Πέμπτη, 19 Μαΐου 2016

Identification of bone morphogenetic protein 9 (BMP9) as a novel profibrotic factor in vitro

Publication date: Available online 18 May 2016
Source:Cellular Signalling
Author(s): José M. Muñoz-Félix, Cristina Cuesta, Nuria Perretta-Tejedor, Mariela Subileau, Francisco J. López-Hernández, José M. López-Novoa, Carlos Martínez-Salgado
Upregulated synthesis of extracellular matrix (ECM) proteins by myofibroblasts is a common phenomenon in the development of fibrosis. Although the role of TGF-β in fibrosis development has been extensively studied, the involvement of other members of this superfamily of cytokines, the bone morphogenetic proteins (BMPs) in organ fibrosis has given contradictory results. BMP9 is the main ligand for activin receptor-like kinase-1 (ALK1) TGF-β1 type I receptor and its effect on fibrosis development is unknown. Our purpose was to study the effect of BMP9 in ECM protein synthesis in fibroblasts, as well as the involved receptors and signaling pathways.In cultured mice fibroblasts, BMP9 induces an increase in collagen, fibronectin and connective tissue growth factor expression, associated with Smad1/5/8, Smad2/3 and Erk1/2 activation. ALK5 inhibition with SB431542 or ALK1/2/3/6 with dorsomorphin-1, inhibition of Smad3 activation with SIS3, and inhibition of the MAPK/Erk1/2 with U0126, demonstrates the involvement of these pathways in BMP9-induced ECM synthesis in MEFs. Whereas BMP9 induced Smad1/5/8 phosphorylation through ALK1, it also induces Smad2/3 phosphorylation through ALK5 but only in the presence of ALK1.Summarizing, this is the first study that accurately identifies BMP9 as a profibrotic factor in fibroblasts that promotes ECM protein expression through ALK1 and ALK5 receptors.



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Inflammatory biomarkers and risk of cancer in 84,000 individuals from the general population

Abstract

Inflammation and cancer are tightly linked. This study tests the hypothesis that an inflammatory score based on plasma levels of C-reactive protein (CRP) and fibrinogen and whole blood leukocyte count is associated with risk of colorectal, lung, breast, and prostate cancer. A score ranging from none through three elevated biomarkers was constructed in 84,000 individuals from the Danish general population. During a median follow-up time of 4.8 years, 4,081 incident cancers occurred. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of incident cancer. Multifactor-adjusted HRs for colorectal cancer were 1.28 (95% CI, 1.01 to 1.62), 1.79 (95% CI, 1.41 to 2.27), and 2.18 (95% CI, 1.67 to 2.86) for individuals with elevated levels of one, two, and three inflammatory biomarkers compared to individuals with none elevated biomarkers. A similar stepwise increasing risk was observed for lung and breast cancer with HRs of 3.03 (95% CI, 2.25 to 4.08) and 1.42 (95% CI, 1.11 to 1.80) for three versus none elevated biomarkers. HRs were highest within the first years of follow-up. Absolute 5-year risk of lung cancer was 7.8 (95% CI, 6.1 to 10)% among older smokers with three elevated biomarkers compared to 3.8 (95% CI, 2.6 to 5.6)% among those with none elevated biomarkers. In conclusion, simultaneously elevated CRP, fibrinogen, and leukocyte count are associated with an increased risk of colorectal, lung, and breast cancer. Cancer as a promoter of inflammation may be more likely to account for our findings than low-grade inflammation promoting cancer development. This article is protected by copyright. All rights reserved.



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Gastrointestinal and liver disease in Adult Life After Childhood Cancer in Scandinavia: A population-based cohort study

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Abstract

Survival after childhood cancer diagnosis has remarkably improved, but emerging evidence suggests that cancer-directed therapy may have adverse gastrointestinal late effects. We aimed to comprehensively assess the frequency of gastrointestinal and liver late effects among childhood cancer survivors and compare this frequency with the general population. Our population-based cohort study included all one-year survivors of childhood and adolescent cancer in Denmark, Finland, Iceland, Norway, and Sweden diagnosed from the 1940s and 1950s. Our outcomes of interest were hospitalization rates for gastrointestinal and liver disorders, which were ascertained from national patient registries. We calculated standardized hospitalization rate ratios (RR) and absolute excess rates (AER) comparing hospitalizations of any gastrointestinal or liver disease and for specific disease entities between survivors and the general population. The study included 31,132 survivors and 207,041 comparison subjects. The median follow-up in the hospital registries were 10 years (range: 0 – 42) with 23% of the survivors being followed at least to the age of 40 years. Overall, survivors had a 60% relative excess of gastrointestinal or liver diseases (RR: 1.6, 95% confidence interval (CI): 1.6 – 1.7), which corresponds to an absolute excess of 360 (95% CI: 330 – 390) hospitalizations per 100,000 person-years. Survivors of hepatic tumors, neuroblastoma, and leukemia had the highest excess of gastrointestinal and liver diseases. In addition, we observed a relative excess of several specific diseases such as esophageal stricture (RR: 13; 95% CI: 9.2 – 20) and liver cirrhosis (RR: 2.9; 95% CI: 2.0 – 4.1). Our findings provide useful information about the breadth and magnitude of late complications among childhood cancer survivors, and can be used for generating hypotheses about potential exposures related to these gastrointestinal and liver late effects. This article is protected by copyright. All rights reserved.



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Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750 – an antisense oligonucleotide against eIF4E – in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer

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Abstract

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160mg/m2-biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control of 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in 7/15 (47%) patients who were progressing prior to study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and post-therapy tumor biopsies penetration of the ASO into the site of metastasis. This article is protected by copyright. All rights reserved.



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Clinicopathogenomic analysis of mismatch repair proficient colorectal adenocarcinoma uncovers novel prognostic subgroups with differing patterns of genetic evolution

Abstract

Cancer somatic genetic evolution is a direct contributor to heterogeneity at the clonal and molecular level in colorectal adenocarcinoma (COAD). We sought to determine the extent to which genetic evolution may be detected in COAD in routinely obtained single clinical specimens and establish clinical significance with regard to clinicopathologic and outcome data. 123 cases of routinely collected mismatch repair proficient COAD was sequenced on the Illumina Truseq Amplicon assay. Measures of intratumoral heterogeneity were assessed and the preferential timing of mutational events was assessed and compared to clinicopathologic data. Survival subanalysis was performed on 55 cases. Patient age (p=0.013) and specimen percent tumor (p=0.033) was associated with clonal diversity, and biopsy (p=0.044) and metastasis (p=0.044) returned fewer mutations per case. APC and TP53 mutations preferentially occurred early while alterations in FBXW7, FLT3, SMAD4, GNAS, and PTEN preferentially occurred as late events. Temporal heterogeneity was evident in KRAS and PIK3CA mutations. Hierarchical clustering revealed a TP53 mutant subtype and a MAPK-PIK3CA subtype with differing patterns of late mutational events. Survival subanalysis showed a decreased median progression free survival for the MAPK-PIK3CA subtype (8 months vs. 13 months; univariate logrank p=0.0380, cox model p= 0.018). Neoadjuvant therapy associated mutations were found for ERBB2 (p=0.0481) and FBXW7 (p=0.015). Our data indicate novel molecular subtypes of mismatch repair proficient COAD display differing patterns of genetic evolution which correlate with clinical outcomes. Furthermore, we report treatment acquired and/or selected mutations in ERBB2 and FBXW7. This article is protected by copyright. All rights reserved.



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Knockdown of COUP-TFII inhibits cell proliferation and induces apoptosis through upregulating BRCA1 in renal cell carcinoma cells

Abstract

COUP-TFII belongs to the nuclear receptor family, which is highly expressed in many kinds of tumors. Previous studies have shown that COUP-TFII can promote tumor progression through regulating tumor angiogenesis and cell proliferation and migration of certain cancer cells. However, the function of COUP-TFII in renal cell carcinoma (RCC) is not clear. Here we showed that clinical RCC tumor tissues showed much higher COUP-TFII expression level than adjacent normal tissues. When COUP-TFII was knocked down in RCC 769-P and 786-O cells by siRNA or shRNA-expressing lentivirus, the cell proliferation was markedly inhibited, and apoptosis increased. Moreover, the tumor growth of COUP-TFII knockdown 769-P and 786-O xenografts in nude mice was also obviously inhibited. By using RT-PCR and Western blot, we showed that the expression of the tumor suppressor gene BRCA1 was upregulated in COUP-TFII knockdown cells. Simultaneously knockdown of BRCA1 and COUP-TFII partially rescued the inhibited cell proliferation and increased apoptosis in COUP-TFII single knockdown cells. These results indicate that COUP-TFII may play an oncogenic role in RCC, and COUP-TFII may promote tumor progression through inhibiting BRCA1. This article is protected by copyright. All rights reserved.



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Carbon-rich presolar grains from massive stars. Subsolar 12C/13C and 14N/15N ratios and the mystery of 15N

Carbon-rich grains with isotopic anomalies compared to the Sun are found in primitive meteorites. They were made by stars, and carry the original stellar nucleosynthesis signature. Silicon carbide grains of Type X and C, and low-density graphites condensed in the ejecta of core-collapse supernovae. We present a new set of models for the explosive He shell and compare them with the grains showing 12C/13C and 14N/15N ratios lower than solar. In the stellar progenitor H was ingested into the He shell and not fully destroyed before the explosion. Different explosion energies and H concentrations are considered. If the SN shock hits the He-shell region with some H still present, the models can reproduce the C and N isotopic signatures in C-rich grains. Hot-CNO cycle isotopic signatures are obtained, including a large production of 13C and 15N. The short-lived radionuclides 22Na and 26Al are increased by orders of magnitude. The production of radiogenic 22Ne from the decay of 22Na in the He shell might solve the puzzle of the Ne-E(L) component in low-density graphite grains. This scenario is attractive for the SiC grains of type AB with 14N/15N ratios lower than solar, and provides an alternative solution for SiC grains originally classified as nova grains. Finally, this process may contribute to the production of 14N and 15N in the Galaxy, helping to produce the 14N/15N ratio in the solar system.

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Simulations of the symbiotic recurrent nova V407 Cyg. I. Accretion and shock evolutions

The shock interaction and evolution of nova ejecta with a wind from a red giant star in a symbiotic binary system are investigated via three-dimensional hydrodynamics simulations. We specifically model the March 2010 outburst of the symbiotic recurrent nova V407~Cygni from the quiescent phase to its eruption phase. The circumstellar density enhancement due to wind-white dwarf interaction is studied in detail. It is found that the density-enhancement efficiency depends on the ratio of the orbital speed to the red giant wind speed. Unlike another recurrent nova, RS~Ophiuchi, we do not observe a strong disk-like density enhancement, but instead observe an aspherical density distribution with ∼20% higher density in the equatorial plane than at the poles. To model the 2010 outburst, we consider several physical parameters, including the red giant mass loss rate, nova eruption energy, and ejecta mass. A detailed study of the shock interaction and evolution reveals that the interaction of shocks with the red giant wind generates strong Rayleigh-Taylor instabilities. In addition, the presence of the companion and circumstellar density enhancement greatly alter the shock evolution during the nova phase. The ejecta speed after sweeping out most of the circumstellar medium decreases to ∼100−300 km-s−1, depending on model, which is consistent with the observed extended redward emission in [N~II] lines in April 2011.

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Cinnamomum verum ingredient 2-methoxycinnamaldehyde: a new antiproliferative drug targeting topoisomerase I and II in human lung squamous cell carcinoma NCI-H520 cells.

Cinnamomum verum has been used as a Chinese herbal medication. We investigated the antiproliferative effect of 2-methoxycinnamaldehyde (2-MCA), a constituent of the cortex of the plant, and the molecular biomarkers associated with tumorigenesis in human lung squamous cell carcinoma NCI-H520 cells. The effects of 2-MCA on cell growth, cytotoxicity, apoptosis, and topoisomerase I and II activities in human lung squamous cell carcinoma NCI-H520 cells were evaluated in vitro and in vivo. The results showed that 2-MCA inhibited proliferation and induced apoptosis as implicated by mitochondrial membrane potential ([DELTA][PSI]m) loss, activation of both caspase 3 and caspase 9, as well as morphological characteristics of apoptosis. Furthermore, 2-MCA also induced lysosomal vacuolation with elevated volume of acidic compartment and cytotoxicity, and inhibited topoisomerase I as well as II activities. Additional study showed the antiproliferative effect of 2-MCA in a nude mice model. In short, our data imply that the antiproliferative activity of 2-MCA in vitro involved downregulation of cell growth markers, both topoisomerase I and II, and upregulation of proapoptotic molecules, associated with increased lysosomal vacuolation. In vivo, 2-MCA reduced the tumor size, which could have had a significant clinical impact. Our data imply that 2-MCA may be a potential agent for chemoprevention as well as anticancer therapy. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Induction of apoptosis by HBI-8000 in adult T-cell leukemia/lymphoma is associated with activation of Bim and NLRP3

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Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell malignancy caused by human T-cell lymphotropic virus 1 (HTLV-1). Treatment options for acute ATL patients include chemotherapy, stem cell transplantation, and recently the anti-CCR4 antibody, though most patients still have a poor prognosis and there is a clear need for additional options. HBI-8000 is a novel oral histone deacetylase inhibitor (HDACi) with proven efficacy for treatment of T-cell lymphomas that recently received approval in China. In the present study, we evaluated the effects of HBI-8000 on ATL-derived cell lines and primary cells obtained from Japanese ATL patients. In most cases HBI-8000 induced apoptosis in both primary ATL cells and cell lines. In addition, findings obtained with DNA microarray suggested the Bim activation, and, interestingly, contribution of the NLRP3 inflammasome pathway in HBI-8000-induced ATL cell death. Further investigations using siRNAs confirmed that Bim contributes to HBI-8000-induced apoptosis. Our results provide a rationale for a clinical investigation of the efficacy of HBI-8000 in patients with ATL. Although the role of NLRP3 inflammasome activation in ATL cell death remains to be verified, HBI-8000 may be part of a novel therapeutic strategy for cancer based on the NLRP3 pathway.

This article is protected by copyright. All rights reserved.



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A new variant of acute promyelocytic leukemia with IRF2BP2-RARA fusion

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Summary

We present an acute promyelocytic leukemia (APL) patient with two subtypes of IRF2BP2-RARA, in which the IRF2BP2 gene showed completely new breakpoints. Bone marrow examination revealed morphologic features indicative of APL. However, promyelocytic leukemia-RARA fusion was not detected. Generation paired-end mRNA sequencing followed by RT-PCR and direct sequencing revealed two types of fusion transcripts between exon 1B of IRF2BP2 and exon 3 of RARA. The patient received all-trans retinoic acid and conventional chemotherapy, but showed resistance. This is the second report of IRF2BP2 involvement in APL, and we describe various breakpoints for the IRF2BP2-RARA fusion gene.

This article is protected by copyright. All rights reserved.



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Cardiac troponin T is necessary for normal development in the embryonic chick heart

Abstract

The heart is the first functioning organ to develop during embryogenesis. The formation of the heart is a tightly regulated and complex process, and alterations to its development can result in congenital heart defects. Mutations in sarcomeric proteins, such as alpha myosin heavy chain and cardiac alpha actin, have now been associated with congenital heart defects in humans, often with atrial septal defects. However, cardiac troponin T (cTNT encoded by gene TNNT2) has not. Using gene-specific antisense oligonucleotides, we have investigated the role of cTNT in chick cardiogenesis. TNNT2 is expressed throughout heart development and in the postnatal heart. TNNT2-morpholino treatment resulted in abnormal atrial septal growth and a reduction in the number of trabeculae in the developing primitive ventricular chamber. External analysis revealed the development of diverticula from the ventricular myocardial wall which showed no evidence of fibrosis and still retained a myocardial phenotype. Sarcomeric assembly appeared normal in these treated hearts. In humans, congenital ventricular diverticulum is a rare condition, which has not yet been genetically associated. However, abnormal haemodynamics is known to cause structural defects in the heart. Further, structural defects, including atrial septal defects and congenital diverticula, have previously been associated with conduction anomalies. Therefore, to provide mechanistic insights into the effect that cTNT knockdown has on the developing heart, quantitative PCR was performed to determine the expression of the shear stress responsive gene NOS3 and the conduction gene TBX3. Both genes were differentially expressed compared to controls. Therefore, a reduction in cTNT in the developing heart results in abnormal atrial septal formation and aberrant ventricular morphogenesis. We hypothesize that alterations to the haemodynamics, indicated by differential NOS3 expression, causes these abnormalities in growth in cTNT knockdown hearts. In addition, the muscular diverticula reported here suggest a novel role for mutations of structural sarcomeric proteins in the pathogenesis of congenital cardiac diverticula. From these studies, we suggest TNNT2 is a gene worthy of screening for those with a congenital heart defect, particularly atrial septal defects and ventricular diverticula.



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Health gurus, show us the evidence for your diet advice

Belle Gibson and her publisher have been held to account – so should all the other self-appointed lifestyle experts beloved of mass media

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Biopsies of the Internal Mammary Sentinel Lymph Nodes in Breast Cancer

The post Biopsies of the Internal Mammary Sentinel Lymph Nodes in Breast Cancer appeared first on Welcome to Avens.



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Software as good as hardware for PET gating

Researchers have demonstrated that software is as good as, if not better than,...


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JCM, Vol. 5, Pages 54: Comparison of Intravenous Anesthetic Agents for the Treatment of Refractory Status Epilepticus

Status epilepticus that cannot be controlled with first- and second-line agents is called refractory status epilepticus (RSE), a condition that is associated with significant morbidity and mortality. Most experts agree that treatment of RSE necessitates the use of continuous infusion intravenous anesthetic drugs such as midazolam, propofol, pentobarbital, thiopental, and ketamine, each of which has its own unique characteristics. This review compares the various anesthetic agents while providing an approach to their use in adult patients, along with possible associated complications.

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TORS, A Better Quality Of Life For Head And Neck Cancer Ppatients - FOX Illinois


TORS, A Better Quality Of Life For Head And Neck Cancer Ppatients
FOX Illinois
It is usually in the tonsil or base of tongue," said Dr. Sharma. Dr. Sharma specializes in head and neck cancer. His research focus area is on Trans Oral Robotic Surgery or T.O.R.S. It is an innovative breakthrough technology that allows Dr. Sharma to ...



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More agony for Fife family as mother endures pioneering cancer treatment in USA - The Courier


The Courier

More agony for Fife family as mother endures pioneering cancer treatment in USA
The Courier
Leigh Smith, who lost her little daughter Gemma Campbell in a horror road accident near Springfield 13 years ago, has been diagnosed with a rare cancer in the base of her skull. Having endured one tragedy, now the family are facing up to a whole new ...



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Prevalence and genetic variation of porcine circovirus type 2 in Hebei, China from 2004 to 2014

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Limin Li, Wanzhe Yuan, Haiyong Guo, Zengjun Ma, Qinye Song, Xiaobo Wang, Hongyuan Li
Porcine circovirus type 2 (PCV2), the primary causative agent of porcine circovirus-associated disease (PCVAD), causes severe economic losses to the pig industry in China since 2002. To investigate the molecular epidemic characteristics and genetic evolution of PCV2, 12 PCV2 isolates obtained from different pig farms with various clinical symptoms of PCVAD in Hebei, China from 2004 to 2014 were sequenced and analyzed. The phylogenetic analysis showed that the 12 isolates were divided into two distinct genotypes, PCV2b (7/12) and PCV2d (5/12), based on the sequences of either viral complete genome or open reading frame 2 (ORF2). Of the 7 PCV2b strains, 5 were isolated from 2004 to 2008 while all PCV2d were isolated from 2009 to 2014. This exhibited that PCV2b isolates were the most common before 2009 and then PCV2d isolates became predominant and widely distributed in pig farms. Sequence comparisons among total isolates indicated that the nucleotide identity ranged from 95.5% to 100% for complete genome and 93.1%–100% for ORF2. Compared with seven PCV2b isolates, there were thirteen amino-acid substitutions in the ORF2 region and one additional amino-acid K at this region terminal for five PCV2d isolates. The results suggest that a higher genetic variation and a distinct genotype shift occurred among the PCV2 isolates collected from 2004 to 2014 in Hebei.



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A comparative analysis of the ‘other roles’ of transcriptional factors from pathogenic organisms

Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Angshuman Bagchi
Transcription factors are the proteins that regulate gene expressions by binding to the promoter DNA regions of the corresponding genes. There are a number of different transcription factors and all of them have DNA-binding signature sequences. Transcription factors are structurally classified as belonging to different families on the basis of the distribution of their secondary structural patterns. The amino acid sequences of the DNA-binding regions of the transcription factors belonging to the same family should therefore be identical. But careful analyses of these sequences reveal the presence of different mutations in them. On further analyses, the mutations are found to create new domains in the transcription factors thereby conferring them with some new functionality in addition to their regulatory roles. Here, an attempt has been made to analyze the mutations present in the transcription factors of pathogenic organisms. The possible effects of these mutations have been identified and correlated with the mechanisms of disease pathogenesis. So far this is the first report that predicts the presence of the new functionality of the transcription factors, which also can augment disease propagation by the pathogens. This analysis would therefore be beneficial to future genetic studies to identify the effects of the mutations in the transcription factors for disease propagation.

Graphical abstract

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Non-coding RNAs as emerging molecular targets of gallbladder cancer

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Publication date: 15 August 2016
Source:Gene, Volume 588, Issue 1
Author(s): Dinesh Singh Tekcham, Pramod Kumar Tiwari
Gallbladder cancer is one of the most common cancers of biliary tract with aggressive pathophysiology, now emerging as a global health issue. Although minority of gallbladder cancer patients could receive such curative resection due to late diagnosis, this increases the survival rate. Lack of potential target molecule (s) for early diagnosis, better prognosis and effective therapy of gallbladder cancer has triggered investigators to look for novel technological or high throughput approaches to identify potential biomarker for gallbladder cancer. Intervention of non-coding RNAs in gallbladder cancer has been revealed recently. Non-coding RNAs are now widely implicated in cancer. Recent reports have revealed association of non-coding RNAs (microRNAs or miRNAs and long non-coding RNAs or lncRNAs) with gallbladder cancer. Here, we present an updated overview on the biogenesis, mechanism of action, role of non-coding RNAs, the identified cellular functions in gallbladder tumorigenesis, their prognostic & therapeutic potentials (efficacies) and future significance in developing effective biomarker(s), in future, for gallbladder.



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Editorial Board

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2





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Upregulation of lncRNA HOTAIR contributes to IL-1β-induced MMP overexpression and chondrocytes apoptosis in temporomandibular joint osteoarthritis

Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Chunping Zhang, Peng Wang, Pengfei Jiang, Yongbin Lv, Changxia Dong, Xiuyu Dai, Lixia Tan, Zhenlin Wang
Temporomandibular joint osteoarthritis (TMJ OA) is a common and heterogeneous disease that causes painful and progressive joint degeneration, which restricts daily activities, including talking and chewing. Long noncoding RNAs (lncRNAs) are an important class of genes involved in various physiological and pathological functions, including osteoarthritis (OA).The present study aimed to identify the lncRNAs that are important in TMJ OA and their potential functions. Here, we found that HOTAIR was significantly upregulated in the synovial fluid of TMJ OA patients compared with that of normal controls. Increased HOTAIR was similarly observed in the synovial fluid of TMJ OA rabbits as compared to control rabbits. Furthermore, in interleukin-1β (IL-1β)-induced TMJ OA in vitro model (primary rabbit condylar chondrocytes), the expressions of matrix metalloproteinase (MMP)-1, MMP3, MMP9 and HOTAIR were all dramatically increased. Most importantly, knockdown of HOTAIR in IL-1β-induced TMJ OA in vitro model could not only reverse the IL-1β-stimulated expressions of MMP1, MMP3 and MMP9, but also significantly decrease the apoptosis rate induced by IL-1β in primary rabbit condylar chondrocytes. Our data provides new insight into the mechanisms of chondrocytes destruction in TMJ OA.



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Comparative transcriptome analyses indicate enhanced cellular protection against FMDV in PK15 cells pretreated with IFN-γ

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Yin Fu, Zesen Zhu, Huiyun Chang, Zaixin Liu, Jing Liu, Huiyong Chen
Interferon gamma (IFN-γ) can induce a host antiviral response to foot and mouth disease virus (FMDV) in vivo and in vitro. To elucidate the mechanism of IFN-γ anti FMDV infection in host cells, high-throughput RNA sequencing was analyzed for systemic changes in gene expression profiles in PK15 cells infected by FMDV with or without IFN-γ pretreatment. More than 25 million reads, covering 1.2–1.5 Gb, were analyzed from each experiment panel. FMDV challenge altered the transcription of genes involved in positively and negatively regulating cell death or apoptosis; however, the expected immune suppression response was not obvious. IFN-γ pretreatment combined with FMDV infection normalized the increase in apoptosis. Furthermore, the transcription factors required for IFN-γ functioning, STAT1 and IRF1 were up-regulated by IFN-γ pretreatment and stimulated downstream IFN-stimulated genes (ISGs). These induced ISGs are mainly responsible for antigen processing, antigen presentation or antiviral defense. Interestingly, a synergistic effect on some ISGs, including OAS1, OAS2, MX1, MX2, RIG-I and IFIT1, was observed in the combined treatment compared to the IFN-γ treatment alone. The suggested effects identified by RNA sequencing were consistent with cellular morphology changes and confirmed by related protein markers. This is the first report exploring transcriptome alterations introduced by FMDV infection with or without IFN-γ pretreatment. The identified key host genes that control cell survival in vitro broaden our comprehensive understanding of how IFN-γ inhibits FMDV infection and may shed light on developing improved FMD control approaches.



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Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Robin Kobbe, Manuela Kolster, Sebastian Fuchs, Ulf Schulze-Sturm, Jutta Jenderny, Lothar Kochhan, Julia Staab, Eva Tolosa, Bodo Grimbacher, Thomas Meyer
Recently, gain-of-function (GOF) mutations in the gene encoding signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis (CMC). This case report describes a 10-year-old boy presenting with signs of common variable immunodeficiency (CVID), failure to thrive, impaired neurological development, and a history of recurrent mucocutaneous Candida infections. Sequencing of the STAT1 gene identified a heterozygous missense mutation in exon 7 encoding the STAT1 coiled-coil domain (c.514T>C, p.Phe172Leu). In addition to hypogammaglobulinemia with B-cell deficiency, and a low percentage of Th17 cells, immunological analysis of the patient revealed a marked depletion of forkhead-box P3+-expressing regulatory T cells (Tregs). In vitro stimulation of T cells from the patient with interferon-α (IFNα) and/or IFNɣ resulted in a significantly increased expression of STAT1-regulated target genes such as MIG1, IRF1, MX1, MCP1/CCL2, IFI-56K, and CXCL10 as compared to IFN-treated cells from a healthy control, while no IFNα/ɣ-mediated up-regulation of the FOXP3 gene was found. These data demonstrate that the STAT1 GOF mutation F172L, which results in impaired stability of the antiparallel STAT1 dimer conformation, is associated with inhibited Treg cell development and neurological symptoms.



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The associations of HLA-A, -B, DRB1 alleles and haplotypes in Turkish lymphoma patients

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Fahri Uçar, Mehmet Sönmez, Nilay Ermantaş, Hasan Mücahit Özbaş, Abide Cansız, Mustafa Balcı, Mustafa Yılmazz
A significant association between lymphomas and HLA alleles has been shown in previous studies. However, the frequency of HLA alleles and haplotypes has not been studied in Turkish lymphoma patients. We studied HLA-A, -B, -DRB1 alleles and haplotypes in 80 adult lymphomas and 360 unrelated normal subjects by PCR-SSOP method using Luminex technology. The allele frequencies of HLA-A*29, B*07, and DRB1*11 were higher in patients with Hodgkin's lymphoma (HL) compared with the controls [OR; 5.65 (95%CI; 2.16–14.81), P=0.001], [OR; 3.00 (95%CI; 1.50–5.99), P=0.003)], and [OR; 1.80 (95%CI; 1.08–3.01), P=0.002); respectively]. In patients with non-Hodgkin's lymphoma (NHL) HLA-B*51 and DRB1*04 allele frequencies were higher than controls [OR; 2.25 (95%CI; 1.27–4.00), P=0.007] and [OR; 2.14 (95%CI; 1.20–3.78), P=0.01]. The most frequently observed haplotypes were A*02 B*35 DRB1*11 (7.50% vs. 1.89%) in HL patients, A*02 B*51 DRB1*11 (5.00% vs. 1.96%) in NHL patients, and A*02 B*35 DRB1*13 (2.19%) in the controls. We detected four haplotypes specific to NHL, five haplotypes to HL patients. Seven haplotypes were unique to controls. Our findings suggest that in HL patients, HLA-A*29, B*07, and DRB1*11 alleles, and in NHL patients, HLA-B*51 and DRB1*04 alleles might be presumptive predisposing factors.



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Corrigendum to “dsRNA interference on expression of a RNA-dependent RNA polymerase gene of Bombyx mori cytoplasmic polyhedrosis virus” [GENE 565/1 (2015) 56–61]

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Zhong-Hua Pan, Kun Gao, Cheng-Xiang Hou, Ping Wu, Guang-Xing Qin, Tao Geng, Xi-Jie Guo




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Investigation of juglone effects on metastasis and angiogenesis in pancreatic cancer cells

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Publication date: 15 August 2016
Source:Gene, Volume 588, Issue 1
Author(s): Ebru Avcı, Hilal Arıkoğlu, Dudu Erkoç Kaya
Juglone, a natural component, is shown to have cytotoxic and apoptotic effects in several cancer cell lines. However, little is known about its effects on invasion and metastasis. In this study, we aimed to determine the antimetastatic effect of juglone in the BxPC-3 and PANC-1 pancreatic cancer cell lines. Cytotoxic effect of juglone was evaluated by using MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide) test. The cells were treated with juglone at <IC50 doses (5, 10, 15 and 20μM ) for 24h. After the cell adhesion and invasion analysis, expression profiles of the MMP-2, MMP-9 and Phactr-1 genes were determined by qPCR. The IC50 dose of juglone was found to be 21.05μM in the BxPC-3 cell line and 21.25μM in the PANC-1 cell line for 24h. According to the cell adhesion and invasion analysis, treatment of juglone for 24h reduced the adhesion and invasion features of pancreatic cancer cells. A significant reduction of MMP-2, MMP-9 and Phactr-1 expressions was observed in pancreatic cancer cells after the treatment of juglone at <IC50 doses. By this study, it has been shown for the first time that juglone inhibits cell invasion and metastasis in pancreatic cancer line and can be evaluated as an effective anticancer agent in pancreatic cancer.



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Editorial Board

Publication date: 1 August 2016
Source:Gene, Volume 587, Issue 1





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Tenogenic modulating insider factor: Systematic assessment on the functions of tenomodulin gene

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Publication date: 1 August 2016
Source:Gene, Volume 587, Issue 1
Author(s): Sarah Dex, Dasheng Lin, Chisa Shukunami, Denitsa Docheva
Tenomodulin (TNMD, Tnmd) is a gene highly expressed in tendon known to be important for tendon maturation with key implications for the residing tendon stem/progenitor cells as well as for the regulation of endothelial cell migration in chordae tendineae cordis in the heart and in experimental tumour models. This review aims at providing an encompassing overview of this gene and its protein. In addition, its known expression pattern as well as putative signalling pathways will be described. A chronological overview of the discovered functions of this gene in tendon and other tissues and cells is provided as well as its use as a tendon and ligament lineage marker is assessed in detail and discussed. Last, information about the possible connections between TNMD genomic mutations and mRNA expression to various diseases is delivered. Taken together this review offers a solid synopsis on the up-to-date information available about TNMD and aids at directing and focusing the future research to fully uncover the roles and implications of this interesting gene.



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Genomic structure of the α-amylase gene in the pearl oyster Pinctada fucata and its expression in response to salinity and food concentration

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Publication date: 1 August 2016
Source:Gene, Volume 587, Issue 1
Author(s): Guiju Huang, Yihui Guo, Lu Li, Sigang Fan, Ziniu Yu, Dahui Yu
Amylase is one of the most important digestive enzymes for phytophagous animals. In this study, the cDNA, genomic DNA, and promoter region of the α-amylase gene of the pearl oyster Pinctada fucata were cloned by using reverse transcription–polymerase chain reaction (RT-PCR), rapid amplification of cDNA ends, and genome-walking methods. The full-length cDNA sequence was 1704bp long and consisted of a 5′-untranslated region of 17bp, a 3′-untranslated region of 118bp, and a 1569-bp open reading frame encoding a 522-aa polypeptide with a 20-aa signal peptide. Sequence alignment revealed that P. fucata α-amylase (Pfamy) shared the highest identity (91.6%) with Pinctada maxima. The phylogenetic tree showed that it was closely related to P. maxima, based on the amino acid sequences. The genomic DNA was 10850bp and contained nine exons, eight introns, and a promoter region of 3932bp. Several transcriptional factors such as GATA-1, AP-1, and SP1 were predicted in the promoter region. Quantitative RT-PCR assay indicated that the relative expression level of Pfamy was significantly higher in the digestive gland than in other tissues (gonad, gills, muscle, and mantle) (P<0.001). The expression level at salinity 27‰ was significantly higher than that at other salinities (P<0.05). Expression reached a minimum when the algal food concentration was 16×104cells/mL, which was significantly lower than the level observed at 8×104cells/mL and 20×104 cells/mL (P<0.05). Our findings provide a genetic basis for further research on Pfamy activity and will facilitate studies on the growth mechanisms and genetic improvement of the pearl oyster P. fucata.



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Identification of Aadnr1, a novel gene related to innate immunity and apoptosis in Aedes albopictus

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Publication date: 1 August 2016
Source:Gene, Volume 587, Issue 1
Author(s): Xiaomei Li, Kun Meng, Jialu Qiao, Hao Liu, Chunyan Zhong, Qingzhen Liu
Innate immunity and apoptosis play critical roles in defending pathogens in insects. In Drosophila, Dnr1 was reported as a negative regulator of apoptosis and immune deficiency (Imd) pathway which belongs to innate immunity. Aedes albopictus is an important kind of arbovirus vector and becoming a significant threat to public health due to its rapid global expansion. Here we identified an ortholog of dnr1 from A. albopictus, named as Aadnr1. Aadnr1 encoded a putative protein containing an N-terminal FERM domain and a C-terminal RING domain. AaDnr1 shared high identity with dipteran insects Dnr1 orthologs. Phylogenetic analyses showed that the closest relative of AaDnr1 was Aedes aegypti Dnr1. Real-time PCR proved that Aadnr1 mRNA was expressed ubiquitously during developmental and adult stages. Transcriptional levels of Aadnr1 were decreased drastically in C6/36 cells underwent apoptosis induced by Actinomycin D (Act D) treatment. Partial silence of Aadnr1 enhanced Act D-induced caspase activity. When challenged by heat-inactivated E. coli, transcriptional level of Aadnr1 was also decreased dramatically in C6/36 cells. While when C6/36 cells were infected with Sindbis virus TE/GFP, transcriptional level of Aadnr1 was reduced and recovered repeatedly, with an overall decreasing trend. It was also shown in this study that similar to Drosophila Dnr1, RING domain destabilized AaDnr1 protein. Taken together, the study identified an innate immunity and apoptosis related gene Aadnr1 in A. albopictus.



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Small Maf proteins (MafF, MafG, MafK): History, structure and function

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Fumiki Katsuoka, Masayuki Yamamoto
The small Maf proteins (sMafs) are basic region leucine zipper (bZIP)-type transcription factors. The basic region of the Maf family is unique among the bZIP factors, and it contributes to the distinct DNA-binding mode of this class of proteins. MafF, MafG and MafK are the three vertebrate sMafs, and no functional differences have been observed among them in terms of their bZIP structures. sMafs form homodimers by themselves, and they form heterodimers with cap ‘n’ collar (CNC) proteins (p45 NF-E2, Nrf1, Nrf2, and Nrf3) and also with Bach proteins (Bach1 and Bach2). Because CNC and Bach proteins cannot bind to DNA as monomers, sMafs are indispensable partners that are required by CNC and Bach proteins to exert their functions. sMafs lack the transcriptional activation domain; hence, their homodimers act as transcriptional repressors. In contrast, sMafs participate in transcriptional activation or repression depending on their heterodimeric partner molecules and context. Mouse genetic analyses have revealed that various biological pathways are under the regulation of CNC-sMaf heterodimers. In this review, we summarize the history and current progress of sMaf studies in relation to their partners.



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Expression of nucleostemin gene in primary osteoarthritis

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Publication date: 1 August 2016
Source:Gene, Volume 587, Issue 1
Author(s): Manal L. Louka, Zeiad M. Zakaria, Magda M. Nagaty, Mahmoud A. Elsebaie, Lobna M. Nabil
IntroductionThe identification of genes associated with osteoarthritis can help reveal underlying biological mechanisms that may lead to development of new therapeutic targets or biomarkers for early detection and risk stratification. Nucleostemin (GNL3) is a nucleolar GTPase initially identified in the nucleolus of rat neural stem cells. The current study was conducted to determine the expression of nucleostemin gene in the synovium and synovial fluid of patients with primary osteoarthritis and to correlate its expression to the different clinicopathological factors of the disease.Patients and methodsIt included 31 patients with primary knee osteoarthritis and 25 osteoarthritis free patients served as a control group. Synovial tissue and synovial fluid samples were obtained directly from each patient for real time PCR of GNL3.ResultsRelative expression of GNL3 in synovial tissue and fluid samples was significantly higher in the osteoarthritic group as compared to the non-osteoarthritic group. GNL3 relative expression in both samples showed a significant difference among different BMI categories and among different radiographic grades of osteoarthritis. A high significant correlation was found between GNL3 relative expression levels in synovial tissue samples and those of synovial fluid samples with concordance of 85.7%.ConclusionNucleostemin could serve as a powerful prognostic marker for clinical use in osteoarthritis and its usefulness needs to be standardized and validated in a large-scale prospective multicentric study.



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Experimental evidences for hsa-miR-497-5p as a negative regulator of SMAD3 gene expression

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Meisam Jafarzadeh, Bahram M. Soltani, Sadat Dokanehiifard, Maryam Kay, Nasser Aghdami, Saman Hosseinkhani
The SMAD family comprises of transcription factors that function as signal transducers of transforming growth factor (TGFβ) superfamily members. MiRNAs are a class of small noncoding RNAs that may play a major role in post transcriptional regulation of SMAD genes. Here, we intended to investigate if hsa-miR-497-5p is capable of regulating SMAD3 gene expression. Hsa-miR-497-5p was bioinformatically predicted as a candidate regulator of SMAD3 gene expression and then, hsa-miR-497-5p expression status was analyzed in different cell lines using RT-qPCR. Overexpression of hsa-miR-497-5p in HEK293t cells resulted in downregulation of SMAD3 which was detected by RT-qPCR and western analysis. Further, dual luciferase assay results supported direct interaction of hsa-miR-497-5p with 3′-UTR sequences of SMAD3 transcript. Overexpression of hsa-miR-497-5p in HEK293t cells resulted in cell cycle arrest in G0/G1 phase, detected by flow cytometry. Overall, accumulative results indicated that hsa-miR-497-5p by targeting SMAD3 is potentially one of the regulators of the TGFβ signaling pathway.



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Heat shock increases lifetime of a small RNA and induces its accumulation in cells

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Publication date: 1 August 2016
Source:Gene, Volume 587, Issue 1
Author(s): Karina A. Tatosyan, Dmitri A. Kramerov
4.5SH and 4.5SI RNA are two abundant small non-coding RNAs specific for several related rodent families including Muridae. These RNAs have a number of common characteristics such as the short length (about 100nt), transcription by RNA polymerase III, and origin from Short Interspersed Elements (SINEs). However, their stabilities in cells substantially differ: the half-life of 4.5SH RNA is about 20min, while that of 4.5SI RNA is 22h. Here we studied the influence of cell stress such as heat shock or viral infection on these two RNAs. We found that the level of 4.5SI RNA did not change in stressed cells; whereas heat shock increased the abundance of 4.5SH RNA 3.2–10.5 times in different cell lines; and viral infection, 5 times. Due to the significant difference in the turnover rates of these two RNAs, a similar activation of their transcription by heat shock increases the level of the short-lived 4.5SH RNA and has minor effect on the level of the long-lived 4.5SI RNA. In addition, the accumulation of 4.5SH RNA results not only from the induction of its transcription but also from a substantial retardation of its decay. To our knowledge, it is the first example of a short-lived non-coding RNA whose elongated lifetime contributes significantly to its accumulation in stressed cells.



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Association of glutathione S-transferases M1, T1 and P1 gene polymorphisms with attention deficit and hyperactivity disorder in Korean children

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Publication date: 25 July 2016
Source:Gene, Volume 586, Issue 2
Author(s): Ji-Yeon Lee, In-Wook Hwang, Myung-Ho Lim, Ho-Jang Kwon, Han-Jun Jin
Attention deficit and hyperactivity disorder (ADHD) is highly heritable disorder and common in school-age children characterized by inattention, hyperactivity and impulsivity. Although its heritability was estimated at 80–90% from family, adoption and twin studies, the molecular etiology of this disorder has not elucidated. Meanwhile, an impaired balance of oxidant-antioxidant status and increased oxidative stress is observed in ADHD, and it may imply a possible relationship between oxidative stress and etiology of ADHD. Glutathione S-transferase (GST) is antioxidant enzymes that play a key role in the cellular detoxification. In the present study, we examined the association between the genetic polymorphisms of GSTM1, GSTP1 and GSTT1, and ADHD in Korean children. Case–control study was conducted with 243 ADHD children and 327 controls. There were no significant associations between the polymorphisms and the incidence of ADHD (p>0.05). However, significant associations were observed in the stratified analyses. The frequency of GSTP1 Ile/Ile genotype is reached to the significant level in the hyperactivity subtype (88.2%) compared to controls (64.8%) (p=0.035) and the frequency of GSTT1-null genotype is significantly higher in the inattentive boys (p=0.005). Similarly, GSTT1-null genotype showed significant associations in combined subtype (p=0.016) and hyperactivity subtype (p=0.036) of the ADHD girls. Thus our result imply that the polymorphisms in the GST genes may affect ADHD, however, replication study for larger sample set and functional studies are crucial to confirm these findings.



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HMGCR is up-regulated in gastric cancer and promotes the growth and migration of the cancer cells

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Publication date: 1 August 2016
Source:Gene, Volume 587, Issue 1
Author(s): Li Chushi, Wu Wei, Xie Kangkang, Feng Yongzeng, Xie Ning, Chen Xiaolei
Alteration of metabolic profile is one of the hallmarks of cancer cells. Statin, the inhibitors for synthesis of cholesterol, has shown anti-cancer effects on the gastric cancer cells. However, the functions of its target, HMGCR, in the progression of gastric cancer remain unknown. In the present study, we investigated the expression profile and the biological functions of HMGCR in gastric cancer. It was found that the expression of HMGCR was increased in gastric cancer tissues. Over-expression of HMGCR promoted the growth and migration of gastric cancer cells, while knocking down the expression of HMGCR inhibited the growth, migration and tumorigenesis of gastric cancer cells. In the further molecular mechanism study, HMGCR was shown to activate Hedgehog/Gli1 signaling and promoted the expression of Gli1 target genes. Taken together, this study demonstrated the tumor-promoting effects of HMGCR in gastric cancer and suggested HMGCR as a promising therapeutic target.



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