Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

PMCID: PMC3544714This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

FORMULATION AND STABILITY EVALUATION OF KETOPROFEN LOADED VIRGIN COCONUT OIL BASED CREAMY EMULSION

Objective: To formulate and optimize a topical formulation; a virgin coconut oil (VCO) based Ketoprofen loaded creamy emulsion containing Tween 80® as the surfactant and to evaluate the stability of samples. Methods: In preformulatory studies optimization of the formulae was done using ternary phase diagrams with water titration method and emulsions were formulated using two methods; spontaneous emulsification and homogenization. Their stability was analyzed under visual observation to optimize the best formulae for Ketoprofen incorporated creamy emulsion. 2.5% w/w Ketoprofen topical formulations are available in the market. Results: Centrifugation provided more comparable data than visual observation. Phase separation was the main instability condition observed in unstable emulsions. Composition 23.60% VCO: 29.53% Tween 80®: 45.87% water was identified as the best optimized formulae in both with and without Ketoprofen formulations and all the samples with different Ketoprofen concentrations were stable for 14 days under centrifugation and visual observation stability studies. Conclusion: Homogenization was more effective in stable emulsion formation than spontaneous emulsification in VCO, Tween 80®,water emulsion. The best optimized formula was 23.60% VCO: 29.53% Tween 80®: 45.87% water

Senataxin, defective in ataxia oculomotor apraxia type 2, is involved in the defense against oxidative DNA damage.

A defective response to DNA damage is observed in several human autosomal recessive ataxias with oculomotor apraxia, including ataxia-telangiectasia. We report that senataxin, defective in ataxia oculomotor apraxia (AOA) type 2, is a nuclear protein involved in the DNA damage response. AOA2 cells are sensitive to H2O2, camptothecin, and mitomycin C, but not to ionizing radiation, and sensitivity was rescued with full-length SETX cDNA. AOA2 cells exhibited constitutive oxidative DNA damage and enhanced chromosomal instability in response to H2O2. Rejoining of H2O2-induced DNA double-strand breaks (DSBs) was significantly reduced in AOA2 cells compared to controls, and there was no evidence for a defect in DNA single-strand break repair. This defect in DSB repair was corrected by full-length SETX cDNA. These results provide evidence that an additional member of the autosomal recessive AOA is also characterized by a defective response to DNA damage, which may contribute to the neurodegeneration seen in this syndrome

Smooth-muscle myosin mutations in hereditary non-polyposis colorectal cancer syndrome

We examined adenomas and cancers from hereditary non-polyposis colorectal cancer (HNPCC) syndrome patients for the presence of frameshift mutations in the smooth-muscle myosin gene, MYH11. Our results show that mutations in MYH11 occur more frequently in cancers than adenomas (P=0.008) and are dependent on microsatellite instability (MSI+)

Clinical and Molecular Characterization of Ataxia with Oculomotor Apraxia Patients In Saudi Arabia

<p>Abstract</p> <p>Background</p> <p>Autosomal recessive ataxias represent a group of clinically overlapping disorders. These include ataxia with oculomotor apraxia type1 (AOA1), ataxia with oculomotor apraxia type 2 (AOA2) and ataxia-telangiectasia-like disease (ATLD). Patients are mainly characterized by cerebellar ataxia and oculomotor apraxia. Although these forms are not quite distinctive phenotypically, different genes have been linked to these disorders. Mutations in the <it>APTX </it>gene were reported in AOA1 patients, mutations in <it>SETX </it>gene were reported in patients with AOA2 and mutations in <it>MRE11 </it>were identified in ATLD patients. In the present study we describe in detail the clinical features and results of genetic analysis of 9 patients from 4 Saudi families with ataxia and oculomotor apraxia.</p> <p>Methods</p> <p>This study was conducted in the period between 2005-2010 to clinically and molecularly characterize patients with AOA phenotype. Comprehensive sequencing of all coding exons of previously reported genes related to this disorder (<it>APTX</it>, <it>SETX </it>and <it>MRE11</it>).</p> <p>Results</p> <p>A novel nonsense truncating mutation c.6859 C > T, R2287X in <it>SETX </it>gene was identified in patients from one family with AOA2. The previously reported missense mutation W210C in <it>MRE11 </it>gene was identified in two families with autosomal recessive ataxia and oculomotor apraxia.</p> <p>Conclusion</p> <p>Mutations in <it>APTX </it>, <it>SETX </it>and <it>MRE11 </it>are common in patients with autosomal recessive ataxia and oculomotor apraxia. The results of the comprehensive screening of these genes in 4 Saudi families identified mutations in <it>SETX </it>and <it>MRE11 </it>genes but failed to identify mutations in <it>APTX </it>gene.</p

Aberrant Splicing of the Senataxin Gene in a Patient with Ataxia with Oculomotor Apraxia Type 2

Ataxia with oculomotor apraxia type 2 (AOA2) is caused by a diversity of mutations within the coding region of the senataxin gene. Recently, rare noncoding senataxin mutations affecting RNA processing have been identified in AOA2. Here, we report the case of an 18-year-old woman, with classic clinical features of AOA2, who was found to harbor a mutation within senataxin intron 16. This mutation disrupts the local 5′ splice site architecture via a novel intronic frameshift mechanism, causing skipping of exon 16 with predicted disruption of the conserved DNA/RNA helicase domain. RNA processing mutations expand the growing complexity of pathogenic senataxin mutations

SelTarbase, a database of human mononucleotide-microsatellite mutations and their potential impact to tumorigenesis and immunology

About 15% of human colorectal cancers and, at varying degrees, other tumor entities as well as nearly all tumors related to Lynch syndrome are hallmarked by microsatellite instability (MSI) as a result of a defective mismatch repair system. The functional impact of resulting mutations depends on their genomic localization. Alterations within coding mononucleotide repeat tracts (MNRs) can lead to protein truncation and formation of neopeptides, whereas alterations within untranslated MNRs can alter transcription level or transcript stability. These mutations may provide selective advantage or disadvantage to affected cells. They may further concern the biology of microsatellite unstable cells, e.g. by generating immunogenic peptides induced by frameshifts mutations. The Selective Targets database (http://www.seltarbase.org) is a curated database of a growing number of public MNR mutation data in microsatellite unstable human tumors. Regression calculations for various MSI–H tumor entities indicating statistically deviant mutation frequencies predict TGFBR2, BAX, ACVR2A and others that are shown or highly suspected to be involved in MSI tumorigenesis. Many useful tools for further analyzing genomic DNA, derived wild-type and mutated cDNAs and peptides are integrated. A comprehensive database of all human coding, untranslated, non-coding RNA- and intronic MNRs (MNR_ensembl) is also included. Herewith, SelTarbase presents as a plenty instrument for MSI-carcinogenesis-related research, diagnostics and therapy

Microsatellite instability analysis in hereditary non-polyposis colon cancer using the Bethesda consensus panel of microsatellite markers in the absence of proband normal tissue

BACKGROUND: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant syndrome predisposing to the early development of various cancers including those of colon, rectum, endometrium, ovarium, small bowel, stomach and urinary tract. HNPCC is caused by germline mutations in the DNA mismatch repair genes, mostly hMSH2 or hMLH1. In this study, we report the analysis for genetic counseling of three first-degree relatives (the mother and two sisters) of a male who died of colorectal adenocarcinoma at the age of 23. The family fulfilled strict Amsterdam-I criteria (AC-I) with the presence of extracolonic tumors in the extended pedigree. We overcame the difficulty of having a proband post-mortem non-tumor tissue sample for MSI testing by studying the alleles carried by his progenitors. METHODS: Tumor MSI testing is described as initial screening in both primary and metastasis tumor tissue blocks, using the reference panel of 5 microsatellite markers standardized by the National Cancer Institute (NCI) for the screening of HNPCC (BAT-25, BAT-26, D2S123, D5S346 and D17S250). Subsequent mutation analysis of the hMLH1 and hMSH2 genes was performed. RESULTS: Three of five microsatellite markers (BAT-25, BAT-26 and D5S346) presented different alleles in the proband's tumor as compared to those inherited from his parents. The tumor was classified as high frequency microsatellite instability (MSI-H). We identified in the HNPCC family a novel germline missense (c.1864C>A) mutation in exon 12 of hMSH2 gene, leading to a proline 622 to threonine (p.Pro622Thr) amino acid substitution. CONCLUSION: This approach allowed us to establish the tumor MSI status using the NCI recommended panel in the absence of proband's non-tumor tissue and before sequencing the obligate carrier. According to the Human Gene Mutation Database (HGMD) and the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Database this is the first report of this mutation

Snakebite Mortality in India: A Nationally Representative Mortality Survey

Earlier hospital based reports estimate about 1,300 to 50,000 annual deaths from snakebites per year in India. Here, we present the first ever direct estimates from a national mortality survey of 1.1 million homes in 2001–03. Full-time, non-medical field workers interviewed living respondents about all deaths. The underlying causes were independently coded by two of 130 trained physicians. The study found 562 deaths (0.47% of total deaths) were assigned to snakebites, mostly in rural areas, and more commonly among males than females and peaking at ages 15–29. Snakebites also occurred more often during the rainy monsoon season. This proportion represents about 45,900 annual snakebite deaths nationally (99% CI 40,900 to 50,900) or an annual age-standardised rate of 4.1/100,000 (99% CI 3.6–4.5), with higher rates in rural areas (5.4) and with the highest rate in the state of Andhra Pradesh (6.2). Annual snakebite deaths were greatest in the states of Uttar Pradesh (8,700), Andhra Pradesh (5,200), and Bihar (4,500). Thus, snakebite remains an underestimated cause of accidental death in modern India, causing about one death for every two HIV-related deaths. Because a large proportion of global totals of snakebites arise from India, global snakebite totals might also be underestimated. Effective interventions involving education and antivenom provision would reduce snakebite deaths in India

NCF1 gene and pseudogene pattern: association with parasitic infection and autoimmunity

<p>Abstract</p> <p>Background</p> <p>Neutrophil cytosolic factor 1, p47^phox(NCF1) is a component of the leukocyte NADPH oxidase complex mediating formation of reactive oxygen intermediates (ROI) which play an important role in host defense and autoimmunity. An individual genomic pattern of <it>ncf1 </it>and its two types of pseudogenes (reflected by the ΔGT/GTGT ratio) may influence the individual capacity to produce ROI.</p> <p>Methods</p> <p>NCF1ΔGT/GTGT ratios were correlated with clinical parameters and ROI production during <it>Plasmodium falciparum </it>malaria and with susceptibility to the autoimmune disease multiple sclerosis (MS).</p> <p>Results</p> <p>Among Gabonese children with severe malaria, ROI production from peripheral blood tended to be higher in individuals with a ΔGT/GTGT ratio ≤ 1:1. ΔGT/GTGT ratios were not associated with susceptibility to MS, but to age-of-onset among MS patients.</p> <p>Conclusion</p> <p>The genomic pattern of <it>NCF1 </it>and its pseudogenes might influence ROI production but only marginally influence susceptibility to and outcome of malaria and MS.</p