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Showing 100 Latest Publications
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Anatomical Network Comparison of Human Upper and Lower, Newborn and Adult, and Normal and Abnormal Limbs, with Notes on Development, Pathology and Limb Serial Homology vs. Homoplasy.Friday, October 09, 2015
Diogo R, Esteve-Altava B, Smith C, Boughner JC, Rasskin-Gutman D,
PloS one.
How do the various anatomical parts (modules) of the animal body evolve into very different integrated forms (integration) yet still function properly without decreasing the individual's survival? This long-standing question remains unanswered for multiple reasons, including lack of consensus about conceptual definitions and approaches, as well as a reasonable bias toward the study of hard tissues over soft tissues. A major difficulty concerns the non-trivial technical hurdles of addressing this problem, specifically the lack of quantitative tools to quantify and compare variation across multiple disparate anatomical parts and tissue types. In this paper we apply for the first time a powerful new quantitative tool, Anatomical Network Analysis (AnNA), to examine and compare in detail the musculoskeletal modularity and integration of normal and abnormal human upper and lower limbs. In contrast to other morphological methods, the strength of AnNA is that it allows efficient and direct empirical comparisons among body parts with even vastly different architectures (e.g. upper and lower limbs) and diverse or complex tissue composition (e.g. bones, cartilages and muscles), by quantifying the spatial organization of these parts-their topological patterns relative to each other-using tools borrowed from network theory. Our results reveal similarities between the skeletal networks of the normal newborn/adult upper limb vs. lower limb, with exception to the shoulder vs. pelvis. However, when muscles are included, the overall musculoskeletal network organization of the upper limb is strikingly different from that of the lower limb, particularly that of the more proximal structures of each limb. Importantly, the obtained data provide further evidence to be added to the vast amount of paleontological, gross anatomical, developmental, molecular and embryological data recently obtained that contradicts the long-standing dogma that the upper and lower limbs are serial homologues. In addition, the AnNA of the limbs of a trisomy 18 human fetus strongly supports Pere Alberch's ill-named "logic of monsters" hypothesis, and contradicts the commonly accepted idea that birth defects often lead to lower integration (i.e. more parcellation) of anatomical structures.
Liver X receptor reduces proliferation of human oral cancer cells by promoting cholesterol efflux via up-regulation of ABCA1 expression.Friday, October 09, 2015
Kaneko T, Kanno C, Ichikawa-Tomikawa N, Kashiwagi K, Yaginuma N, Ohkoshi C, Tanaka M, Sugino T, Imura T, Hasegawa H, Chiba H,
Oncotarget. 1-Oct-2015
Liver X receptors (LXRs) contribute not only to maintain cholesterol homeostasis but also to control cell growth. However, the molecular mechanisms behind the LXR-mediated anti-proliferative effects are largely unknown. Here we show, by immunohistochemistry, that LXRα and LXRβ are differentially distributed in oral stratified squamous epithelia. By immunohistochemical and Western blot analyses, we also reveal that LXRα is abundantly expressed in human oral squamous cell carcinoma (HOSCC) tissues and cell lines. Cell counting, BrdU labeling and cell cycle assay indicated that LXR stimulation led to significant reduction of proliferation in HOSCC cells. Importantly, our study highlights, by using RNA interference, that the ATP-binding cassette transporter A1 (ABCA1)-accelerated cholesterol efflux is critical for the growth inhibitory action of LXRs in HOSCC cells. Moreover, we demonstrate that LXR activation reduces the growth of xenograft tumour of HOSCC cells in mice accompanied by the upregulation of ABCA1 expression and the decline of cholesterol levels in the tumour. These findings strongly suggested that targeting the LXR-regulated cholesterol transport, yielding in lowering intracellular cholesterol levels, could be a promising therapeutic option for certain types of cancers.
Clostridium Perfringens Epsilon Toxin Binds to Membrane Lipids and Its Cytotoxic Action Depends on Sulfatide.Friday, October 09, 2015
Gil C, Dorca-Arévalo J, Blasi J,
PloS one. 1-10-2015
Epsilon toxin (Etx) is one of the major lethal toxins produced by Clostridium perfringens types B and D, being the causal agent of fatal enterotoxemia in animals, mainly sheep and goats. Etx is synthesized as a non-active prototoxin form (proEtx) that becomes active upon proteolytic activation. Etx exhibits a cytotoxic effect through the formation of a pore in the plasma membrane of selected cell targets where Etx specifically binds due to the presence of specific receptors. However, the identity and nature of host receptors of Etx remain a matter of controversy. In the present study, the interactions between Etx and membrane lipids from the synaptosome-enriched fraction from rat brain (P2 fraction) and MDCK cell plasma membrane preparations were analyzed. Our findings show that both Etx and proEtx bind to lipids extracted from lipid rafts from the two different models as assessed by protein-lipid overlay assay. Lipid rafts are membrane microdomains enriched in cholesterol and sphingolipids. Binding of proEtx to sulfatide, phosphatidylserine, phosphatidylinositol (3)-phosphate and phosphatidylinositol (5)-phosphate was detected. Removal of the sulphate groups via sulfatase treatment led to a dramatic decrease in Etx-induced cytotoxicity, but not in proEtx-GFP binding to MDCK cells or a significant shift in oligomer formation, pointing to a role of sulfatide in pore formation in rafts but not in toxin binding to the target cell membrane. These results show for the first time the interaction between Etx and membrane lipids from host tissue and point to a major role for sulfatides in C. perfringens epsilon toxin pathophysiology.
Klotho Protects Dopaminergic Neuron Oxidant-Induced Degeneration by Modulating ASK1 and p38 MAPK Signaling Pathways.Friday, October 09, 2015
Brobey RK, German D, Sonsalla PK, Gurnani P, Pastor J, Hsieh CC, Papaconstantinou J, Foster PP, Kuro-O M, Rosenblatt KP,
PloS one. 9-10-2015
Klotho transgenic mice exhibit resistance to oxidative stress as measured by their urinal levels of 8-hydroxy-2-deoxyguanosine, albeit this anti-oxidant defense mechanism has not been locally investigated in the brain. Here, we tested the hypothesis that the reactive oxygen species (ROS)-sensitive apoptosis signal-regulating kinase 1 (ASK1)/p38 MAPK pathway regulates stress levels in the brain of these mice and showed that: 1) the ratio of free ASK1 to thioredoxin (Trx)-bound ASK1 is relatively lower in the transgenic brain whereas the reverse is true for the Klotho knockout mice; 2) the reduced p38 activation level in the transgene corresponds to higher level of ASK1-bound Trx, while the KO mice showed elevated p38 activation and lower level of-bound Trx; and 3) that 14-3-3ζ is hyper phosphorylated (Ser-58) in the transgene which correlated with increased monomer forms. In addition, we evaluated the in vivo robustness of the protection by challenging the brains of Klotho transgenic mice with a neurotoxin, MPTP and analyzed for residual neuron numbers and integrity in the substantia nigra pars compacta. Our results show that Klotho overexpression significantly protects dopaminergic neurons against oxidative damage, partly by modulating p38 MAPK activation level. Our data highlight the importance of ASK1/p38 MAPK pathway in the brain and identify Klotho as a possible anti-oxidant effector.
MAGI3 negatively regulates Wnt/β-catenin signaling and suppresses malignant phenotypes of glioma cells.Friday, October 09, 2015
Ma Q, Yang Y, Feng D, Zheng S, Meng R, Fa P, Zhao C, Liu H, Song R, Tao T, Yang L, Dai J, Wang S, Jiang WG, He J,
Oncotarget. 6-Oct-2015
Gliomas are the most common primary brain malignancies and are associated with a poor prognosis. Here, we showed that the PDZ domain-containing protein membrane-associated guanylate kinase inverted 3 (MAGI3) was downregulated at the both mRNA and protein levels in human glioma samples. MAGI3 inhibited proliferation, migration, and cell cycle progression of glioma cells in its overexpression and knockdown studies. By using GST pull-down and co-immunoprecipitation assays, we found that MAGI3 bound to β-catenin through its PDZ domains and the PDZ-binding motif of β-catenin. MAGI3 overexpression inhibited β-catenin transcriptional activity via its interaction with β-catenin. Consistently, MAGI3 overexpression in glioma cells C6 suppressed expression of β-catenin target genes including Cyclin D1 and Axin2, whereas MAGI3 knockdown in glioma cells U373 and LN229 enhanced their expression. MAGI3 overexpression decreased growth of C6 subcutaneous tumors in mice, and inhibited expression of β-catenin target genes in xenograft tumors. Furthermore, analysis based on the Gene Expression Omnibus (GEO) glioma dataset showed association of MAGI3 expression with overall survival and tumor grade. Finally, we demonstrated negative correlation between MAGI3 expression and activity of Wnt/β-catenin signaling through GSEA of three public glioma datasets and immunohistochemical staining of clinical glioma samples. Taken together, these results identify MAGI3 as a novel tumor suppressor and provide insight into the pathogenesis of glioma.
Primary Pulmonary Lymphomas.Friday, October 09, 2015
Piña-Oviedo S, Weissferdt A, Kalhor N, Moran CA,
Advances in anatomic pathology. Nov-2015
Primary lung lymphoma (PLL) is a rare disease that comprises <0.5% of all primary lung tumors. It is defined as lymphoma confined to the lung with or without hilar lymph node involvement at the time of diagnosis or up to 3 months thereafter. Patients with PLL may be asymptomatic or manifest nonspecific clinical symptoms, for example, cough, chest pain, and dyspnea. Some individuals may be immunosupressed or have an autoimmune disorder. Radiologically, PLL can mimic pneumonia, lung carcinoma, or metastasis, and therefore, histologic confirmation is mandatory for definitive diagnosis. Primary lung marginal zone lymphoma of mucosa-associated lymphoid tissue type comprises 70% to 80% of cases. Less common B-cell lymphomas include diffuse large B-cell lymphoma, lymphomatoid granulomatosis (LyG), plasmacytoma, and other small lymphocytic lymphomas. PLLs of T-cell origin, largely represented by anaplastic large cell lymphoma, are extremely rare. LyG is an Epstein-Barr virus (EBV)-driven B-cell lymphoid neoplastic proliferation rich in T cells that produces vasculitis. The disease may present at different stages of progression. Differential diagnosis of PLL varies according to the lymphoma subtype: pulmonary mucosa-associated lymphoid tissue lymphoma should be distinguished from reactive inflammatory conditions, whereas high-grade lymphomas may resemble poorly differentiated lung carcinoma, metastatic disease, and other lymphomas. LyG can resemble inflammatory, infectious, and other lymphoid neoplastic processes. A panel of immunohistochemical markers, flow cytometry, and molecular methods are necessary to confirm the diagnosis in the majority of cases. In this article we review the clinical, radiologic, pathologic, and molecular characteristics of several B-cell and T-cell PLLs with exception of Hodgkin lymphoma and posttransplant lymphoproliferative disorder.
Clinical Applications of Molecular Markers in Bone Tumors.Friday, October 09, 2015
Hameed M,
Advances in anatomic pathology. Nov-2015
Pathologic diagnosis of primary bone neoplasms can be challenging primarily due to rarity of the disease entities, overlapping imaging and histologic findings, and lack of tumor-specific immunohistochemical stains. Although slow to evolve, in recent years there has been a rapid advance in the discovery of new and novel molecular markers in primary bone neoplasms, which has enhanced diagnostic accuracy and has shed light into their pathogenesis. Modern technological approaches such as next-generation sequencing including RNA sequencing are serving as "rapid discovery platforms" for new and novel mutations and translocations with diagnostic, prognostic, and possible therapeutic applicability. As next-generation sequencing technologies are finding their place in clinical laboratories, one could envision routine testing for mutations spanning across a gene or translocations with multiple breakpoints and partner genes. This review will focus on the clinical relevance and applicability of molecular markers in primary bone neoplasms with examples.
Proteomics of Cerebrospinal Fluid: Throughput and Robustness Using a Scalable Automated Analysis Pipeline for Biomarker Discovery.Friday, October 09, 2015
Nunez Galindo A, Kussmann M, Dayon L,
Analytical chemistry. 9-Oct-2015
Cerebrospinal fluid (CSF) is a body fluid of high clinical relevance and an important source of potential biomarkers for brain-associated damages such as traumatic brain injury, stroke, and for brain diseases like Alzheimer's and Parkinson's . Herein, we have implemented, evaluated and validated a scalable automated proteomic pipeline (ASAP2) for the sample preparation and proteomic analysis of CSF, enabling increased throughput and robustness for biomarker discovery. Human CSF samples were depleted from abundant proteins, and submitted to automated reduction, alkylation, protein digestion, tandem mass tag (TMT) 6-plex labeling, pooling, and sample clean-up in a 96-well plate format before reversed-phase liquid chromatography tandem mass spectrometry (RP-LC MS/MS). First, we showed the impact on the CSF proteome coverage of applying the depletion of abundant proteins, which is usually performed on blood plasma or serum samples. Using ASAP2 to analyze 96 identical CSF samples, we determined the analytical figures of merit of our shotgun proteomic approach regarding proteome coverage consistency (i.e., 387 proteins), quantitative accuracy, and individual protein variability. We demonstrated that, as for human plasma samples,1 ASAP2 is efficient in analyzing large numbers of human CSF samples and is a valuable tool for biomarker discovery. The data has been deposited to the ProteomeXchange with identifier PXD003024.
Occurrence of Neuroblastoma among TP53 p.R337H Carriers.Friday, October 09, 2015
Seidinger AL, Fortes FP, Mastellaro MJ, Cardinalli IA, Zambaldi LG, Aguiar SS, Yunes JA,
PloS one. 9-10-2015
The high incidence of adrenocortical tumors and choroid plexus carcinoma in children from South and Southeastern regions of Brazil is associated with the germline p.R337H mutation of TP53 gene. The concomitant occurrence of neuroblastoma and adrenocortical tumors in pediatric patients harboring the p.R337H mutation at our institution prompted us to investigate the putative association between p.R337H and pediatric neuroblastoma. Genomic DNA samples from 83 neuroblastoma patients referred to a single institution during the period of 2000-2014 were screened for the p.R337H mutation. Available samples from carriers were investigated for both nuclear p53 accumulation and loss of heterozigosity in tumor. Clinical data were obtained from medical records in order to assess the impact of 337H allele on manifestation of the disease. Seven out 83 neuroblastoma patients (8.4%) were carriers of the TP53 p.R337H mutation in our cohort. Immunohistochemical analysis of p.R337H-positive tumors revealed nuclear p53 accumulation. Loss of heterozigosity was not found among available samples. The presence of 337H allele was associated with increased proportion of stage I tumors. Our data indicate that in addition to adrenocortical tumors, choroid plexus carcinoma, breast cancer and osteosarcoma, genetic counseling and clinical surveillance should consider neuroblastoma as a potential neoplasia affecting p.R337H carriers.
High expression of CTHRC1 promotes EMT of epithelial ovarian cancer (EOC) and is associated with poor prognosis.Friday, October 09, 2015
Hou M, Cheng Z, Shen H, He S, Li Y, Pan Y, Feng C, Chen X, Zhang Y, Lin M, Wang L, Ke Z,
Oncotarget. 3-Oct-2015
Collagen triple helix repeat-containing 1 (CTHRC1) is aberrantly overexpressed in multiple malignant tumors. However, the expression characteristics and function of CTHRC1 in epithelial ovarian cancer (EOC) remain unclear. We found that CTHRC1 expression was up-regulated in the paraffin-embedded EOC tissues compared to borderline or benign tumor tissues. CTHRC1 expression was positively correlated with tumor size (p = 0.008), menopause (p = 0.037), clinical stage (p = 0.002) and lymph node metastasis (p < 0.001) and was also an important prognostic factor for the overall survival of EOC patients, as revealed by Kaplan-Meier analysis. CTHRC1 increased the invasive capabilities of EOC cells in vitro by activating the Wnt/β-catenin signaling pathway. We showed that ectopic transfection of CTHRC1 in EOC cells up-regulated the expression of EMT markers such as N-cadherin and vimentin, and EMT-associated transcriptional factor Snail. Knockdown of CTHRC1 expression in EOC cells resulted in down-regulation of N-cadherin, vimentin, Snail and translocation of β-catenin. Collectively, CTHRC1 may promote EOC metastasis through the induction of EMT process and serve as a potential biomarker for prognosis as well as a target for therapy.
Biology of the eyelash hair follicle: an enigma in plain sight.Friday, October 09, 2015
Paus R, Burgoa I, Platt CI, Griffiths T, Poblet E, Izeta A,
The British journal of dermatology. 9-Oct-2015
Because of their crucial impact on our perception of beauty, eyelashes constitute a prime target for the cosmetic industry. However, when compared to other hair shafts and the mini-organs that produce them (eyelash hair follicles [ELHFs]), knowledge on the biology underlying growth and pigmentation of eyelashes is still rudimentary. This is due in part to the extremely restricted availability of human ELHFs for experimental study, under-appreciation of their important sensory and protective functions and insufficient interest in understanding why they are distinct from scalp HFs (e.g. ELHFs produce shorter hair shafts, do not possess an arrector pili muscle, have a shorter hair cycle and undergo greying significantly later than scalp HFs). Here we synthesize the limited current knowledge on the biology of ELHFs, in humans and other species, their role in health and disease, the known similarities and differences with other HF populations, and their intrinsic inter-ethnic variations. We define major open questions in the biology of these intriguing mini-organs and conclude by proposing future research directions. These include dissecting the molecular and cellular mechanisms that underlie trichomegaly and the development of in vitro models in order to interrogate the molecular controls of ELHF growth, cycling, and pigmentation and to probe novel strategies for the therapeutic and cosmetic manipulation of ELHFs beyond prostaglandin receptor stimulation. This article is protected by copyright. All rights reserved.
Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study.Friday, October 09, 2015
Papaxoinis G, Kotoula V, Alexopoulou Z, Kalogeras KT, Zagouri F, Timotheadou E, Gogas H, Pentheroudakis G, Christodoulou C, Koutras A, Bafaloukos D, Aravantinos G, Papakostas P, Charalambous E, Papadopoulou K, Varthalitis I, Efstratiou I, Zaramboukas T, Patsea H, Scopa CD, Skondra M, Kosmidis P, Pectasides D, Fountzilas G,
PloS one. 9-10-2015
The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.
The androgen receptor controls expression of the cancer-associated sTn antigen and cell adhesion through induction of ST6GalNAc1 in prostate cancer.Friday, October 09, 2015
Munkley J, Oltean S, Vodák D, Wilson BT, Livermore KE, Zhou Y, Star E, Floros VI, Johannessen B, Knight B, McCullagh P, McGrath J, Crundwell M, Skotheim RI, Robson CN, Leung HY, Harries LW, Rajan P, Mills IG, Elliott DJ,
Oncotarget. 7-Oct-2015
Patterns of glycosylation are important in cancer, but the molecular mechanisms that drive changes are often poorly understood. The androgen receptor drives prostate cancer (PCa) development and progression to lethal metastatic castration-resistant disease. Here we used RNA-Seq coupled with bioinformatic analyses of androgen-receptor (AR) binding sites and clinical PCa expression array data to identify ST6GalNAc1 as a direct and rapidly activated target gene of the AR in PCa cells. ST6GalNAc1 encodes a sialytransferase that catalyses formation of the cancer-associated sialyl-Tn antigen (sTn), which we find is also induced by androgen exposure. Androgens induce expression of a novel splice variant of the ST6GalNAc1 protein in PCa cells. This splice variant encodes a shorter protein isoform that is still fully functional as a sialyltransferase and able to induce expression of the sTn-antigen. Surprisingly, given its high expression in tumours, stable expression of ST6GalNAc1 in PCa cells reduced formation of stable tumours in mice, reduced cell adhesion and induced a switch towards a more mesenchymal-like cell phenotype in vitro. ST6GalNAc1 has a dynamic expression pattern in clinical datasets, beingsignificantly up-regulated in primary prostate carcinoma but relatively down-regulated in established metastatic tissue. ST6GalNAc1 is frequently upregulated concurrently with another important glycosylation enzyme GCNT1 previously associated with prostate cancer progression and implicated in Sialyl Lewis X antigen synthesis. Together our data establishes an androgen-dependent mechanism for sTn antigen expression in PCa, and are consistent with a general role for the androgen receptor in driving important coordinate changes to the glycoproteome during PCa progression.
Functional and molecular characterization of cancer stem-like cells in bladder cancer: a potential signature for muscle-invasive tumors.Friday, October 09, 2015
Ferreira-Teixeira M, Parada B, Rodrigues-Santos P, Alves V, Ramalho JS, Caramelo F, Sousa V, Reis F, Gomes CM,
Oncotarget. 5-Oct-2015
Striking evidence associates cancer stem cells (CSCs) to the high recurrence rates and poor survival of patients with muscle-invasive bladder cancer (BC). However, the prognostic implication of those cells in risk stratification is not firmly established, mainly due to the functional and phenotypic heterogeneity of CSCs populations, as well as, to the conflicting data regarding their identification based on a single specific marker. This emphasizes the need to exploit putative CSC-related molecular markers with potential prognostic significance in BC patients.This study aimed to isolate and characterize bladder CSCs making use of different functional and molecular approaches. The data obtained provide strong evidence that muscle-invasive BC is enriched with a heterogeneous stem-like population characterized by enhanced chemoresistance and tumor initiating properties, able to recapitulate the heterogeneity of the original tumor. Additionally, a logistic regression analysis identified a 2-gene stem-like signature (SOX2 and ALDH2) that allows a 93% accurate discrimination between non-muscle-invasive and invasive tumors.Our findings suggest that a stemness-related gene signature, combined with a cluster of markers to more narrowly refine the CSC phenotype, could better identify BC patients that would benefit from a more aggressive therapeutic intervention targeting CSCs population.
MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients.Friday, October 09, 2015
De Mattos-Arruda L, Bottai G, Nuciforo PG, Di Tommaso L, Giovannetti E, Peg V, Losurdo A, Pérez-Garcia J, Masci G, Corsi F, Cortés J, Seoane J, Calin GA, Santarpia L,
Oncotarget. 7-Oct-2015
Patients with primary HER2-positive breast cancer benefit from HER2-targeted therapies. Nevertheless, a significant proportion of these patients die of disease progression due to mechanisms of drug resistance. MicroRNAs (miRNAs) are emerging as critical core regulators of drug resistance that act by modulating the epithelial-to-mesenchymal transition (EMT) and cancer-related immune responses. In this study, we investigated the association between the expression of a specific subset of 14 miRNAs involved in EMT processes and immune functions and the response to neoadjuvant trastuzumab and chemotherapy in 52 patients with HER2-overexpressing breast tumors. The expression of only a single miRNA, miR-21, was significantly associated with residual disease (p = 0.030) and increased after trastuzumab-chemotherapy (p = 0.012). A target prediction analysis coupled with in vitro and in vivo validations revealed that miR-21 levels inversely correlated with the expression of PTEN (rs = -0.502; p = 0.005) and PDCD4 (rs = -0.426; p = 0.019), which differentially influenced the drug sensitivity of HER2-positive breast cancer cells. However, PTEN expression was only marginally associated with residual disease. We further demonstrated that miR-21 was able to affect the response to both trastuzumab and chemotherapy, triggering an IL-6/STAT3/NF-κB-mediated signaling loop and activating the PI3K pathway. Our findings support the ability of miR-21 signaling to sustain EMT and shape the tumor immune microenvironment in HER2-positive breast cancer. Collectively, these data provide a rationale for using miR-21 expression as a biomarker to select trastuzumab-chemotherapy-resistant HER2-positive breast cancer patients who may benefit from treatments containing PI3K inhibitors or immunomodulatory drugs.
High glucose uptake unexpectedly is accompanied by high levels of the mitochondrial ß-F1-ATPase subunit in head and neck squamous cell carcinoma.Friday, October 09, 2015
Huebbers CU, Adam AC, Preuss SF, Schiffer T, Schilder S, Guntinas-Lichius O, Schmidt M, Klussmann JP, Wiesner RJ,
Oncotarget. 6-Oct-2015
A hallmark of solid tumors is the consumption of large amounts of glucose and production of lactate, also known as Warburg-like metabolism. This metabolic phenotype is typical for aggressive tumor growth, and can be visualized by 18F-fluorodeoxyglucose (18F-FDG) uptake detected by positron emission tomography (PET). High 18F-FDG uptake inversely correlates with survival and goes along with reduced expression of the catalytic beta-subunit of the H+-ATP synthase (ß-F1-ATPase) in several tumor entities analyzed so far.For this study we characterized a series of 15 head and neck squamous cell carcinoma (HNSCC) by (i) determining 18F-FDG-uptake; (ii) quantitative expression analysis of ß-F1-ATPase (Complex V), NDUF-S1 (Complex I) and COX1 (Complex IV) of the mitochondrial electron transport chain (ETC), as well as Hsp60 (mitochondrial mass) and GAPDH (glycolysis) in tumor cells; (iii) sequencing of the mtDNA of representative tumor samples.Whereas high 18F-FDG-uptake also correlates with poor prognosis in HNSCC, it surprisingly is accompanied by high levels of ß-F1-ATPase, but not by any of the other analyzed proteins.In conclusion, we here describe a completely new phenotype of metabolic adaptation possibly enabling those tumors with highest levels of ß-F1-ATPase to rapidly proliferate even in hypoxic zones, which are typical for HNSCC.
Hes1 triggers epithelial-mesenchymal transition (EMT)-like cellular marker alterations and promotes invasion and metastasis of nasopharyngeal carcinoma by activating the PTEN/AKT pathway.Friday, October 09, 2015
Wang SC, Lin XL, Wang HY, Qin YJ, Chen L, Li J, Jia JS, Shen HF, Yang S, Xie RY, Wei F, Gao F, Rong XX, Yang J, Zhao WT, Zhang TT, Shi JW, Yao KT, Luo WR, Sun Y, Xiao D,
Oncotarget. 2-Oct-2015
Overexpression of the transcriptional factor Hes1 (hairy and enhancer of split-1) has been observed in numerous cancers, but the precise roles of Hes1 in epithelial-mesenchymal transition (EMT), cancer invasion and metastasis remain unknown. Our current study firstly revealed that Hes1 upregulation in a cohort of human nasopharyngeal carcinoma (NPC) biopsies is significantly associated with the EMT, invasive and metastatic phenotypes of cancer. In the present study, we found that Hes1 overexpression triggered EMT-like cellular marker alterations of NPC cells, whereas knockdown of Hes1 through shRNA reversed the EMT-like phenotypes, as strongly supported by Hes1-mediated EMT in NPC clinical specimens described above. Gain-of-function and loss-of-function experiments demonstrated that Hes1 promoted the migration and invasion of NPC cells in vitro. In addition, exogenous expression of Hes1 significantly enhanced the metastatic ability of NPC cells in vivo. Chromatin immunoprecipitation (ChIP) assays showed that Hes1 inhibited PTEN expression in NPC cells through binding to PTEN promoter region. Increased Hes1 expression and decreased PTEN expression were also observed in a cohort of NPC biopsies. Additional studies demonstrated that Hes1-induced EMT-like molecular changes and increased motility and invasion of NPC cells were mediated by PTEN. Taken together, our results suggest, for what we believe is the first time, that Hes1 plays an important role in the invasion and metastasis of NPC through inhibiting PTEN expression to trigger EMT-like phenotypes.
Biomarker-based prognostic stratification of young adult glioblastoma.Friday, October 09, 2015
Zhang RQ, Shi Z, Chen H, Chung NY, Yin Z, Li KK, Chan DT, Poon WS, Wu J, Zhou L, Chan AK, Mao Y, Ng HK,
Oncotarget. 5-Oct-2015
While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF, H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF-V600E (15%), H3F3A-K27M (15.9%), H3F3A-G34R/V (2.8%) and IDH1-R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERTp mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF-V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A-K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1-R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF, H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF, H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas.
Expression pattern of invasion-related molecules in the peritumoral brain.Friday, October 09, 2015
Klekner Á, Hutóczki G, Virga J, Reményi-Puskár J, Tóth J, Scholtz B, Csősz É, Kalló G, Steiner L, Hortobágyi T, Bognár L,
Clinical neurology and neurosurgery. 26-Sep-2015
Our results bring some ECM molecules into focus that probably play key role in arresting tumour cell invasion around the metastatic tumour, and also in the lack of impeding tumour cell migration in case of glioblastoma.
Predicting In-Hospital Treatment Failure (≤7 days) in Patients with COPD Exacerbation Using Antibiotics and Systemic Steroids.Friday, October 09, 2015
Crisafulli E, Torres A, Huerta A, Guerrero M, Gabarrús A, Gimeno A, Martinez R, Soler N, Fernández L, Wedzicha JA, Menéndez R,
COPD. 9-Oct-2015
Although pharmacological treatment of COPD exacerbation (COPDE) includes antibiotics and systemic steroids, a proportion of patients show worsening of symptoms during hospitalization that characterize treatment failure. The aim of our study was to determine in-hospital predictors of treatment failure (≤ 7 days). Prospective data on 110 hospitalized COPDE patients, all treated with antibiotics and systemic steroids, were collected; on the seventh day of hospitalization, patients were divided into treatment failure (n = 16) or success (n = 94). Measures of inflammatory serum biomarkers were recorded at admission and at day 3; data on clinical, laboratory, microbiological, and severity, as well data on mortality and readmission, were also recorded. Patients with treatment failure had a worse lung function, with higher serum levels of C-reactive protein (CRP), procalcitonin (PCT), tumour necrosis factor-alpha (TNF-α), interleukin (IL) 8, and IL-10 at admission, and CRP and IL-8 at day 3. Longer length of hospital stay and duration of antibiotic therapy, higher total doses of steroids and prevalence of deaths and readmitted were found in the treatment failure group. In the multivariate analysis, +1 mg/dL of CRP at admission (OR, 1.07; 95% CI, 1.01 to 1.13) and use of penicillins or cephalosporins (OR, 5.63; 95% CI, 1.26 to 25.07) were independent variables increasing risk of treatment failure, whereas cough at admission (OR, 0.20; 95% CI, 0.05 to 0.75) reduces risk of failure. In hospitalized COPDE patients CRP at admission and use of specific class of antibiotics predict in-hospital treatment failure, while presence of cough has a protective role.
Galectin-1 Prevents Infection and Damage Induced by Trypanosoma cruzi on Cardiac Cells.Friday, October 09, 2015
Benatar AF, García GA, Bua J, Cerliani JP, Postan M, Tasso LM, Scaglione J, Stupirski JC, Toscano MA, Rabinovich GA, Gómez KA,
PLoS neglected tropical diseases. Oct-2015
Our results indicate that Gal-1 modulates T. cruzi infection of cardiac cells, highlighting the relevance of galectins and their ligands as regulators of host-parasite interactions.
Label-Free MicroRNA Detection Based on Fluorescence Quenching of Gold Nanoparticles with a Competitive Hybridization.Friday, October 09, 2015
Wang W, Kong T, Zhang D, Zhang J, Cheng G,
Analytical chemistry. 9-Oct-2015
MiRNAs, critical biomarkers of acute and chronic diseases, play key regulatory roles in many biological processes. As a result, there is great demand for robust assay platforms to enable an accurate and efficient detection of low-level miRNAs in complex biological samples. In this work, a label-free and Au nanoparticles (NPs) quenching-based competition assay system was developed. In the designed system, Au NPs with diameter sizes of 10 and 20 nm displayed fluorescence quenching efficiencies of 84% and 82% for Cy3 dye on slide surface, whereas the quenching efficiency of commercial BHQ2 quencher was roughly 50%. Assay conditions were optimized for miRNA-205 detection. A limit of detection of 3.8 pM and a detection range covering from 3.8 pM to 10 nM were achieved. Furthermore, the proposed system was capable of specifically discriminating miRNAs with slight variations in their nucleotide sequence, and was also qualified for assessing miRNA levels in human serum. Our strategy has the potential to provide new perspectives in profiling the pattern of miRNA expression and biomedical utilizations.
A Validated High Resolution Mass Spectrometry-based Approach for Metabolomic Fingerprinting of the Human Gut Phenotype.Friday, October 09, 2015
Vanden Bussche J, Marzorati M, Laukens D, Vanhaecke L,
Analytical chemistry. 9-Oct-2015
Fecal samples are an obvious choice for metabolomic approaches, since they can be obtained non-invasively and allow studying interactions between the gut microbiota and the host. The use of ultrahigh performance liquid chromatography hyphenated to Orbitrap high-resolution mass spectrometry (UHPLC-Orbitrap HRMS) in this field is unique. Hence, this study relied on Orbitrap HRMS to develop and validate a metabolic fingerprinting workflow for human feces and in vitro digestive fluids. After chemometric sample extraction optimization, an aqueous dilution appeared necessary to comply to the dynamic range of the MS. The method was proven 'fit-for-purpose' through a validation procedure that monitored endogenous metabolites in quality control samples, which displayed in both matrices an excellent linearity (R(2)>0.990), recoveries ranging from 93-105%, and precision with CVs <15%. Finally, feces from 10 healthy individuals and 13 patients diagnosed with inflammatory bowel disease were subjected to metabolomic fingerprinting. 9553 ions were detected, as well as differentiating profiles between Crohn's disease or ulcerative colitis by means of (O)PLS-DA models. Additionally, samples from the dynamic gastrointestinal tract simulator (SHIME(®) platform) were analyzed resulting in 6446 and 5010 ions for the proximal and distal colonic samples, respectively. Supplementing SHIME feed with antibiotics resulted in a significant shift (P<0.05) of 27.7 % of the metabolites from the proximal dataset and 34.3% for the distal one. As a result, the presented fingerprinting approach provided predictive modeling of the gastrointestinal metabolome in vivo and in vitro, offering a window to reveal disease related biomarkers and potential insight into the mechanisms behind pathologies.
The use of personalized biomarkers and liquid biopsies to monitor treatment response and disease recurrence in locally advanced rectal cancer after neoadjuvant chemoradiation.Friday, October 09, 2015
Carpinetti P, Donnard E, Bettoni F, Asprino P, Koyama F, Rozanski A, Sabbaga J, Habr-Gama A, Parmigiani RB, Galante PA, Perez RO, Camargo AA,
Oncotarget. 6-Oct-2015
Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the mainstay treatment for locally advanced rectal cancer. Variable degrees of tumor regression are observed after nCRT and alternative treatment strategies, including close surveillance without immediate surgery, have been investigated to spare patients with complete tumor regression from potentially adverse outcomes of radical surgery. However, clinical and radiological assessment of response does not allow accurate identification of patients with complete response. In addition, surveillance for recurrence is similarly important for these patients, as early detection of recurrence allows salvage resections and adjuvant interventions. We report the use of liquid biopsies and personalized biomarkers for monitoring treatment response to nCRT and detecting residual disease and recurrence in patients with rectal cancer. We sequenced the whole-genome of four rectal tumors to identify patient-specific chromosomal rearrangements that were used to monitor circulating tumor DNA (ctDNA) in liquid biopsies collected at diagnosis and during nCRT and follow-up. We compared ctDNA levels to clinical, radiological and pathological response to nCRT. Our results indicate that personalized biomarkers and liquid biopsies may not be sensitive for the detection of microscopic residual disease. However, it can be efficiently used to monitor treatment response to nCRT and detect disease recurrence, preceding increases in CEA levels and radiological diagnosis. Similar good results were observed when assessing tumor response to systemic therapy and disease progression. Our study supports the use of personalized biomarkers and liquid biopsies to tailor the management of rectal cancer patients, however, replication in a larger cohort is necessary to introduce this strategy into clinical practice.
Circulating microRNA signature as liquid-biopsy to monitor lung cancer in low-dose computed tomography screening.Friday, October 09, 2015
Sestini S, Boeri M, Marchiano A, Pelosi G, Galeone C, Verri C, Suatoni P, Sverzellati N, La Vecchia C, Sozzi G, Pastorino U,
Oncotarget. 6-Oct-2015
Liquid biopsies can detect biomarkers carrying information on the development and progression of cancer. We demonstrated that a 24 plasma-based microRNA signature classifier (MSC) was capable of increasing the specificity of low dose computed tomography (LDCT) in a lung cancer screening trial. In the present study, we tested the prognostic performance of MSC, and its ability to monitor disease status recurrence in LDCT screening-detected lung cancers. Between 2000 and 2010, 3411 heavy smokers enrolled in two screening programmes, underwent annual or biennial LDCT. During the first five years of screening, 84 lung cancer patients were classified according to one of the three MSC levels of risk: high, intermediate or low. Kaplan-Meier survival analysis was performed according to MSC and clinico-pathological information. Follow-up MSC analysis was performed on longitudinal plasma samples (n = 100) collected from 31 patients before and after surgical resection. Five-year survival was 88.9% for low risk, 79.5% for intermediate risk and 40.1% for high risk MSC (p = 0.001). The prognostic power of MSC persisted after adjusting for tumor stage (p = 0.02) and when the analysis was restricted to LDCT-detected cases after exclusion of interval cancers (p < 0.001). The MSC risk level decreased after surgery in 76% of the 25 high-intermediate subjects who remained disease free, whereas in relapsing patients an increase of the MSC risk level was observed at the time of detection of second primary tumor or metastatic progression. These results encourage exploiting the MSC test for lung cancer monitoring in LDCT screening for lung cancer.
PI3K/AKT/mTOR and sonic hedgehog pathways cooperate together to inhibit human pancreatic cancer stem cell characteristics and tumor growth.Friday, October 09, 2015
Sharma N, Nanta R, Sharma J, Gunewardena S, Singh KP, Shankar S, Srivastava RK,
Oncotarget. 5-Oct-2015
Cancer stem cells (CSCs) play major roles in cancer initiation, progression, and metastasis. It is evident from growing reports that PI3K/Akt/mTOR and Sonic Hedgehog (Shh) signaling pathways are aberrantly reactivated in pancreatic CSCs. Here, we examined the efficacy of combining NVP-LDE-225 (PI3K/mTOR inhibitor) and NVP-BEZ-235 (Smoothened inhibitor) on pancreatic CSCs characteristics, microRNA regulatory network, and tumor growth. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting pancreatic CSC's characteristics and tumor growth in mice by acting at the level of Gli. Combination of NVP-LDE-225 and NVP-BEZ-235 inhibited self-renewal capacity of CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2 and c-Myc, and transcription of Gli. NVP-LDE-225 co-operated with NVP-BEZ-235 to inhibit Lin28/Let7a/Kras axis in pancreatic CSCs. Furthermore, a superior interaction of these drugs was observed on spheroid formation by pancreatic CSCs isolated from Pankras/p53 mice. The combination of these drugs also showed superior effects on the expression of proteins involved in cell proliferation, survival and apoptosis. In addition, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting EMT through modulation of cadherin, vimentin and transcription factors Snail, Slug and Zeb1. In conclusion, these data suggest that the combined inhibition of PI3K/Akt/mTOR and Shh pathways may be beneficial for the treatment of pancreatic cancer.
Biomarkers of Nutrition for Development-Folate Review.Friday, October 09, 2015
Bailey LB, Stover PJ, McNulty H, Fenech MF, Gregory JF, Mills JL, Pfeiffer CM, Fazili Z, Zhang M, Ueland PM, Molloy AM, Caudill MA, Shane B, Berry RJ, Bailey RL, Hausman DB, Raghavan R, Raiten DJ,
The Journal of nutrition. Jul-2015
The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.
Neutrophil Gelatinase-Associated Lipocalin, but Not Kidney Injury Marker 1, Correlates with Duration of Delayed Graft Function.Friday, October 09, 2015
van den Akker EK, Hesselink DA, Manintveld OC, IJzermans JN, de Bruijn RW, Dor FJ,
European surgical research. Europaische chirurgische Forschung. Recherches chirurgicales europeennes. 10-Oct-2015
NGAL in the perfusate correlates with known donor risk factors for DGF. For the first time, we describe that serum NGAL at day 1 can discriminate between DGF and immediate graft function. Also, serum NGAL levels at day 1, 4, and 7 correlate with the duration of DGF. No association with KIM-1 was found. These data suggest that NGAL may be used as an early biomarker to detect DGF and warrants further study.
Relationship of Serum Vitamin D Concentrations and Allostatic Load as a Measure of Cumulative Biological Risk among the US Population: A Cross-Sectional Study.Friday, October 09, 2015
Frei R, Haile SR, Mutsch M, Rohrmann S,
PloS one. 10-10-2015
Vitamin D had a consistent and statistically significant inverse association with all tested models of high AL, which remained consistent after adjusting for biological, socioeconomic, lifestyle and health variables. Our study adds evidence linking low 25(OH)D concentrations with poorer health, further-reaching than bone health.
Mitochondrial Damage-Associated Molecular Patterns (MTDs) Are Released during Hepatic Ischemia Reperfusion and Induce Inflammatory Responses.Friday, October 09, 2015
Hu Q, Wood CR, Cimen S, Venkatachalam AB, Alwayn IP,
PloS one. 9-10-2015
Ischemia / reperfusion injury (IRI) during the course of liver transplantation enhances the immunogenicity of allografts and thus impacts overall graft outcome. This sterile inflammatory insult is known to activate innate immunity and propagate organ damage through the recognition of damage-associate molecular pattern (DAMP) molecules. The purpose of the present study was to investigate the role of mitochondrial DAMPs (MTDs) in the pathogenesis of hepatic IRI. Using in vitro models we observed that levels of MTDs were significantly higher in both transplantation-associated and warm IR, and that co-culture of MTDs with human and rat hepatocytes significantly increased cell death. MTDs were also released in an in vivo rat model of hepatic IRI and associated with increased secretion of inflammatory cytokines (TNF-α, IL-6, and IL-10) and increased liver injury compared to the sham group. Our results suggest that hepatic IR results in a significant increase of MTDs both in vitro and in vivo suggesting that MTDs may serve as a novel marker in hepatic IRI. Co-culture of MTDs with hepatocytes showed a decrease in cell viability in a concentration dependent manner, which indicates that MTDs is a toxic mediator participating in the pathogenesis of liver IR injury.
Epithelial and Erythrocyte Microvesicles From Bronchoalveolar Lavage Fluid Are Elevated and Associated With Outcome in Chronic Lung Allograft Dysfunction.Friday, October 09, 2015
Harms A, Fuehner T, Warnecke G, Haverich A, Gottlieb J, Trummer A,
Transplantation. 8-Oct-2015
Epithelial and RBC BALF-MV are elevated at CLAD diagnosis, have a potential as biomarkers, and support the hypothesis of a pathway, including activation of coagulation and complement, endothelial barrier dysfunction, and microangiopathy.
Association of Metabolic Syndrome with Serum Adipokines in Community-Living Elderly Japanese Women.Friday, October 09, 2015
Takeuchi M, Tsuboi A, Kurata M, Fukuo K, Kazumi T,
Metabolic syndrome and related disorders. 9-Oct-2015
Although proinflammatory, prothrombotic, and anti-inflammatory states were associated with MetS, higher PAI-1 was associated with MetS independent of fat mass index and insulin resistance in elderly Japanese women, in whom obesity is rare.
Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.Friday, October 09, 2015
Ciriello G, Gatza ML, Beck AH, Wilkerson MD, Rhie SK, Pastore A, Zhang H, McLellan M, Yau C, Kandoth C, Bowlby R, Shen H, Hayat S, Fieldhouse R, Lester SC, Tse GM, Factor RE, Collins LC, Allison KH, Chen YY, Jensen K, Johnson NB, Oesterreich S, Mills GB, Cherniack AD, Robertson G, Benz C, Sander C, Laird PW, Hoadley KA, King TA, Perou CM,
Cell. 8-Oct-2015
Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity.Friday, October 09, 2015
Fonseca DM, Hand TW, Han SJ, Gerner MY, Zaretsky AG, Byrd AL, Harrison OJ, Ortiz AM, Quinones M, Trinchieri G, Brenchley JM, Brodsky IE, Germain RN, Randolph GJ, Belkaid Y,
Cell. 8-Oct-2015
Infections have been proposed as initiating factors for inflammatory disorders; however, identifying associations between defined infectious agents and the initiation of chronic disease has remained elusive. Here, we report that a single acute infection can have dramatic and long-term consequences for tissue-specific immunity. Following clearance of Yersinia pseudotuberculosis, sustained inflammation and associated lymphatic leakage in the mesenteric adipose tissue deviates migratory dendritic cells to the adipose compartment, thereby preventing their accumulation in the mesenteric lymph node. As a consequence, canonical mucosal immune functions, including tolerance and protective immunity, are persistently compromised. Post-resolution of infection, signals derived from the microbiota maintain inflammatory mesentery remodeling and consequently, transient ablation of the microbiota restores mucosal immunity. Our results indicate that persistent disruption of communication between tissues and the immune system following clearance of an acute infection represents an inflection point beyond which tissue homeostasis and immunity is compromised for the long-term. VIDEO ABSTRACT.
Visual detection of thrombin using a strip biosensor through aptamer-cleavage reaction with enzyme catalytic amplification.Friday, October 09, 2015
Qin C, Wen W, Zhang X, Gu H, Wang S,
The Analyst. 9-Oct-2015
A new class of strip biosensors has been established based on well-distributed thrombin aptamer-linked gold nanoparticle aggregates, which will undergo a cracking reaction when the target recognizes its homologous aptamer. Combining the aptamer-cleavage reaction with the enzyme catalytic amplification system, our proposed lateral flow strip biosensor (LFB) is capable of visually detecting 6.4 pM of thrombin without instrumentation within 12 minutes. Under the optimal conditions, the quantitative detection of thrombin by a portable strip reader exhibited a linear relationship between the peak area and the concentration of thrombin in the range of 6.4 pM-500 nM with a detection limit of 4.9 pM, which is three orders of magnitude lower than that of the aptamer-functionalized gold nanoparticle-based LFB (2.5 nM, Xu et al., Anal. Chem., 2009, 81, 669-675). As the aptamers have no special requirements and the gold nanoparticles can also be replaced by other metallic nanoparticles, this method for strip sensing is expected to be generally applicable in point of care testing, home testing, medical diagnostics, clinical diagnosis, and environmental monitoring.
Fuchs Endothelial Corneal Dystrophy: Strong Association with rs613872 Not Paralleled by Changes in Corneal Endothelial TCF4 mRNA Level.Friday, October 09, 2015
Ołdak M, Ruszkowska E, Udziela M, Oziębło D, Bińczyk E, Ścieżyńska A, Płoski R, Szaflik JP,
BioMed research international. 2015
Fuchs endothelial corneal dystrophy (FECD) is a common corneal endotheliopathy with a complex and heterogeneous genetic background. Different variants in the TCF4 gene have been strongly associated with the development of FECD. TCF4 encodes the E2-2 transcription factor but the link between the strong susceptibility locus and disease mechanism remains elusive. Here, we confirm a strong positive association between TCF4 single nucleotide polymorphism rs613872 and FECD in Polish patients (OR = 12.95, 95% CI: 8.63-19.42, χ (2) = 189.5, p < 0.0001). We show that TCF4 expression at the mRNA level in corneal endothelium (n = 63) does not differ significantly between individuals with a particular TCF4 genotype. It is also not altered in FECD patients as compared to control samples. The data suggest that changes in the transcript level containing constitutive TCF4 exon encoding the amino-terminal part of the protein seem not to contribute to disease pathogenesis. However, considering the strong association of TCF4 allelic variants with FECD, genotyping of TCF4 risk alleles may be important in the clinical practice.
The Genetics and the Genomics of Primary Congenital Glaucoma.Friday, October 09, 2015
Cascella R, Strafella C, Germani C, Novelli G, Ricci F, Zampatti S, Giardina E,
BioMed research international. 2015
The sight is one of the five senses allowing an autonomous and high-quality life, so that alterations of any ocular component may result in several clinical phenotypes (from conjunctivitis to severe vision loss and irreversible blindness). Most parts of clinical phenotypes have been significantly associated with mutations in genes regulating the normal formation and maturation of the anterior segments of the eye. Among the eye anterior segment disorders, special attention is given to Glaucoma as it represents one of the major causes of bilateral blindness in the world, with an onset due to Mendelian or multifactorial genetic-causative traits. This review will point out the attention on the Primary Congenital Glaucoma (PCG), which is usually transmitted according to an autosomal-recessive inheritance pattern. Taking into consideration the genetic component of the PCG, it is possible to observe a strong heterogeneity concerning the disease-associated loci (GLC3), penetrance defects, and expressivity of the disease. Given the strong PGC heterogeneity, pre- and posttest genetic counseling plays an essential role in the achievement of an appropriate management of PCG, in terms of medical, social, and psychological impact of the disease.
Molecular Markers in the Diagnosis and Treatment of Cancer.Friday, October 09, 2015
Gokden M, Ariza A, Arnaoutakis K,
BioMed research international. 2015
Application of a Systems Pharmacology-Based Placebo Population Model to Analyze Long-Term Data of Postmenopausal Osteoporosis.Friday, October 09, 2015
Berkhout J, Stone JA, Verhamme KM, Stricker BH, Sturkenboom MC, Danhof M, Post TM,
CPT: pharmacometrics & systems pharmacology. Sep-2015
Osteoporosis is a progressive bone disease characterized by decreased bone mass resulting in increased fracture risk. The objective of this investigation was to test whether a recently developed disease systems analysis model for osteoporosis could describe disease progression in a placebo-treated population from the Early Postmenopausal Intervention Cohort (EPIC) study. First, we qualified the model using a subset from the placebo arm of the EPIC study of 222 women who had similar demographic characteristics as the 149 women from the placebo arm of the original population. Second, we applied the model to all 470 women. Bone mineral density (BMD) dynamics were changed to an indirect response model to describe lumbar spine and total hip BMD in this second population. This updated disease systems analysis placebo model describes the dynamics of all biomarkers in the corresponding datasets to a very good approximation; a good description of an individual placebo response will be valuable for evaluating treatments for osteoporosis.
Natural killer cell mediated immunosurveillance of pediatric neuroblastoma.Friday, October 09, 2015
Semeraro M, Rusakiewicz S, Zitvogel L, Kroemer G,
Oncoimmunology. Nov-2015
Until recently, the pathophysiological impact of natural killer (NK) lymphocytes has been largely elusive. Capitalizing on our previous discovery that NK cells mediate immunosurveillance against gastrointestinal stromal tumors (GISTs), we have now investigated the potential influence of immunostimulatory and immunosuppressive isoforms of the NK receptor NKp30 on the fate of infants with neuroblastoma. In three independent cohorts of high-risk neuroblastoma, we observed a similar prognostic impact of the ratio of immunostimulatory vs. immunosuppressive NKp30 isoforms. Patients with high-risk neuroblastoma that are in remission after induction chemotherapy have a higher risk of relapse if their circulating and bone marrow NK cells express the preponderantly immunosuppressive NKp30 C isoform, as determined by a robust RT-PCR-based assay. We also found that neuroblastoma cells express the NKp30 ligand B7-H6, which can be shed from the tumor cells. Elevated soluble B7-H6 levels contained in patient sera inhibited NK functions in vitro and correlated with downregulation of NK-p30 on NK cells, as well as with bone marrow metastasis and chemoresistance. Altogether, these results support the contention that NK cells play a decisive role in the immunosurveillance of neuroblastoma. In light of these results, efforts should be undertaken to investigate NK cell functions in all major cancer types, with the obvious expectation of identifying additional NK cell-related prognostic or predictive biomarkers and improving NK cell based immunotherapeutic strategies against cancer.
Genetics and immunology: reinvigorated.Friday, October 09, 2015
Snyder A, Makarov V, Hellmann M, Rizvi N, Merghoub T, Wolchok JD, Chan TA,
Oncoimmunology. Oct-2015
Immune checkpoint blockade therapy is changing oncology by improving the outcome of patients with advanced malignancies. Our research has revealed the genetic features of tumors present in patients who initiate a successful antitumor immune response and derive clinical benefit from immune checkpoint blockade therapy versus non-responders.
Progressive loss of anti-HER2 CD4(+) T-helper type 1 response in breast tumorigenesis and the potential for immune restoration.Friday, October 09, 2015
Datta J, Rosemblit C, Berk E, Showalter L, Namjoshi P, Mick R, Lee KP, Brod AM, Yang RL, Kelz RR, Fitzpatrick E, Hoyt C, Feldman MD, Zhang PJ, Xu S, Koski GK, Czerniecki BJ,
Oncoimmunology. Oct-2015
Genomic profiling has identified several molecular oncodrivers in breast tumorigenesis. A thorough understanding of endogenous immune responses to these oncodrivers may provide insights into immune interventions for breast cancer (BC). We investigated systemic anti-HER2/neu CD4(+) T-helper type-1 (Th1) responses in HER2-driven breast tumorigenesis. A highly significant stepwise Th1 response loss extending from healthy donors (HD), through HER2(pos)-DCIS, and ultimately to early stage HER2(pos)-invasive BC patients was detected by IFNγ ELISPOT. The anti-HER2 Th1 deficit was not attributable to host-level T-cell anergy, loss of immune competence, or increase in immunosuppressive phenotypes (Treg/MDSCs), but rather associated with a functional shift in IFNγ:IL-10-producing phenotypes. HER2(high), but not HER2(low), BC cells expressing IFNγ/TNF-α receptors were susceptible to Th1 cytokine-mediated apoptosis in vitro, which could be significantly rescued by neutralizing IFNγ and TNF-α, suggesting that abrogation of HER2-specific Th1 may reflect a mechanism of immune evasion in HER2-driven tumorigenesis. While largely unaffected by cytotoxic or HER2-targeted (trastuzumab) therapies, depressed Th1 responses in HER2(pos)-BC patients were significantly restored following HER2-pulsed dendritic cell (DC) vaccinations, suggesting that this Th1 defect is not "fixed" and can be corrected by immunologic interventions. Importantly, preserved anti-HER2 Th1 responses were associated with pathologic complete response to neoadjuvant trastuzumab/chemotherapy, while depressed responses were observed in patients incurring locoregional/systemic recurrence following trastuzumab/chemotherapy. Monitoring anti-HER2 Th1 reactivity following HER2-directed therapies may identify vulnerable subgroups at risk of clinicopathologic failure. In such patients, combinations of existing HER2-targeted therapies with strategies to boost anti-HER2 CD4(+) Th1 immunity may decrease the risk of recurrence and thus warrant further investigation.
Circulating nucleosomes as epigenetic biomarkers in pancreatic cancer.Friday, October 09, 2015
Bauden M, Pamart D, Ansari D, Herzog M, Eccleston M, Micallef J, Andersson B, Andersson R,
Clinical epigenetics. 2015
The present study suggests that global epigenetic profiling of cfnucleosomes in serum using a simple NuQ(®) immunoassay-based approach can provide novel diagnostic biomarkers in pancreatic cancer.
Two dimensions of social anxiety disorder: a pilot study of the Questionnaire for Social Anxiety and Social Competence Deficits for Adolescents.Friday, October 09, 2015
Fernandez Castelao C, Naber K, Altstädt S, Kröner-Herwig B, Ruhl U,
Child and adolescent psychiatry and mental health. 2015
The results of this pilot study provide initial support for the clinical use of the SASKO-J in the diagnostic process. Future research should address the question of psychometric properties in a social anxiety disorder sample as well as the questionnaire's sensitivity for detecting change in symptoms during therapy.
Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing.Friday, October 09, 2015
Wang YH, Yu XH, Luo SS, Han H,
Immunity & ageing : I & A. 2015
This study is the first to employ circular RNA profiling to investigate circular RNA-micro RNA interactions in ageing human CD8(+)T cell populations and the accompanying loss of CD28 expression. The overlapping expression of circular RNA100783 may represent a novel biomarker for the longitudinal tracking ofCD28-related CD8(+) T cell ageing and global immunosenescence.
Evaluation of an Epitypified Ophiocordyceps formosana (Cordyceps s.l.) for Its Pharmacological Potential.Friday, October 09, 2015
Wang YW, Hong TW, Tai YL, Wang YJ, Tsai SH, Lien PT, Chou TH, Lai JY, Chu R, Ding ST, Irie K, Li TK, Tzean SS, Shen TL,
Evidence-based complementary and alternative medicine : eCAM. 2015
The substantial merit of Cordyceps s.l. spp. in terms of medicinal benefits is largely appreciated. Nevertheless, only few studies have characterized and examined the clinical complications of the use of health tonics containing these species. Here, we epitypified C. formosana isolates that were collected and characterized as Ophiocordyceps formosana based on morphological characteristics, molecular phylogenetic analyses, and metabolite profiling. Thus, we renamed and transferred C. formosana to the new protologue Ophiocordyceps formosana (Kobayasi & Shimizu) Wang, Tsai, Tzean & Shen comb. nov. Additionally, the pharmacological potential of O. formosana was evaluated based on the hot-water extract from its mycelium. The relative amounts of the known bioactive ingredients that are unique to Cordyceps s.l. species in O. formosana were found to be similar to the amounts in O. sinensis and C. militaris, indicating the potential applicability of O. formosana for pharmacological uses. Additionally, we found that O. formosana exhibited antioxidation activities in vitro and in vivo that were similar to those of O. sinensis and C. militaris. Furthermore, O. formosana also displayed conspicuously effective antitumor activity compared with the tested Cordyceps s.l. species. Intrinsically, O. formosana exhibited less toxicity than the other Cordyceps species. Together, our data suggest that the metabolites of O. formosana may play active roles in complementary medicine.
Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer.Friday, October 09, 2015
Advani P, Cornell L, Chumsri S, Moreno-Aspitia A,
Breast cancer (Dove Medical Press). 2015
Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%-20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed.
Expression of Fascin-1 on human lung cancer and paracarcinoma tissue and its relation to clinicopathological characteristics in patients with lung cancer.Friday, October 09, 2015
Zhao W, Gao J, Wu J, Liu QH, Wang ZG, Li HL, Xing LH,
OncoTargets and therapy. 2015
In lung cancer, Fascin-1 expression was closely related to tumor invasion and metastasis, and the difference in expression of Fascin-1 had a significant effect on the survival time of the lung cancer patients. Therefore, Fascin-1 might be expected to serve as a possible potential biomarker of lung cancer.
Liposomal n-butylidenephthalide protects the drug from oxidation and enhances its antitumor effects in glioblastoma multiforme.Friday, October 09, 2015
Lin YL, Chang KF, Huang XF, Hung CL, Chen SC, Chao WR, Liao KW, Tsai NM,
International journal of nanomedicine. 2015
LPPC encapsulation technology is able to protect BP's structural stability and enhance its antitumor effects, thus providing a better tool for use in cancer therapy.
Chitosan nanofiber scaffold improves bone healing via stimulating trabecular bone production due to upregulation of the Runx2/osteocalcin/alkaline phosphatase signaling pathway.Friday, October 09, 2015
Ho MH, Yao CJ, Liao MH, Lin PI, Liu SH, Chen RM,
International journal of nanomedicine. 2015
Osteoblasts play critical roles in bone formation. Our previous study showed that chitosan nanofibers can stimulate osteoblast proliferation and maturation. This translational study used an animal model of bone defects to evaluate the effects of chitosan nanofiber scaffolds on bone healing and the possible mechanisms. In this study, we produced uniform chitosan nanofibers with fiber diameters of approximately 200 nm. A bone defect was surgically created in the proximal femurs of male C57LB/6 mice, and then the left femur was implanted with chitosan nanofiber scaffolds for 21 days and compared with the right femur, which served as a control. Histological analyses revealed that implantation of chitosan nanofiber scaffolds did not lead to hepatotoxicity or nephrotoxicity. Instead, imaging analyses by X-ray transmission and microcomputed tomography showed that implantation of chitosan nanofiber scaffolds improved bone healing compared with the control group. In parallel, microcomputed tomography and bone histomorphometric assays further demonstrated augmentation of the production of new trabecular bone in the chitosan nanofiber-treated group. Furthermore, implantation of chitosan nanofiber scaffolds led to a significant increase in the trabecular bone thickness but a reduction in the trabecular parameter factor. As to the mechanisms, analysis by confocal microscopy showed that implantation of chitosan nanofiber scaffolds increased levels of Runt-related transcription factor 2 (Runx2), a key transcription factor that regulates osteogenesis, in the bone defect sites. Successively, amounts of alkaline phosphatase and osteocalcin, two typical biomarkers that can simulate bone maturation, were augmented following implantation of chitosan nanofiber scaffolds. Taken together, this translational study showed a beneficial effect of chitosan nanofiber scaffolds on bone healing through stimulating trabecular bone production due to upregulation of Runx2-mediated alkaline phosphatase and osteocalcin gene expressions. Our results suggest the potential of chitosan nanofiber scaffolds for therapy of bone diseases, including bone defects and bone fractures.
Proteoglycan 4 is a diagnostic biomarker for COPD.Friday, October 09, 2015
Lee KY, Chuang HC, Chen TT, Liu WT, Su CL, Feng PH, Chiang LL, Bien MY, Ho SC,
International journal of chronic obstructive pulmonary disease. 2015
PRG4 may be a biomarker for identification of severity in COPD. It was related to the 1-year forced vital capacity decline in COPD patients.
Utilization of cytogenetic biomarkers as a tool for assessment of radiation injury and evaluation of radiomodulatory effects of various medicinal plants - a review.Friday, October 09, 2015
Samarth RM, Samarth M, Matsumoto Y,
Drug design, development and therapy. 2015
Systematic biological measurement of "cytogenetic endpoints" has helped phenomenally in assessment of risks associated with radiation exposure. There has been a surge in recent times for the usage of radioactive materials in health care, agriculture, industrial, and nuclear power sectors. The likelihood of radiation exposure from accidental or occupational means is always higher in an overburdened ecosystem that is continuously challenged to meet the population demands. Risks associated with radiation exposure in this era of modern industrial growth are minimal as international regulations for maintaining the safety standards are stringent and strictly adhered to, however, a recent disaster like "Fukushima" impels us to think beyond. The major objective of radiobiology is the development of an orally effective radio-modifier that provides protection from radiation exposure. Once available for mass usage, these compounds will not only be useful for providing selective protection against accidental and occupational radiation exposure but also help to permit use of higher doses of radiation during treatment of various malignancies curtailing unwarranted adverse effects imposed on normal tissues. Bio-active compounds isolated from natural sources enriched with antioxidants possess unique immune-modulating properties, thus providing a double edged benefit over synthetic radioprotectors. We aim to provide here a comprehensive overview of the various agents originating from plant sources that portrayed promising radioprotection in various experimental models with special emphasis on studies that used cytogenetic biomarkers. The agents will include crude extracts of various medicinal plants, purified fractions, and herbal preparations.
Biomarkers of Guillain-Barré Syndrome: Some Recent Progress, More Still to Be Explored.Friday, October 09, 2015
Wang Y, Sun S, Zhu J, Cui L, Zhang HL,
Mediators of inflammation. 2015
Guillain-Barré syndrome (GBS), the axonal subtype of which is mainly triggered by C. jejuni with ganglioside-mimicking lipooligosaccharides (LOS), is an immune-mediated disorder in the peripheral nervous system (PNS) accompanied by the disruption of the blood-nerve barrier (BNB) and the blood-cerebrospinal fluid barrier (B-CSF-B). Biomarkers of GBS have been extensively explored and some of them are proved to assist in the clinical diagnosis and in monitoring disease progression as well as in assessing the efficacy of immunotherapy. Herein, we systemically review the literature on biomarkers of GBS, including infection-/immune-/BNB, B-CSF-B, and PNS damage-associated biomarkers, aiming at providing an overview of GBS biomarkers and guiding further investigations. Furthermore, we point out further directions for studies on GBS biomarkers.
Copeptin and Long-Term Risk of Recurrent Vascular Events After Transient Ischemic Attack and Ischemic Stroke: Population-Based Study.Friday, October 09, 2015
Greisenegger S, Segal HC, Burgess AI, Poole DL, Mehta Z, Rothwell PM,
Stroke; a journal of cerebral circulation. 8-Oct-2015
In patients with TIA and ischemic stroke, copeptin predicted recurrent vascular events and death, particularly after cardioembolic TIA/stroke. Further validation is required, in particular, in studies using more extensive cardiac evaluation.
Smad 1/5/8 are myogenic regulators of murine and human mesoangioblasts.Friday, October 09, 2015
Costamagna D, Quattrocelli M, van Tienen F, Umans L, de Coo IF, Zwijsen A, Huylebroeck D, Sampaolesi M,
Journal of molecular cell biology. 8-Oct-2015
Mesoangioblasts (MABs) are vessel-associated stem cells that express pericyte marker genes and participate in skeletal muscle regeneration. Molecular circuits that regulate the myogenic commitment of MABs are still poorly characterized. The critical role of bone morphogenetic protein (BMP) signalling during proliferation and differentiation of adult myogenic precursors, such as satellite cells, has recently been established. We evaluated whether BMP signalling impacts on the myogenic potential of embryonic and adult MABs both in vitro and in vivo. Addition of BMP inhibited MAB myogenic differentiation, whereas interference with the interactions between BMPs and receptor complexes induced differentiation. Similarly, siRNA-mediated knockdown of Smad8 in Smad1/5-null MABs or inhibition of SMAD1/5/8 phosphorylation with Dorsomorphin (DM) also improved myogenic differentiation, demonstrating a novel role of SMAD8. Moreover, using a transgenic mouse model of Smad8 deletion, we demonstrated that the absence of SMAD8 protein improved MAB myogenic differentiation. Furthermore, once injected into α-Sarcoglycan (Sgca)-null muscles, DM-treated MABs were more efficacious to restore α-sarcoglycan (αSG) protein levels and re-establish functional muscle properties. Similarly, in acute muscle damage, DM-treated MABs displayed a better myogenic potential compared with BMP-treated and untreated cells. Finally, SMADs also control the myogenic commitment of human MABs (hMABs). BMP signalling antagonists are therefore novel candidates to improve the therapeutic effects of hMABs.
Effect of Aging on Adipose Tissue Inflammation in the Knee Joints of F344BN Rats.Friday, October 09, 2015
Fu Y, Huebner JL, Kraus VB, Griffin TM,
The journals of gerontology. Series A, Biological sciences and medical sciences. 8-Oct-2015
The infrapatellar fat pad (IFP) secretes inflammatory mediators in osteoarthritic knees, but the effect of aging on IFP inflammation is unknown. We tested the hypothesis that aging increases basal and interleukin-1β (IL-1β)-stimulated IFP inflammation in 10-, 20-, and 30-month-old male F344BN F1-hybrid rats. IFPs were cultured ex vivo for 24 hours and treated ±1ng/mL IL-1β to simulate injury-induced inflammation. IFP inflammation was evaluated by measuring secreted cytokine concentrations and by quantitative expression of immunoregulatory and pro- and anti-adipogenic genes. With age, osteoarthritis pathology increased and IFP mass decreased. Although adipocyte size did not change with age, variation in adipocyte size was positively associated with synovial thickness independent of age whereas associations with cartilage damage were age dependent. In the absence of IL-1β, aging was associated with a significant increase in IFP secretion of tumor necrosis factor α by 67% and IL-13 by 35% and a reduction in the expression of immunoregulatory M2 macrophage genes. However, following an IL-1β challenge, adipogenesis markers decreased and pro- and anti-inflammatory cytokines increased independent of age. The lone exception was leptin, which decreased >70% with age. Thus, although aging promotes osteoarthritis risk by increasing basal inflammation, our findings also revealed a potentially protective effect of aging by decreasing IL-1β-stimulated leptin production.
Contribution of Gut Bacteria to Lipid Levels: Another Metabolic Role for Microbes?Friday, October 09, 2015
Allayee H, Hazen SL,
Circulation research. 9-Oct-2015
Characterizing PCDH19 in human induced pluripotent stem cells (iPSCs) and iPSC-derived developing neurons: emerging role of a protein involved in controlling polarity during neurogenesis.Friday, October 09, 2015
Compagnucci C, Petrini S, Higuraschi N, Trivisano M, Specchio N, Hirose S, Bertini E, Terracciano A,
Oncotarget. 29-Sep-2015
PCDH19 (Protocadherin 19), a member of the cadherin superfamily, is involved in the pathogenic mechanism of an X-linked model of neurological disease. The biological function of PCHD19 in human neurons and during neurogenesis is currently unknown. Therefore, we decided to use the model of the induced pluripotent stem cells (iPSCs) to characterize the location and timing of expression of PCDH19 during cortical neuronal differentiation. Our data show that PCDH19 is expressed in pluripotent cells before differentiation in a homogeneous pattern, despite its localization is often limited to one pole of the cell. During neuronal differentiation, positional information on the progenitor cells assumes an important role in acquiring polarization. The proper control of the cell orientation ensures a fine balancing between symmetric (giving rise to two progenitor sister cells) versus asymmetric (giving rise to one progenitor cell and one newborn neuron) division. This process results in the polar organization of the neural tube with a lumen indicating the basal part of the polarized neuronal progenitor cell; in the iPSC model the cells are organized in the 'neural rosette' and interestingly, PCDH19 is located at the center of the rosette, with other well-known markers of the lumen (N-cadherin and ZO-1). These data suggest that PCDH19 has a role in instructing the apico-basal polarity of the progenitor cells, thus regulating the development of a properly organized human brain.
Technological advances in bovine mastitis diagnosis: an overview.Friday, October 09, 2015
Duarte CM, Freitas PP, Bexiga R,
Journal of veterinary diagnostic investigation : official publication of the American Association of Veterinary Laboratory Diagnosticians, Inc. 8-Oct-2015
Bovine mastitis is an economic burden for dairy farmers and preventative control measures are crucial for the sustainability of any dairy business. The identification of etiological agents is necessary in controlling the disease, reducing risk of chronic infections and targeting antimicrobial therapy. The suitability of a detection method for routine diagnosis depends on several factors, including specificity, sensitivity, cost, time in producing results, and suitability for large-scale sampling of milk. This article focuses on current methodologies for identification of mastitis pathogens and for detection of inflammation, as well as the advantages and disadvantages of different methods. Emerging technologies, such as transcriptome and proteome analyses and nano- and microfabrication of portable devices, offer promising, sensitive methods for advanced detection of mastitis pathogens and biomarkers of inflammation. The demand for alternative, fast, and reliable diagnostic procedures is rising as farms become bigger. Several examples of technological and scientific advances are summarized which have given rise to more sensitive, reliable and faster diagnostic results.
Erratum to: Targeted BRAF and CTNNB1 next-generation sequencing allows proper classification of nonadenomatous lesions of the sellar region in samples with limiting amounts of lesional cells.Friday, October 09, 2015
Marucci G, de Biase D, Zoli M, Faustini-Fustini M, Bacci A, Pasquini E, Visani M, Mazzatenta D, Frank G, Tallini G,
Pituitary. 8-Oct-2015
Low-level Ki-67 expression as an independent predictor of bladder tumour recurrence in patients with primary upper tract urothelial carcinoma after radical nephroureterectomy.Friday, October 09, 2015
Wu P, Liu S, Zhang W, Zhang Y, Zhu G, Wei D, Wan B, Wang J,
Japanese journal of clinical oncology. 8-Oct-2015
Low-level Ki-67 expression was an independent predictor for bladder tumour recurrence, while Ki-67 overexpression was associated with adverse clinicopathological parameters and poor prognosis in patients with primary upper tract urothelial carcinoma after radical nephroureterectomy.
Erratum to: Cross-validation of biomarkers for the early differential diagnosis and prognosis of dementia in a clinical setting.Friday, October 09, 2015
Perani D, Cerami C, Caminiti SP, Santangelo R, Coppi E, Ferrari L, Pinto P, Passerini G, Falini A, Iannaccone S, Cappa SF, Comi G, Gianolli L, Magnani G,
European journal of nuclear medicine and molecular imaging. 8-Oct-2015
The extent of mercury (Hg) exposure among Saudi mothers and their respective infants.Friday, October 09, 2015
Al-Saleh I, Abduljabbar M, Al-Rouqi R, Eltabache C, Al-Rajudi T, Elkhatib R, Nester M,
Environmental monitoring and assessment. Nov-2015
A total of 1016 healthy Saudi mothers and their respective infants (aged 3-12 months) were recruited from 57 Primary Health Care Centers (PHCCs) in Riyadh, Saudi Arabia, to evaluate the extent of mercury (Hg) exposure and predict its sources in the healthy Saudi population. Total Hg levels were measured in maternal urine, breast milk, blood, and hair and in the infants' urine and hair. Only 1.9 % of the mothers had urinary Hg (UHg) >10 μg/l, the limit for asymptomatic adults recommended by the World Health Organization, but the median (0.99 μg/l) was higher than in other countries. Also, 49.3 % of the mothers had UHg >1 μg/l, the German reference value for adults. Median infant UHg was 0.729 μg/l, and 77 and 93 % of the infants had levels higher than 0.4 and 0.1 μg/l, the reference values of the Centers for Disease Control and Prevention and for Germany, respectively. The median Hg level in breast milk was 0.884 μg/l. Even though 43.2 % of the milk samples were above the background level for Hg in human milk (1 μg/l), our results were lower than those reported from other countries. Median maternal total Hg in blood was 0.637 μg/l, and only 0.4 and 6.9 % of samples were higher than the Hg reference levels of 5.8 μg/l of the Environmental Protection Agency (EPA) and of 2 μg/l for Germany, respectively. Total Hg levels in hair (HHg) varied widely among mothers and infants, but only 3.9 % of the mothers and 2.8 % of the infants had HHg >1 μg/g (the EPA reference level). Median HHg values were 0.117 μg/g dry weight in mothers and 0.1 μg/g dry weight in infants; both were lower than in other countries. The Hg levels in mothers and their respective infants were relatively low, but our results were consistent with other studies indicating that dental amalgam fillings and fish consumption were the main predictors of maternal Hg exposure. Among the several biomarkers of Hg exposure, Hg levels in maternal hair and urine were the strongest predictors of infant exposure. The lack of an association between Hg in breast milk and Hg in infant urine and hair suggested that the infants were exposed to Hg predominately during pregnancy rather than during breastfeeding. We expect that our data can serve as a baseline for further biomonitoring and follow-up studies, particularly of the long-term impact of Hg on childhood neurodevelopment.
Urinary laminin-γ2 is a novel biomarker of non-muscle invasive urothelial carcinoma.Friday, October 09, 2015
Kamada M, Koshikawa N, Minegishi T, Kawada C, Karashima T, Shuin T, Seiki M,
Cancer science. 9-Oct-2015
Since lack of appropriate biomarkers has hampered early detection of urothelial cancer (UC), development of biomarkers for its diagnosis at earlier stages is of importance. Laminin-332 (Ln-332, formerly Ln-5), a component of basement membranes, consists of Ln-α3, Ln-β3, and Ln-γ2 polypeptides. However, monomeric Ln-γ2 alone is frequently expressed in malignant neoplasms. If Ln-γ2 is also expressed in UC and secreted into the urine, its detection could be useful for UC diagnosis. Here, we evaluated Ln-γ2 levels from 60 patients with urinary diseases (including UC) via western blotting, and detected it in approximately 53% of UC cases. Using immunohistochemistry, we confirmed Ln-γ2 expression in UC tissues that were positive for Ln-γ2, while Ln-α3 expression was absent. We next developed a sandwich enzyme-linked immunosorbent assay and applied it for screening 39 patients with non-muscle invasive UC and 61 patients with benign urologic diseases. The Ln-γ2 levels were higher in UC patients than in those with benign urologic diseases. Ln-γ2 was detected even in patients with earlier stages of UC, such as Ta, T1, or carcinoma in situ (CIS). The sensitivity of Ln-γ2 testing for UC was 97.4%, and the specificity was 45.9%, using a cut-off of 0.5 μg/g∙crn. Ln-γ2 had greater diagnostic value for detecting non-muscle invasive UC compared to conventional urine cytology and available biomarkers for UC, and may be useful as a urine biomarker for the diagnosis and monitoring of UC. This article is protected by copyright. All rights reserved.
A Mediterranean diet supplemented with extra virgin olive oil or nuts improves endothelial markers involved in blood pressure control in hypertensive women.Friday, October 09, 2015
Storniolo CE, Casillas R, Bulló M, Castañer O, Ros E, Sáez GT, Toledo E, Estruch R, Ruiz-Gutiérrez V, Fitó M, Martínez-González MA, Salas-Salvadó J, Mitjavila MT, Moreno JJ,
European journal of nutrition. 8-Oct-2015
The changes in NO and ET-1 as well as ET-1 receptors gene expression explain, at least partially, the effect of EVOO or nuts on lowering BP among hypertensive women.
c-Myc-miR-29c-REV3L signalling pathway drives the acquisition of temozolomide resistance in glioblastoma.Friday, October 09, 2015
Luo H, Chen Z, Wang S, Zhang R, Qiu W, Zhao L, Peng C, Xu R, Chen W, Wang HW, Chen Y, Yang J, Zhang X, Zhang S, Chen D, Wu W, Zhao C, Cheng G, Jiang T, Lu D, You Y, Liu N, Wang H,
Brain : a journal of neurology. 8-Oct-2015
Resistance to temozolomide poses a major clinical challenge in glioblastoma multiforme treatment, and the mechanisms underlying the development of temozolomide resistance remain poorly understood. Enhanced DNA repair and mutagenesis can allow tumour cells to survive, contributing to resistance and tumour recurrence. Here, using recurrent temozolomide-refractory glioblastoma specimens, temozolomide-resistant cells, and resistant-xenograft models, we report that loss of miR-29c via c-Myc drives the acquisition of temozolomide resistance through enhancement of REV3L-mediated DNA repair and mutagenesis in glioblastoma. Importantly, disruption of c-Myc/miR-29c/REV3L signalling may have dual anticancer effects, sensitizing the resistant tumours to therapy as well as preventing the emergence of acquired temozolomide resistance. Our findings suggest a rationale for targeting the c-Myc/miR-29c/REV3L signalling pathway as a promising therapeutic approach for glioblastoma, even in recurrent, treatment-refractory settings.
Pulmonary mucinous adenocarcinomas: architectural patterns in correlation with genetic changes, prognosis and survival.Friday, October 09, 2015
Geles A, Gruber-Moesenbacher U, Quehenberger F, Manzl C, Al Effah M, Grygar E, Juettner-Smolle F, Popper HH,
Virchows Archiv : an international journal of pathology. 8-Oct-2015
Of pulmonary adenocarcinomas, about 25-30 % of cases is of a mucinous type. Mucinous adenocarcinomas are regarded as more aggressive compared to their non-mucinous counterparts. Invasive mucinous adenocarcinoma, colloid, and enteric adenocarcinomas are variants within adenocarcinomas. We investigated 76 invasive mucinous adenocarcinomas, including colloid variants, for predominant and secondary patterns, their different form of mucin storage and release, expression of cytokeratin 7 and 20, TTF1 and CDX2, MUC1, 2, and 5AC proteins, p14 and p16 proteins, possible rearrangements for EML4ALK and ROS1, as well as KRAS mutational status, and correlated this with survival. For comparison, 259 non-mucinous adenocarcinomas were selected. Overall survival for invasive mucinous adenocarcinomas corrected for T and N stage was not different from their non-mucinous counterpart. Most were of an acinar pattern. Neither pattern, nor type of mucin storage and release, such as luminal, extracellular, or goblet cell type had any influence on survival. Of adenocarcinomas expressing CK20, all but one expressed TTF1 either strongly or at least focally, and 8 co-expressed CDX2 focally. Most mucinous adenocarcinomas expressed either MUC1 or MUC5AC proteins, but rarely MUC2, while a few cases co-expressed both or all three. Loss of p16 expression correlated with worse outcome. KRAS mutation was found in 56 % of mucinous adenocarcinomas. Mutational status was neither correlated with architectural pattern nor survival. Codon 12 mutations were most frequent, and one case presented with KRAS mutations in codon 12 and 61. Goblet cell variants of mucinous adenocarcinomas presented predominantly with codon 12 mutations, while all colloid variants had KRAS mutation. Two cases had EML4 and ALK1 rearranged; ROS1 rearrangement was not found. Mucinous adenocarcinomas behave similar to non-mucinous variants. TNM stage is the most important factor followed by p16 loss predicting overall survival.
Urine metabolomics of women from small villages exposed to high environmental cadmium levels.Friday, October 09, 2015
Xu Y, Wang J, Liang X, Gao Y, Chen W, Huang Q, Liang C, Tang L, Yang X,
Environmental toxicology and chemistry / SETAC. 9-Oct-2015
This study aimed to identify urine metabolites in women exposed to high cadmium levels. 21 women exposed to environmental Cd and 12 age-matched controls were categorized as high (Urine Cd ≥ 15 µg/g creatinine [Cr]) (n = 9) or low (15 µg/g Cr > UCd > 5 µg/g Cr) (n = 12) exposure. Low molecular weight metabolites in urine were analyzed by gas chromatography and mass spectrometry after derivatization. An orthogonal partial least-squares discriminant analysis (OPLS-DA) model was constructed, and metabolites from the dimensional model were selected according to the variable importance in projection (VIP > 1). Metabolites differing significantly in abundance between different exposure groups were identified by searching mass spectral databases, and related pathways were analyzed by Kyoto Encyclopedia of Genes and Genomes (KEGG). Around 110 significantly different metabolites were detected with VIP > 1 and 48 of them were found to markedly differ in abundance among the three groups. 27 matched with known metabolites, including 22 significantly increased and 5 markedly decreased in the high exposure group (p < 0.01). KEGG results indicated that carbohydrate, amino acid, bone and intestinal flora metabolism and the tricarboxylic acid cycle were affected by cadmium exposure. This study identified metabolites that differed in abundance in response to Cd exposure. Further studies may connect these biomarkers to early damages caused by Cd. This article is protected by copyright. All rights reserved.
Analysis of in vitro ADCC and clinical response to trastuzumab: possible relevance of FcγRIIIA/FcγRIIA gene polymorphisms and HER-2 expression levels on breast cancer cell lines.Friday, October 09, 2015
Boero S, Morabito A, Banelli B, Cardinali B, Dozin B, Lunardi G, Piccioli P, Lastraioli S, Carosio R, Salvi S, Levaggi A, Poggio F, D'Alonzo A, Romani M, Del Mastro L, Poggi A, Pistillo MP,
Journal of translational medicine. 2015
Although this study was performed in a limited number of patients, it would indicate a correlation of FcγR gene polymorphisms to the ADCC extent in combination with the HER-2 expression levels on tumor target cells in BC patients. However, to confirm our findings further experimental evidences obtained from a larger cohort of BC patients are mandatory.
Genetic sharing and heritability of paediatric age of onset autoimmune diseases.Friday, October 09, 2015
Li YR, Zhao SD, Li J, Bradfield JP, Mohebnasab M, Steel L, Kobie J, Abrams DJ, Mentch FD, Glessner JT, Guo Y, Wei Z, Connolly JJ, Cardinale CJ, Bakay M, Li D, Maggadottir SM, Thomas KA, Qui H, Chiavacci RM, Kim CE, Wang F, Snyder J, Flatø B, Førre Ø, Denson LA, Thompson SD, Becker ML, Guthery SL, Latiano A, Perez E, Resnick E, Strisciuglio C, Staiano A, Miele E, Silverberg MS, Lie BA, Punaro M, Russell RK, Wilson DC, Dubinsky MC, Monos DS, Annese V, Munro JE, Wise C, Chapel H, Cunningham-Rundles C, Orange JS, Behrens EM, Sullivan KE, Kugathasan S, Griffiths AM, Satsangi J, Grant SF, Sleiman PM, Finkel TH, Polychronakos C, Baldassano RN, Luning Prak ET, Ellis JA, Li H, Keating BJ, Hakonarson H,
Nature communications. 2015
Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
Urinary Tract Infection during Pregnancy, Angiogenic Factor Profiles, and Risk of Preeclampsia.Friday, October 09, 2015
Easter SR, Cantonwine DE, Zera CA, Lim KH, Parry SI, McElrath TF,
American journal of obstetrics and gynecology. 5-Oct-2015
Presence of UTI in pregnancy, particularly in the third trimester, is strongly associated with PE. This association supports the hypothesis that the risk of PE is enhanced by an increased maternal inflammatory burden. Prophylaxis against UTI represents a potentially low-cost global intervention to slow or halt the development of PE.
Diurnal rhythms in the human urine metabolome during sleep and total sleep deprivation.Friday, October 09, 2015
Giskeødegård GF, Davies SK, Revell VL, Keun H, Skene DJ,
Scientific reports. 2015
Understanding how metabolite levels change over the 24 hour day is of crucial importance for clinical and epidemiological studies. Additionally, the association between sleep deprivation and metabolic disorders such as diabetes and obesity requires investigation into the links between sleep and metabolism. Here, we characterise time-of-day variation and the effects of sleep deprivation on urinary metabolite profiles. Healthy male participants (n = 15) completed an in-laboratory study comprising one 24 h sleep/wake cycle prior to 24 h of continual wakefulness under highly controlled environmental conditions. Urine samples were collected over set 2-8 h intervals and analysed by (1)H NMR spectroscopy. Significant changes were observed with respect to both time of day and sleep deprivation. Of 32 identified metabolites, 7 (22%) exhibited cosine rhythmicity over at least one 24 h period; 5 exhibiting a cosine rhythm on both days. Eight metabolites significantly increased during sleep deprivation compared with sleep (taurine, formate, citrate, 3-indoxyl sulfate, carnitine, 3-hydroxyisobutyrate, TMAO and acetate) and 8 significantly decreased (dimethylamine, 4-DTA, creatinine, ascorbate, 2-hydroxyisobutyrate, allantoin, 4-DEA, 4-hydroxyphenylacetate). These data indicate that sampling time, the presence or absence of sleep and the response to sleep deprivation are highly relevant when identifying biomarkers in urinary metabolic profiling studies.
Survival after ultramassive transfusion: a review of 1360 cases.Friday, October 09, 2015
Dzik WS, Ziman A, Cohen C, Pai M, Lozano M, Kaufman RM, Delaney M, Selleng K, Murphy MF, Hervig T, Yazer M,
Transfusion. 9-Oct-2015
Trauma was not the leading cause of UMT. Increasing RBC requirements were significantly associated with decreasing survival. However, survival was more strongly associated with diagnostic category than total RBCs transfused, with highest survival rates in solid organ transplant surgery.
Nitroproteins in Human Astrocytomas Discovered by Gel Electrophoresis and Tandem Mass Spectrometry.Friday, October 09, 2015
Peng F, Li J, Guo T, Yang H, Li M, Sang S, Li X, Desiderio DM, Zhan X,
Journal of the American Society for Mass Spectrometry. 8-Oct-2015
Protein tyrosine nitration is involved in the pathogenesis of highly fatal astrocytomas, a type of brain cancer. To understand the molecular mechanisms of astrocytomas and to discover new biomarkers/therapeutic targets, we sought to identify nitroproteins in human astrocytoma tissue. Anti-nitrotyrosine immunoreaction-positive proteins from a high-grade astrocytoma tissue were detected with two-dimensional gel electrophoresis (2DGE)-based nitrotyrosine immunoblots, and identified with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Fifty-seven nitrotyrosine immunopositive protein spots were detected. A total of 870 proteins (nitrated and non-nitrated) in nitrotyrosine-immunopositive 2D gel spots were identified, and 18 nitroproteins and their 20 nitrotyrosine sites were identified with MS/MS analysis. These nitroproteins participate in multiple processes, including drug-resistance, signal transduction, cytoskeleton, transcription and translation, cell proliferation and apoptosis, immune response, phenotypic dedifferentiation, cell migration, and metastasis. Among those nitroproteins that might play a role in astrocytomas was nitro-sorcin, which is involved in drug resistance and metastasis and might play a role in the spread and treatment of an astrocytoma. Semiquantitative immune-based measurements of different sorcin expressions were found among different grades of astrocytomas relative to controls, and a semiquantitative increased nitration level in high-grade astrocytoma relative to control. Nitro-β-tubulin functions in cytoskeleton and cell migration. Semiquantitative immunoreactivity of β-tubulin showed increased expression among different grades of astrocytomas relative to controls and semiquantitatively increased nitration level in high-grade astrocytoma relative to control. Each nitroprotein was rationalized and related to the corresponding functional system to provide new insights into tyrosine nitration and its potential role in the pathogenesis of astrocytoma formation. Graphical Abstract ᅟ.
On the role of HNS and HSN as light-sensitive NO-donors for delivery in biological media.Friday, October 09, 2015
Trabelsi T, Linguerri R, Ben Yaghlane S, Jaidane NE, Mogren Al-Mogren M, Francisco JS, Hochlaf M,
The Journal of chemical physics. 7-Oct-2015
Results are presented that suggest that thiazyl hydride (HSN)/thionitrosyl hydride (sulfimide, HNS) can be used as light-sensitive compounds for NO-delivery in biological media, as well as markers for the possible detection of intermediates in nitrites + H2S reactions at the cellular level. They are expected to be more efficient than the HNO/HON isovalent species and hence they should be considered instead. A set of characteristic spectroscopic features are identified that could aid in the possible detection of these species in the gas phase or in biological environments. The possibility of intramolecular dynamical processes involving excited states that are capable of interconverting HNS and its isomeric form HSN is examined.
High prevalence of HPV59 in cytologically abnormal cervical samples.Friday, October 09, 2015
Ye F, Chan N, Feng T, Wu J, Jiang S, Sperling R, Zhang DY,
Experimental and molecular pathology. 5-Oct-2015
The results demonstrate that geographical distribution of HPV genotypes may play an important role in clinical management of HPV infection, particularly when treating cervical dysplasia and recommending HPV vaccination.
Quantitative sensory testing of temperature thresholds: Possible biomarkers for persistent pain?Friday, October 09, 2015
Malmström EM, Stjerna J, Högestätt ED, Westergren H,
Journal of rehabilitation medicine. 9-Oct-2015
Thermal detection and pain thresholds are reproducible over time, allowing longitudinal assessment of sensory function using QST. Although increased sensitivity to cold pain was the most prominent finding in this cohort of patients with persistent pain, calculation of the differences between thermal detection and pain thresholds may prove superior in detecting sensory alterations.
DIAGNOSIS OF ENDOCRINE DISEASE: High-yield thyroid fine-needle aspiration cytology: an update focused on ancillary techniques improving its accuracy.Friday, October 09, 2015
Bongiovanni M, Trimboli P, Rossi ED, Fadda G, Nobile A, Giovanella L,
European journal of endocrinology / European Federation of Endocrine Societies. 8-Oct-2015
Thyroid fine-needle aspiration (FNA) cytology is a fast growing field. One of the most developing areas is represented by molecular tests applied to cytological material. Patients that could benefit the most from these tests are those that have been diagnosed as "indeterminate" on FNA. They could be better stratified in terms of malignancy risk and thus oriented with more confidence to the appropriate management. Taking in consideration this need to improve and keep high the yield of thyroid FNA, professionals from various fields (i.e. molecular biologists, endocrinologists, nuclear medicine physicians and radiologists) are refining and fine-tuning their diagnostic instruments. In particular, all these developments aim at increasing the negative predictive value of FNA to improve the selection of patients for diagnostic surgery. These advances involve terminology, the application of next-generation sequencing (NGS) to thyroid FNA, the use of immunocyto- and histochemistry, the development of new sampling techniques and the increasing use of nuclear medicine as well as molecular imaging in the management of patient with a thyroid nodule. Herein, we review the recent advances in thyroid FNA cytology that could be of interest for the "thyroid-care" community, with particular focus on the indeterminate diagnostic category.
Asthma-COPD overlap syndrome (ACOS): A diagnostic challenge.Friday, October 09, 2015
Tho NV, Park HY, Nakano Y,
Respirology (Carlton, Vic.). 8-Oct-2015
Asthma-chronic obstructive pulmonary disease (COPD) overlap syndrome (ACOS) is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD. ACOS may be a special phenotype of a spectrum of chronic obstructive airway diseases, in which asthma and COPD are at the two opposite ends. The prevalence of ACOS varies considerably due to differing criteria being applied for diagnosis. Patients with ACOS utilize a large proportion of medical resources. They are associated with more frequent adverse outcomes than those with asthma or COPD alone. ACOS is currently a diagnostic challenge for physicians because there are no specific biomarkers to differentiate ACOS from asthma or COPD. The approach to diagnosing ACOS depends on the population from which the patient originated. The management of ACOS should be individualized to ensure the most effective treatment with minimal side effects. In this paper, we review the diagnostic criteria of ACOS used in previous studies, propose practical approaches to diagnosing and managing ACOS and raise some research questions related to ACOS.
The stress response and exploratory behaviour in Yucatan minipigs (Sus scrofa): Relations to sex and social rank.Friday, October 09, 2015
Adcock SJ, Martin GM, Walsh CJ,
Physiology & behavior. 5-Oct-2015
According to the coping styles hypothesis, an individual demonstrates an integrated behavioural and physiological response to environmental challenge that is consistent over time and across situations. Individual consistency in behavioural responses to challenge has been documented across the animal kingdom. Comparatively few studies, however, have examined inter-individual variation in the physiological response, namely glucocorticoid and catecholamine levels, the stress hormones secreted by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, respectively. Variation in coping styles between individuals may be explained in part by differences in social rank and sex. Using 20 Yucatan minipigs (Sus scrofa) we: (1) investigated the existence of consistent inter-individual variation in exploratory behaviour and the hormonal stress response, and tested for correlations as predicted by the coping styles hypothesis; and (2) evaluated whether inter-individual behavioural and hormonal variation is related to social rank and sex. Salivary stress biomarkers (cortisol, alpha-amylase, chromogranin A) were assessed in the presence and absence of a stressor consisting of social isolation in a crate for 10min. Principal components analysis on a set of behavioural variables revealed two traits, which we labelled exploratory tendency and neophobia. Neither exploratory tendency nor neophobia predicted the physiological stress response. Subordinate pigs exhibited higher catecholamine levels compared to dominant conspecifics. We observed sex differences in the repeatability of salivary stress markers and reactivity of the stress systems. The results do not provide support for the existence of behavioural-physiological coping styles in pigs. Sex is an important determinant of the physiological stress response and warrants consideration in research addressing behavioural and hormonal variation.
Effect of Concomitant Radiochemotherapy on Invasion Potential of Glioblastoma.Friday, October 09, 2015
Hutóczki G, Bognár L, Tóth J, Scholtz B, Zahuczky G, Hanzély Z, Csősz É, Reményi-Puskár J, Kalló G, Hortobágyi T, Klekner A,
Pathology oncology research : POR. 9-Oct-2015
Glioblastoma (GBM) is the most common primary brain tumor in adults with inevitable recurrence after oncotherapy. The insufficient effect of "gold standard" temozolomide-based concomitant radiochemotherapy may be due to the inability to prevent tumor cell invasion. Peritumoral infiltration depends mainly on the interaction between extracellular matrix (ECM) components and cell membrane receptors. Changes in invasive behaviour after oncotherapy can be evaluated at the molecular level by determining the RNA expression and protein levels of the invasion-related ECM components. The expression of nineteen ECM molecules was determined at both RNA and protein levels in thirty-one GBM samples. Fifteen GBM samples originated from the first surgical procedure on patients before oncotherapy, and sixteen GBM samples were collected at the second surgery due to local recurrence after concomitant chemoirradiation. RNA expressions were measured with qRT-PCR, and protein levels were determined by quantitative analysis of Western blots. Only MMP-9 RNA transcript level was reduced (p < 0.05) whereas at protein level, eight molecules showed changes concordant with RNA expression with significant decrease in brevican only. The results suggest that concomitant radiochemotherapy does not have sufficient impact on the expression of invasion-related ECM components of glioblastoma, oncotherapy does not significantly affect its invasive behavior. To avoid the spread of tumors into the brain parenchyma, supplementation of antiproliferative treatment with anti-invasive agents may be worth consideration in oncotherapy for glioblastoma.
The JAK2 V617F Allele Burden in Latent Myeloproliferative Neoplasms Presenting with Splanchnic Vein Thrombosis.Friday, October 09, 2015
Goodyer M, Langabeer SE, Haslam K, Murphy K,
Pathology oncology research : POR. 8-Oct-2015
Localized control of oxidized RNA.Friday, October 09, 2015
Zhan Y, Dhaliwal J, Adjibade P, Uniacke J, Mazroui R, Zerges W,
Journal of cell science. 8-Oct-2015
The oxidation of biological molecules by reactive oxygen species can render them inactive or toxic. This includes the oxidation of RNA, which appears to underlie detrimental effects of oxidative stress, aging, and certain neurodegenerative diseases. Here we investigate the management of oxidized RNA in the chloroplast of the green alga Chlamydomonas reinhardtii. Our results of immunofluorescence microscopy reveal oxidized RNA (with 8-hydroxyguanine) localized in the pyrenoid, a chloroplast microcompartment where CO2 is assimilated by the Calvin cycle enzyme Rubisco. Results of genetic analyses support a requirement for the Rubisco large subunit, but not Rubisco, in the management of oxidized RNA. An RBCL pool that could carry out such a 'moonlighting' function is revealed by results of biochemical fractionation experiments. We also show that human (HeLa) cells localize oxidized RNA to cytoplasmic foci which are distinct from stress granules, processing bodies, and mitochondria. Our results suggest that the compartmentalization of oxidized RNA management is a general phenomenon and therefore has some fundamental significance.
Detection of Typhoidal and Paratyphoidal Salmonella in Blood by Real-time Polymerase Chain Reaction.Friday, October 09, 2015
Tennant SM, Toema D, Qamar F, Iqbal N, Boyd MA, Marshall JM, Blackwelder WC, Wu Y, Quadri F, Khan A, Aziz F, Ahmad K, Kalam A, Asif E, Qureshi S, Khan E, Zaidi AK, Levine MM,
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 1-Nov-2015
Based on lessons learned, we recommend that future field trials of this and other novel diagnostics that detect typhoidal and nontyphoidal Salmonella employ multiple methodologies to define a "positive" sample.
Emerging Therapeutic Targets for Male Germ Cell Tumors.Friday, October 09, 2015
Fankhauser CD, Honecker F, Beyer J, Bode PK,
Current oncology reports. Dec-2015
Male germ cell tumors (GCTs) are curable cancers, yet 10-15 % of patients with metastatic disease fail cisplatin-based first-line treatments. While therapeutic options have increased for various other cancers, little progress has been made in the management of GCT in the last decades. A better understanding of the molecular alterations underlying the disease and identification of new therapeutic targets are needed. Several phase I/II studies with promising new agents are ongoing or have been completed, but most of those trials have been small and have not included translational research. Therefore, molecular profiles predictive for response or new agents have not been identified in male GCT so far. The purpose of this review is to highlight emerging targets and therapies with the potential to improve systemic treatment of metastatic male GCT and to develop strategies for future clinical trials.
Serum biomarkers evaluation to predict chemotherapy-induced cardiotoxicity in breast cancer patients.Friday, October 09, 2015
De Iuliis F, Salerno G, Taglieri L, De Biase L, Lanza R, Cardelli P, Scarpa S,
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 8-Oct-2015
Anti-neoplastic chemotherapy can determine various side effects, including cardiotoxicity, and no real guidelines for its early detection and management have been developed. The aim of this study is to find some plasmatic markers able to identify breast cancer patients that are at greater risk of developing cardiovascular complications during chemotherapy, in particular heart failure. A prospective study on 100 breast cancer patients with mean age of 66 years in adjuvant treatment with anthracyclines, taxanes, and trastuzumab was performed. Patients underwent cardiological examination before starting treatment (T0) and at 3 months (T1), 6 months (T2), and 1 year (T3) after treatment. Evaluation of serum cardiac markers and N-terminal pro-brain natriuretic peptide (NT-proBNP) was performed at T0, T1, T2, and T3, simultaneously to electrocardiogram and echocardiogram, showing a significant increase in NT-proBNP concentration (p > 0.0001) at T1, T2, and T3, before left ventricular ejection fraction decrease became evident. Human epidermal growth factor receptor 2 (HER2)-negative patients were more susceptible to mild hematological cardiotoxicity, while HER2-positive patients were more susceptible to severe cardiotoxicity. A significant correlation between NT-proBNP increased values after chemotherapy and prediction of mortality at 1 year was evidenced. From our experience, serum biomarker detection was able to support an early diagnosis of cardiac damage, also in the absence of left ventricular ejection fraction decrease. Therefore, the evaluation of specific plasmatic markers for cardiac damage is more sensitive than echocardiography in the early diagnosis of chemotherapy-related cardiotoxicity; furthermore, it can also add a prognostic value on outcome.
Predicting asthma outcomes.Friday, October 09, 2015
Sears MR,
The Journal of allergy and clinical immunology. Oct-2015
This review addresses predictors of remission or persistence of wheezing and asthma from early childhood through adulthood. Early childhood wheezing is common, but predicting who will remit or have persistent childhood asthma remains difficult. By adding parental history of asthma and selected infant biomarkers to the history of recurrent wheezing, the Asthma Predictive Index and its subsequent modifications provide better predictions of persistence than simply the observation of recurrent wheeze. Sensitization, especially to multiple allergens, increases the likelihood of development of classic childhood asthma. Remission is more likely in male subjects and those with milder disease (less frequent and less severe symptoms), less atopic sensitization, a lesser degree of airway hyperresponsiveness, and no concomitant allergic disease. Conversely, persistence is linked strongly to allergic sensitization, greater frequency and severity of symptoms, abnormal lung function, and a greater degree of airway hyperresponsiveness. A genetic risk score might predict persistence more accurately than family history. Remission of established adult asthma is substantially less common than remission during childhood and adolescence. Loss of lung function can begin early in life and tracks through childhood and adolescence. Despite therapy which controls symptoms and exacerbations, the outcomes of asthma appear largely resistant to pharmacologic therapy.
Protein-Bound Plasma Nε-(Carboxymethyl)lysine Is Inversely Associated With Central Obesity and Inflammation and Significantly Explain a Part of the Central Obesity-Related Increase in Inflammation: The Hoorn and CODAM Studies.Friday, October 09, 2015
Gaens KH, Ferreira I, Van De Waarenburg MP, van Greevenbroek MM, van der Kallen CJ, Dekker JM, Nijpels G, Rensen SS, Stehouwer CD, Schalkwijk CG,
Arteriosclerosis, thrombosis, and vascular biology. 8-Oct-2015
Obesity, in particular central obesity, is characterized by greater levels of LGI but by lower levels of circulating CML; the latter significantly explaining a portion of the positive association between central obesity and inflammation.
Fibronectin stimulates the osteogenic differentiation of murine embryonic stem cells.Friday, October 09, 2015
Kang Y, Georgiou AI, MacFarlane RJ, Klontzas ME, Heliotis M, Tsiridis E, Mantalaris A,
Journal of tissue engineering and regenerative medicine. 9-Oct-2015
Conditioned medium from human hepatocarcinoma cells (HepG2-CM) has been shown to stimulate the osteogenic/chondrogenic differentiation of murine embryonic stem cells (mESCs). HepG2-CM is considered to contain visceral endoderm (VE)-like signals and attempts have recently been made to characterize it, using proteomic profiling, with fibronectin being identified as one promising candidate. Herein, we investigated whether fibronectin is able to mimic the activities of HepG2-CM during the osteogenic differentiation of mESCs. Specifically, the addition of RGD peptides and heparin in HepG2-CM significantly reduced the growth- and adhesion-promoting effects of HepG2-CM, in addition to suppressing its osteogenic-inductive activity. Furthermore, direct addition of fibronectin to basal medium was able to reproduce, at least partially, the function of HepG2-CM. In particular, fibronectin induced the early onset of osteogenic differentiation in mESCs, as confirmed by gene expression of osteogenic markers, and resulted in the three-fold higher calcium deposition at day 11 of osteogenic culture compared to the control group. These data clearly suggest that fibronectin contributes to the biological activities of HepG2-CM and plays a stimulatory role during the process of osteogenesis in mESCs. Copyright © 2015 John Wiley & Sons, Ltd.
Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis.Friday, October 09, 2015
González-Fernández R, Hernández J, Martín-Vasallo P, Puopolo M, Palumbo A, Ávila J,
Reproductive sciences (Thousand Oaks, Calif.). 8-Oct-2015
Oxidative stress (OS) plays an important role in all physiological processes. The effect of OS on cellular processes is modulated by the ability of the cell to express genes implicated in the reversal of lipid, protein, and DNA injury. Aldehyde dehydrogenase 3, member A2 (ALDH3A2) is a ubiquitous enzyme involved in lipid detoxification. The objective of this study was to investigate the expression of ALDH3A2 in human granulosa-lutein (GL) cells of women undergoing in vitro fertilization (IVF) and its relationship with age, infertility diagnosis, and IVF outcome variables. Relative expression levels of ALDH3A2 were determined by quantitative reverse transcription-polymerase chain reaction. To investigate the effect of age on ALDH3A2 expression, 72 women between 18 and 44 years of age with no ovarian factor (NOF) were analyzed. To evaluate the effect of infertility diagnosis on ALDH3A2 expression, the following groups were analyzed: 22 oocyte donors (ODs), 24 women >40 years old (yo) with tubal or male factor and no ovarian pathology, 18 poor responders (PRs), 19 cases with endometriosis (EM), and 18 patients with polycystic ovarian syndrome (PCOS). In NOF, ALDH3A2 expression correlated positively with age and with the doses of follicle-stimulating hormone and luteinizing hormone administered and negatively with the number of total and mature oocytes. When different groups were analyzed, ALDH3A2 expression levels were higher in patients >40 yo and in PR compared to OD. On the contrary, EM and PCOS levels were lower than expected for age. These data suggest that GL cell ALDH3A2 expression levels correlate with age, cause of infertility, and ovarian response to stimulation.
Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms.Friday, October 09, 2015
Pietra D, Rumi E, Ferretti VV, Di Buduo CA, Milanesi C, Cavalloni C, Sant'Antonio E, Abbonante V, Moccia F, Casetti IC, Bellini M, Renna MC, Roncoroni E, Fugazza E, Astori C, Boveri E, Rosti V, Barosi G, Balduini A, Cazzola M,
Leukemia. 9-Oct-2015
A quarter of patients with essential thrombocythemia or primary myelofibrosis carry a driver mutation of CALR, the calreticulin gene. A 52-bp deletion (type-1) and a 5-bp insertion (type-2 mutation) are the most frequent variants. These indels might differentially impair the calcium binding activity of mutant calreticulin. We studied the relationship between mutation subtype and biologic/clinical features of the disease. Thirty-two different types of CALR variants were identified in 311 patients. Based on their predicted effect on calreticulin C-terminal, mutations were classified as: i) type 1-like (65%), ii) type 2-like (32%), and iii) other types (3%). Corresponding CALR mutants had significantly different estimated isoelectric points. Patients with type-1 mutation, but not those with type-2, showed abnormal cytosolic calcium signals in cultured megakaryocytes. Type 1-like mutations were mainly associated with a myelofibrosis phenotype and a significantly higher risk of myelofibrotic transformation in essential thrombocythemia. Type 2-like CALR mutations were preferentially associated with an essential thrombocythemia phenotype, low risk of thrombosis despite very high platelet counts, and indolent clinical course. Thus, mutation subtype contributes to determining clinical phenotype and outcomes in CALR-mutant myeloproliferative neoplasms. CALR variants that markedly impair the calcium binding activity of mutant calreticulin are mainly associated with a myelofibrosis phenotype.Leukemia accepted article preview online, 09 October 2015. doi:10.1038/leu.2015.277.
Tumor-forming plasmacytoid dendritic cells associated with myeloid neoplasms. Report of a peculiar case with histopathologic features masquerading as lupus erythematosus.Friday, October 09, 2015
Dargent JL, Henne S, Pranger D, Balzarini P, Sartenaer D, Bulliard G, Rack K, Facchetti F,
Journal of cutaneous pathology. 9-Oct-2015
Plasmacytoid dendritic cells (PDC) belong to a subtype of dendritic cells that are normally absent in healthy skin. In some inflammatory diseases of the skin, especially lupus erythematosus (LE), these cells are occasionally recruited in great amounts, which can be used as a helpful clue for diagnosis. Rarely, PDC may also accumulate in the skin of patients with myeloid leukemia, a yet poorly known condition currently called "tumor-forming PDC associated with myeloid neoplasms". In this study, we describe a patient with unsuspected chronic myelomonocytic leukemia who developed cutaneous lesions characterized by a dermal infiltrate rich in PDC. Similarly to LE, such neoplastic PDC were accompanied by interface dermatitis-like changes, but displayed an aberrant phenotype and shared the same chromosomal abnormality with the leukemic cells identified in the bone marrow, thus revealing the neoplastic nature of the process. This observation illustrates that tumor-forming PDC associated with myeloid neoplasms may microscopically mimic LE in some patients. Accordingly, a hematologic workup is recommended in any skin lesion featuring excessive numbers of PDC, even if morphological alterations suggestive of interface dermatitis are found.
Safety, tolerability, pharmacokinetics, and efficacy of AMG 403, a human anti-nerve growth factor monoclonal antibody, in two phase I studies with healthy volunteers and knee osteoarthritis subjects.Friday, October 09, 2015
Gow JM, Tsuji WH, Williams GJ, Mytych D, Sciberras D, Searle SL, Mant T, Gibbs JP,
Arthritis research & therapy. 2015 NCT02348879 . Registered 23 December 2014. NCT02318407 . Registered 2 December 2014.
Effects of Focal Cerebral Ischemia on Exosomal Versus Serum miR126.Friday, October 09, 2015
Chen F, Du Y, Esposito E, Liu Y, Guo S, Wang X, Lo EH, Xing C, Ji X,
Translational stroke research. 9-Oct-2015
Emerging data suggest that exosomal microRNA (miRNA) may provide potential biomarkers in acute ischemic stroke. However, the effects of ischemia-reperfusion on total versus exosomal miRNA responses in circulating blood remain to be fully defined. Here, we quantified levels of miR-126 in whole serum versus exosomes extracted from serum and compared these temporal profiles against reperfusion and outcomes in a rat model of acute focal cerebral ischemia. First, in vitro experiments confirmed the vascular origin and changes in miR-126 in brain endothelial cultures subjected to oxygen-glucose deprivation. Then in vivo experiments were performed by inducing permanent or transient focal cerebral ischemia in rats, and total serum and exosomal miR-126 levels were quantified, along with measurements of infarction and neurological outcomes. Exosomal levels of miR-126 showed a transient reduction at 3 h post-ischemia that appeared to normalize back close to pre-ischemic baselines after 24 h. There were no detectable differences in exosomal miR-126 responses in permanent or transient ischemia. Serum miR-126 levels appeared to differ in permanent versus transient ischemia. Significant reductions in serum miR-126 were detected at 3 h after permanent ischemia but not transient ischemia. By 24 h, serum miR-126 levels were back close to baseline in both permanent and transient ischemia. Overall, there were no correlations between serum miR-126 and exosomal miR-126. This proof-of-concept study suggests that changes in serum miR-126 may be able to distinguish severe permanent ischemia from milder injury after transient ischemia.
RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis.Friday, October 09, 2015
Craciun FL, Bijol V, Ajay AK, Rao P, Kumar RK, Hutchinson J, Hofmann O, Joshi N, Luyendyk JP, Kusebauch U, Moss CL, Srivastava A, Himmelfarb J, Waikar SS, Moritz RL, Vaidya VS,
Journal of the American Society of Nephrology : JASN. 8-Oct-2015
CKD is the gradual, asymptomatic loss of kidney function, but current tests only identify CKD when significant loss has already happened. Several potential biomarkers of CKD have been reported, but none have been approved for preclinical or clinical use. Using RNA sequencing in a mouse model of folic acid-induced nephropathy, we identified ten genes that track kidney fibrosis development, the common pathologic finding in patients with CKD. The gene expression of all ten candidates was confirmed to be significantly higher (approximately ten- to 150-fold) in three well established, mechanistically distinct mouse models of kidney fibrosis than in models of nonfibrotic AKI. Protein expression of these genes was also high in the folic acid model and in patients with biopsy-proven kidney fibrosis. mRNA expression of the ten genes increased with increasing severity of kidney fibrosis, decreased in response to therapeutic intervention, and increased only modestly (approximately two- to five-fold) with liver fibrosis in mice and humans, demonstrating specificity for kidney fibrosis. Using targeted selected reaction monitoring mass spectrometry, we detected three of the ten candidates in human urine: cadherin 11 (CDH11), macrophage mannose receptor C1 (MRC1), and phospholipid transfer protein (PLTP). Furthermore, urinary levels of each of these three proteins distinguished patients with CKD (n=53) from healthy individuals (n=53; P<0.05). In summary, we report the identification of urinary CDH11, MRC1, and PLTP as novel noninvasive biomarkers of CKD.
[Detection of disease markers in the breath using optoelectronic methods].Friday, October 09, 2015
Stacewicz T, Targowski T, Bielecki Z, Buszewski B, Ligor T, Wojtas J, Garlińska M,
Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 28-Sep-2015
Developed sensors are characterized by high sensitivity (ppb-level) and high selectivity, simple and fast measurement procedure. Therefore, they can be applied as medical screening tools enabling biomarkers detection in exhaled air at the molecular level.
Directed Differentiation of Embryonic Stem Cells Into Cardiomyocytes by Bacterial Injection of Defined Transcription Factors.Friday, October 09, 2015
Bai F, Ho Lim C, Jia J, Santostefano K, Simmons C, Kasahara H, Wu W, Terada N, Jin S,
Scientific reports. 2015
Forced expression of defined transcriptional factors has been well documented as an effective method for cellular reprogramming or directed differentiation. However, transgene expression is not amenable for therapeutic application due to potential insertional mutagenesis. Here, we have developed a bacterial type III secretion system (T3SS)-based protein delivery tool and shown its application in directing pluripotent stem cell differentiation by a controlled delivery of transcription factors relevant to early heart development. By fusing to an N-terminal secretion sequence for T3SS-dependent injection, three transcriptional factors, namely Gata4, Mef2c, and Tbx5 (abbreviated as GMT), were translocated into murine embryonic stem cells (ESCs), where the proteins are effectively targeted to the nucleus with an average intracellular half-life of 5.5 hours. Exogenous GMT protein injection activated the cardiac program, and multiple rounds of GMT protein delivery significantly improved the efficiency of ESC differentiation into cardiomyocytes. Combination of T3SS-mediated GMT delivery and Activin A treatment showed an additive effect, resulting in on average 60% of the ESCs differentiated into cardiomyocytes. ESC derived cardiomyocytes displayed spontaneous rhythmic contractile movement as well as normal hormonal responses. This work serves as a foundation for the bacterial delivery of multiple transcription factors to direct cell fate without jeopardizing genomic integrity.
The cytotoxicity of the α1-adrenoceptor antagonist prazosin is linked to an endocytotic mechanism equivalent to Transport-P.Friday, October 09, 2015
Fuchs R, Stracke A, Ebner N, Zeller CW, Raninger AM, Schittmayer M, Kueznik T, Absenger-Novak M, Birner-Gruenberger R,
Toxicology. 5-Oct-2015
Since the α1-adrenergic antagonist prazosin (PRZ) was introduced into medicine as a treatment for hypertension and benign prostate hyperplasia, several studies have shown that PRZ induces apoptosis in various cell types and interferes with endocytotic trafficking. Because PRZ is also able to induce apoptosis in malignant cells, its cytotoxicity is a focus of interest in cancer research. Besides inducing apoptosis, PRZ was shown to serve as a substrate for an amine uptake mechanism originally discovered in neurones called transport-P. In line with our hypothesis that transport-P is an endocytotic mechanism also present in non-neuronal tissue and linked to the cytotoxicity of PRZ, we tested the uptake of QAPB, a fluorescent derivative of PRZ, in cancer cell lines in the presence of inhibitors of transport-P and endocytosis. Early endosomes and lysosomes were visualised by expression of RAB5-RFP and LAMP1-RFP, respectively; growth and viability of cells in the presence of PRZ and uptake inhibitors were also tested. Cancer cells showed co-localisation of QAPB with RAB5 and LAMP1 positive vesicles as well as tubulation of lysosomes. The uptake of QAPB was sensitive to transport-P inhibitors bafilomycin A1 (inhibits v-ATPase) and the antidepressant desipramine. Endocytosis inhibitors pitstop(®) 2 (general inhibitor of endocytosis), dynasore (dynamin inhibitor) and methyl-β-cyclodextrin (cholesterol chelator) inhibited the uptake of QAPB. Bafilomycin A1 and methyl-β-cyclodextrin but not desipramine were able to preserve growth and viability of cells in the presence of PRZ. In summary, we confirmed the hypothesis that the cellular uptake of QAPB/PRZ represents an endocytotic mechanism equivalent to transport-P. Endocytosis of QAPB/PRZ depends on a proton gradient, dynamin and cholesterol, and results in reorganisation of the LAMP1 positive endolysosomal system. Finally, the link seen between the cellular uptake of PRZ and cell death implies a still unknown pro-apoptotic membrane protein with affinity towards PRZ.
Regulation of IL-8 gene expression in gliomas by microRNA miR-93.Friday, October 09, 2015
Fabbri E, Brognara E, Montagner G, Ghimenton C, Eccher A, Cantù C, Khalil S, Bezzerri V, Provezza L, Bianchi N, Finotti A, Borgatti M, Moretto G, Chilosi M, Cabrini G, Gambari R,
BMC cancer. 2015
In conclusion, our results suggest an increasing role of miR-93 in regulating the level of expression of several genes involved in the angiogenesis of gliomas.
MicroRNA-139-5p acts as a tumor suppressor by targeting ELTD1 and regulating cell cycle in glioblastoma multiforme.Friday, October 09, 2015
Dai S, Wang X, Li X, Cao Y,
Biochemical and biophysical research communications. 5-Oct-2015
MicroRNA-139-5p was identified to be significantly down-regulated in glioblastoma multiform (GBM) by miRNA array. In this report we aimed to clarify its biological function, molecular mechanisms and direct target gene in GBM. Twelve patients with GBM were analyzed for the expression of miR-139-5p by quantitative RT-PCR. miR-139-5p overexpression was established by transfecting miR-139-5p-mimic into U87MG and T98G cells, and its effects on cell proliferation were studied using MTT assay and colony formation assays. We concluded that ectopic expression of miR-139-5p in GBM cell lines significantly suppressed cell proliferation and inducing apoptosis. Bioinformatics coupled with luciferase and western blot assays also revealed that miR-139-5p suppresses glioma cell proliferation by targeting ELTD1 and regulating cell cycle.
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