抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

A thermostable DNA polymerase was used in an in vitro DNA amplification procedure, the polymerase chain reaction. The enzyme, isolated from Thermus aquaticus, greatly simplifies the procedure and, by enabling the amplification reaction to be performed at higher temperatures, significantly improves the specificity, yield, sensitivity, and length of products that can be amplified. Single-copy genomic sequences were amplified by a factor of more than 10 million with very high specificity, and DNA segments up to 2000 base pairs were readily amplified. In addition, the method was used to amplify and detect a target DNA molecule present only once in a sample of 10(5) cells.

/pdf/primer-directed-enzymatic-amplification-of-dna-with-a-4w71pk8nlz.pdf

Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase

A genetic model for colorectal tumorigenesis

Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

https://eprints.gla.ac.uk/121/1/Davis%2CH_2002_pdf.pdf

Mutations of the BRAF gene in human cancer

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

/pdf/free-radicals-in-the-physiological-control-of-cell-function-g3w3iyr0ph.pdf

Free Radicals in the Physiological Control of Cell Function

Over the past three decades, molecular genetic studies have revealed some critical mutations underlying the pathogenesis of the sporadic and inherited forms of colorectal cancer (CRC). A relatively limited number of oncogenes and tumor-suppressor genes—most prominently the APC, KRAS, and p53 genes—are mutated in a sizeable fraction of CRCs, and a larger collection of genes that are mutated in subsets of CRC have begun to be defined. Together with DNA-methylation and chromatin-structure changes, the mutations act to dysregulate conserved signaling networks that exert context-dependent effects on critical cell phenotypes, including the regulation of cellular metabolism, proliferation, differentiation, and survival. Much work remains to be done to fully understand the nature and significance of the individual and collective genetic and epigenetic defects in CRC. Some key concepts for the field have emerged, two of which are emphasized in this review. Specifically, the gene defects in CRC often target protein...

Molecular Genetics of Colorectal Cancer

Wnt signaling plays a key role in development and adult tissues via effects on cell proliferation, motility, and differentiation. The cellular response to Wnt ligands largely depends on their ability to stabilize beta-catenin and the ability of beta-catenin to bind and activate T-cell factor (TCF) transcription factors. Roughly 40% of ovarian endometrioid adenocarcinomas (OEA) have constitutive activation of Wnt signaling as a result of oncogenic mutations in the beta-catenin protein or inactivating mutations in key negative regulators of beta-catenin, such as the adenomatous polyposis coli and Axin tumor suppressor proteins. We used oligonucleotide microarrays to identify genes of which expression was activated in OEAs with beta-catenin dysregulation compared with OEAs lacking Wnt/beta-catenin pathway defects. Using microarray and quantitative PCR-based approaches, we found that fibroblast growth factor (FGF9) expression was increased >6-fold in primary OEAs with Wnt/beta-catenin pathway defects compared with OEAs lacking such defects. Evidence that beta-catenin and TCFs regulate FGF9 expression in several epithelial cell lines was obtained. We found FGF9 was mitogenic for epithelial cells and fibroblasts and FGF9 could stimulate invasion of epithelial and endothelial cells through Matrigel in transwell assays. Furthermore, FGF9 could promote neoplastic transformation of the E1A-immortalized RK3E epithelial cell line, and short hairpin RNA-mediated inhibition of endogenous FGF9 expression in the OEA cell line TOV112D, which carries a beta-catenin mutation, inhibited neoplastic growth properties of the cells. Our findings support the notion that FGF9 is a key factor contributing to the cancer phenotype of OEAs carrying Wnt/beta-catenin pathway defects.

https://cancerres.aacrjournals.org/content/canres/66/3/1354.full.pdf

Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas

Wnts have key roles in many developmental processes, including hair follicle growth and differentiation. Stabilization of beta-catenin is essential in the canonical Wnt signaling pathway. We developed transgenic mice expressing a regulated form of beta-catenin in the skin. Chronic activation of beta-catenin in resting (telogen) hair follicles resulted in changes consistent with induction of an exaggerated, aberrant growth phase (anagen). Transient activation of beta-catenin produced a normal anagen. Our data lend strong support to the notion that a Wnt/beta-catenin signal operating on hair follicle precursor cells serves as a crucial proximal signal for the telogen-anagen transition.

/pdf/transient-activation-of-b-catenin-signaling-in-cutaneous-ezzgdoagy9.pdf

Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice

Clinical and molecular findings suggest that the four major histological subtypes of ovarian carcinoma (serous, clear cell, mucinous, and endometrioid) likely represent distinct disease entities Prior studies have shown that ovarian endometrioid adenocarcinomas (OEAs) often carry mutations in the CTNNB1 gene, which encodes beta-catenin, a critical component of the Wnt signaling pathway However, the nature of other defects in the Wnt signaling pathway in ovarian carcinomas remains largely unknown Thus, in 45 primary OEAs and two OEA-derived cell lines, we sought to comprehensively address the prevalence of and mechanisms underlying beta-catenin and Wnt pathway deregulation CTNNB1 missense mutations were detected in 14 primary tumors All mutations affected the NH(2)-terminal regulatory domain of beta-catenin, presumably rendering the mutant proteins resistant to degradation Immunohistochemical studies revealed nuclear accumulation of beta-catenin in all but two tumors with CTNNB1 mutations Two primary tumors lacking CTNNBI mutations showed strong nuclear immunoreactivity for beta-catenin In one of the two tumors, biallelic inactivation of the APC gene was found In the remaining 29 primary OEAs, unequivocal nuclear beta-catenin immunoreactivity was not observed, though a nonsense mutation in AXIN1 was observed in one tumor and a truncating frameshift mutation in AXIN2 was seen in another case Both OEA-derived cell lines studied (TOV-112D and MDAH-2774) had elevated constitutive T-cell factor/lymphoid enhancer factor transcriptional activity TOV-112D cells were shown to harbor mutant beta-catenin, whereas a missense AXIN1 sequence alteration was identified in MDAH-2774 cells Collectively, our findings demonstrate frequent defects of the Wnt signaling pathway in a particular subtype of ovarian carcinomas, ie, OEAs Although mutations in the CTNNB1 gene are the most common mechanism of beta-catenin deregulation in OEAs, beta-catenin deregulation may also result from mutations in the APC, AXIN1, and AXIN2 genes

https://cancerres.aacrjournals.org/content/canres/61/22/8247.full.pdf

Diverse Mechanisms of β-Catenin Deregulation in Ovarian Endometrioid Adenocarcinomas

https://www.cell.com/immunity/pdf/S1074-7613(14)00435-X.pdf

Eric R. Fearon

Papers

Molecular Genetics of Colorectal Cancer

Fibroblast Growth Factor 9 Has Oncogenic Activity and Is a Downstream Target of Wnt Signaling in Ovarian Endometrioid Adenocarcinomas

Transient activation of β-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice

Diverse Mechanisms of β-Catenin Deregulation in Ovarian Endometrioid Adenocarcinomas

Interleukin-17 receptor a signaling in transformed enterocytes promotes early colorectal tumorigenesis