cycle function: correlations with beverage intakes and associations with race, reproductive hormones, and anovulation in the BioCycle Study.Thursday, May 26, 2016
Schliep KC, Schisterman EF, Wactawski-Wende J, Perkins NJ, Radin RG, Zarek SM, Mitchell EM, Sjaarda LA, Mumford SL,
The American journal of clinical nutrition. 25-May-2016
Caffeine intake, irrespective of the beverage source, may be associated with reduced testosterone and improved menstrual cycle function in healthy premenopausal women.
Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels.Thursday, May 26, 2016
Bonilla C, Lewis SJ, Rowlands MA, Gaunt TR, Smith GD, Gunnell D, Palmer T, Donovan JL, Hamdy FC, Neal DE, Eeles R, Easton D, Kote-Jarai Z, Olama AA, Benlloch S, Muir K, Giles GG, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Pashayan N, Khaw KT, Stanford JL, Blot WJ, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Pandha H, Lathrop M, Martin RM, Holly JM,
International journal of cancer. 26-May-2016
Circulating insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are associated with prostate cancer. Using genetic variants as instruments for IGF peptides, we investigated whether these associations are likely to be causal. We identified from the literature 56 single nucleotide polymorphisms (SNPs) in the IGF axis previously associated with biomarker levels (8 from a genome-wide association study [GWAS] and 48 in reported candidate genes). In ∼700 men without prostate cancer and two replication cohorts (N∼900 and ∼9,000), we examined the properties of these SNPS as instrumental variables (IVs) for IGF-I, IGF-II, IGFBP-2 and IGFBP-3. Those confirmed as strong IVs were tested for association with prostate cancer risk, low (< 7) vs high (≥ 7) Gleason grade, localised vs advanced stage, and mortality, in 22,936 controls and 22,992 cases. IV analysis was used in an attempt to estimate the causal effect of circulating IGF peptides on prostate cancer. Published SNPs in the IGFBP1/IGFBP3 gene region, particularly rs11977526, were strong instruments for IGF-II and IGFBP-3, less so for IGF-I. Rs11977526 was associated with high (vs low) Gleason grade (OR per IGF-II/IGFBP-3 level-raising allele 1.05; 95% CI 1.00, 1.10). Using rs11977526 as an IV we estimated the causal effect of a one SD increase in IGF-II (∼265 ng/ml) on risk of high vs low grade disease as 1.14 (95% CI 1.00, 1.31). Because of the potential for pleiotropy of the genetic instruments, these findings can only causally implicate the IGF pathway in general, not any one specific biomarker. This article is protected by copyright. All rights reserved.
A missense mutation in TUBD1 is associated with high juvenile mortality in Braunvieh and Fleckvieh cattle.Thursday, May 26, 2016
Schwarzenbacher H, Burgstaller J, Seefried FR, Wurmser C, Hilbe M, Jung S, Fuerst C, Dinhopl N, Weissenböck H, Fuerst-Waltl B, Dolezal M, Winkler R, Grueter O, Bleul U, Wittek T, Fries R, Pausch H,
BMC genomics. 2016
A missense mutation in TUBD1 is associated with high perinatal and juvenile mortality in Braunvieh and Fleckvieh cattle. The mutation is located on a common haplotype likely originating from an ancient ancestor of Braunvieh and Fleckvieh cattle. Our findings demonstrate for the first time that deleterious alleles may segregate across closed cattle breeds without recent admixture. Homozygous calves suffer from chronic airway disease resulting in poor growth performance and high juvenile mortality. The respiratory manifestations resemble key features of diseases resulting from impaired function of airway cilia.
Expression of PD-L1 Identifies a Subgroup of More Aggressive Non-Small Cell Carcinomas of the Lung.Thursday, May 26, 2016
Sterlacci W, Fiegl M, Droeser RA, Tzankov A,
Pathobiology : journal of immunopathology, molecular and cellular biology. 27-May-2016
Should the expression of PD-L1 be on the verge of becoming an additional biomarker for routine diagnostics in NSCLC, our findings will provide important further insight and could contribute towards more effectively stratifying patients. These results may single out certain patient groups with a potential for increased benefit from anti PD-1/PD-L1 treatment strategies and should be considered in future trials.
IgE and mast cells in host defense against parasites and venoms.Thursday, May 26, 2016
Mukai K, Tsai M, Starkl P, Marichal T, Galli SJ,
Seminars in immunopathology. 25-May-2016
IgE-dependent mast cell activation is a major effector mechanism underlying the pathology associated with allergic disorders. The most dramatic of these IgE-associated disorders is the fatal anaphylaxis which can occur in some people who have developed IgE antibodies to otherwise innocuous antigens, such as those contained in certain foods and medicines. Why would such a highly "maladaptive" immune response develop in evolution and be retained to the present day? Host defense against parasites has long been considered the only beneficial function that might be conferred by IgE and mast cells. However, recent studies have provided evidence that, in addition to participating in host resistance to certain parasites, mast cells and IgE are critical components of innate (mast cells) and adaptive (mast cells and IgE) immune responses that can enhance host defense against the toxicity of certain arthropod and animal venoms, including enhancing the survival of mice injected with such venoms. Yet, in some people, developing IgE antibodies to insect or snake venoms puts them at risk for having a potentially fatal anaphylactic reaction upon subsequent exposure to such venoms. Delineating the mechanisms underlying beneficial versus detrimental innate and adaptive immune responses associated with mast cell activation and IgE is likely to enhance our ability to identify potential therapeutic targets in such settings, not only for reducing the pathology associated with allergic disorders but perhaps also for enhancing immune protection against pathogens and animal venoms.
Role of ATG10 expression quantitative trait loci in non-small cell lung cancer survival.Thursday, May 26, 2016
Xie K, Liang C, Li Q, Yan C, Wang C, Gu Y, Zhu M, Du F, Wang H, Dai J, Liu X, Jin G, Shen H, Ma H, Hu Z,
International journal of cancer. 26-May-2016
To evaluate whether genetic variants in autophagy-related genes affect the overall survival (OS) of non-small cell lung cancer (NSCLC) patients. We analyzed 14 single nucleotide polymorphisms (SNPs) in core autophagy-related genes for OS in 1001 NSCLC patients. Three promising SNPs in ATG10 were subsequently annotated by the expression quantitative trait loci (eQTL) and methylation quantitative trait loci (meQTL) analyses based on Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. We observed that the variants of rs10514231, rs1864182 and rs1864183 were associated with poor lung cancer survival (HR = 1.33, 95% CI = 1.07-1.65; HR = 1.43, 95%CI = 1.13-1.81; HR = 1.38, 95%CI = 1.14-1.68, respectively) and positively correlated with ATG10 expression (all P <0.05) from GTEx and TCGA datasets. The elevated expression of ATG10 may predict shorter survival time in lung cancer patients in TCGA dataset (HR = 2.10, 95%CI = 1.33-3.29). Moreover, the variants of rs10514231 and rs1864182 were associated with the increased methylation levels of cg17942617 (meQTL), which in turn contributed to the elevated ATG10 expression and decreased survival time. Further functional assays revealed that ATG10 facilitated lung cancer cell proliferation and migration. Our findings suggest that eQTL/meQTL variations of ATG10 could influence lung cancer survival through regulating ATG10 expression. This article is protected by copyright. All rights reserved.
Reply to Lesho and Clifford.Thursday, May 26, 2016
Evans S, Kreiswirth B, Fowler V, Chambers H, Patel R, Hujer AM, Perez F, Bonomo RA,
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 25-May-2016
Source: NCBI - Disclaimer and Copyright notice
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