Occupational hearing loss: Screening with distortion-product otoacoustic emissions

Hearing assessment of applicants for occupational hearing loss compensation can be a time-consuming process. An accurate screening procedure that is sensitive to occupational hearing loss may have application in many situations. The present study developed distortin-product otoacoustic emission (DPOAE) screening criteria to identify subjects likely to meet the Hong Kong requirements for occupational hearing loss compensation, namely a bilateral sensorineural loss ≥ 40 dB HL (average of 1000, 2000 and 3000 Hz). The screening criteria of 1500 and/ or 2000 Hz, with a signal-to-noise ratio of >0 of 3 dB, yielded high sensitivity and specificity. DPOAE measures therefore have the potential to accurately indicate possible occupational hearing loss. However DPOAEs should be used as a screening tool only, as conventional pure-tone audiometry remains the more comprehensive measure of hearing sensitivity.link_to_subscribed_fulltex

Investigation of signaling pathways that regulate human colon crypt maturation and their dysregulation in tumorigenesis

Intestinal epithelial cell polarity and lineages along the crypt-villus axis provide an excellent model in studying genetic programs controlling cellular proliferation and differentiation. Multipotent stem cells residing at the bottom of the intestinal crypts undergo cell division, where daughter cells will migrate upwards and undergo cell cycle arrest and differentiation. Although the biological and genetic regulation of these processes still remains unclear, there has been report on several key pathways regarding this regulation, including Wnt, Notch and TGF signaling pathways. This study is based on the hypothesis that perturbation of the signaling pathways that regulate cellular polarity and maturation along the colon crypt axis is closely related to tumor development and progression in gastrointestinal tract cancers. To study the differential gene expression between upper and bottom part of colon crypt, a total of 18 cDNA microarray experiments were performed using RNA extracted from 9 paired upper and bottom parts of the colon crypts. Gene expression data were extracted, and Significance Analysis of Microarrays (SAM) was performed to identify genes with significant correlating expression at bottom compartment of the crypts. 969 cDNA clones with significant differential expression were identified, in which 367 and 602 cDNA clones were preferentially upregulated and downregulated respectively in bottom proliferative compartment of the crypts. A significant correlation of these 969 SAM list genes with WNT target genes (obtained from inducible dominant negative TCF4 transfection in CRC cell lines by van de Watering et al) was observed, demonstrating that colon development is tightly regulated by WNT-signaling pathway through TCF4 transcription regulation. Biological pathway analysis using GenMapp illustrated that the colon crypt development involved multiple molecular pathways, including cell cycle, apoptosis, MAP kinase, WNT and BMP pathways etc. Strikingly, we have identified a set of genes that code for secretory proteins of several key pathways where most of them have been previously demonstrated to be expressed in connective tissues, postulating that intestinal myofibroblasts were playing important roles in maintaining the microenvironment for epithelial cells development. With the help of the colon top/bottom array data set obtained here, we hope to provide a comprehensive picture for understanding the global regulation in colonic epithelial cells maturation by in depth analysis of the gene expression profile

Study of the mechanisms underlying heritable germline epimutation of MSH2 in a Hereditary Nonpolyposis Colorectal Cancer family

Colorectal cancer (CRC) is one of the most common cancers world-wide. Among various forms of familial cancers, Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is the most frequent type of hereditary cancer syndromes. It is well known that inactivation of DNA mismatch repair (MMR) genes are responsible for HNPCC. Germline mutations in either the MSH2 or the MLH1 genes can be detected in the majority of HNPCC patients. Alternatively, methylation of the MLH1 promoter in the germline have been observed in a few individuals with HNPCC. More recently, we have first identified a family with inheritance in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene promoter, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal (CRC) or endometrial cancers, all with microsatellite instability and MSH2 protein loss [Chan et al Nat Genet 2006]. To further elucidate the underlying mechanism of this germline epimutation, we have performed linkage analysis using microsatellite markers flanking the MSH2 gene. Based on the presence of recombination events, we have successfully narrowed down the chromosomal region to less than 20Mb that is linked with the occurrence of germline MSH2 methylation. Methylation status of the genes with CpG island within this region was examined. The promoter of all genes located upstream of MSH2 were unmethylated. The MSH6 gene which is located downstream of MSH2 also showed no sign of methylation. Our result suggests a possible existence of a cis-acting element that may contribute to the MSH2 methylation. Further study of this chromosomal region may reveal novel mechanisms involved in the regulation of methylation in humans

Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer

Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy. © 2006 Nature Publishing Group.link_to_subscribed_fulltex

An evaluation of a pilot counselling model in Hong Kong for individuals with mild-to-moderate psychological issues

Title on author's file: An evaluation of the effectiveness of a pilot 3-session counselling model with individuals with mild and moderate psychological issues in Hong Kong202305 bcwwAccepted ManuscriptSelf-fundedPublishe

Frequent Inactivation of Axon Guidance Molecule RGMA in Human Colon Cancer Through Genetic and Epigenetic Mechanisms

Background & Aims: Repulsive guidance molecule member A (RGMA) is a glycosylphosphatidylinositol-anchored glycoprotein and axon guidance molecule that signals through its receptor, neogenin (NEO1), a homologue of the deleted-in-colorectal cancer (DCC) gene. RGMA also functions as a bone morphogenetic protein (BMP) coreceptor. We studied the potential roles of RGMA and NEO1 in colorectal cancer (CRC) pathogenesis. Methods: We analyzed expression of RGMA and NEO1, as well as their epigenetic and genetic changes, in a large series of CRC samples, normal colon tissues, adenomas, and cell lines. These studies were accompanied by in vitro functional assay. Results: RGMA and NEO1 expression were significantly down-regulated in most CRCs, adenomas, and cell lines. RGMA was frequently silenced by promoter methylation in CRCs (86.7%), adenomas (90.9%), and CRC cell lines (92.3%) but not in normal colon tissues; allelic imbalance of RGMA and NEO1 was observed in 40% and 49% of CRCs, respectively. In CRC samples, reduced RGMA levels were significantly associated with mismatch repair deficiency or mutations in KRAS or BRAF. Exposure to 5-aza-2′-deoxycytidine restored RGMA expression in CRC cell lines. Transfection of RGMA into CRC cells suppressed cell proliferation, migration, and invasion and also increased apoptosis in response to DNA-damaging agent. Conclusions: The frequent genetic and epigenetic inactivation of RGMA in CRCs and adenomas along with its in vitro function collectively support its role as a tumor suppressor in colon cells. These findings add to the expanding list of axon guidance molecules with disrupted function during colon carcinogenesis and create new opportunities for early detection and drug development. © 2009 AGA Institute.link_to_subscribed_fulltex