Biomedical subjects

Yu Wang

Publications and source records attributed to Yu Wang.

At least 55 records · Page 3Linked to original sources

PubMed2006

Shape memory effect and superelasticity in a strain glass alloy.

The shape memory effect and superelasticity are usually found in alloys exhibiting spontaneous martensitic transformation. Thus it is hard to imagine that such interesting effects can appear in a system without a martensitic transformation. In this Letter we show shape memory and the superelasticity effect in a nonmartensitic Ti48.5Ni51.5 alloy, which has no martensitic transformation but undergoes a "strain glass" transition. In situ x-ray diffraction experiment showed that the shape memory and superelasticity in strain glass stem from a stress-induced strain glass to martensite transformation and its reverse transformation. The new shape memory and superelasticity in strain glass extends the regime of the shape memory effect and superelasticity and may lead to novel applications.

Journal Article↗

PubMed2006

Adiponectin modulates the glycogen synthase kinase-3beta/beta-catenin signaling pathway and attenuates mammary tumorigenesis of MDA-MB-231 cells in nude mice.

Adiponectin is an adipokine that has pleiotropic beneficial roles in systemic insulin resistance and inflammation. Several recent clinical studies suggest that low serum levels of adiponectin are associated with increased risks of breast cancer. Here, we investigated the direct effects of adiponectin on breast cancer development in vitro and in vivo. Our results showed that adiponectin significantly attenuated the proliferations of two typical human breast cancer cells, MDA-MB-231 and T47D, in a cell type-specific manner. Further analysis revealed that adiponectin could induce apoptosis and arrest the cell cycle progression at G(0)-G(1) phase in MDA-MB-231 cells. Prolonged treatment with adiponectin in this cell line blocked serum-induced phosphorylation of Akt and glycogen synthase kinase-3beta (GSK-3beta), suppressed intracellular accumulation of beta-catenin and its nuclear activities, and consequently reduced expression of cyclin D1. Adiponectin-mediated suppression of cyclin D1 expression and attenuation of cell proliferation was abrogated by the GSK-3beta inhibitor lithium chloride. These results suggest that the inhibitory role of adiponectin on MDA-MB-231 cell growth might be attributed to its suppressive effects on the GSK-3beta/beta-catenin signaling pathway. Furthermore, our in vivo study showed that both supplementation of recombinant adiponectin and adenovirus-mediated overexpression of this adipokine substantially reduced the mammary tumorigenesis of MDA-MB-231 cells in female nude mice. Taken together, these data support the role of adiponectin as a negative regulator of breast cancer development and also suggest that adiponectin might represent a novel therapeutic target for this disease.

Active Transport, Cell Nucleus↗

PubMed2006

Meta-analysis on inoperable pancreatic cancer: a comparison between gemcitabine-based combination therapy and gemcitabine alone.

AIM: To compare gemcitabine-based combination therapy and gemcitabine (GEM) alone in patients with advanced pancreatic cancer (APCa) through meta-analysis. METHODS: MEDLINE and EMBASE searches were supplemented by information from trial registers of randomized controlled trials (RCTs) for GEM-based combination therapy and GEM alone for APCa. A quantitative meta-analysis was carried out by two reviewers based on the inclusion criteria from all available RCTs. The meta-analysis involved overall survival (OS), objective remission rate (ORR), clinical benefit rate (CBR), time to progress/progress free survival (TTP/PFS) and toxicity. RESULTS: The meta-analysis included 22 RCTs. There was significant improvement in the GEM combination group with regard to the 6-mo survival rate (RD = 0.04, 95% CI 0.01-0.06, P = 0.008), 1-year survival rate (RD = 0.03, 95% CI 0.01-0.05, P = 0.01), ORR (RD = 0.04, 95% CI 0.01-0.07, P = 0.02), CBR (RD = 0.10, 95% CI 0.02-0.17, P = 0.01) and 6-mo TTP/PFS (RD = 0.07, 95% CI 0.04-0.10, P < 0.00001). However, the Grade 3-4 toxicity set by WHO was higher for the GEM combination group for neutropenia (RD = 0.05, 95% CI 0.01-0.10, P = 0.02), thrombocytopenia (RD = 0.05, 95% CI 0.02-0.08, P = 0.002) and vomiting/nausea (RD = 0.03, 95% CI 0.00-0.05, P = 0.02). CONCLUSION: GEM-based combination therapy may improve the overall survival and palliation in optimal patients with APCa as compared with GEM alone.

Antimetabolites, Antineoplastic↗

PubMed2006

The protein kinase TOUSLED is required for maintenance of transcriptional gene silencing in Arabidopsis.

TOUSLED-like kinases (TLKs) are highly conserved in plants and animals, but direct evidence linking TLKs and transcriptional gene silencing is lacking. We isolated two new alleles of TOUSLED (TSL). Mutations of TSL in ros1 reactivate the transcriptionally silent 35S-NPTII transgene and the transcriptionally silent endogenous loci TSI (TRANSCRIPTIONAL SILENCING INFORMATION). Chromatin immunoprecipitation (ChIP) analysis shows that histone H3Lys9 dimethylation is decreased in the reactivated transgene and endogenous TSI loci in the tsl ros1 mutant. However, there is no change in DNA methylation in the affected loci. Western blot and ChIP assay suggest that TSL might not be responsible for histone H3Ser10 phosphorylation. The tsl seedlings were more sensitive to DNA damage reagent methyl methanesulphonate and UV-B light. Our results provide direct evidence for a crucial role of the TOUSLED protein kinase in the maintenance of transcriptional gene silencing in some genomic regions in a DNA-methylation-independent manner in Arabidopsis.

Arabidopsis↗

PubMed2006

Enhanced survival in perineural invasion of pancreatic cancer: an in vitro approach.

Pancreatic cancer (PanCa) is characterized by perineural invasion (PNI), early lymph node and liver metastasis, and poor prognosis. PNI is one of the important causes of local recurrence. Little is known about the mechanism of PNI in PanCa. We presented a novel model system that may shed light on the mystery of PNI in PanCa. In this study, mouse dorsal root ganglia (DRGs) and human PanCa cell line (MIA PaCa-2) were cocultured in Matrigel matrix (BD Biosciences, San Jose, CA) to build this PNI model. MIA PaCa-2 cell line alone (control 1) or DRG alone (control 2) was cultured with Matrigel matrix as controls. Neurite outgrowth, cell colony growth, neurite-colony contact, and retrograde extension were observed under inverted microscopy and then were photographed and quantitated with the Optimas imaging system (Optimas Corp., Bothell, MA). At day 14, both the experimental and control 2 samples were harvested and subjected to total RNA isolation and fixed in paraffin-embedded blocks. Slides cut from paraffin blocks were studied with Ki-67 immunostaining and TUNEL assay. Gene profiling was performed using complementary DNA microarray. Overexpressed target genes were verified by quantitative reverse transcriptase polymerase chain reaction. The results showed that reciprocity was observed between neurites and MIA PaCa colonies with 24 hours of coculture. Neurite outgrowth was stimulated in the presence of pancreatic carcinoma cells, which showed 2-fold more area than did control 2. After 72 hours, MIA PaCa colonies cocultured with DRG exhibited 58% more colony area than did control 1. The Ki-67 index of the DRG/MIA PaCa cells (mean, 5.02%) was significantly higher than that in control 1 (mean, 1.18%) (P < .05); in contrast, the apoptotic index in the DRG/MIA PaCa cells was significantly lower (mean, 0.45%) than that in the control 1 (mean, 1.85%) (P < .001). Prosurvival genes MALT1 and TRAF were increased 2-fold in DRG/MIA PaCa compared with controls. We demonstrated that neural-epithelial interaction is a mutually beneficial process for the growth of nerves and PanCa cells. It is possible that oncogenes and growth factors might act synergistically in promoting proliferation and/or inhibiting apoptosis, a survival strategy crucial to the development of PNI in PanCa.

Animals↗

PubMed2006

Comparison of alpha1-adrenergic receptor cell-membrane stationary phases prepared from expressed cell line and from rabbit hepatocytes.

A G-protein-coupled receptor-cell-membrane stationary phase (CMSP) has been prepared by immobilizing cell membranes on the surface of silica, as carrier. The resulting HEK293 alpha1A adrenoceptor cell-membrane stationary phase can be used for rapid on-line chromatographic determination of potential subtype-selective alpha1-adrenoceptor ligand-binding affinities for alpha 1-adrenoceptor subtypes. The objective of the research was to study whether cell lines stably overexpressing subtype receptors could improve the sensitivity and specificity of cell-membrane chromatography (CMC) compared with use of homogenized tissue and cells in primary culture. Effects of mobile-phase ionic strength, sample concentration, and the presence of competitive agents on ligand-receptor interaction in CMSP were also evaluated. We found that cell lines stably overexpressing subtype receptors led to improved sensitivity and specificity in CMC. The technique leads to useful procedures-cell-membrane stationary phases may, for example, facilitate exploration of ligand-receptor interaction and determination of ligand-receptor binding affinity in initial screening and separation of lead compounds or active components in Chinese traditional natural medicine and herbs. This might eventually be an important contribution and an addition to our collection of techniques.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed2006

Coplanarity in the backbones of ladder-type oligo(p-phenylene) homologues and derivatives.

p-Tolyl-substituted ladder-type oligo(p-phenylene)s containing three, four, and five phenylene rings were readily synthesized. The uniform aryl substitution of these systems allowed us to determine the coplanarity of the pi-conjugated backbones crystallographically. The intramolecular annulations eliminate almost all of the conformational disorder and enhance the degree of pi-conjugation of the backbones, resulting in significant red shifts in the absorption and emission maxima and lower oxidation potentials in the higher homologues. [structure: see text]

Journal Article↗

PubMed2006

Syntheses and structures of novel heteroarene-fused coplanar pi-conjugated chromophores.

We have synthesized a series of novel coplanar chromophores in which heteroarenes, namely, thiophene, benzothiophene, and carbazole, were fused to neighboring phenylene ring(s) through intramolecular annulation via sp(3)-hybridized carbon atoms bearing two p-tolyl groups as peripheral substituents. The molecular configurations of the pi-conjugated backbones were determined by X-ray crystallographic analysis; the heteroarene-fused molecular frameworks of these novel molecules exhibit nearly coplanar conformations. [structure: see text]

Journal Article↗

PubMed2006

Effects of hepatotrophic factors on the liver after portacaval shunt in rats with portal hypertension.

BACKGROUND: Portacaval shunt (PCS) prevent hepatotrophic factors from flowing into the liver, but they enter directly the systemic circulation and worsen liver injury. This study was designed to investigate the effects of hepatotrophic factors through the portal vein on the liver in rats with portal hypertension after portacaval shunt. METHODS: Intrahepatic portal hypertension (IHPH) was induced by intragastric administration of carbon tetrachloride, and end-to-side PCS was performed. Eight normal rats served as controls, and eight rats with IHPH served as IHPH model (IHPH group). Another 32 rats with IHPH-PCS were randomly subdivided into 4 groups: normal saline (NS) given to 8 rats, hepatocyte growth factor (HGF) 8, insulin (INS) 8, hepatocyte growth factor and insulin (HGF + INS) 8. Hepatotrophic factors were infused into the portal vein through an intravenous catheter. Portal venous pressure (PVP) was measured. The levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were tested biochemically and those of hyaluronic acid (HA) and laminin (LN) were measured by radioimmunoassay. Hepatic fibrosis was assessed histologically and the expression of collagens type I and III were detected immunohistochemically. Ultrastructural change of hepatocytes and the number of mitochondria were observed under an electron microscope. The data were compared between groups and subgroups by Student-Newman-Keuls procedure with SPSS10.0. RESULTS: PVP was significantly higher in the IHPH rats than in the control rats (P < 0.05). The levels of serum ALT, AST, HA, and LN, hepatic fibrosis score, the amount of collagen deposition, collagens type I and III increased more significantly in the IHPH group than in the control rats (P < 0.05). The number of mitochondria decreased more significantly in the IHPH rats than in the control rats (P < 0.05). The levels of serum ALT, AST, HA and LN as well as hepatic fibrosis score, the amount of collagen deposition, and the amount of collagens type I and III in the HGF and HGF + INS rats were significantly lower than those in the NS rats (P < 0.05). The damage to hepatocyte ultrastructure was markedly alleviated and the number of mitochondria was increased more significantly in the HGF and HGF + INS rats than in the NS rats under an electron microscope. CONCLUSIONS: Perfusion of exogenous hepatotrophic factors through the portal vein can alleviate liver injury, minimize the damage to the ultrastructure of hepatocyte, protect liver function, and lessen hepatic fibrosis in rats with portal hypertension after PCS.

Alanine Transaminase↗

PubMed2006

Dual alterations in casein kinase I-epsilon and GSK-3beta modulate beta-catenin stability in hyperproliferating colonic epithelia.

Casein kinase I (CKI)-epsilon and GSK-3beta phosphorylate beta-catenin at Ser(45) (beta-cat(45)) and Thr(41)/Ser(37,33) (beta-cat(33,37,41)) residues, thereby facilitating its ubiquitination and proteasomal degradation. We used a Citrobacter rodentium-induced transmissible murine colonic hyperplasia (TMCH) model to determine Ser/Thr phosphorylation and biological function of beta-catenin during crypt hyperproliferation. TMCH was associated with 3-fold and 3.3-fold increases in CKI-epsilon cellular abundance and 2-fold and 1.8-fold increase in its activity at 6 and 12 days after infection, respectively. beta-Catenin coimmunoprecipitated with both cellular and nuclear CKI-epsilon and cellular axin at these time points. Cellular beta-catenin was constitutively phosphorylated at Ser(45) and underwent subcellular redistribution to cytoskeletal and nuclear fractions at days 6 and 12 of TMCH, respectively. beta-cat(33,37,41), however, exhibited only subtle changes in either phosphorylation status or subcellular distribution even after blocking proteasomal degradation in vivo. Interestingly, GSK-3beta underwent increased phosphorylation at Ser(9), leading to 40% and 70% decreases in its activity at these time points, respectively. Coimmunoprecipitation studies exhibited strong association of GSK-3beta with PKC-zeta at either time point. Cellular beta-cat(45) stabilized and, along with unphosphorylated beta-catenin, underwent nuclear translocation, associated with nuclear accumulated Tcf-4 and cAMP response element binding protein binding protein, and was significantly acetylated, leading to increases in DNA binding. Priming of beta-catenin at Ser(45) exists in vivo. However, beta-cat(45) does not necessarily enter the degradation pathway. Impairment in linking beta-cat(45) to subsequent GSK-3beta-mediated phosphorylation and degradation may account for increased steady-state levels of both unphosphorylated as well as Ser(45)-phosphorylated beta-catenin, which may be causally linked to increases in cell census during TMCH.

Animals↗

PubMed2006

Lipocalin-2 is an inflammatory marker closely associated with obesity, insulin resistance, and hyperglycemia in humans.

BACKGROUND: Lipocalin-2, a 25-kDa secreted glycoprotein, is a useful biomarker for early detection of various renal injuries. Because lipocalin-2 is abundantly expressed in adipose tissue and liver, we investigated its relevance to obesity-related pathologies. METHODS: We used real-time PCR and in-house immunoassays to quantify the mRNA and serum concentrations of lipocalin-2 in C57BL/KsJ db/db obese mice and their age- and sex-matched lean littermates. We analyzed the association between serum lipocalin-2 concentrations and various metabolic and inflammatory variables in 229 persons (121 men and 108 women) recruited from a previous cross-sectional study, and we evaluated the effect of the insulin-sensitizing drug rosiglitazone on serum lipocalin-2 concentrations in 32 diabetic patients (21 men and 11 women). RESULTS: Compared with the lean littermates, lipocalin-2 mRNA expression in adipose tissue and liver and its circulating concentrations were significantly increased in db/db diabetic/obese mice (P <0.001). These changes were normalized after rosiglitazone treatment. In humans, circulating lipocalin-2 concentrations were positively correlated (P <0.005) with adiposity, hypertriglyceridemia, hyperglycemia, and the insulin resistance index, but negatively correlated (P = 0.002) with HDL cholesterol. There was also a strong positive association between lipocalin-2 concentrations and high sensitivity C-reactive protein (hs-CRP), independent of age, sex, and adiposity (P = 0.007). Furthermore, rosiglitazone-mediated decreases in lipocalin-2 concentrations correlated significantly with increases in insulin sensitivity (r = 0.527; P = 0.002) and decreases in hs-CRP concentrations (r = 0.509; P = 0.003). CONCLUSIONS: Lipocalin-2 is an inflammatory marker closely related to obesity and its metabolic complications. Measurement of serum lipocalin-2 might be useful for evaluating the outcomes of various clinical interventions for obesity-related metabolic and cardiovascular diseases.

Acute-Phase Proteins↗

PubMed2006

Molecular simulations of the pressure, temperature, and chemical potential dependencies of clay swelling.

A new method for the determination of clay swelling thermodynamics from computer simulation is discussed and evaluated. This method allows for the determination of temperature, pressure, and water chemical potential dependence of clay swelling from simulations at a single thermodynamic state point. The temperature dependence and pressure dependence of clay swelling are shown to be directly related to the composite system entropy and volume change, respectively, that accompany swelling. Expressions for the chemical potential dependence of clay swelling are used to determine constant pressure layer spacing and adsorption isotherms, quantities that are well suited for comparison with experimental measurements. This method is evaluated through grand isoshear ensemble simulations of Na-montmorillonite, a prototypical swelling clay. Approximations associated with all expressions are discussed with explicit calculations used to demonstrate their regimes of validity.

Journal Article↗

PubMed2006

Characterization and expression profile of CMTM3/CKLFSF3.

CMTM/CKLFSF is a novel family of proteins linking chemokines and TM4SF. In humans, these proteins are encoded by nine genes, CKLF and CMTM1-8/CKLFSF1-8. Here we report the characteristics and expression profile of CMTM3/CKLFSF3. Human CMTM3/CKLFSF3 has a high sequence identity among various species and similar characteristics as its mouse and rat homologues. Established by results both of RT-PCR and Quantitative Real-time PCR, the gene is highly transcribed in testis, leukocytes and spleen. For further verification, we generated a polyclonal antibody against human CMTM3/CKLFSF3 and found that the protein is highly expressed in the testis and some cells of PBMCs. Therefore, CMTM3/CKLFSF3 is an evolutionarily conserved gene that may have important roles in the male reproductive system and immune system. Further studies are necessary to validate its functions in the two systems.

Amino Acid Sequence↗

PubMed2006

Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex.

Following central nervous system injury, adult mammalian neurons do not regenerate through regions of scar formation. This regenerative failure is due in part to the inhibitory environment of the glial scar at the lesion site. Following injury, transforming growth factor beta (TGF-beta) is strongly induced and is important to many aspects of the response to injury, including deposition of extracellular matrix (ECM) in the glial scar. However, the pathways through which TGF-beta signals to mediate these effects are not known. In order to examine the contribution of the TGF-beta-induced transcription factor, Smad3, to formation of the glial scar after traumatic brain injury, we utilized mice that do not express Smad3. We report that Smad3 null mice heal stab wounds to the cerebral cortex more rapidly than do wild-type mice. In Smad3 null mice many aspects of glial scar formation and the immune response to injury were altered. Fewer neutrophils, macrophages/microglia, NG2-positive cells and GFAP-positive cells were detected immediately around the lesion in Smad3 null mice. Expression of fibronectin and laminin was also reduced. Injury-induced cell proliferation was significantly lower in Smad3 null mice around the lesion. There was no overall difference between wild-type and Smad3 null mice in immunoreactivity for TGF-beta(1) after injury. Thus, our experiments suggest that TGF-beta signaling through Smad3 contributes significantly to the immune response and scar formation after cortical stab wound injury, delaying recovery through multiple mechanisms.

Animals↗

PubMed2006

Safety and immunogenicity of an inactivated adjuvanted whole-virion influenza A (H5N1) vaccine: a phase I randomised controlled trial.

BACKGROUND: Avian influenza A virus H5N1 has caused widespread infections that have resulted in severe disease or death in poultry and wild birds as well as human beings. This virus has the potential to emerge as a pandemic threat and H5N1 vaccines are being developed in many countries. Our aim was to assess the safety and immunogenicity of an inactivated adjuvanted whole-virion H5N1 vaccine. METHODS: A stratified randomised, placebo-controlled, double-blind phase I clinical trial was done in 120 volunteers aged 18-60 years. Volunteers were assigned to receive two doses of placebo (n=24) or an inactivated whole-virion influenza A (H5N1) vaccine with 1.25 microg (24), 2.5 microg (24), 5 microg (24), or 10 microg (24) haemagglutinin per dose with aluminium hydroxide adjuvant on day 0 and 28. Serum samples were obtained on day 0, 14, 28, 42, and 56 for haemagglutination inhibition and virus neutralisation assays. This trial is registered with the ClinicalTrials.gov registry with the number NCT00356798. FINDINGS: All four formulations of vaccines were well tolerated. No serious adverse event was reported and most local and systemic reactions were mild and transient. All formulations induced antibody responses after the first dose; the highest immune response of 78% seropositivity was seen in the 10 mug group after two vaccine doses. Two individuals dropped out: one in the 1.25 microg group (withdrew consent) and one in the 10 microg group (discontinued); one individual was also excluded from the final analysis. INTERPRETATION: A two-dose regimen of an adjuvanted 10 microg inactivated whole-virion H5N1 vaccine met all European regulatory requirements for annual licensing of seasonal influenza vaccine. Lower doses of this vaccine could achieve immune responses equivalent to those elicited by adjuvanted or non-adjuvanted split-virion vaccines. The use of a whole virion vaccine could be more adaptable to the antigen-sparing strategy recommended by WHO for protection against an influenza pandemic.

Adjuvants, Immunologic↗

PubMed2006

Ex-vivo analysis of CD8+ T cells infiltrating colorectal tumors identifies a major effector-memory subset with low perforin content.

Previous studies have indicated that the infiltration of CD8+ T cells in colorectal cancer is an independent predictor of increased survival but clinical observations have suggested that the cytotoxic function of CD8+ T cells infiltrating colorectal cancer may often be limited. In this study, we have assessed the phenotype of colorectal cancer CD8+ tumor-infiltrating lymphocytes (TILs) isolated ex vivo from tumor tissue, and assessed the perforin content of TIL with respect to their location using immunohistochemistry. We found that CD8+ T cells TILs isolated from colorectal cancer are mainly composed of antigen-experienced cells of effector memory type (TEM, CD45RA-CCR7-, and CD27+/CD28- or CD27-/CD28-), and contain only minor proportions of terminally differentiated CD8+ T cells (TEMRA, CD45RA+CCR7-). The perforin content of these TILs, however, is significantly lower than that of antigen-experienced T cells in PBMCs due to the much lower levels of perforin found in the CD27-CD28- subset in TILs compared with CD8+ T cells of similar phenotype in PBMCs.

Adenocarcinoma↗

PubMed2006

Brainstem thyrotropin-releasing hormone regulates food intake through vagal-dependent cholinergic stimulation of ghrelin secretion.

The brainstem is essential for mediating energetic response to starvation. Brain stem TRH is synthesized in caudal raphe nuclei innervating brainstem and spinal vagal and sympathetic motor neurons. Intracisternal injection (ic) of a stable TRH analog RX77368 (7.5-25 ng) dose-dependently stimulated solid food intake by 2.4- to 3-fold in freely fed rats, an effect that lasted for 3 h. By contrast, RX77368 at 25 ng injected into the lateral ventricle induced a delayed and insignificant orexigenic effect only in the first hour. In pentobarbital-anesthetized rats, RX77368 (50 ng) ic induced a significant bipeak increase in serum total ghrelin levels from the basal of 8.7+/-1.7 ng/ml to 13.4+/-2.4 ng/ml at 30 min and 14.5+/-2.0 ng/ml at 90 min, which was prevented by either bilateral vagotomy (-60 min) or atropine pretreatment (2 mg/kg, -30 min) but magnified by bilateral adrenalectomy (-60 min). TRH analog ic-induced food intake in freely fed rats was abolished by either peripheral atropine or ghrelin receptor antagonist (D-Lys-3)-GHRP-6 (10 micromol/kg) or ic Y1 receptor antagonist 122PU91 (10 nmol/5 microl). Brain stem TRH mRNA and TRH receptor 1 mRNA increased by 57-58 and 33-35% in 24- and 48-h fasted rats and returned to the fed levels after a 3-h refeeding. Natural food intake in overnight fasted rats was significantly reduced by ic TRH antibody, ic Y1 antagonist, and peripheral atropine. These data establish a physiological role of brainstem TRH in vagal-ghrelin-mediated stimulation of food intake, which involves interaction with brainstem Y1 receptors.

Anesthesia↗

PubMed2006

Mutation screening of mismatch repair gene Mlh3 in familial esophageal cancer.

AIM: To shed light on the possible role of mismatch repair gene Mlh3 in familial esophageal cancer (FEC). METHODS: A total of 66 members from 10 families suggestive of a genetic predisposition to hereditary esophageal cancer were screened for germline mutations in Mlh3 with denaturing high performance liquid chromatography (DHPLC), a newly developed method of comparative sequencing based on heteroduplex detection. For all samples exhibiting abnormal DHPLC profiles, sequence changes were evaluated by cycle sequencing. For any mutation in family members, we conducted a segregation study to compare its prevalence in sporadic esophageal cancer patients and normal controls. RESULTS: Exons of Mlh3 in all samples were successfully examined. Overall, 4 missense mutations and 3 polymorphisms were identified in 4 families. Mlh3 missense mutations in families 9 and 10 might be pathogenic, but had a reduced penetrance. While in families 1 and 7, there was no sufficient evidence supporting the monogenic explanations of esophageal cancers in families. The mutations were found in 33% of high-risk families and 50% of low-risk families. CONCLUSION: Mlh3 is a high risk gene with a reduced penetrance in some families. However, it acts as a low risk gene for esophageal cancer in most families. Mutations of Mlh3 may work together with other genes in an accumulated manner and result in an increased risk of esophageal tumor. DHPLC is a robust and sensitive technique for screening gene mutations.

Carrier Proteins↗