Publications by authors named "Qi-Cai Liu"

52 Publications

High serum lactate dehydrogenase and dyspnea: Positive predictors of adverse outcome in critical COVID-19 patients in Yichang.

World J Clin Cases 2020 Nov;8(22):5535-5546

Department of Reproductive Medicine Centre, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China.

Background: Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in China, constitutes a Public Health Emergency of International Concern. It is well known that COVID-19 patients may have increased serum lactate dehydrogenase (LDH) levels in the early stage. The clinical changes in LDH may have predictive value in disease evolution and prognosis in critically ill COVID-19 patients.

Aim: To examine serum LDH and clinical characteristics in patients with COVID-19 and their predictive value for prognosis.

Methods: This retrospective study analyzed the clinical data of forty-seven critical COVID-19 patients in the intensive care unit of the Third People's Hospital of Yichang City from January 27 to March 25, 2020 and divided them into survivors and non-survivors. The patients were diagnosed according to the World Health Organization interim guidance and critical cases met any one of the following criteria: Respiratory failure and required mechanical ventilation, the occurrence of shock, and the combined failure of other organs that required intensive care unit monitoring and treatments, according to the diagnostic criteria of critical COVID-19. Clinical data including symptoms, detection of SARS-CoV-2, chest computed tomography (CT) images, changes in serum LDH in different clinical phases, and prognosis were collected. Statistical analysis of the data was performed. Continuous variables were expressed as median (interquartile range) and compared with the Mann-Whitney U test. Categorical variables were compared with the Chi-square test. Survival data were analyzed using Kaplan-Meier survival curves and log-rank tests.

Results: According to chest CT images, we observed the alveolitis and fibrosis stages in all critical patients in this study. Most non-survivors died in the fibrosis stage. Non-survivors had fewer days of hospitalization, shorter disease duration, shorter duration of alveolitis and fibrosis, and had dyspnea symptoms at disease onset ( = 0.05). Both first and lowest LDH values in the alveolitis stage were more pronounced in non-survivors than in survivors (449.0 U/L 288.0 U/L, = 0.0243; 445.0 U/L 288.0 U/L, = 0.0199, respectively), while the first, lowest and highest values of serum LDH in non-survivors were all significantly increased compared to survivors in the fibrosis phase (449.0 U/L 225.5 U/L, = 0.0028; 432.0 U/L 191.0 U/L, = 0.0007; 1303.0 U/L 263.5 U/L, = 0.0001, respectively). The cut-off points of first LDH values in the alveolitis and fibrosis phase for distinction of non-survivors from survivors were 397.0 U/L and 263.0 U/L, respectively. In the fibrosis stage, non-survivors had more days with high LDH than survivors (7.0 d 0.0 d, = 0.0002). Importantly, patients with high LDH had a significantly shorter median survival time than patients with low LDH in the alveolitis phase (22.0 d 36.5 d, = 0.0002), while patients with high LDH also had a significantly shorter median survival time than patients with low LDH in the fibrosis phase (27.5 d 40.0 d, = 0.0008). The proportion of non-survivors with detectable SARS-CoV-2 until death in the alveolitis stage was significantly increased compared with that in the fibrosis stage (100% 35.7%, = 0.0220).

Conclusion: High LDH and dyspnea symptoms were positive predictors of an adverse outcome in critical COVID-19. The rapid progressive fibrosis stage was more perilous than the alveolitis stage, even if SARS-CoV-2 is undetectable.
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http://dx.doi.org/10.12998/wjcc.v8.i22.5535DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716337PMC
November 2020

HNF-1 binding point mutation of the AFP gene promotes cirrhosis in post-menopausal women.

Int J Biol Markers 2020 Mar 29;35(1):41-46. Epub 2020 Jan 29.

Department of Pathology, 1st Affiliated Hospital, Fujian Medical University, Fuzhou, China.

Objective: α-fetoprotein (AFP) expression is activated during the embryonic stage or hepatocellular carcinogenesis, so it is presumed that AFP is a key endogenous molecule to promote cell proliferation or differentiation. We carried out gene screening in an unknown family with hyper-alpha-fetoproteinemia and some sporadic menopausal women, and discussed the relationship between AFP expression and liver cirrhosis.

Methods: Peripheral blood samples from family members, patients with malignant liver tumors, and normal controls were collected. Full-length sequence of AFP was amplified and directly sequenced, and compared with normal controls. HNF-1α and HNF-1β in plasma levels of family members, patients with liver cancer, newborns, pregnant women, and normal subjects were detected by ELISA, and the relationship between HNF-1 and AFP mutation or high expression was evaluated.

Results: There was a mutation in AFP promoter region at c.-200 C>T, which was located at the binding site of AFP hepatocyte nuclear factor 1 (HNF-1). AFP was higher than 4000 ng/L in all members carrying the mutation, but liver cancer was excluded in the family with hyper-alpha-fetoprotein. However, cirrhosis occurred in post-menopausal women. The cases reviewed showed that unknown hyper-alpha-fetoprotein was closely related to HNF-1 binding point of AFP in post-menopausal women with cirrhosis (7/11), while the plasma levels of HNF-1α and HNF-1β were not significantly different.

Conclusion: The mutation of the HNF-1 binding point of AFP may lead to an abnormal high expression of AFP by altering the binding of HNF transcription factors, which is closely related to cirrhosis in menopausal women.
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http://dx.doi.org/10.1177/1724600819900510DOI Listing
March 2020

Spermidine-enhanced autophagic flux improves cardiac dysfunction following myocardial infarction by targeting the AMPK/mTOR signalling pathway.

Br J Pharmacol 2019 09 17;176(17):3126-3142. Epub 2019 Jul 17.

Laboratory of Heart Center and Department of Cardiology, Heart Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Background And Purpose: Spermidine, a natural polyamine, is abundant in mammalian cells and is involved in cell growth, proliferation, and regeneration. Recently, oral spermidine supplements were cardioprotective in age-related cardiac dysfunction, through enhancing autophagic flux. However, the effect of spermidine on myocardial injury and cardiac dysfunction following myocardial infarction (MI) remains unknown.

Experimental Approach: We determined the effects of spermidine in a model of MI, Sprague-Dawley rats with permanent ligation of the left anterior descending artery, and in cultured neonatal rat cardiomyocytes (NRCs) exposed to angiotensin II (Ang II). Cardiac function in vivo was assessed with echocardiography. In vivo and in vitro studies used histological and immunohistochemical techniques, along with western blots.

Key Results: Spermidine improved cardiomyocyte viability and decreased cell necrosis in NRCs treated with angiotensin II. In rats post-MI, spermidine reduced infarct size, improved cardiac function, and attenuated myocardial hypertrophy. Spermidine also suppressed the oxidative damage and inflammatory cytokines induced by MI. Moreover, spermidine enhanced autophagic flux and decreased apoptosis both in vitro and in vivo. The protective effects of spermidine on cardiomyocyte apoptosis and cardiac dysfunction were abolished by the autophagy inhibitor chloroquine, indicating that spermidine exerted cardioprotective effects at least partly through promoting autophagic flux, by activating the AMPK/mTOR signalling pathway.

Conclusions And Implications: Our findings suggest that spermidine improved MI-induced cardiac dysfunction by promoting AMPK/mTOR-mediated autophagic flux.
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http://dx.doi.org/10.1111/bph.14706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692641PMC
September 2019

Adropin deficiency worsens HFD-induced metabolic defects.

Cell Death Dis 2017 08 24;8(8):e3008. Epub 2017 Aug 24.

Department of Pathology, 1st Affiliated Hospital, Fujian Medical University, Fuzhou, China.

The limited efficacy of current treatment methods and increased type 2 diabetes mellitus (T2DM) incidence constitute an incentive for investigating how metabolic homeostasis is maintained, to improve treatment efficacy and identify novel treatment methods. We analyzed a three-generation family of Chinese origin with the common feature of T2DM attacks and fatty pancreas (FP), alongside 19 unrelated patients with FP and 58 cases with T2DM for genetic variations in Enho, serum adropin, and relative T amounts. Functional studies with adropin knockout (AdrKO) in C57BL/6J mice were also performed. It showed serum adropin levels were significantly lower in FP and T2DM patients than in healthy subjects; relative T amounts were also significantly decreased in FP and T2DM patients, and positively associated with adropin (r=0.7220, P=0.0001). Sequencing revealed that the patients shared a Cys56Trp mutation in Enho. In vivo, adropin-deficiency was associated with increased severity of glucose homeostasis impairment and fat metabolism disorder. AdrKO mice exhibited reduced endothelial nitric oxide synthase (eNOS) phosphorylation (Ser1177), impaired glycosphingolipid biosynthesis, adipocytes infiltrating, and loss of T, and developed FP and T2DM. Adropin-deficiency contributed to loss of T and the development of FP disease and T2DM.
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http://dx.doi.org/10.1038/cddis.2017.362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596552PMC
August 2017

Diagnostic value of brain natriuretic peptide and β-endorphin plasma concentration changes in patients with acute left heart failure and atrial fibrillation.

Medicine (Baltimore) 2017 Aug;96(34):e7526

Department of Emergency, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.

Rationale: This study aims to evaluate the diagnostic value of beta-endorphin (β-EP) and brain natriuretic peptid (BNP) plasma concentrations for the early diagnosis of acute left heart failure and atrial fibrillation.

Patient Concerns: A total of 45 patients were included. These patients comprised 23 male and 22 female patients,and 20 healthy subjects who underwent physical examinations in the Outpatient Department during the same periodwere included and assigned to the control group.

Diagnoses: The diagnos stand was that of the Chinese guidelines for the diagnosis and treatment of heart failure.

Interventions: Enzyme-linked immunosorbent assay was performed to detect the plasma concentration of β-EP and BNP in the treatment and control groups, and electrocardiogram targeting was performed to determine the left ventricular ejection fraction (LVEF).

Outcomes: BNP, β-EP, and LVEF levels were higher in the treatment group (688.01 ± 305.78 ng/L, 394.06 ± 180.97 ng/L, and 70.48 ± 16.62%) compared with the control group (33.90 ± 8.50 ng/L, 76.87 ± 57.21 ng/L, and 32.11 ± 5.25%). The P-values were .015, .019, and .026, respectively, which were <.05. The difference was statistically significant. The BNP and β-EP's 4 correlations (r = 0.895, P <.001), BNP, β-EP, and the combination of BNP and β-EP for acute left heart failure diagnosis in maximizing Youden index sensitivity, specific degree, area under the ROC curve (AUC), and 95% confidence interval (CI) were respectively 93.5%, 81.3%, 0.921, 0.841, 0.921; 80.5%, 78.6%, 0.697, 0.505, 0.697; 94.1%, 83.5%, 0.604 to 0.979, and 0.604. Acute left heart failure in patients with LVEF acuity plasma BNP and β-EP 50% group was obviously lower than that in the LVEF <50% group (P <.01). BNP, β-EP, and LVEF were negatively correlated (r = -0.741, -0.635, P = .013, .018).

Lessons: β-EP and BNP have high specificity and sensitivity for detecting early acute left heart failure and atrial fibrillation in patients, which is convenient, easy to perform, and suitable for clinical applications.
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http://dx.doi.org/10.1097/MD.0000000000007526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571992PMC
August 2017

CALCB splice region pathogenic variants leading to plasma cell neurotropic enrichment in type 1 autoimmune pancreatitis.

Cell Death Dis 2017 02 2;8(2):e2591. Epub 2017 Feb 2.

Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, China.

Recently, we have demonstrated that PRSS1 mutations cause ectopic trypsinogen activation and thereby result in type 1 autoimmune pancreatitis (AIP). However, the molecules involved in inducing obliterative vasculitis and perineural inflammation in the pancreas are not well-described. The present study applied whole-exome sequencing (WES) to determine the underlying etiology and revealed novel missense splice region variants, CALCB c.88T>C (p.Ser30Pro) and IR [1]-mutants, in 2 of the 3 families and 2 of 26 unrelated patients with type 1 AIP. In vitro, both of the mutants displayed decreased βCGRP, ERK1/2 phosphorylation, and co-localized with endoplasmic reticulum and Golgi apparatus. The novel pathogenic variant identified in this case should contribute to our understanding of the expanding spectrum of AIP.
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http://dx.doi.org/10.1038/cddis.2017.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386480PMC
February 2017

Long non-coding RNA SPRY4-IT1 pormotes colorectal cancer metastasis by regulate epithelial-mesenchymal transition.

Oncotarget 2017 Feb;8(9):14479-14486

Department of General Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, P.R. China.

Colorectal cancer (CRC) remains one of the most common cancers worldwide. Increasing evidence indicates that SPRY4 intronic transcript 1 (SPRY4-IT1) regulate cell growth, differentiation, apoptosis, and cancer progression. However, the expression and function of SPRY4-IT1 in the progression of CRC remains largely unknown. Here, we reported that SPRY4-IT1 was upregulated in CRC. Increased SPRY4-IT1 expression in CRC was associated with larger tumor size and higher clinical stage. In vitro experiments revealed that SPRY4-IT1 knockdown significantly inhibited CRC cell proliferation by causing G1 arrest and promoting apoptosis, whereas SPRY4-IT1 overexpression promoted cell proliferation. Further functional assays indicated that SPRY4-IT1 overexpression significantly promoted cell migration and invasion by regulate the epithelial-mesenchymal transition (EMT). Taken together, our study demonstrates that SPRY4-IT1 could act as a functional oncogene in CRC, as well as a potential therapeutic target to inhibit CRC metastasis.
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http://dx.doi.org/10.18632/oncotarget.10407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5362419PMC
February 2017

Chromatin-wide and transcriptome profiling integration uncovers p38α MAPK as a global regulator of skeletal muscle differentiation.

Skelet Muscle 2016 15;6. Epub 2016 Mar 15.

Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative diseases (CIBERNED), Barcelona, Spain ; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.

Background: Extracellular stimuli induce gene expression responses through intracellular signaling mediators. The p38 signaling pathway is a paradigm of the mitogen-activated protein kinase (MAPK) family that, although originally identified as stress-response mediator, contributes to establishing stem cell differentiation fates. p38α is central for induction of the differentiation fate of the skeletal muscle stem cells (satellite cells) through not fully characterized mechanisms.

Methods: To investigate the global gene transcription program regulated by p38α during satellite cell differentiation (myogenesis), and to specifically address whether this regulation occurs through direct action of p38α on gene promoters, we performed a combination of microarray gene expression and genome-wide binding analyses. For experimental robustness, two myogenic cellular systems with genetic and chemical loss of p38α function were used: (1) satellite cells derived from mice with muscle-specific deletion of p38α, and (2) the C2C12 murine myoblast cell line cultured in the absence or presence of the p38α/β inhibitor SB203580. Analyses were performed at cell proliferation and early differentiation stages.

Results: We show that p38α binds to a large set of active promoters during the transition of myoblasts from proliferation to differentiation stages. p38α-bound promoters are enriched with binding motifs for several transcription factors, with Sp1, Tcf3/E47, Lef1, FoxO4, MyoD, and NFATc standing out in all experimental conditions. p38α association with chromatin correlates very well with high levels of transcription, in agreement with its classical function as an activator of myogenic differentiation. Interestingly, p38α also associates with genes repressed at the onset of differentiation, thus highlighting the relevance of p38-dependent chromatin regulation for transcriptional activation and repression during myogenesis.

Conclusions: These results uncover p38α association and function on chromatin at novel classes of target genes during skeletal muscle cell differentiation. This is consistent with this MAPK isoform being a transcriptional regulator.
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http://dx.doi.org/10.1186/s13395-016-0074-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791895PMC
October 2016

Antibodies to Type IV Collagen Induce Type 1 Autoimmune Pancreatitis.

Inflammation 2016 Apr;39(2):592-600

Department of Pharmaceutical Analysis, Fujian Medical University, Fuzhou, China.

Type 1 autoimmune pancreatitis (AIP) is prototypic autoantibody-mediated diseases. Sclerosis accompanied by fiber deposition is generally regarded as the primary lesion in the development of obliterative vasculitis. However, why collagens or their antibodies play a crucial role in the pathogenesis of AIP has not been demonstrated. This study was performed to investigate if anti-collagen type IV antibodies (ACIVAbs) are the key factor of fiber deposition and recruit leukocytes, resulting in obliterative vasculitis in pancreas. Enzyme-linked immunosorbent analyses (ELISA) were used to measure the expression of Col IV and ACIVAbs in serum of patients with and without AIP. In vitro, adhesion and proliferation were determined by human lymphocytes incubated with Col IV and ACIVAbs. In vivo, C57BL0/6 mice were immunized with IgG-ACIVAbs, followed by analysis of clinical phenotype. IgG-ACIVAbs were recognized by the serum specimens from 12 of 22 patients with type 1 AIP, 3 of 9 patients with Crohn's disease, and 2 of 18 patients with pancreatic cancer, but not in healthy controls and acute pancreatitis. In patient's biopsy, ACIVAb staining increased and co-localized with subepithelial IgG4 deposits along the capillary walls and surrounding nerve fibers. In vitro, recombinant IgG-ACIVAbs increased leukocyte adhesion and proliferation. What is more, AIP could be induced in mice by immunization with IgG-ACIVAbs into adult mice.
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http://dx.doi.org/10.1007/s10753-015-0284-0DOI Listing
April 2016

Downregulation of CDK-8 inhibits colon cancer hepatic metastasis by regulating Wnt/β-catenin pathway.

Biomed Pharmacother 2015 Aug 15;74:153-7. Epub 2015 Aug 15.

Department of General Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou 510180, People's Republic of China. Electronic address:

Liver metastasis is a major cause of mortality from colon cancer. To investigate the role of cyclin-dependent kinase 8 (CDK8) in the progression of colon cancer hepatic metastasis. In this present study, human colon cancer HCT116 or HCT116-LUC-GFP cells were transfected with Lentiviral vector-mediated knockdown of CDK-8. After transfection, metastasis and invasion potential of colon cancer cell was investigated by wound healing and transwell invasion assays, respectively. A mice model of colon cancer liver metastases was established and observed with bioluminescence imaging. The protein expression of CDK-8, β-catenin, E2F1, MMP-7 and E-cadherin in liver tissues were detected by Western Blot. Our results revealed that lentiviral vector-mediated knockdown of CDK-8 inhibited metastasis and invasion of colon cancer cells in vitro and in vivo, respectively. Protein expression of CDK-8, β-catenin, MMP-7 and E-cadherin were inhibited, but protein expression of E2F1 was enhanced. In sum, our data provided compelling evidence that CDK-8 played a significant role in colon cancer hepatic metastasis by regulating the Wnt/β-catenin signal pathway and might sever as a potential therapeutic target for colon cancer patients.
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http://dx.doi.org/10.1016/j.biopha.2015.08.015DOI Listing
August 2015

MACC1 induces metastasis in ovarian carcinoma by upregulating hepatocyte growth factor receptor c-MET.

Oncol Lett 2014 Aug 27;8(2):891-897. Epub 2014 May 27.

Experimental Medical Research Center of Guangzhou Medical University, Guangzhou, Guangdong 510182, P.R. China.

Metastasis-associated in colon cancer 1 (MACC1) is a newly identified gene that has been shown to promote tumor cell invasion and metastasis. The present study investigated the effect of MACC1 downregulation on the biological characteristics of the ovarian cancer OVCAR3 cell line. In this study, MACC1 expression was blocked using the RNA interference technique. The downregulation of MACC1 mRNA and protein expression was confirmed using quantitative polymerase chain reaction and western blot analysis. The proliferative activity and adhesion rate of the cells were detected using cell counting kit-8 and a cell adhesion assay, while cell invasion was determined using a Matrigel invasion assay and migration capacity was observed using migration and wound-healing assays. A tube formation assay was also used to examine the angiogenic capacity of cells, and a luciferase assay was performed to assess whether MACC1 binds to the c-MET gene. The MACC1 mRNA and protein expression levels were significantly downregulated using sequence-specific small interfering RNA (siRNA). The inhibition of MACC1 expression markedly decreased the invasive, metastatic and angiogenic capacities of the cells, but only slightly inhibited growth and adhesion. In addition, a putative MACC1-binding site was identified in the 3'-untranslated region of c-MET. MACC1-siRNA was also found to significantly reduce the expression of the c-MET protein and a luciferase reporter assay confirmed that c-MET was the target gene of MACC1. These results demonstrated that the attenuation of MACC1 suppresses cell invasion and migration and that MACC1 may regulate cell metastasis through targeting the expression of c-MET. Inhibition of the function of MACC1 may represent a new strategy for treating ovarian cancer.
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http://dx.doi.org/10.3892/ol.2014.2184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081430PMC
August 2014

Synergism from the combination of ulinastatin and curcumin offers greater inhibition against colorectal cancer liver metastases via modulating matrix metalloproteinase-9 and E-cadherin expression.

Onco Targets Ther 2014 18;7:305-14. Epub 2014 Feb 18.

Department of General Surgery, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, People's Republic of China.

Liver metastasis is a major cause of mortality in colorectal cancer (CRC). The current study was to investigate the ability of ulinastatin (UTI) and curcumin (CUR) to inhibit CRC liver metastases via modulating matrix metalloproteinase-9 (MMP-9) and E-cadherin expression. Human CRC HCT-116 cells were treated with compounds individually and in combination in order to understand the effect on cell migration and invasion. The HCT-116 cell line was established to stably express luciferase and green fluorescent protein (GFP) by lentiviral transduction (HCT-116-Luc-GFP). We identified an anti-metastasis effect of UTI and CUR on a CRC liver metastasis mouse model. Tumor development and therapeutic responses were dynamically tracked by bioluminescence imaging. Expression of MMP-9 and E-cadherin in metastatic tumors was detected by immunohistochemical assay. Results of wound healing and cell invasion assays suggest that treatment with UTI, CUR, and UTI plus CUR, respectively, significantly inhibit HCT-116 cell migration and invasion. Furthermore, results of CRC hepatic metastasis on a nude mouse model showed that treatment with UTI, CUR alone, and a combination notably inhibited hepatic metastases from CRC and prolonged survival of tumor-bearing mice, especially in the UTI plus CUR group. These results suggest that the combination of UTI and CUR together may offer greater inhibition against metastasis of CRC.
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http://dx.doi.org/10.2147/OTT.S57126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933719PMC
February 2014

Serum trypsin and TCR as novel markers for predicting disease activity in IgG4-related disease.

Cent Eur J Immunol 2014 27;39(2):193-7. Epub 2014 Jun 27.

Department of Laboratory Medicine, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian Province, PR China.

Background: IgG4-related disease (IgG4-RD) is a novel disease named in recent years. Because of its varied clinical manifestations, like tumor but not tumor, it brings a great challenge to clinical diagnosis. Trypsin and T-cell receptor (TCR) are thought to mediate the regulation of B cell maturation, survival and antibody production. In this study, we investigated the clinical features and important novel markers of IgG4-RD.

Material And Methods: A prospective cohort study of 22 patients with IgG4-RD was carried out from May 2009 to December 2012, and 65 cases with acute pancreatitis, 60 cases with pancreatic cancer and 120 healthy individuals were studied as controls. Serum TCR, trypsin and IgG4 levels were measured during pre- and post-treatment in the patients with IgG4-RD and their correlations with IgG4 were also assessed.

Results: Serum IgG4 and IgE levels in all patients were significantly increased, and tumor markers (carbohydrate antigen 19-9 and/or carbohydrate antigen 125) were also increased (12/22). Serum trypsin in patients with IgG4-RD was lower than in the ones with acute pancreatitis, pancreatic cancer, and healthy individuals. But serum TCR of IgG4-RD was significantly higher than in the pancreatic cancer group and normal controls and it was inversely correlated with the levels of IgG4 (r = -3.160, p = 0.042).

Conclusions: The results indicate that serum TCR and trypsin might be useful markers for predicting disease activity in IgG4-RD.
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http://dx.doi.org/10.5114/ceji.2014.43722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440023PMC
July 2015

Multiple gene mutations in patients with type 2 autoimmune pancreatitis and its clinical features.

Cent Eur J Immunol 2014 17;39(1):77-82. Epub 2014 Apr 17.

Department of Laboratory Medicine, Medical Technology and Engineering College, Fujian Medical University, Fuzhou, PR China.

Background: It is now clear that there are two histological types (type 1 and type 2) of autoimmune pancreatitis (AI P). The histological substance of type 1 AI P is known as lymphoplasmacytic sclerosing pancreatitis (LPSP) or traditional AIP, and type 2 AIP is characterized by distinct histology called idiopathic duct centric pancreatitis (IDCP). Serum IgG4 increase is considered as a marker for type 1 AI P. Far less is known about type 2 and it lacks predicting markers, so it easily leads to missed diagnosis and misdiagnosis.

The Aim Of This Study: The aim of this study was to describe multi-gene mutations in patients with type 2 AI P and its clinical features.

Material And Methods: Three unrelated patients with type 2 AI P, 10 cases with type 1 AIP, 15 cases with other chronic pancreatitis and 120 healthy individuals were studied. The mutations and polymorphisms of 6 genes involved in chronic pancreatitis or pancreatic cancer - PRSS1, SPINK1, CFTR, MEN1, PKHD1, and mitochondrial DNA - were sequenced. Information of clinical data was collected by personal interview using a structured questionnaire.

Results: Novel mutations were found in the genes encoding for MEN1 (p.546 Ala > The) and PKHD1 (c. 233586 A > G and c. 316713 C > T) from patients with type 2 AIP. What is more, the serum TCR (T cell receptor) level is relatively higher in patients with type 2 AIP than in patients with type 1 AIP and other chronic pancreatitis or normal controls. Weight loss was the major manifestation and no patients had extrapancreatic involvement in type 2 AIP.

Conclusions: Type 2 AIP may occur with multi-gene mutations. For screening purposes, it is more reasonable to evaluate TCR levels in serum.
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http://dx.doi.org/10.5114/ceji.2014.42129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439988PMC
July 2015

PRSS1_p.Leu81Met mutation results in autoimmune pancreatitis.

World J Gastroenterol 2013 Jun;19(21):3332-8

Department of Pathology, First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, Fujian Province, China.

Aim: To describe protease serine 1 (PRSS1) gene mutations in patients with autoimmune pancreatitis (AIP) and the clinical features of AIP.

Methods: Fourteen patients with AIP, 56 with other chronic pancreatitis, 254 with pancreatic cancer and 120 normal controls were studied. The mutations and polymorphisms of four genes involved with pancreatitis or pancreatic cancer, PRSS1, SPINK1, CFTR and MEN1, were sequenced. The pathogenic mechanism of AIP was investigated by comparing the wild-type expression system with the p.81Leu→Met mutant expression system.

Results: Two novel mutations (p.81Leu→Met and p.91Ala→Ala) were found in PRSS1 gene from four patients with AIP. PRSS1_p.81Leu→Met mutation led to a trypsin display reduction (76.2%) combined with phenyl agarose (Ca(2+) induced failure). Moreover, the ratio of trypsin/amylase in patients with AIP was higher than in the patients with pancreatic cancer and other pancreatitis. A large number of lymphocytes and plasma cells were found in the bile ducts accompanied by hyperplasia of myofibroblasts.

Conclusion: Autoimmune pancreatitis may be related to PRSS1 gene mutations.
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http://dx.doi.org/10.3748/wjg.v19.i21.3332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3671086PMC
June 2013

Tissue-specific splicing of a ubiquitously expressed transcription factor is essential for muscle differentiation.

Genes Dev 2013 Jun 30;27(11):1247-59. Epub 2013 May 30.

Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.

Alternate splicing contributes extensively to cellular complexity by generating protein isoforms with divergent functions. However, the role of alternate isoforms in development remains poorly understood. Mef2 transcription factors are essential transducers of cell signaling that modulate differentiation of many cell types. Among Mef2 family members, Mef2D is unique, as it undergoes tissue-specific splicing to generate a muscle-specific isoform. Since the ubiquitously expressed (Mef2Dα1) and muscle-specific (Mef2Dα2) isoforms of Mef2D are both expressed in muscle, we examined the relative contribution of each Mef2D isoform to differentiation. Using both in vitro and in vivo models, we demonstrate that Mef2D isoforms act antagonistically to modulate differentiation. While chromatin immunoprecipitation (ChIP) sequencing analysis shows that the Mef2D isoforms bind an overlapping set of genes, only Mef2Dα2 activates late muscle transcription. Mechanistically, the differential ability of Mef2D isoforms to activate transcription depends on their susceptibility to phosphorylation by protein kinase A (PKA). Phosphorylation of Mef2Dα1 by PKA provokes its association with corepressors. Conversely, exon switching allows Mef2Dα2 to escape this inhibitory phosphorylation, permitting recruitment of Ash2L for transactivation of muscle genes. Thus, our results reveal a novel mechanism in which a tissue-specific alternate splicing event has evolved that permits a ubiquitously expressed transcription factor to escape inhibitory signaling for temporal regulation of gene expression.
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http://dx.doi.org/10.1101/gad.215400.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690398PMC
June 2013

Ulinastatin reduces cancer recurrence after resection of hepatic metastases from colon cancer by inhibiting MMP-9 activation via the antifibrinolytic pathway.

Biomed Res Int 2013 23;2013:437950. Epub 2013 Apr 23.

Department of General Surgery, Guangzhou First People's Hospital, Guangzhou Medical College, 1 Panfu Road, Yuexiu District, Guangzhou 510180, China.

High recurrence of colon cancer liver metastasis is observed in patients after hepatic surgery, and the cause is believed to be mostly due to the growth of residual microscopic metastatic lesions within the residual liver. Therefore, triggering the progression of occult metastatic foci may be a novel strategy for improving survival from colon cancer liver metastases. In the present study, we identified an anti-recurrence effect of ulinastatin on colon cancer liver metastasis in mice after hepatectomy. Transwell cell invasion assays demonstrated that ulinastatin significantly inhibited the in vitro invasive ability of colon cancer HCT116 cells. Moreover, gelatin zymography and ELISA analysis showed that MMP-9 activity and plasmin activity of colon cancer HCT116 cells were inhibited by ulinastatin, respectively. Furthermore, in vivo BALB/C nu/nu mice model indicated that ulinastatin effectively reduced recurrence after resection of hepatic metastases from colon cancer. The optimum timing for ulinastatin administration was one week after hepatectomy. Taken together, our findings point to the potential of ulinastatin as an effective approach in controlling recurrence of hepatic metastases from colon cancer after hepatectomy via its anti-plasmin activity.
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http://dx.doi.org/10.1155/2013/437950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655446PMC
December 2013

Effect of hepatocyte growth factor and angiotensin II on rat cardiomyocyte hypertrophy.

Braz J Med Biol Res 2012 Dec 9;45(12):1150-6. Epub 2012 Oct 9.

Department of Cardiology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.

Angiotensin II (Ang II) plays an important role in cardiomyocyte hypertrophy. The combined effect of hepatocyte growth factor (HGF) and Ang II on cardiomyocytes is unknown. The present study was designed to determine the effect of HGF on cardiomyocyte hypertrophy and to explore the combined effect of HGF and Ang II on cardiomyocyte hypertrophy. Primary cardiomyocytes were isolated from neonatal rat hearts and cultured in vitro. Cells were treated with Ang II (1 µM) alone, HGF (10 ng/mL) alone, and Ang II (1 µM) plus HGF (10 ng/mL) for 24, 48, and 72 h. The amount of [³H]-leucine incorporation was then measured to evaluate protein synthesis. The mRNA levels of β-myosin heavy chain and atrial natriuretic factor were determined by real-time PCR to evaluate the presence of fetal phenotypes of gene expression. The cell size of cardiomyocytes was also studied. Ang II (1 µM) increased cardiomyocyte hypertrophy. Similar to Ang II, treatment with 1 µM HGF promoted cardiomyocyte hypertrophy. Moreover, the combination of 1 µM Ang II and 10 ng/mL HGF clearly induced a combined pro-hypertrophy effect on cardiomyocytes. The present study demonstrates for the first time a novel, combined effect of HGF and Ang II in promoting cardiomyocyte hypertrophy.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854218PMC
http://dx.doi.org/10.1590/s0100-879x2012007500159DOI Listing
December 2012

Comparative expression profiling identifies differential roles for Myogenin and p38α MAPK signaling in myogenesis.

J Mol Cell Biol 2012 Dec 30;4(6):386-97. Epub 2012 Jul 30.

Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada K1H 8L6.

Skeletal muscle differentiation is mediated by a complex gene expression program requiring both the muscle-specific transcription factor Myogenin (Myog) and p38α MAPK (p38α) signaling. However, the relative contribution of Myog and p38α to the formation of mature myotubes remains unknown. Here, we have uncoupled the activity of Myog from that of p38α to gain insight into the individual roles of these proteins in myogenesis. Comparative expression profiling confirmed that Myog activates the expression of genes involved in muscle function. Furthermore, we found that in the absence of p38α signaling, Myog expression leads to the down-regulation of genes involved in cell cycle progression. Consistent with this, the expression of Myog is sufficient to induce cell cycle exit. Interestingly, p38α-defective, Myog-expressing myoblasts fail to form multinucleated myotubes, suggesting an important role for p38α in cell fusion. Through the analysis of p38α up-regulated genes, the tetraspanin CD53 was identified as a candidate fusion protein, a role confirmed both ex vivo in primary myoblasts, and in vivo during myofiber regeneration in mice. Thus, our study has revealed an unexpected role for Myog in mediating cell cycle exit and has identified an essential role for p38α in cell fusion through the up-regulation of CD53.
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http://dx.doi.org/10.1093/jmcb/mjs045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580549PMC
December 2012

Loss of breast cancer metastasis suppressor 1 promotes ovarian cancer cell metastasis by increasing chemokine receptor 4 expression.

Oncol Rep 2012 Apr 19;27(4):1011-8. Epub 2011 Dec 19.

Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical College, Guangzhou 510150, PR China.

Breast cancer metastasis suppressor 1 (BRMS1) is a predominantly nuclear protein that differentially regulates the expression of multiple genes, leading to suppression of metastasis without affecting orthotopic tumor growth. It has been demonstrated that BRMS1 may be correlated with advanced ovarian cancer. The aim of this study was to investi-gate the mechanisms of BRMS1 involvement in ovarian cancer metastasis. We constructed a plasmid containing a short hairpin RNA (shRNA) against BRMS1 and transfected it into the ovarian cancer cell line OVCAR3. Real-time reverse transcription polymerase chain reaction (real-time PCR) and Western blot analyses demonstrated that BRMS1 expression was efficiently downregulated. Stable suppression of BRMS1 significantly enhanced cell adhesion, migration, invasion and angiogenesis. We also found that chemokine receptor 4 (CXCR4) was upregulated at both the mRNA and protein levels. When approaching for the mechanism, we discovered that activation of the nuclear factor-κB (NF-κB) signaling pathway mediated CXCR4 upregulation, as demonstrated by the electrophoretic mobility shift assay (EMSA). Collectively, these results suggest that attenuation of BRMS1 may play a critical role in promoting migration, invasion and angiogenesis of ovarian cancer cells and BRMS1 may regulate the metastatic potential at least in part through upregulation of CXCR4 via NF-κB activation. Restoration of BRMS1 function is thus a potential new strategy for treating human ovarian cancer.
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http://dx.doi.org/10.3892/or.2011.1596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583538PMC
April 2012

PRSS1 intron mutations in patients with pancreatic cancer and chronic pancreatitis.

Mol Med Rep 2012 Feb 21;5(2):449-51. Epub 2011 Nov 21.

Department of Pathology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, PR China.

Genetic risk factors of chronic pancreatitis (CP) have been identified and a number of studies have found that CP can lead to pancreatic cancer. Therefore, the detection of pancreatitis-associated gene mutations can aid the pancreatic cancer diagnostic process. Mutations in three genes, the cationic trypsinogen (PRSS1) gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene and the pancreatic secretory trypsin inhibitor (SPINK1) gene, have been identified as risk factors for CP. The aim of this study was to describe specific novel mutations in the intron of the PRSS1 gene in patients with pancreatic cancer and CP. A total of 65 unrelated patients with pancreatic cancer and 29 with CP were reviewed. Mutations and polymorphisms of the PRSS1 gene were analyzed by direct sequencing. Information regarding clinical data and smoking exposure was collected by personal interviews using a structured questionnaire. IVS 3+36 A>G mutation in the PRSS1 gene was found in 2 cases with pancreatic cancer, and these 2 patients were classified as never-smokers. IVS 3+127 T>A and IVS 3+157 G>C double mutations were identified in one patient with CP. All patients were found to have serum trypsin levels lower than that of the normal controls. Therefore, the PRSS1 gene mutation may be a special common cause of pancreatic cancer and CP.
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http://dx.doi.org/10.3892/mmr.2011.684DOI Listing
February 2012

PRSS1 intron mutations in patients with pancreatic cancer and chronic pancreatitis.

Mol Med Rep 2012 Feb 21;5(2):449-51. Epub 2011 Nov 21.

Department of Pathology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, PR China.

Genetic risk factors of chronic pancreatitis (CP) have been identified and a number of studies have found that CP can lead to pancreatic cancer. Therefore, the detection of pancreatitis-associated gene mutations can aid the pancreatic cancer diagnostic process. Mutations in three genes, the cationic trypsinogen (PRSS1) gene, the cystic fibrosis transmembrane conductance regulator (CFTR) gene and the pancreatic secretory trypsin inhibitor (SPINK1) gene, have been identified as risk factors for CP. The aim of this study was to describe specific novel mutations in the intron of the PRSS1 gene in patients with pancreatic cancer and CP. A total of 65 unrelated patients with pancreatic cancer and 29 with CP were reviewed. Mutations and polymorphisms of the PRSS1 gene were analyzed by direct sequencing. Information regarding clinical data and smoking exposure was collected by personal interviews using a structured questionnaire. IVS 3+36 A>G mutation in the PRSS1 gene was found in 2 cases with pancreatic cancer, and these 2 patients were classified as never-smokers. IVS 3+127 T>A and IVS 3+157 G>C double mutations were identified in one patient with CP. All patients were found to have serum trypsin levels lower than that of the normal controls. Therefore, the PRSS1 gene mutation may be a special common cause of pancreatic cancer and CP.
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http://dx.doi.org/10.3892/mmr.2011.684DOI Listing
February 2012

Novel mutations of PRSS1 gene in patients with pancreatic cancer among Han population.

Chin Med J (Engl) 2011 Jul;124(13):2065-7

Department of Anesthesiology, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian 350005, China.

Background: A high mortality rate of pancreatic cancer becomes a bottleneck for further treatment with long-term efficacy. It is urgent to find a new mean to predict the early onset of pancreatic cancer accurately. The authors hypothesized that genetic variants of cationic trypsinogen (PRSS1) gene could affect trypsin expression/function and result in abnormal activation of protease activated receptor-2 (PAR-2), then lead to pancreatic cancer. The aim of this study was to elaborate some novel mutations of PRSS1 gene in the patients with pancreatic cancer.

Methods: Totally 156 patients with pancreatic cancer and 220 unrelated individuals as controls were enrolled in this study. The mutations of PRSS1 gene were analyzed by direct sequencing. K-ras Mutation Detection Kit was used to find the general k-ras gene disorder in the pancreatic cancer tissue. Then the clinical data were collected and analyzed simultaneously.

Results: There were two patients who carried novel mutations which was IVS 3 + 157 G > C of PRSS1 gene in peripheral blood specimens and pancreatic cancer tissue. What's more, it was surprising to find a novel complicated mutation of exon 3 in PRSS1 gene (c.409 A > G and c.416 C > T) in another young patient. The complicated mutation made No. 135 and No. 137 amino acid transfer from Thr to Ala and Thr to Met respectively. No any mutation was found in the normal controls while no mutations of k-ras gene were detected in the three patients.

Conclusion: Mutations of PRSS1 gene may be an important factor of pancreatic cancer.
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July 2011

Teashirt-3, a novel regulator of muscle differentiation, associates with BRG1-associated factor 57 (BAF57) to inhibit myogenin gene expression.

J Biol Chem 2011 Jul 4;286(26):23498-510. Epub 2011 May 4.

Institut de Biologie du Développement de Marseille Luminy, UMR 6216, CNRS-Université de la Méditerranée, Campus de Luminy, Case 907, 13288 Marseille Cedex 09, France.

In adult muscles and under normal physiological conditions, satellite cells are found in a quiescent state but can be induced to enter the cell cycle by signals resulting from exercise, injury-induced muscle regeneration, or specific disease states. Once activated, satellite cells proliferate, self-renew, and differentiate to form myofibers. In the present study, we found that the zinc finger-containing factor Teashirt-3 (TSHZ3) was expressed in quiescent satellite cells of adult mouse skeletal muscles. We showed that following treatment with cardiotoxin TSHZ3 was strongly expressed in satellite cells of regenerating muscles. Moreover, immunohistochemical analysis indicated that TSHZ3 was expressed in both quiescent and activated satellite cells on intact myofibers in culture. TSHZ3 expression was maintained in myoblasts but disappeared with myotube formation. In C2C12 myoblasts, we showed that overexpression of Tshz3 impaired myogenic differentiation and promoted the down-regulation of myogenin (Myog) and up-regulation of paired-box factor 7 (Pax7). Moreover, knockdown experiments revealed a selective effect of Tshz3 on Myog regulation, and transcriptional reporter experiments indicated that TSHZ3 repressed Myog promoter. We identified the BRG1-associated factor 57 (BAF57), a subunit of the SWI/SNF complex, as a partner of TSHZ3. We showed that TSHZ3 cooperated with BAF57 to repress MYOD-dependent Myog expression. These results suggest a novel mechanism for transcriptional repression by TSHZ3 in which TSHZ3 and BAF57 cooperate to modulate MyoD activity on the Myog promoter to regulate skeletal muscle differentiation.
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http://dx.doi.org/10.1074/jbc.M110.206003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3123113PMC
July 2011

Development and applications of a nasopharyngeal carcinoma Tet-Off cell line.

Oncol Lett 2011 May 1;2(3):525-530. Epub 2011 Mar 1.

Department of Histology and Embryology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080.

The conditional activation and inactivation of target gene expression in a nasopharyngeal carcinoma (NPC) cell line is beneficial for the study of the roles of NPC-related genes. Based on the Tet-Off Advanced system, a NPC S18 Tet-Off cell line was developed by stable transfection of a pTet-Off Advanced vector (regulator plasmid in Tet-Off Advanced system) into NPC S18 cells. Doxycycline-dependent regulators expressed in the S18 Tet-Off cells were examined by transient and stable transfection of pTRE-Tight-Luc. The S18 Tet-Off-Luc clone selected by stable transfection of pTRE-Tight-Luc into S18 Tet-Off cells expressed firefly luciferase under tight control of doxycycline in a time- and dose-dependent manner. To test applications of the S18 Tet-Off cell line in the study of gene function, the impact of ferritin heavy chain (FTH1) gene on NPC cell growth was examined. The S18 Tet-Off-FTH1 clone was developed by stably transfecting pTRE-Tight-FTH1 (response plasmid harboring FTH1) into S18 Tet-Off cells. FTH1 levels in the S18 Tet-Off-FTH1 clone were semi-quantitatively regulated in response to varying concentrations of doxycycline. A cell proliferation assay showed that a high expression of FTH1 (cells grown in the absence of doxycycline) reduced cell growth, while moderate FTH1 overexpression (cells grown in 0.1 ng/ml doxycycline) had no adverse effect on cell growth. In conclusion, the S18 Tet-Off cell line provides a proven genetic background for convenient access to controllable gene expression in NPC.
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http://dx.doi.org/10.3892/ol.2011.262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410500PMC
May 2011

[The therapeutic effects of highly active anti-retroviral therapy in 74 treatment-naive patients with AIDS in China].

Zhonghua Nei Ke Za Zhi 2011 Jan;50(1):59-62

No 8 People's Hospital of Guangzhou, Guangzhou 510060, China.

Objective: To evaluate the therapeutic effect of highly active anti-retroviral therapy (HAART) in treatment-naïve Chinese patients with AIDS, to provide evidences for standardizing HAART.

Methods: Seventy-four treatment-naive AIDS patients were initiated with HAART and followed up regularly for 3 years. The clinical and laboratory data, side effects and drug resistance were observed and analyzed during the follow-up period.

Results: Of the 74 patients, 46 were males and 28 were females, with the average age being 42 years. The mean HIV viral load was (2.2 ± 2.0) × 10(5) copies/ml and the baseline mean CD(4)(+)T lymphocyte count was (62 ± 71) cells/µl before treatment. After treatment for 3, 6, 12, 18, 24, 30 and 36 months, the percentage of undetectable HIV viral road (less than 50 copies/ml) was 71.6%, 83.8%, 75.7%, 77.0%, 82.4%, 81.1% and 79.7% respectively, and CD(4)(+)T lymphocyte count ascended to (167 ± 105), (177 ± 129), (238 ± 137), (290 ± 158), (304 ± 191), (331 ± 175) and (352 ± 202) cells/µl. The increase in amplitude of CD(4)(+)T lymphocyte count in different periods examined was different, with the period of 0-3 months post-treatment demonstrating the most obvious augmentation (P < 0.01). The most common adverse reactions were liver function injury (52/74, 70.3%), hyperlipemia (52/74, 70.3%), hematopoietic inhibition of the bone marrow (33/74, 44.6%), peripheral neuritis (32/74, 43.2%) and lipoatrophy (26/74, 35.1%). Clinical drug resistance were found in nine patients and HIV gene mutations were detected in these patients.

Conclusions: Chinese treatment-naive AIDS patients have achieved good virological and immunological response to generic-drug-predominant HAART regimes with low drug resistance, but relatively more side effects.
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January 2011

Regulating a master regulator: establishing tissue-specific gene expression in skeletal muscle.

Epigenetics 2010 Nov-Dec;5(8):691-5. Epub 2010 Nov 1.

Sprott Center for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, CA.

MyoD is a master regulator of the skeletal muscle gene expression program. ChIP-Seq analysis has recently revealed that MyoD binds to a large number of genomic loci in differentiating myoblasts, yet only activates transcription at a subset of these genes. Here we discuss recent data suggesting that the ability of MyoD to mediate gene expression is regulated through the function of Polycomb and Trithorax Group proteins. Based on studies of the muscle-specific myog gene, we propose a model where the transcriptional activators Mef2d and Six4 mediate recruitment of Trithorax Group proteins Ash2L/MLL2 and UTX to MyoD-bound promoters to overcome the Polycomb-mediated repression of muscle genes. Modulation of the interaction between Ash2L/MLL2 and Mef2d by the p38α MAPK signaling pathway in turns provides fine-tuning of the muscle-specific gene expression program. Thus Mef2d, Six4, and p38α MAPK function coordinately as regulators of a master regulator to mediate expression of MyoD target genes.
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http://dx.doi.org/10.4161/epi.5.8.13045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3052885PMC
March 2011

UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis.

EMBO J 2010 Apr 18;29(8):1401-11. Epub 2010 Mar 18.

Regenerative Medicine Program, Sprott Center for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Polycomb (PcG) and Trithorax (TrxG) group proteins act antagonistically to establish tissue-specific patterns of gene expression. The PcG protein Ezh2 facilitates repression by catalysing histone H3-Lys27 trimethylation (H3K27me3). For expression, H3K27me3 marks are removed and replaced by TrxG protein catalysed histone H3-Lys4 trimethylation (H3K4me3). Although H3K27 demethylases have been identified, the mechanism by which these enzymes are targeted to specific genomic regions to remove H3K27me3 marks has not been established. Here, we demonstrate a two-step mechanism for UTX-mediated demethylation at muscle-specific genes during myogenesis. Although the transactivator Six4 initially recruits UTX to the regulatory region of muscle genes, the resulting loss of H3K27me3 marks is limited to the region upstream of the transcriptional start site. Removal of the repressive H3K27me3 mark within the coding region then requires RNA Polymerase II (Pol II) elongation. Interestingly, blocking Pol II elongation on transcribed genes leads to increased H3K27me3 within the coding region, and formation of bivalent (H3K27me3/H3K4me3) chromatin domains. Thus, removal of repressive H3K27me3 marks by UTX occurs through targeted recruitment followed by spreading across the gene.
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http://dx.doi.org/10.1038/emboj.2010.37DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868576PMC
April 2010

[Correlation between degree of mitochondrial DNA 1555 mutation and clinical phenotype of nonsyndromic hearing loss].

Zhonghua Yi Xue Za Zhi 2009 Sep;89(36):2536-9

Department of Laboratory Medicine, Department of Otolaryngology, First Affiliated Hospital, Department of Gene Diagnosis, Fujian Medical University, Fuzhou, China.

Objective: To study the correlation between the number of mtDNA (mitochondrial DNA) copies containing mtDNA A1555G mutation site and phenotype and further elucidate the molecular genetic basis of phenotype diversity of nonsyndromic hearing loss.

Methods: Real time-amplification refractory mutation system-quantitative PCR was employed to detect the number of mtDNA copies in mild type and mutant type of mtDNA 1555.

Results: In the sporadic group, there was no significant correlation between mtDNA A1555G homogeneity mutation copies and phenotype (R = 0.001, P = 0.997) while significant correlation existed between mtDNA A1555G heteroplasmic mutations and phenotype (R = 0.771, P = 0.003). In the familial group there was significant correlation mtDNA 1555 homogeneity mutation copies and phenotype (R = 0.341, P = 0.022) and significant correlation existed between mtDNA 1555 heterogenicity mutation copies and phenotype (R = 0.85, P = 0.015).

Conclusion: There is significant correlation between the mtDNA A1555G mutation copies and the severity of hearing loss.
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September 2009

Prevalence of pancreatic diabetes in patients carrying mutations or polymorphisms of the PRSS1 gene in the Han population.

Diabetes Technol Ther 2009 Dec;11(12):799-804

Department of Laboratory Medicine, The First Affiliated Hospital, Fuzhou, China.

Objective: This study updated the estimated prevalence of type 3c diabetes damage to the pancreas through different genotypes of PRSS1 and their clinical characteristics in the Han population.

Subjects And Methods: Cross-sectional analysis was performed of the most recent (2003-2007) patients with pancreatitis from six hospitals of the Han population in South China (n = 253).

Results: There were 32 patients with pancreatitis carrying a PRSS1 gene abnormality within intron region among 253 cases of pancreatitis, including 27 patients carrying novel single nucleotide polymorphisms, namely, IVS 3 +75 A --> G conversion, and five patients with the mutation IVS3 + 10 T --> G. Among these patients, there were only three cases of patients with diabetes (9.37%). This was lower than the prevalence of abnormalities in the exons of the PRSS1 gene (51.92%): 12 patients with c.361 G --> A, eight patients with c.415 T --> A, and five patients with c.365G --> A. Among them were 12 persons with diabetes, including five requiring insulin to regulate blood sugar. What is more, among the 27 patients carrying PRSS1 gene polymorphism (c.486 C --> T, within the exon 4), there were 15 persons with diabetes symptoms. More than 40% of these patients required insulin to regulate blood sugar.

Conclusions: An abnormality within the intron region of the PRSS1 gene represents one of the causes of pancreatitis in Chinese patients, but it is not related to pancreatic diabetes. However, the exon abnormality obviously raises the morbidity rate of type 3c diabetes, which relies on insulin.
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http://dx.doi.org/10.1089/dia.2009.0051DOI Listing
December 2009