Analysis of large deletions in <Emphasis Type="Italic">BRCA1</Emphasis>, <Emphasis Type="Italic">BRCA2</Emphasis> and <Emphasis Type="Italic">PALB2</Emphasis> genes in Finnish breast and ovarian cancer families

Background  

BRCA1 and BRCA2 are the two most important genes associated with familial breast and ovarian cancer susceptibility. In addition, PALB2 has recently been identified as a breast cancer susceptibility gene in several populations. Here we have evaluated whether large genomic rearrangement in these genes could explain some of Finnish breast and/or ovarian cancer families.     

The Biology of <Emphasis Type="Italic">K-Ras</Emphasis> and <Emphasis Type="Italic">B-Raf</Emphasis> Mutations in Colorectal Cancer

Ras and Raf proteins are two major players in the MAP kinase pathway. They are crucial downstream regulators of multiple receptor tyrosine kinase-mediated cell growth, transformation, and maintenance of the malignant phenotype in human cancers. Mutations have been identified in K-Ras and B-Raf in patients with colorectal cancer. Clinical studies in colorectal cancers demonstrate that the therapeutic efficacy of cetuximab, a chimeric monoclonal antibody against epidermal growth factor receptor, depends on the presence of wild-type K-Ras. However, mutations in B-Raf do not predict cetuximab resistance. These observations have led to the use of K-Ras as a predictive biomarker, allowing clinicians to direct the therapy of cancer patients based on their K-Ras mutational status.     

Anti-Tumor Effect of Curcumin on Human Cervical Carcinoma HeLa Cells In Vitro and In Vivo

Objective: To investigate the anti-tumor effect of curcumin on human cervical carcinoma HeLa cells in vitro and in vivo. Methods: (1) Human cervical carcinoma cell line HeLa was cultured in vitro. HeLa cells were treated with 5-50 μmol/L curcumin for 24. 48, 72 h and the growth inhibition rates of HeLa cells were measured by MTT method. Cell apoptosis was inspected by electron microscopy and flow cytometry (FCM). (2) A transplanted tumor model by injecting HeLa cells into subcutaneous tissue of BABL/C mice was established and its growth curve was measured. 30 BABL/C mice with tumors were divided into 2 groups at random and 0.2 ml saline or 0.2 ml 250 μmol/L curcumin was injected into abdominal cavity respectively once everyday and lasted for ten days. The changes of tumor volume were measured continuously and tumor inhibition rate was calculated. At last the expressions of caspase-3 and bax protein in transplanted tumors were detected by immunohistochemistry. Results: (1) Curcumin inhibited the proliferation of Lela cells on a dose-depending manner. Apoptosis of cells could be observed by FCM. Partial cells presented the characteristic morphological changes of apoptosis under electron microseope. (2) When 1×107 HeLa cells were inoculated for each mouse, 100% of the mice developed growing tumors after seven days. An inhibition effect was observed in treatment group, and the inhibition rate of curcumin was 74.33%. The expressions of caspase-3 and bax in the transplanted tumors were increased in curcumin group. Conclusion: Curcumin is effective as an anti-cancer drug not only in vitro but also in vivo.     

Triphala inhibits both <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> xenograft growth of pancreatic tumor cells by inducing apoptosis

Background  

Triphala is commonly used in Ayurvedic medicine to treat variety of diseases; however its mechanism of action remains unexplored. This study elucidates the molecular mechanism of Triphala against human pancreatic cancer in the cellular and in vivo model.     

ABO blood type, <Emphasis Type="Italic">Lewis </Emphasis>and <Emphasis Type="Italic">Secretor </Emphasis>genotypes,and chronic atrophic gastritis: a cross-sectional study in Japan

Background: The H type I structure, synthesized by the secretor (Se) enzyme in gastric foveolar cells, and its metabolite, Lewis b (Le ^b ) antigen, mediate the adhesion of Helicobacter pylori ( H. pylori ) to the gastric epithelium, whereas H. pylori does not bind to modified forms of Le ^b specific for blood types A and B. Such host factors as Le and Se genotypes and ABO blood type may affect the establishment of H. pylori infection and, once infected, the risk of chronic atrophic gastritis. Methods: We investigated the cross-sectional relation of ABO blood type and Le and Se genotypes to gastric atrophy, assessed by serum pepsinogen levels, in Japanese residents from two sources. Results: Among the 151 H. pylori -positive participants of the H. pylori eradication program, odds ratios (ORs) for gastric atrophy, adjusted for age, sex, and smoking, were elevated for blood types A (OR = 5.35; 95% confidence interval (CI), 2.11–13.58) and B (OR = 4.79; 95% CI, 1.77–12.93) relative to type O. ORs for blood types A and B were also elevated in H. pylori -negative subjects. These associations were not observed among 250 H. pylori -positive health check-up examinees. The Le genotype was not associated with gastric atrophy in either study population. The se / se genotype was associated with statistically nonsignificant elevation of gastric atrophy risk in both populations. Conclusions: The present data showed a strong association of blood types A and B with gastric atrophy in one, but not the other, study population. Discrepant results between the two populations warrant further investigation. Received: July 29, 2002 / Accepted: September 17, 2002 Acknowledgments The authors thank Dr. Hidemi Ito, Ms. Michiyo Tani, Ms. Naomi Takeuchi, and Ms. Mayumi Kato for their assistance in laboratory assays. This work was supported in part by a Grant-in-Aid for the Second Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor, and Welfare, Japan, and grant R01CA73011 from the National Cancer Institute, the National Institutes of Health, USA. Offprint requests to: N. Hamajima     

Treatment of low-grade gastric MALT-lymphoma unresponsive to <Emphasis Type="Italic">Helicobacter</Emphasis> <Emphasis Type="Italic">pylori</Emphasis> therapy

The most favourable therapeutic strategy for gastric MALT-lymphoma not responding to Helicobacter pylori eradication still remains unclear, neither official guidelines nor randomised studies being available. We therefore performed a systematic review of the literature to evaluate the efficacy of different therapeutic approaches in these patients. Data regarding 315 patients were valuable, and lymphoma remission following the first therapeutic attempt was achieved in 90.1% cases. The most used therapy was radiotherapy (112 patients), followed by surgery (80 patients) and chemotherapy (68 patients), whilst a combination therapy was less frequent. Radiotherapy achieved a higher remission rate as compared to chemotherapy (97.3 vs. 85.3%; P = 0.007), being similar to surgery (97.3 vs. 92.5%; P = 0.2). No difference emerged when comparing lymphoma remission rate achieved by a single therapy with that of combined treatments (89.6 vs. 96.4%; P = 0.6). This is the first pooled-data analysis assessing the efficacy of different oncologic therapeutic approaches to treat gastric MALT-lymphoma unresponsive to H. pylori eradication. Radiotherapy seems to be the most suitable treatment in these patients.     

<Emphasis Type="Italic">BRAF</Emphasis>, <Emphasis Type="Italic">KRAS</Emphasis> and <Emphasis Type="Italic">PIK3CA</Emphasis> mutations in colorectal serrated polyps and cancer: Primary or secondary genetic events in colorectal carcinogenesis?

Background  

BRAF, KRAS and PIK3CA mutations are frequently found in sporadic colorectal cancer (CRC). In contrast to KRAS and PIK3CA mutations, BRAF mutations are associated with tumours harbouring CpG Island methylation phenotype (CIMP), MLH1 methylation and microsatellite instability (MSI). We aimed at determine the frequency of KRAS, BRAF and PIK3CA mutations in the process of colorectal tumourigenesis using a series of colorectal polyps and carcinomas. In the series of polyps CIMP, MLH1 methylation and MSI were also studied.     

<Emphasis Type="Italic">CDKN1C</Emphasis>/p57<Superscript>kip2</Superscript>is a candidate tumor suppressor gene in human breast cancer

Background  

CDKN1C (also known as p57^KIP2) is a cyclin-dependent kinase inhibitor previously implicated in several types of human cancer. Its family members (CDKN1A/p21^CIP1 and B/p27^KIP1) have been implicated in breast cancer, but information about CDKN1C's role is limited. We hypothesized that decreased CDKN1C may be involved in human breast carcinogenesis in vivo.     

Subjects with <Emphasis Type="Italic">TNF-A-857TT</Emphasis> and <Emphasis Type="Italic">-1031TT</Emphasis> genotypes showed the highest <Emphasis Type="Italic">Helicobacter pylori</Emphasis> seropositive rate compared with those with other genotypes

Background A possible association between Helicobacter pylori seropositivity and tumor necrosis factor (TNF) A G-308A has been reported in Korea. The present study examined the associations of H. pylori with functional polymorphisms, TNF-A G-308A, C-857T, and T-1031C, and TNF-B A252G in Japanese subjects.Methods The total of 1374 study subjects included 241 outpatients who participated in an H. pylori eradication program (HPE), 679 first-visit outpatients (FVO) at a regional cancer hospital, and 454 local residents who received a health checkup examination (HCE).Results The frequency of the TNF-A -308A allele was only 1.3% of 480 chromosomes in the HPE group, so the FVO and HCE groups were not genotyped for that polymorphism. The genotype frequency of TNF-A C-857T was 69.2% CC, 27.7% CT, and 3.1% TT; that of TNF-A T-1031C was 69.4% TT, 28.1% TC, and 2.5% CC; and that of TNF-B A252G was 36.8% AA, 48.2% AG, and 15.0% GG. TNF-A -857T was tightly linked to TNF-A -1031T and TNF-B 252A. No significant associations between H. pylori seropositivity and polymorphisms of TNF-A C-857T and TNF-B A252G were observed. However, a reduced odds ratio adjusted for sex, age, and recruitment source was observed for TNF-A -1031CC (0.43; 95% confidence interval, 0.20–0.91) relative to TNF-A -1031TT. Subjects with TNF-A -857CC and -1031CC showed the lowest seropositivity (38.2% of 34 participants), while those with TNF-A -857TT and -1031TT showed the highest (66.7% of 42 participants).Conclusions This study suggests that the possibly high expression genotype of TNF-A may increase susceptibility to persistent H. pylori infection.     

Cathepsin B inhibition interferes with metastatic potential of human melanoma: an <Emphasis Type="Italic">in vitro</Emphasis> and <Emphasis Type="Italic">in vivo</Emphasis> study

Background  

Cathepsins represent a group of proteases involved in determining the metastatic potential of cancer cells. Among these are cysteinyl- (e.g. cathepsin B and cathepsin L) and aspartyl-proteases (e.g. cathepsin D), normally present inside the lysosomes as inactive proenzymes. Once released in the extracellular space, cathepsins contribute to metastatic potential by facilitating cell migration and invasiveness.     

Genetic polymorphisms of <Emphasis Type="Italic">RANTES,IL1-A,MCP-1</Emphasis> and <Emphasis Type="Italic">TNF-A</Emphasis> genes in patients with prostate cancer

Background  

Inflammation has been implicated as an etiological factor in several human cancers, including prostate cancer. Allelic variants of the genes involved in inflammatory pathways are logical candidates as genetic determinants of prostate cancer risk. The purpose of this study was to investigate whether single nucleotide polymorphisms of genes that lead to increased levels of pro-inflammatory cytokines and chemokines are associated with an increased prostate cancer risk.     

Genetic variability in <Emphasis Type="Italic">CYP3A4</Emphasis> and <Emphasis Type="Italic">CYP3A5</Emphasis>in primary liver,gastric and colorectal cancer patients

Background  

Drug-metabolizing enzymes play a role in chemical carcinogenesis through enzymatic activation of procarcinogens to biologically reactive metabolites. The role of gene polymorphisms of several cytochrome P450 enzymes in digestive cancer risk has been extensively investigated. However, the drug-metabolizing enzymes with the broader substrate specificity, CYP3A4 and CYP3A5, have not been analyzed so far. This study aims to examine associations between common CYP3A4 and CYP3A5 polymorphisms and digestive cancer risk.     

The immunomodulator PSK induces <Emphasis Type="Italic">in vitro</Emphasis> cytotoxic activity in tumour cell lines <Emphasis Type="Italic">via</Emphasis> arrest of cell cycle and induction of apoptosis

Background  

Protein-bound polysaccharide (PSK) is derived from the CM-101 strain of the fungus Coriolus versicolor and has shown anticancer activity in vitro and in in vivo experimental models and human cancers. Several randomized clinical trials have demonstrated that PSK has great potential in adjuvant cancer therapy, with positive results in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunomodulator of biological responses. The precise molecular mechanisms responsible for its biological activity have yet to be fully elucidated.     

Gene expression deregulation by <Emphasis Type="Italic">KRAS</Emphasis> G12D and G12V in a <Emphasis Type="Italic">BRAF</Emphasis> V600E context

Background  

KRAS and BRAF mutations appear of relevance in the genesis and progression of several solid tumor types but the co-occurrence and interaction of these mutations have not yet been fully elucidated. Using a microsatellite stable (MSS) colorectal cancer (CRC) cell line (Colo741) having mutated BRAF and KRAS ^WT , we also aimed to investigate the KRAS-BRAF interaction. Gene expression profiles for control KRAS ^WT , KRAS ^G12V and KRAS ^G12D transfected cells were obtained after cell clone selection and RT-PCR screening. Extensive qPCR was performed to confirm microarray data.