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Biomedical subjects

A S Chan

Publications and source records attributed to A S Chan.

At least 37 records · Page 2Linked to original sources
PubMed2000

A convenient method for the synthesis of DNA-recognizing polyamides in solution.

A convenient method for the synthesis of polyamides containing N-methylpyrrole (Py) and N-methylimidazole (Im) in solution has been developed. Most of the building blocks have been prepared by a haloform reaction in a simple way that column chromatography can be avoided. By use of the DCC/HOBT coupling reaction, the building blocks prepared have been effectively connected to construct a variety of subchains and polyamides without employing amino protection and deprotection. By use of the present method, an eight-ring polyamide, PyPyPyPygammaPyImImPybetaDp (gamma is gamma-aminobutyric acid, beta is beta-alanine, Dp is N, N-dimethylpropyldiamine), has been synthesized by the coupling of two four-ring subchains in one step.

DNA↗
PubMed2000

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation.

We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbetaRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was different. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor amplification was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its effects differ greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 - 4083.

Adenocarcinoma↗
PubMed2000

Distinct clinical features associated with microsatellite instability in colorectal cancers of young patients.

The Hong Kong Chinese population has an unusually high incidence of colorectal cancer in the young, suggestive of hereditary susceptibility. To search for a genetic basis for this predisposition, we studied the incidence of microsatellite instability (MSI) in paraffin-embedded colectomy specimens of 124 young (<50 years old) Chinese colorectal cancer patients referred to the Hong Kong Hereditary Gastrointestinal Cancer Registry from 1995 to 1998. By medical record review and personal interview, we searched for distinct clinical features associated with the manifestation of MSI in this group of patients. For patients with MSI tumours, blood was taken for detection of germline mutation in 2 mismatch repair (MMR) genes. MSI was present in 33 tumours from 23 males and 10 females (26.6%). Ongoing mutation analysis has so far identified MMR gene mutations in 8 patients with MSI tumours. The incidence of MSI increased significantly with decreasing age at cancer diagnosis. For patients aged 30 to 49, MSI tumours were located mainly at the proximal colon. However, for exceptionally young patients (<30 years), MSI tumours tended to be at the distal large bowel. This observation suggested a differential activity of the MMR pathway in colorectal carcinogenesis in different age groups. On multivariate analysis, young age at cancer diagnosis, proximal tumour location, a strong family history of colorectal cancer, and a personal history of metachronous cancer were independent predictors for MSI status. This knowledge may have an impact on the management of young colorectal cancer patients and their families.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Localized brain activation by selective tasks improves specific cognitive functions in humans.

Neuroimaging studies have identified cognitive tasks that can selectively activate specific parts of the brains. However, the subsequent effect of localized brain activation on the cognitive functioning remains unclear. We discovered that after being engaged in the novel picture encoding task to activate hippocampus for 2 min, individuals demonstrated better memory, but not motor function. Similarly, after performing the finger sequencing task to activate the primary motor cortex, individuals showed improvement in motor function, but not in memory. These double dissociation results suggest that when we selectively activate specific part of the brain, the cognitive function mediated by that particular region but not the others can consequently be improved.

Adult↗
PubMed2000

Lack of expression for the suppressor PML in human small cell lung carcinoma.

The promyelocytic leukemia (PML) gene, which encodes a transformation and growth suppressor, was first identified at the chromosomal translocation break point t(15;17) in acute promyelocytic leukemia (PML). To determine if the PML gene might be involved in other neoplasias such as lung cancer, PML expression was analyzed by immunohistochemical staining and in situ hybridization. Considerable PML protein expression in the PML-oncogenic domain (POD) structure was found in adenocarcinomas (ADC) and squamous cell carcinomas (SCC) of the lung, but was almost completely absent in all the small cell lung carcinomas (SCLC) examined. In situ hybridization showed that both mRNA and DNA of PML were present in SCLC and in normal lung, suggesting that the decreased protein expression was due to either a defect in translation or protein instability, rather than the consequence of decreased transcription or gene deletion. Double staining showed that PML expression was inversely correlated with the proliferation marker Ki-67 and positively correlated with levels of apoptotic cells in these tumors. To determine if the precursor cells of SCLC, the neuroendocrine-producing cells, express PML, double labeling was performed with PML and chromogranin A, a bio-marker for neuroendocrine cells. Neuroendocrine cells from normal tissues were found to be PML positive, indicating that the lack of PML protein in SCLC is associated with the tumorigenic phenotype and is not the result of cell-lineage specificity. Thus, the decreased PML expression may play an important role in SCLC development.

Adenocarcinoma↗
PubMed2000

Memory and organizational strategies in chronic and acute schizophrenic patients.

The memory profile of acute and chronic schizophrenic patients was examined according to the information processing model, with which encoding, retention and retrieval processes of these patients were compared. The effects of an external organizational strategy on their verbal learning and memory were also examined. Twenty chronic and 20 acute schizophrenic patients were tested with a list learning task consisting of a random (i.e., words presented randomly) and a blocked (i.e., words presented in clusters) word-list. The schizophrenic patients, as compared with age- and education-matched normal control subjects, demonstrated impaired learning, and the duration of their illness was not a significant factor in the severity of their learning impairment. However, the acute and chronic schizophrenic patients seem able to retain most of the newly acquired materials, regardless of the presentation format, after 30 min. In addition, the learning and subjective organizational strategy of the chronic patients, but not that of the acute patients, improved significantly by the blocked presentation. However, semantic organization could facilitate both the chronic and acute schizophrenic patients to retain more newly learned items.

Acute Disease↗
PubMed2000

Cognitive function of patients with nasopharyngeal carcinoma with and without temporal lobe radionecrosis.

BACKGROUND: Radiotherapy is the primary treatment for nasopharyngeal carcinoma, and temporal lobe necrosis is observed in about 7% of patients after radiotherapy. Although some studies reported that these patients demonstrated cognitive impairment after radiotherapy, it is still unclear if the cognitive deficits are related to the radiation exposure or the radiation-induced necrosis. OBJECTIVE: To compare the cognitive function of patients with and without temporal lobe necrosis after radiotherapy for nasopharyngeal carcinoma. METHODS: A comprehensive neuropsychological battery was administered to 53 patients with nasopharyngeal carcinoma who had completed their radiotherapy at least 1 year previously. As evidenced by magnetic resonance imaging, 31 patients developed necrosis after treatment. Thirty-one age- and education-matched individuals were recruited as normal control subjects. RESULTS: Whereas the performance of patients without temporal lobe necrosis was similar to that of normal control subjects, patients with temporal lobe necrosis demonstrated significant impairment on tests of verbal (P<.001) and visual memory (range, P<.001 to P =.03), language (range, P<.001 to P =.01), motor ability (P =.02), planning (P =.02), cognitive ability (P =.007), and abstract thinking (range, P =.009 to P =.04). However, the performance of patients with necrosis on tests of general intelligence (range, P =.08 to P =.15), attention (range, P =.06 to P =.55), and visual abilities (range, P =.06 to P =.47) was not significantly different from that of normal control subjects and patients without necrosis. CONCLUSIONS: Radiotherapy for nasopharyngeal carcinoma seemed to have adverse but insignificant effects on the cognitive functions of the patients. However, for patients who developed temporal lobe necrosis after radiotherapy, memory, language, motor ability, and executive functions were significantly impaired, although their general intelligence remained relatively intact.

Cognition Disorders↗
PubMed2000

Electron impact mass spectral fragmentation patterns of 2a,4-disubstituted 5-benzoyl-2-chloro-2a,3,4,5-tetrahydroazeto[1,2-a][1,5]benzodiazepin-1( 2H)-ones.

The mass spectrometric behaviour of six 2a,4-disubstituted 5-benzoyl-2-chloro-2a,3,4,5-tetrahydroazeto[1,2-a][1,5]benzodia zepin-1(2H)-ones has been studied with the aid of mass-analysed ion kinetic energy spectrometry and accurate mass measurements under electron impact ionization. All compounds show a tendency to eliminate a chlorine atom, a chlorine atom plus benzaldehyde, benzoyl radical, chloroketene or chlorine atom plus CO and H2O molecules to yield, respectively, [M-Cl]+ ions, 2a,4-disubstituted 2a,3-dihydroazeto[1,2-a][1,5]benzodiazepin-1(2H)-one ions, [M-PhCO]+ ions, 2,4-disubstituted 1-benzoyl-2,3-dihydro-1H-1,5-benzodiazepine ions, or 1,2,4-trisubstituted 1H-1,7-benzodiazonine ions, which could also be formed from [M-Cl]+ ions by loss of CO and H2O molecules simultaneously. The [M-Cl]+ ions could further lose benzoyl radical to form [M-Cl-PhCO]+ ions, or lose benzoyl amide and undergo a rearrangement to form 4,6-disubstituted 1-benzoazocine-2(1H)-one ions. The [M-PhCO]+ ions could eliminate NH to produce 2a,4-disubstituted 2,2a,3,4-tetrahydroazeto[1,2,-a]quinolin-1-one ions, which could further eliminate chloroketene, CO and/or HCl to produce some important ions, respectively. 2,4-Disubstituted 1-benzoyl-2,3-dihydro-1H-1,5-benzodiazepine ions could lose benzoyl radical to yield 2,4-disubstituted 2,3-dihydro-1H-1,5-benzodiazepine ions, which could further yield other small fragment ions by loss of propene/styrene or small fragments.

Benzodiazepinones↗
PubMed2000

Synthesis of a new chiral ligand, 6, 6'-dihydroxy-5, 5'-biquinoline (BIQOL) and its applications in the asymmetric addition of diethylzinc to aldehydes.

A new chiral ligand 6, 6'-dihydroxy-5, 5'-biquinoline (BIQOL, 2) was prepared via Cu2+ mediated coupling. The resolution was carried out by separating the corresponding ditrifluomethanesulfonate on chiral column. When applied to the enantioselective addition of diethylzinc to aromatic aldehydes, this ligand induced the reaction with enantioselectivity equivalent to that induced by BINOL. The effects of solvent and reaction temperature on enantioselectivity were also studied.

Journal Article↗
PubMed2000

Sequence variations of precore/core and precore promoter regions of hepatitis B virus in patients with or without viral reactivation during cytotoxic chemotherapy.

Reactivation of the hepatitis B virus (HBV) is a well-described complication among cancer patients undergoing cytotoxic chemotherapy. Mutations in the preC/C and the preC promoter regions of HBV have been reported in some patients who developed this condition. A G-to-A mutation at nt 1896 in the preC/C region (HBeAg negative/ anti-HBe positive) has been associated with more severe liver disease than that caused by wild type virus. In addition, it has been suggested that patients with these mutations may be more likely to reactivate than those with the wild type virus. Whether or not such mutations were present before the commencement of or developed during the course of cytotoxic chemotherapy is not known. In this study, 28 cancer patients (consisting of 14 consecutive patients who developed HBV reactivation and another 14 who had no reactivation during cytotoxic chemotherapy) are reported. The objectives were firstly, to determine the prechemotherapy HBeAg status and nucleotide sequences of the preC/C and preC promoter regions of HBV in order to determine if these parameters affected the rate of reactivation, and secondly, for those who developed reactivation, to determine whether the mutations were present before chemotherapy or developed during, possibly as a result of, cytotoxic chemotherapy. HBV DNA was amplified by PCR and nucleotide sequencing performed on samples taken prior to chemotherapy and at the time of reactivation. Results revealed that 16 of the 28 patients were HBeAg negative/anti-HBe positive. Of these 16, four (57%) of the seven patients who had nt 1896 mutation, but only one (17%) of the six who had the wild type HBV genome, developed reactivation. Three had no detectable HBV DNA. In the majority of cases, the type of virus, i.e. wild/mutant at preC/C, that was detected during the reactivation was identical to that detected in the pretreatment samples. With respect to the preC promoter region, the two commonest mutations detected were at nt 1762 (A to T) and nt 1764 (G to A). When this region was translated into amino acid sequences, stop codons leading to truncated X protein at carboxyl terminus were found in four patients, three of whom developed HBV reactivation. We conclude that chronic HBV carriers who are HBeAg negative/anti-HBe positive with nt 1896 mutation (G to A) may be more likely to develop HBV reactivation during cytotoxic chemotherapy than those with the wild type virus. Cytotoxic chemotherapy does not appear to select out mutant HBV, or to be consistently mutagenic in patients who develop HBV reactivation. The occurrence of stop codons in the amino acid sequences of the X protein in three patients who developed HBV reactivation, including one who was detected only at the time of reactivation, is of particular interest, as such mutant viruses remain replication competent.

Adult↗
PubMed2000

Regulation of c-Jun N-terminal kinase by the ORL(1) receptor through multiple G proteins.

Nociceptin is an endogenous peptide that produces its biological effects by binding to the opioid receptor-like (ORL(1)) receptor. It has been shown that activation of ORL(1) receptor leads to inhibition of the adenylyl cyclase activity, but stimulation of the extracellular signal-regulated kinase and p38 subgroups of mitogen-activated protein kinases. In this report, we demonstrate that activation of the G protein-coupled ORL(1) receptor in transfected COS-7 cells leads to stimulation of the JNK subgroup of mitogen-activated protein kinases in a Ras/Rac-dependent manner, and it was insensitive to wortmannin. This increased JNK activity was mainly mediated by PTX-sensitive G(i) proteins, and partially contributed by a PTX-insensitive component. Among all known PTX-insensitive G proteins, G(z), G(12), G(14), and G(16) seemed to have functional coupling with the ORL(1) receptor in terms of JNK activation. Stimulation of the endogenous ORL(1) receptor in NG108-15 cells also led to activation of a PTX-sensitive JNK activity in a wortmannin-insensitive manner. The induced JNK activation is accompanied by the active phosphorylation of c-Jun and activating transcription factor-2. This is the first report that demonstrates the stimulatory effect of ORL(1) receptor on JNK, and the subsequent activation of c-Jun and activating transcription factor-2.

Adenylate Cyclase Toxin↗
PubMed1999

Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer.

BACKGROUND: The incidence of colorectal cancer in persons under 46 years of age is substantially higher in Hong Kong than in Scotland and many other countries. Consequently, we examined whether there is a hereditary predisposition for colorectal cancer in this Southern Chinese population. METHODS: We investigated the incidence of microsatellite instability (MSI) at 10 DNA sites in 117 colorectal cancer specimens from Chinese patients of various ages. Those tumors with new alleles at 40% or more of the sites investigated were identified as highly unstable MSI (MSI-H). In young patients, we also searched for germline mutations in three mismatch repair genes (hMSH2, hMLH1, and hMSH6). RESULTS: The incidence of MSI-H varied statistically significantly with age, being observed in more than 60% of those younger than age 31 years at diagnosis and in fewer than 15% of those age 46 years or older. In 15 patients (<46 years old) whose colorectal cancers showed MSI-H, eight possessed germline mutations in either hMSH2 or hMLH1. When mutations in hMSH6 were included, more than 80% of Chinese colorectal cancer patients younger than 31 years had germline mutations in mismatch repair genes. We found a novel germline missense mutation in hMSH6 in a 29-year-old man whose tumor showed no MSI. Two patients had a 4-base-pair insertion in exon 10 causing a truncated protein; this insertion is a common polymorphism with a population allele frequency in Chinese of 5.6%. CONCLUSIONS: Our results indicate that germline mutations in mismatch repair genes contribute substantially to the pathogenesis and high incidence of colorectal cancer in young Hong Kong Chinese. However, because young Chinese and Caucasians show similar proportions of colorectal cancers with MSI-H, despite the higher incidence in the former, additional factors may underlie the high susceptibility of young Chinese to colorectal cancer.

Adenocarcinoma↗
PubMed1999

hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability.

Mutation of DNA mismatch repair genes has rarely been documented in sporadic gastric carcinoma with microsatellite instability (MSI). In sporadic colorectal carcinoma, hMLH1 promoter methylation associated with protein loss is found in the majority of high-frequency MSI cases. We investigated a series of 35 sporadic gastric carcinomas stratified into high-frequency MSI (MSI-H), low-frequency MSI (MSI-L) and microsatellite stable (MSS) groups and found that hypermethylation of the CpG island in the hMLH1 promoter region was present in 100% of MSI-H sporadic gastric carcinomas. In 90% of cases, there was an associated complete loss of hMLH1 protein, as detected by immunohistochemistry, and a markedly lowered hMLH1 mRNA level. This loss of hMLH1 protein occurred in the MSI-H invasive tumor but not in the adjacent carcinoma-in situ or dysplastic components that were MSS. The MSI-L and MSS forms of gastric carcinoma all showed predominantly unmethylated hMLH1 promoter, positive hMLH1 protein and high hMLH1 mRNA level. On the other hand, hMSH2 protein was expressed in all of the tumors irrespective of the MSI status. Our results suggest that high-frequency MSI in sporadic gastric cancer is mostly due to epigenetic inactivation of hMLH1 in association with promoter methylation, and the loss of hMLH1 protein is a significant event in the development of invasive tumor.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Performance of 7- to 95-year-old individuals in a Chinese version of the category fluency test.

A version of the category fluency test including the categories of animal and transportation, was administered to 316 Chinese native speakers ranging in age from 7 to 95. Results indicated that the number of items generated in the category fluency test increases with age from childhood to adulthood with a peak performance in adults aged from 19 to 30, and then declines subsequently into late life. All participants, regardless of their age, generated more animal than transportation names. Educational level, but not gender, was a significant factor affecting their performance. The participants in all age groups committed very few intrusion and perseveration errors. The results of the present study were in general consistent with those reported in the western countries. Thus, it seems to be appropriate to apply the category fluency test, which was originally developed in western countries, for clinical use in Hong Kong.

Adolescent↗
PubMed1999

The deterioration of semantic memory in Alzheimer's disease.

Semantic memory impairment is a common feature of dementia of the Alzheimer type (DAT). Recent research has shown that patients with DAT are more impaired (relative to non-demented controls) in generating exemplars from a particular semantic category (e.g., animals) than words beginning with a particular letter, exhibit an altered temporal dynamic during the production of category exemplars, are impaired on confrontation naming tasks and make predominantly superordinate or semantically related errors, consistently misidentify the same objects across a variety of semantic tasks, and have alterations in multi-dimensional scaling models of their semantic network that are indicative of a loss of concepts and associations. These results are consistent with the view that Alzheimer's disease results in a breakdown in the organization and structure of semantic knowledge as neurodegeneration spreads to the association cortices that presumably store semantic representations.

Aged↗
PubMed1999

Conceptual and perceptual contributions to the acquisition and retention of text-specific reading skill in Alzheimer's disease.

In the first experiment, patients with Alzheimer's disease (AD) and normal control (NC) participants read each of two passages three times and then again after either a 1-min or 10-min delay interval. Reading time decreased with practice for both groups, and this facilitation was text-specific. Although both groups retained the facilitation in reading speed after 1 min, it was reduced only in the AD group after 10 min. In the second experiment, the same task was repeated with new passages that encouraged the use of either conceptual or perceptual processing during reading. Patients with AD acquired the facilitation in reading speed normally in both conditions, but were impaired in retaining it over a 10-min delay interval only in the conceptually-weighted condition

Aged↗
PubMed1999

Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome.

Turcot's syndrome is characterized clinically by the occurrence of primary brain tumor and colorectal tumor and has in previous reports been shown to be associated with germline mutations in the genes APC, hMLH1, and hPMS2. Here we describe three patients with Turcot's syndrome, each having colorectal adenocarcinoma and malignant glioma. All the colorectal and brain tumors from these patients showed replication errors in most of the microsatellite loci investigated. Search for underlying germline mutations in the nucleotide mismatch repair genes revealed three different hMSH2 mutations. All colorectal tumors showed a frameshift in the A(10) tract in the coding sequence of the transforming growth factor beta type II receptor (TGFBRII) gene, but no such change was detected in any of the brain tumors. Frameshift mutation in the BAX gene was found in one colon carcinoma and mutations in insulin-like growth factor type II receptor (IGFIIR) gene in one glioma. Our data have broadened the possible mutation spectrum of patients with Turcot's syndrome. The difference in the mutation spectrum of TGFBRII, BAX, and IGFIIR between brain and colorectal tumors in these individuals suggests that the mutator phenotype may target different pathogenic pathways in the oncogenic process of the two organs.

Adenomatous Polyposis Coli↗