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Staphylococcal superantigens (SAgs) comprise a large family of exotoxins produced by Staphylococcus aureus strains. These exotoxins are important in a variety of serious human diseases, including menstrual and nonmenstrual toxic shock syndrome (TSS), staphylococcal pneumonias, and a recently described staphylococcal purpura fulminans. In addition, these SAg exotoxins are being increasingly recognized for their possible roles in many other human diseases, such as atopic dermatitis, Kawasaki syndrome, nasal polyposis, and certain autoimmune disorders. To clarify the full spectrum of human diseases caused by staphylococcal SAgs, it is necessary to have assays for them. At present there are 17 well-characterized, serologically distinct SAgs made by S. aureus: TSS toxin-1; staphylococcal enterotoxins (SEs) A, B, C (multiple minor variant forms exist), D, E, and I; and SE-like G, H, J, K, L, M, N, O, P, and Q. In addition, SE-like proteins R, S, T, and U have been identified but remain poorly characterized. The most straightforward way to analyze S. aureus strains for the well-characterized SAgs is through polymerase chain reaction for their genes; we provide here our method for this analysis. Although it would be ideal to confirm that all of the same SAgs are produced by S. aureus strains that have the genes, antibody reagents for SAg detection are only available for TSS toxin-1; SEs A-E; and enterotoxin-like proteins G, H, and Q. We provide a Western immunoblot procedure that allows in vitro quantification of these SAgs.
Methods Mol Biol 2007
PMID:Molecular analysis of staphylococcal superantigens. 1802 73

The aim of this study was to examine the pathophysiological role of NO (nitric oxide) and MDA (malondialdehyde) in tissue in patients with nasal polyposis. We measured nitrite/nitrate (Nitrite/Nitrate; NO2-/NO3-) and MDA in tissue and plasma of NP patients (n=20) and controls (n=20). MDA level expressed as the concentration of substances reacting to thiobarbituric acid and production of NO (concentration of nitrite/nitrate in plasma) by the Griess reaction were determined. The level of NO2- and NO3- in tissue are higher than that of the normal tissue (p<0.05). The level of MDA in tissue are higher than that of the normal tissue (p<0.05). The level of NO2- and NO3- in plasma of two groups are similar (p>0.05). The level of MDA in plasma is higher than that in the normal controls (p<0.05). The change in NO2-/NO3- and MDA levels of nasal polyp patients was demonstrated. Further studies are required concerning the significance of changes in lipid peroxidation and nitrite levels in pathogenesis of nasal polyp.
Cell Mol Biol (Noisy-le-grand) 2008 Oct 28
PMID:Nitrite/nitrate and malondialdehyde levels in nasal polyp. 1895 53

Genetic epidemiology studies in hereditary non-polyposis colorectal cancer (HNPCC) have the potential to radically improve assessment of disease risk such that more individualised information can be provided to patients susceptible to developing disease. Studies of HNPCC initially focused on disease associations and the definition of the disease and its association with different cancers within the context of an inherited predisposition. With the identification of the genetic basis of HNPCC, new insights into the disease have been forthcoming and many advances in our understanding have been made. There have been many reports examining potential modifier genes in HNPCC, yet the results remain controversial as many findings have not been replicated and therefore no clear consensus as to the role of specific modifier genes has been reached. This review focuses on some of the factors associated with disease risk in HNPCC and where some of the difficulties lie in assessing the value of genetic epidemiology studies in this disorder.
Methods Mol Biol 2009
PMID:Genetic epidemiology studies in hereditary non-polyposis colorectal cancer. 1910 30

DNA mismatch repair maintains genomic stability by correcting errors that have escaped polymerase proofreading. Defects on mismatch repair genes lead to an increased mutation rate, microsatellite instability and predisposition to human non-polyposis colorectal cancer (HNPCC). Human MutLalpha is a heterodimer formed by the interaction of MLH1 and PMS2 that coordinates a series of key events in mismatch repair. It has been proposed that nuclear import of MutLalpha may be the first regulatory step on the activation of the mismatch repair pathway. Using confocal microscopy and mismatch repair deficient cells, we have identified the sequence determinants that drive nuclear import of human MLH1, PMS2, and MutLalpha. Transient transfection of the individual proteins reveals that MLH1 has a bipartite and PMS2 has a single monopartite nuclear localization signal. Although dimerization is not required for nuclear localization, the MutLalpha heterodimer is imported more efficiently than the MLH1 or PMS2 monomers. Interestingly, the bipartite localization signal of MLH1 can direct import of MutLalpha even when PMS2 encompasses a mutated localization signal. Hence we conclude that the presence of redundant nuclear localization signals guarantees nuclear transport of MutLalpha and, consequently, efficient mismatch repair.
Mol Carcinog 2009 Aug
PMID:Nuclear import of human MLH1, PMS2, and MutLalpha: redundancy is the key. 1914 96

Mismatch repair mutations are the cause of generalized genomic instability and are particularly evident at microsatellite loci, which is known as microsatellite instability (MSI). MSI is present in 85% to 90% of colorectal cancers and occurs in hereditary non-polyposis colorectal cancer (HNPCC). The National Cancer Institute recommends the "Bethesda panel" for MSI screening. Recently, a novel T(25) mononucleotide marker was described, termed CAT25. This microsatellite marker displays a quasi-monomorphic pattern in normal tissues. The aim of our study was to evaluate the performance of CAT25 in HNPCC patients and to compare its reliability with the results of the Bethesda panel. We tested 55 tumor tissues from HNPCC patients using both the Bethesda panel and the CAT25 mononucleotide marker. One hundred healthy blood donors were used as controls. The CAT25 microsatellite was found to be altered in all 13 colorectal cancers classified as MSI-H using the standard Bethesda panel. Colorectal tumors that showed a stable Bethesda pattern did not show altered CAT25 repeats. Additionally, CAT25 showed a monomorphic allele pattern in all tissue samples. In our series, the concordance between the Bethesda panel and CAT25 in identifying colorectal cancers with high MSI reached 100%. Our results suggest that the CAT25 microsatellite represents a sensitive and specific marker for MSI and could be, at least, included in the panel of markers for the identification of HNPCC patients.
J Mol Diagn 2009 May
PMID:CAT25 is a mononucleotide marker to identify HNPCC patients. 1932 95

Eosinophils are pro-inflammatory cells that make a major contribution to allergic diseases affecting the upper and lower airways, skin and gastrointestinal tract. IL-5 is central to eosinophil maturation and release from the bone marrow, and to the subsequent accumulation, activation and persistence of eosinophils in the tissues. Reslizumab from Ception Therapeutics Inc is a humanized mAb with potent IL-5-neutralizing effects. The agent inhibited eosinophilia in several animal models; reductions in airway hyperactivity and bronchoconstriction were also observed. Clinical trials for reslizumab have been completed in a small number of patients with asthma, nasal polyposis, hypereosinophilic syndrome (HES) and eosinophil gastroenteritis (EG). Eosinophil depletion was observed in all trials, but clinical responses were often limited, particularly in patients with asthma; furthermore, some patients exhibited rebound of disease to levels greater than baseline. At the time of publication, phase II/III and phase III trials were ongoing in patients with eosinophilic esophagitis (EE), and a phase II trial was ongoing in patients with asthma. Reslizumab is a potentially efficacious and well-tolerated treatment for EG, EE, HES and eosinophilic polyposis, although more trials are required to understand the underlying mechanism of disease rebound. However, the rarity of conditions such as HES, EE and EG makes the conduct of such trials difficult.
Curr Opin Mol Ther 2009 Jun
PMID:Reslizumab, a humanized anti-IL-5 mAb for the treatment of eosinophil-mediated inflammatory conditions. 1947 66

Mutations in the MSH2 gene predispose to a number of tumourigenic conditions, including hereditary non-polyposis colon cancer (HNPCC). MSH2 encodes a protein in the mismatch repair (MMR) pathway which is involved in the removal of mispairs originating during replication or from damaged DNA. To identify new therapeutic strategies for the treatment of cancer arising from MMR deficiency, we screened a small molecule library encompassing previously utilized drugs and drug-like molecules to identify agents selectively lethal to cells lacking functional MSH2. This approach identified the drug methotrexate as being highly selective for cells with MSH2 deficiency. Methotrexate treatment caused the accumulation of potentially lethal 8-hydroxy-2'-deoxyguanosine (8-OHdG) oxidative DNA lesions in both MSH2 deficient and proficient cells. In MSH2 proficient cells, these lesions were rapidly cleared, while in MSH2 deficient cells 8-OHdG lesions persisted, potentially explaining the selectivity of methotrexate. Short interfering (si)RNA mediated silencing of the target of methotrexate, dihydrofolate reductase (DHFR), was also selective for MSH2 deficiency and also caused an accumulation of 8-OHdG. This suggested that the ability of methotrexate to modulate folate synthesis via inhibition of DHFR, may explain MSH2 selectivity. Consistent with this hypothesis, addition of folic acid to culture media substantially rescued the lethal phenotype caused by methotrexate. While methotrexate has been used for many years as a cancer therapy, our observations suggest that this drug may have particular utility for the treatment of a subset of patients with tumours characterized by MSH2 mutations.
EMBO Mol Med 2009 Sep
PMID:Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2. 2004 36

MicroRNAs (miRNA), small noncoding RNAs, are potential diagnostic and prognostic markers, as well as therapeutic targets. miRNA profiles of colorectal carcinomas have not been studied extensively in the context of microsatellite instability (MSI) status. We therefore evaluated 55 paired colorectal adenocarcinomas (CRC) and non-neoplastic mucosa samples using a panel of 24 miRNAs selected by literature review and prior studies in our laboratory. Stem-loop reverse transcriptase quantitative (real-time) polymerase chain reaction assays were done on RNA extracted from formalin-fixed, paraffin-embedded tissue of resection specimens. When miRNA expression was compared with clinicopathologic features and MSI status, eleven miRNAs (miR-183, -31, -20, -25, -92, -93, -17, -135a, -203, -133b, and -223) were over-expressed in CRC relative to mucosa, and nine (miR-192, -215, -26b, -143, -145, -191, -196a, -16, and let-7a) were under-expressed in CRC. Relative expression of miR-92, -223, -155, -196a, -31, and -26b were significantly different among MSI subgroups, and miR-31 and miR-223 were overexpressed in CRC of patients with hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). Our findings indicate that miRNA expression in CRC is associated with MSI subgroups, including low MSI and HNPCC-associated cancers, and that miRNAs may have posttranscriptional gene regulatory roles in these MSI subgroups and possible effects on the clinicopathologic and biomarker characteristics.
J Mol Diagn 2010 Jul
PMID:Association of microRNA expression with microsatellite instability status in colorectal adenocarcinoma. 2041 77

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is the most common hereditary colorectal cancer (CRC) syndrome, accounting for approximately 2-5% of all newly diagnosed cases of CRC. Patients with LS have an increased lifetime risk of colorectal (52.2% in women and 68.7% in men) and endometrial cancer (15-70%), as well as certain extra-colonic cancers. Germline mutations in one of several DNA mismatch repair genes underlie LS. Molecular testing has emerged as an indispensable strategy for the diagnosis of LS. The diagnostic work-up of at-risk individuals includes a careful family history evaluation, microsatellite instability, immunohistochemistry and germline DNA analysis. A positive test result can guide clinicians in formulating the appropriate screening, surveillance and management strategies. However, because of the absence of an overt phenotype, such as a diffuse polyposis, it is not always straightforward to recognize LS clinically.
Expert Rev Mol Diagn 2010 Jul
PMID:Application of molecular diagnostics for the detection of Lynch syndrome. 2062 13

Juvenile polyposis (JP) is an autosomal dominant hamartomatous polyposis syndrome where affected individuals are predisposed to colorectal and upper gastrointestinal cancer. Forty-five percent of JP patients have mutations or deletions involving the coding regions of SMAD4 and BMPR1A, but the genetic basis of other cases is unknown. We set out to identify the JP gene in a large kindred having 10 affected members without SMAD4 or BMPR1A coding sequence mutations or deletions. We found a germline deletion segregating in all affected members, mapping 119 kb upstream of the coding region of BMPR1A by multiplex ligation-dependent probe amplification and comparative genomic hybridization. To further understand the genomic structure of BMPR1A, we performed 5' RACE from lymphoblastoid cell lines and normal colon tissue, which revealed four non-coding (NC) exons and two putative promoters. Further analysis of this deletion showed that it encompassed 12 433 bp, including one promoter and NC exon. The activities of each promoter and deletion constructs were evaluated by luciferase assays, and the stronger promoter sequence analyzed for changes in JP patients without SMAD4 or BMPR1A alterations. A total of 6 of 65 JP probands were found to have mutations affecting this promoter. All probands examined had diminished BMPR1A protein by ELISA, and all promoter mutations but one led to significantly reduced luciferase activity relative to the wild-type promoter reporter. We conclude that we have identified the promoter for BMPR1A, in which mutations may be responsible for as many as 10% of JP cases with unknown mutations.
Hum Mol Genet 2010 Dec 01
PMID:Discovery of the BMPR1A promoter and germline mutations that cause juvenile polyposis. 2084 29


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