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Biomedical subjects

W L Lam

Publications and source records attributed to W L Lam.

At least 19 recordsLinked to original sources
PubMed2006

Differential disruption of cell cycle pathways in small cell and non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related mortality in the world, with small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) comprising the two major cell types. Although these cell types can be distinguished readily at the histological level, knowledge of their underlying molecular differences is very limited. In this study, we compared 14 SCLC cell lines against 27 NSCLC cell lines using an integrated array comparative genomic hybridisation and gene expression profiling approach to identify subtype-specific disruptions. Using stringent criteria, we have identified 159 of the genes that are responsible for the different biology of these cell types. Sorting of these genes by their biological functions revealed the differential disruption of key components involved in cell cycle pathways. Our novel comparative combined genome and transcriptome analysis not only identified differentially altered genes, but also revealed that certain shared pathways are preferentially disrupted at different steps in these cell types. Small cell lung cancer exhibited increased expression of MRP5, activation of Wnt pathway inhibitors, and upregulation of p38 MAPK activating genes, while NSCLC showed downregulation of CDKN2A, and upregulation of MAPK9 and EGFR. This information suggests that cell cycle upregulation in SCLC and NSCLC occurs through drastically different mechanisms, highlighting the need for differential molecular target selection in the treatment of these cancers.

Carcinoma, Non-Small-Cell Lung↗
PubMed2005

Pentoxifylline inhibits mature burn scar fibroblasts in culture.

Fibroblasts are thought to be (in part) responsible for the persisting contractile forces that result in burn contractures. Using monolayer and fibroblast populated collagen lattice (FPCL) models we subjected burn scar fibroblasts to the anti-fibrinolytic agent Pentoxifylline (PFX) in an attempt to reduce proliferation and contraction of these cells. Fibroblasts were isolated from mature burn scars at reconstructive surgery. Fibroblasts were grown in monolayer or incorporated into FPCL's and exposed to PFX. Fibroblast numbers and FPCL surface areas were calculated using digital photography and image analysis. PFX showed a dose-dependent inhibition of contraction and reduced proliferation of burn scar fibroblasts. In monolayer, cell number proliferation was markedly reduced. FPCL's containing 0, 0.25, 0.5, 1, and 2 mg/ml of PFX had relative surface areas of 31, 40, 43, 59, and 85%, respectively. One and 2 mg/ml FPCL's contracted significantly less than controls (p < 0.0001). This is the first study to show the dose-dependent effects of Pentoxifylline on the proliferation and contraction of burn scar fibroblasts. This study suggests that Pentoxifylline has a direct effect on inhibiting burn scar fibroblasts. Further study of PFX on burn scars will provide opportunities to reduce burn scar contractures in vivo.

Burns↗
PubMed2005

Genomic and gene expression profiling of minute alterations of chromosome arm 1p in small-cell lung carcinoma cells.

Genetic alterations occurring on human chromosome arm 1p are common in many types of cancer including lung, breast, neuroblastoma, pheochromocytoma, and colorectal. The identification of tumour suppressors and oncogenes on this arm has been limited by the low resolution of current technologies for fine mapping. In order to identify genetic alterations on 1p in small-cell lung carcinoma, we developed a new resource for fine mapping segmental DNA copy number alterations. We have constructed an array of 642 ordered and fingerprint-verified bacterial artificial chromosome clones spanning the 120 megabase (Mb) 1p arm from 1p11.2 to p36.33. The 1p arm of 15 small-cell lung cancer cell lines was analysed at sub-Mb resolution using this arm-specific array. Among the genetic alterations identified, two regions of recurrent amplification emerged. They were detected in at least 45% of the samples: a 580 kb region at 1p34.2-p34.3 and a 270 kb region at 1p11.2. We further defined the potential importance of these genomic amplifications by analysing the RNA expression of the genes in these regions with Affymetrix oligonucleotide arrays and semiquantitative reverse transcriptase-polymerase chain reaction. Our data revealed overexpression of the genes HEYL, HPCAL4, BMP8, IPT, and RLF, coinciding with genomic amplification.

Animals↗
PubMed2004

A new clinical test for radial tunnel syndrome--the Rule-of-Nine test: a cadaveric study.

PURPOSE: Radial tunnel syndrome refers to pain on the lateral aspect of the forearm as a result of compression of the posterior interosseous nerve within a tunnel with specific anatomical boundaries. Diagnosis of the condition is difficult because of its close association with lateral epicondylitis, which warrants different methods of treatment. Based on a cadaveric study, a new clinical test, the Rule-of-Nine test, is proposed to improve the diagnostic accuracy in radial tunnel syndrome. The test involves constructing 9 equal squares on the anterior aspect of the forearm and noting those squares where tenderness can be elicited. METHODS: 19 upper limbs were dissected to delineate the path of the posterior interosseous nerve through the radial tunnel, and the relationship of the path of the nerve with the 9 squares. RESULTS: A consistent mapping of the posterior interosseous nerve to the lateral column of 3 squares was observed. CONCLUSION: The Rule-of-Nine test is proposed as a reliable method of diagnosing radial tunnel syndrome.

Aged↗
PubMed2003

Stabilization of the ulna stump after Darrach's procedure at the wrist.

We studied the outcome of patients with chronic distal radioulnar joint symptoms who were treated with excision of the distal ulna and reconstruction using the flexor carpi ulnaris tendon. Twelve patients with 14 wrists were assessed. Ten patients were posttraumatic, and two had bilateral surgery for rheumatoid arthritis. Average age was 37 years at time of operation. Follow-up averaged 20 months (9 months to 4 years). All patients except one reported improvement in pain symptoms. Grip strength of the operated hand as measured by dynamometer readings was 67% of the strength of the normal hand with five wrists achieving an excellent result in grip strength. Eleven patients reported a subjective improvement in functional activities. An improved range of motion was obtained in all patients. We discuss the importance and basis for ligamentous reconstruction following excision of the distal ulna and review the literature for other previously described procedures.

Adult↗
PubMed2003

Cutting or round-bodied needles for tendon repair.

We carried out a biomechanical study comparing tensile strength after using round-bodied or cutting needles for tendon repair. Swine tendons were repaired in three groups: Group 1 core suture repair only; group 2 core and circumferential suture repair; and group 3 isolated circumferential suture repair. The tendons were tested at longitudinal stress to failure at 5mm/minute. No significant differences were found between the round-bodied and cutting needles in any group. Equal numbers in the core suture repair group failed by suture pullout when comparing cutting and round-bodied needles. We conclude that the choice of needle has no effect on the outcome of tendon repair if there is consistency of surgeon's skill and experience.

Animals↗
PubMed2002

Comparison of HPV infection, p53 mutation and allelic losses in post-transplant and non-posttransplant oral squamous cell carcinomas.

BACKGROUND: Oral squamous cell carcinoma (SCC) is increasingly found in transplant recipients, although little is known of the natural history of the disease or the mechanism underlying this increase. METHODS: In this article we describe the history of development of 5 oral post-transplant SCCs (PSCCs) and compare their genetic profiles to 34 non-posttransplant SCCs (NPSCCs). RESULTS: Of the five patients with PSCCs, 3 had bone marrow transplants and two, kidney. All three PSCCs from bone marrow recipients were preceded locally by graft-vs.-host disease (GVHD). Two of the GVHD were biopsied and demonstrated dysplasia. Similar frequencies of loss of heterozygosity (LOH) occurred in PSCCs and NPSCCs at 3p, 9p, 17p and 8p, with lower frequencies in PSCCs at 4q (39% vs. 0%), 11q (53% vs. 20%) and 13q (45% vs. 20%), although the latter were not significantly different. Only 1 PSCC had a p53 mutation, compared to historical values of 40-60% for NPSCC. Interestingly, human papillomavirus (HPV) DNA was detected in 3 (60%) PSCCs, in comparison to only 4 (12%) of the 34 NPSCCs (P = 0.0346). CONCLUSIONS: Dysplasia in oral GVHD may be a strong indicator of cancer risk and should not be regarded as reactive changes to lichenoid mucosites. The low level of p53 mutation and increased HPV infection support the involvement of HPV in the development of PSCC, while the similarity in LOH patterns suggests that other aspects of carcinogenesis may be comparable in these two types of SCCs.

Adult↗
PubMed2001

Bacterial comparative genomic hybridization: a method for directly identifying lateral gene transfer.

Horizontally transferred DNA is largely responsible for the dissemination of virulence traits amongst bacteria. Rapid identification of acquired DNA remains difficult as whole-genome sequencing of outbreak strains is impractical, and microarray-based approaches, while powerful, are limited to genes present only in the reference strains. Here we present a novel bacterial comparative genomic hybridization method that directly compares the genomes of related strains at sub-kilobase resolution in order to identify acquired DNA. Bacterial comparative genomic hybridization utilizes the concept of metaphase chromosome comparative genomic hybridization, and exploits the resolving power of two-dimensional DNA electrophoresis. Comparison of isogenic variants of the pathogen Pseudomonas aeruginosa detected a single-copy gene insertion responsible for gentamicin resistance.

Bacteria↗
PubMed2001

Increased genetic damage in oral leukoplakia from high risk sites: potential impact on staging and clinical management.

BACKGROUND: Two staging systems for oral leukoplakias have been proposed to better predict prognosis. Although one system includes site as an independent determinant, its use is controversial. METHODS: Recent studies have shown that loss of heterozygosity (LOH) in oral premalignancies is associated with risk of progression. The authors analyzed 127 oral dysplasias for LOH on 3 chromosome arms (3p, 9p, and 17p). The lesions included 71 from the floor of mouth, ventrolateral tongue, and soft palate complex (designated high risk [HR] sites) and 56 from the rest of the oral cavity (low risk [LR] sites). RESULTS: Dysplasias from HR sites contained significantly higher LOH frequencies than LR sites (percentage with any loss, P = 0.0004; percentage with multiple losses, P = 0.0001; percentage loss on each of the arms, P < 0.05). Loss on 3p and/or 9p, a pattern associated with a 24-fold increased risk of progression (Rosin MP, Cheng X, Poh C, Lam WL, Huang Y, Lovas J, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000;6:357-62) was more frequent among HR lesions (P = 0.0005). Loss of heterozygosity frequencies were elevated at HR sites among both genders and among smokers and nonsmokers. For different histologic groups, LOH frequencies were elevated for HR sites in mild dysplasias (P < 0.05) and moderate dysplasias (marginal significance, P = 0.06), but not in severe dysplasias/carcinoma in situ. CONCLUSIONS: Anatomic location of mild and moderate oral dysplasias in Western populations may be an important diagnostic indicator because lesions at HR sites have a greater tendency to include genetic alterations associated with elevated risk of progression.

Adult↗
PubMed2001

Impact of localized treatment in reducing risk of progression of low-grade oral dysplasia: molecular evidence of incomplete resection.

Currently, there is no consensus on the appropriate treatment for low-grade oral dysplasia. This is mainly due to the difficulty in predicting outcome for this heterogeneous group of lesions. In this study, we constructed a detailed clinical history of 66 mild and moderate dysplasias in order to determine how treatment affected outcome, and to evaluate the effect of treatment on lesions with different genetic profiles, which are defined by patterns of loss of heterozygosity (LOH) associated with low, intermediate and high risk of progression [Clin. Cancer Res., 6, 357-62, 2000]. The results showed that although treatment guided by clinical removal of leukoplakia reduced cancer progression risk in all three risk groups, the amount of reduction in our study group did not reach statistical significance. To assess whether completeness of lesion removal was a major factor in recurrence, repeat biopsies at the primary sites were analyzed for persistent LOH status on chromosomes 3p, 4q, 8p, 9p, 11q, 13q and 17p. Strikingly, eight of 17 cases judged clinically removed contained the same molecular clones in the initial and subsequent biopsies, suggesting incomplete removal. When molecular information was included in the assessment of lesion removal, treatment significantly reduced the risk of progression for cases with intermediate (P=0.043) and high risk (P=0.001) genetic profiles, but not cases with low-risk profiles. A 9.1-fold decrease in progression risk was observed for those with high-risk profile. Altogether, these data suggest the use of molecular profiles to guide the treatment of low-grade dysplasia. Our data also suggest that currently an inadequate margin may in part be responsible for the high rate of recurrence, especially in high-risk lesions.

Adult↗
PubMed2001

A high frequency of allelic loss in oral verrucous lesions may explain malignant risk.

Verrucous carcinoma (VC), a variant of squamous cell carcinoma (SCC), is distinct from SCC in morphology and behavior. The underlying genetic changes involved in the development of VC and its precursor verrucous hyperplasia (VH) are unknown. This study determined whether chromosomal regions frequently lost during the development of SCC are also lost in the VH/VC variant. Twenty-five VH and 17 VC were analyzed for loss of heterozygosity (LOH) at 19 loci on 7 chromosome arms using microsatellite analysis. These data were compared with those from 47 reactive hyperplasias, 92 dysplasias (54 low- and 38 high-grade), and 41 SCCS: The results showed that VC/VH shared many of the losses present in dysplasia/SCC but differed in two aspects. First, VC/VH showed early acquisition of loss, compared with a gradual accumulation of losses from dysplasias to SCC. The LOH pattern of VH was similar to that of high-grade dysplasia and sharply different from reactive hyperplasia. The loss in VH often involved multiple arms (in 60% of VH vs 0% of reactive lesions). Only a marginal elevation of loss was observed at 9p (p = 0.06) and 4q (p = 0.05) from VH to VC because of the high degree of loss already present in VH. Second, a strikingly lower frequency of loss at 17p was noted in VH/VC compared with dysplasia/SCC and may indicate human papillomavirus (HPV) involvement. The finding of high-risk LOH profiles in VH may partly account for the high-progression risk seen for VH and also has potentially important clinical implications. The difficult pathological diagnosis of VH/VC from reactive hyperplasia frequently requires repeated biopsies and results in delay in diagnosis and significantly increased mortality/morbidity. Microsatellite analysis might facilitate this differential diagnosis.

Aged↗
PubMed2000

Volar metacarpophalangeal joint dislocation.

Volar dislocation of the metacarpophalangeal joint is a very rare clinical finding. A volar dislocation of the metacarpophalangeal joint of the left index finger in a 44 year old man is reported. Closed reduction proved unsuccessful requiring subsequent open reduction and internal fixation via a combined dorsal and volar approach. The presentation, mechanism of injury and treatment of this case and other previously reported cases are discussed.

Adult↗
PubMed2000

Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia.

One of the best approaches to identifying genetic changes critical to oral cancer progression is to compare progressing and nonprogressing oral premalignant lesions. However, such samples are rare, and they require long-term follow-up. The current study used the large archive network and clinical database in British Columbia to study loss of heterozygosity (LOH) in cases of early oral premalignancies, comparing those with a history of progression to carcinoma in situ or invasive cancer and those without a history of progression (referred to as nonprogressing cases). Each of 116 cases was analyzed for LOH at 19 microsatellite loci on seven chromosome arms (3p, 4q, 8p, 9p, 11q, 13q, and 17p). The progressing and nonprogressing cases showed dramatically different LOH patterns of multiple allelic losses. An essential step for progression seems to involve LOH at 3p and/or 9p because virtually all progressing cases showed such loss. However, LOH at 3p and/or 9p also occurred in nonprogressing cases. Individuals with LOH at 3p and/or 9p but at no other arms exhibit only a slight increase of 3.8-fold in relative risk for developing cancer. In contrast, individuals with additional losses (on 4q, 8p, 11q, or 17p), which appeared uncommon in nonprogressing cases, showed 33-fold increases in relative cancer risk. In conclusion, analysis of LOH at 3p and 9p could serve as an initial screening for cancer risk of early premalignancies. Follow-up investigation for additional losses would be essential for predicting cancer progression.

Chromosome Mapping↗
PubMed1997

Relaxant actions of nonprostanoid prostacyclin mimetics on human pulmonary artery.

The specific prostacyclin (IP) receptor agonist cicaprost relaxed human pulmonary artery preparations precontracted with phenylephrine [50% inhibitory concentration (IC50) approximately 0.6 nM], U-46619 (IC50 approximately 0.9 nM), and K+ (approximately 40% maximal relaxation); endothelium removal had little effect on relaxant activity. Ranking of relaxant potencies for prostacyclin and five of its analogs was 17 alpha, 20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-9063) > or = cicaprost > iloprost > prostacyclin > taprostene > benzodioxane prostacyclin > 15-deoxy-16 alpha-hydroxy-16 beta,20-dimethyl-delta 6,6a-6a-carba PGI1 (TEI-3356). The potency of the isocarbacyclin TEI-3356 may have been under-estimated because of its contractile (EP3 receptor agonist) activity. The potency ranking of four nonprostanoid prostacyclin mimetics was 3-[4-(4,5-diphenyl-2-oxazolyl)-5-oxazolyl]phenoxy] acetic acid (BMY 45778; IC50 approximately 2.5 nM) > > 2-[3-[2-(4, 5-diphenyl-2-oxazolyl)ethyl]phenoxy]acetic acid (BMY 42393) > octimibate > CU 23 (a novel diphenylindole). From IP receptor binding affinities obtained on human platelet membranes, it is suggested that the slightly shallower log concentration-response curves for BMY 45778, BMY 42393, and CU 23 may reflect the near-maximal receptor occupancy required for complete relaxation. A fifth nonprostanoid, CU 602, had much shallower log concentration-response curves than cicaprost against phenylephrine tone but not against U-46619 tone; this may indicate IP receptor partial agonism coupled with TP receptor antagonism. The relaxant actions of the nonprostanoid mimetics were more persistent than those of the prostacyclin analogs on washout of the organ bath; by the inhalation route, this type of compound may be retained within pulmonary tissue and thus afford greater pulmonary/systemic selectivity than currently used pulmonary vasodilators.

Acetates↗
PubMed1996

Bilateral biochemical and biophysical retinal changes after unilateral ocular trauma in the mouse.

The bilateral response of the mouse retinae after puncture and insertion of iron wire in one eye was studied by electrophoretic analysis of protein changes and free radicals quantitation at 4, 15 and 42 days after surgery. The effect of cyclosporine was also studied. Several low molecular weight (< 24 kDa) polypeptide subunits were detected in both the traumatized and contralateral eyes of experimental animals. Free radical levels rose in both traumatized and contralateral eyes although the extent was much greater in the former. Both biochemical and biophysical assays showed that treatment with cyclosporine was effective in suppressing the responses in retinal proteins and free radicals only for up to 15 days. These results substantiated our earlier report that unilateral injury to one eye with retention of the foreign body affects both eyes in the mouse.

Animals↗
PubMed1996

Active transposition in zebrafish.

We have identified a new family of Tc1-like transposons in the zebrafish, Danio rerio. The sequence of a candidate active transposon, deduced from sample Tzf elements, shows limited resemblance to the previously described Tdr1 elements of zebrafish. Both the Tzf and the Tdr elements are extremely abundant in zebrafish. We describe here a general strategy for detecting transposition events in a complex genome and demonstrate its utility by selectively monitoring hundreds of potentially active Tzf copies in the zebrafish genome against a background of other related elements. We have followed members of a zebrafish pedigree, using this two-dimensional transposon display strategy, to identify the first examples of active transposition of such elements in vertebrates.

Amino Acid Sequence↗
PubMed1996

Discovery of amphibian Tc1-like transposon families.

We have discovered transposase sequences in the bull frog (Rana catesbeiana) and in the clawed frog (Xenopus laevis), which demonstrates that there are DNA-mediated transposons in Amphibia. The DNA sequences of 11 new Xenopus elements describe two new vertebrate transposon families. Phylogenetic analysis, using these sequences along with previously defined vertebrate and invertebrate elements, reveals at least five families of Tc1-like elements in Vertebrata. Some of these families co-exist in the same genome. Furthermore, the grouping of one of the amphibian transposon families with a branch of the teleost transposons raises the possibility of horizontal transfer.

Amino Acid Sequence↗