Functional variants in cell death pathway genes and risk of pancreatic cancer.

Purpose: Fas-Fas ligand (FasL)-mediated death pathway is important in the life and death of immune cells and, therefore, influences immune surveillance of carcinogenesis. This study examined the association between functional variants of Fas (-1377G-->A and -670A-->G), FasL (-844T-->C), and caspase-8 (CASP8) six-nucleotide deletion polymorphism (-652 6N ins-->del) and risk of pancreatic cancer.

Experimental Design: Genotypes were determined in 397 cases with pancreatic cancer and 907 controls.

Characterization of functional excision repair cross-complementation group 1 variants and their association with lung cancer risk and prognosis.

Purpose: The excision repair cross-complementation group 1 (ERCC1) plays a pivotal role in DNA repair and has been linked to protection against carcinogenesis and resistance to platinum-based anticancer drugs. We tested whether genetic variants in the ERCC1 gene are associated with susceptibility to lung cancer and efficacy of platinum-chemotherapy in patients with small cell lung cancer (SCLC).

Experimental Design: Thirty individual DNA samples were sequenced to search for single-nucleotide polymorphisms, and the functions of the variants were investigated by a series of biochemical assays.

Preparation and application of polyclonal and monoclonal sequence-specific anti-phosphoamino acid antibodies.

This unit discusses the issues that must be considered in the design, production, and characterization of polyclonal and monoclonal sequence-specific anti-phosphoamino acid antibodies. Protocols are provided for generating and purifying such antibodies, and methods are also provided for producing useful polyclonal antibodies in a non-purified form. Support protocols describe coupling of peptides or phosphotyrosine to a solid support for use in affinity chromatography.

Liposome-incorporated Grb2 antisense oligodeoxynucleotide increases the survival of mice bearing bcr-abl-positive leukemia xenografts.

We previously demonstrated that liposome-incorporated antisense oligodeoxynucleotide specific for the grb2 mRNA (L-Grb2) inhibited Grb2 protein expression and the proliferation of bcr-abl-positive leukemia cell lines. To determine whether L-Grb2 has the potential of being a therapeutic modality against bcr-abl-positive leukemia, we studied the tissue distribution of L-Grb2 in normal mice before studying its effects in mice bearing bcr-abl-positive leukemia xenografts. L-Grb2 was widely distributed in the body.

Interaction of P53 Arg72Pro and MDM2 T309G polymorphisms and their associations with risk of gastric cardia cancer.

The P53 tumor suppressor pathway plays an important role in cancer development. The auto-regulatory feedback mechanism of the P53 and MDM2 expression is critical in keeping proper tumor suppressor function of this pathway. This study examined the effect of P53 Arg72Pro variants on transactivation of polymorphic MDM2 promoter (T309G) and their associations with risk of developing gastric cardia adenocarcinoma (GCA) in a Chinese population.

An activating mutation in the PDGF receptor-beta causes abnormal morphology in the mouse placenta.

An oncogenic D842V mutation in the platelet-derived growth factor (PDGF) alpha-receptor (Pdgfra) has recently been described in patients with gastrointestinal stromal tumors. In order to test if the same mutation would confer oncogenic properties to the homologous PDGF beta-receptor (Pdgfrb), the corresponding aspartic acid residue at position 849 of Pdgfrb was changed into valine (D849V) using a knock-in strategy. This mutation turned out to be dominantly lethal and caused death even in chimeras (from 345 transferred chimeric blastocysts, no living coat chimeras were detected).

Platelet 12-lipoxygenase Arg261Gln polymorphism: functional characterization and association with risk of esophageal squamous cell carcinoma in combination with COX-2 polymorphisms.

Background: Aberrant arachidonic acid metabolism by 12-lipoxygenase (12-LOX) and cyclooxygenase-2 (COX-2) has been implicated in human carcinogenesis. Inherited polymorphisms in 12-LOX and COX-2 contributed to differential expression or activity of these enzymes might confer interindividual susceptibility to cancer.

Objective: To examine the functional significance of 12-LOX 261 Arg> Gln polymorphism and its association, alone and in combination with COX-2 -1195G > A and -765G > C polymorphisms, with risk of developing esophageal squamous cell carcinoma (ESCC).

A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers.

Caspases are important in the life and death of immune cells and therefore influence immune surveillance of malignancies. We tested whether genetic variants in CASP8, CASP10 and CFLAR, three genes important for death receptor-induced cell killing residing in tandem order on chromosome 2q33, are associated with cancer susceptibility. Using a haplotype-tagging SNP approach, we identified a six-nucleotide deletion (-652 6N del) variant in the CASP8 promoter associated with decreased risk of lung cancer.

Role of CD14 promoter polymorphisms in Helicobacter pylori infection--related gastric carcinoma.

Purpose: Genetic variation in CD14 may affect CD14 expression and susceptibility to Helicobacter pylori infection-related cancers. This study examined functional single nucleotide polymorphisms (SNP) in the CD14 promoter and their associations with risk of developing gastric carcinoma in relation to H. pylori infection.

Short cavity single frequency fiber laser for in-situ sensing applications over a wide temperature range.

A novel Er-doped silica fiber, with heavy Er doping, was specially developed for application to a single frequency fiber laser. Two high temperature-sustainable fiber Bragg gratings, written into Bi-Ge codoped photosensitive fiber, were chosen for the application and spliced to the specialist Er doped silica fiber to form a compact, linear cavity, fiber laser. The fiber laser retained single mode oscillation over a wide temperature range, from room temperature to 400 degrees C.

Functional polymorphisms in FAS and FASL contribute to increased apoptosis of tumor infiltration lymphocytes and risk of breast cancer.

The FAS-FASL system plays crucial role in counterattack of cancer cell against immune system. This study examined the effects of FAS (-1377G/A and -670A/G) and FASL (-844T/C and 7896G/C) polymorphisms on breast cancer risk and apoptosis of T lymphocytes. The effect on breast cancer risk was determined by case-control analysis of 840 patients and 840 controls.

Carboxypeptidase E in the mouse placenta.

Carboxypeptidase E (CPE) has important functions in processing of endocrine pro-peptides, such as pro-insulin, pro-opiomelanocortin, or pro-gonadotropin-releasing hormone, as evidenced by the hyper-pro-insulinemia, obesity, and sterility of Cpe mutant mice. Down-regulation of Cpe in enlarged placentas of interspecific hybrid (interspecies hybrid placental dysplasia (IHPD)) and cloned mice suggested that reduced CPE enzyme and receptor activity could underlie abnormal placental phenotypes. In this study, we have explored the role of Cpe in murine placentation by determining its expression at various stages of gestation, and by phenotypic analysis of Cpe mutant placentas.

Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer.

Aberrant arachidonic acid metabolism by cyclooxygenase (COX)-2 and 12-lipoxygenase (LOX) has implicated in carcinogenesis. Genetic polymorphisms in COX-2 and 12-LOX might therefore affect susceptibility to colorectal cancer (CRC). To examine this hypothesis, genotypes of COX-2 -1290A>G, -1195G>A, -765G>C and 12-LOX 261Arg>Gln polymorphisms were determined in 1000 CRC patients and 1300 controls.

Haplotypes in matrix metalloproteinase gene cluster on chromosome 11q22 contribute to the risk of lung cancer development and progression.

Purpose: Matrix metalloproteinases (MMP) play important roles in cancer development and single nucleotide polymorphisms (SNP) in some MMP genes were shown to confer susceptibility to certain cancers. This study examined the association between genotypes and haplotypes in the MMP1-MMP3-MMP12 gene cluster and risk of lung cancer development and metastasis.

Experimental Design: A two-stage investigation was conducted.

Janus kinase 2: a critical target in chronic myelogenous leukemia.

The Bcr-Abl tyrosine kinase is the causative factor in most chronic myelogenous leukemia (CML) patients. We have shown that Bcr-Abl is associated with a cluster of signaling proteins, including Janus kinase (Jak) 2, growth factor receptor binding protein 2-associated binder (Gab) 2, Akt, and glycogen synthase kinase (GSK)-3beta. Treatment of CML cell lines and mouse Bcr-Abl+ 32D cells with either Jak2 short interfering RNA or Jak2 kinase inhibitor AG490 inhibited pTyr Gab2 and pSer Akt formation, inhibited the activation of nuclear factor-kappaB, and caused the activation of GSK-3beta, leading to the reduction of c-Myc.

[Association between genetic polymorphism in STK15 and risk of colorectal cancer in a Chinese population].

Objective: This case-control study was designed to detect the association between STK15 Phe31Ile polymorphism and colorectal cancer.

Methods: Genotypes were determined in 283 patients with colorectal cancer and 283 controls. The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression model.

[Genetic polymorphisms in the promoter region of cyclooxygenase-2 and their association with risk of gastric cancer].

Objective: To examine the genetic polymorphisms in the promoter region of cyclooxygenase-2 ( COX-2) and evaluate their association with the risk of gastric cancer.

Methods: Single-strand conformational polymorphism and DNA sequencing were used to screen the genetic variants of the COX-2 promoter region. Total 323 patients with gastric cancer and 646 frequency-matched controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism method.

Differential expression and regulation of prostaglandin E synthases in the mouse ovary during sexual maturation and luteal development.

Prostaglandin (PGE) 2 is the most common prostanoid and plays an important role in female reproduction. The aim of this study was to examine the expression and regulation of microsomal (m) PGE synthase (PGES)-1 and cytosolic (c) PGES in the mouse ovary during sexual maturation, gonadotropin treatment and luteal development by in situ hybridization and immunohistochemistry. Both mPGES-1 mRNA signals and immunostaining were localized in the granulosa cells, but not in the thecal cells and oocytes.

[Association between genetic polymorphisms in methylentetrahydrofolate reductase and risk of lung cancer].

Objective: To investigate the association between methylentetrahydrofolate reductase (MTHFR) polymorphisms and risk of lung cancer.

Methods: Totally 505 cases with lung cancer and 500 frequency-matched controls were genotyped for the MTHFR C677T and A1298C polymorphisms by polymerase chain reaction-restriction fragment length polymorphism methods. The odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression model.

[Genetic polymorphisms of apoptosis-associated genes FAS and FASL and risk of colorectal cancer].

Objective: The FAS and FASL system plays a key role in regulating apoptotic cell death and corruption of this signaling pathway has been shown to participate in tumorigenesis. We previously have shown that the FAS-1377G/A and FASL-844T/C polymorphisms are associated with esophageal cancer. This case-control study was to examine the contribution of the polymorphisms to susceptibility of colorectal cancer.

Genetic polymorphisms in cell cycle regulatory genes MDM2 and TP53 are associated with susceptibility to lung cancer.

The tumor suppressor TP53 pathway plays a crucial role in preventing carcinogenesis through its ability to impose cell cycle arrest and apoptosis following DNA damage and oncogene activation. MDM2 is a key negative regulator of the TP53 pathway and is overexpressed in many cancers as oncoprotein. We investigated the association between genetic variation in the promoter region of MDM2 (c.

Expression and functional analysis of genes deregulated in mouse placental overgrowth models: Car2 and Ncam1.

Different causes, such as maternal diabetes, cloning by nuclear transfer, interspecific hybridization, and deletion of some genes such as Esx1, Ipl, or Cdkn1c, may underlie placental overgrowth. In a previous study, we carried out comparative gene expression analysis in three models of placental hyperplasias, cloning, interspecies hybridization (IHPD), and Esx1 deletion. This study identified a large number of genes that exhibited differential expression between normal and enlarged placentas; however, it remained unclear how altered expression of any specific gene was related to any specific placental phenotype.

FASL -844C polymorphism is associated with increased activation-induced T cell death and risk of cervical cancer.

The FAS receptor-ligand system plays a key role in regulating apoptotic cell death, and corruption of this signaling pathway has been shown to participate in tumor-immune escape and carcinogenesis. We have recently demonstrated (Sun, T., X.

[Correlation of polymorphisms of UDP-glucuronosyltransferase 1A7 gene to genetic susceptibility of lung cancer].

Background & Objective: UDP-glucuronosyltransferase 1A7 (UGT1A7) plays an important role in detoxification through catalyzing combination of glucuronic acid and tobacco carcinogens, including benzo [alpha] pyrene, nitrosamine, and heterocyclic amine PhIP, therefore, inactivates the carcinogens. This study was to examine the correlation of polymorphisms of UGT1A7 gene to genetic susceptibility of lung cancer.

Methods: Polymorphisms of UGT1A7 gene at 12-131 and 208 sites in peripheral lymph cells of 312 patients and 317 age- and sex-matched controls were detected by polymerase chain reaction-denaturized high performance liquid chromatography (PCR-DHPLC) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP); the correlation of these polymorphisms to genetic susceptibility of lung cancer was analyzed.

AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells.

Background: Previous studies have shown that patients with Bcr-Abl-positive acute lymphoblastic leukemia (ALL) either have primary disease that is refractory to imatinib mesylate or develop disease recurrence after an initial response.

Methods: The authors investigated the effects of a newly designed Bcr-Abl inhibitor, AMN107, by comparing its in vitro inhibitory potency on p190 Bcr-Abl ALL cell lines with that of imatinib.

Results: In two Philadelphia (Ph)-positive ALL cell lines, AMN107 was found to be 30-40 times more potent than imatinib in inhibiting cellular proliferation.