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Biomedical subjects

S Lam

Publications and source records attributed to S Lam.

At least 19 recordsLinked to original sources
PubMed1999

Sex-related differences in bronchial epithelial changes associated with tobacco smoking.

BACKGROUND: Lung cancer is the most common cause of cancer death in North American women. Because smoking-related changes in the bronchial epithelium and in lung function have not been studied in detail in women, we used fluorescence bronchoscopy-directed biopsy to determine the prevalence of high-grade preinvasive lesions in former and current smokers of both sexes. METHODS: Spirometry, white-light bronchoscopy, and fluorescence bronchoscopy were performed in 189 women and 212 men older than 40 years of age who had smoked 20 pack-years or more (pack-years = number of packs of cigarettes smoked per day x number of years of smoking). RESULTS: Carcinoma in situ was found in 1.8% of the subjects, severe dysplasia was found in 6.5%, and moderate dysplasia was found in 14% (all preinvasive lesions). Compared with men, women had a lower prevalence of high-grade preinvasive lesions in the observed airways (14% versus 31%; odds ratio = 0.18; 95% confidence interval = 0.04-0.88), and women with preinvasive lesions had fewer such lesions (two-sided P = .048). The prevalence of preinvasive lesions did not change substantially for more than 10 years after cessation of smoking. Lung function was associated with the prevalence of preinvasive lesions, but the association was weaker in women than in men. If the presence of airflow obstruction was defined by an FEV1/FVC (forced expiratory volume in 1 second/forced vital capacity) value of 70% or less, only 56% of the men and 44% of the women with preinvasive lesions had abnormal lung function. CONCLUSION: In developing strategies for chemoprevention or early detection of lung cancer in high-risk populations, it is important to consider the effect of sex and arbitrarily chosen lung function values on the prevalence of preinvasive airway lesions.

Adult↗
PubMed1999

Allelic losses at chromosome 8p21-23 are early and frequent events in the pathogenesis of lung cancer.

Allelic losses on the short arm of chromosome 8 (8p) have been reported as frequent events in several cancers, including lung. However, no comprehensive mapping analysis of chromosome 8p in lung cancer tumors has been performed, and no data are available about the stage at which these abnormalities occur during the multistage development of lung cancer. Using 26 microsatellite markers, we mapped the chromosome 8 regions frequently deleted in lung cancer in 13 small cell carcinoma and 17 non-small cell lung carcinoma cell lines and in 68 microdissected archival primary lung tumors (22 small cell lung carcinomas, 25 squamous cell carcinomas, and 21 adenocarcinomas). We also studied the role of 8p deletions in lung cancer pathogenesis by examining 95 microdissected normal epithelium and preneoplastic samples from 11 surgically resected squamous cell lung carcinomas and from 58 bronchoscopy biopsy samples obtained from 31 current and former smokers. High frequencies of deletions at 8p21-23 regions were detected in lung cancer cell lines and in primary lung tumors. Deletions commenced early during the multistage development of lung cancer at the hyperplasia/metaplasia stage in cancer patients and in smokers without cancer. Allelic deletions persisted for up to 48 years after smoking cessation. There was a progressive increase of the overall 8p21-23 loss of heterozygosity frequency and in the size of the deleted region with increasing severity of histopathological preneoplastic changes. In epithelial samples from resected squamous cell lung carcinomas, we compared the presence of loss of heterozygosity at 8p21-23 with deletions at chromosomes 3p and 9p. Of interest, the pattern of deletions was not random, and 8p21-23 allelic losses always followed 3p deletions and usually followed 9p deletions. We conclude that 8p21-23 deletions are frequent and early events in the pathogenesis of lung carcinomas.

Adult↗
PubMed1999

Early diagnosis of lung cancer.

Recent advances in computer-assisted image analysis, tumor biology, PCR-based assays, fluorescence bronchoscopy, spiral CT, endobronchial treatment modalities, and chemoprevention make it possible to re-examine the strategy of early detection in the comprehensive management of lung cancer.

Humans↗
PubMed1999

Critically ill medical patients, their demographics and outcome.

There are few reports describing the demographic details and outcome of noncoronary medical patients on adult general intensive care units. It is not known how medical patients differ from other critically ill patients and how this may influence their outcome. Consequently, we recorded the demographic details of 374 critically ill medical patients and followed their survival for up to 3 years. Patients referred from medical specialties are younger, more severely ill and suffer a higher severity-of-illness-adjusted intensive care unit mortality than other patients. The short-term survival of medical patients is poor with a median survival of 40 days. Twenty per cent of medical patients die after discharge from intensive care but before 40 days. However, the long-term survival of medical patients is better than other patients and almost as good as the general population. Further research is required to identify those patients who are likely to survive beyond 40 days.

APACHE↗
PubMed1999

Validation of an enzymatic method for the determination of trace levels of ethanol.

The validation of an enzymatic method for the determination of trace levels of ethanol is described. The method, which involves the use of alcohol dehydrogenase (ADH) and nicotinamide adenine dinucleotide (NAD+), was validated according to USP 23 requirements. The validation parameters, including linearity and range, accuracy (recovery), precision, ruggedness, limit of detection (LOD), and limit of quantitation (LOQ), were established satisfactorily. The method is specific and selective for ethanol except in the presence of propyl, isopropyl, or butyl alcohol.

Alcohol Dehydrogenase↗
PubMed1999

Defective induction of the transcription factor interferon-stimulated gene factor-3 and interferon alpha insensitivity in human trophoblast cells.

During pregnancy, trophoblast cells of the placenta contact maternal immune cells and yet are protected from attack. One mechanism that may account for this is that trophoblasts show altered expression of major histocompatibility complex (MHC) antigens. The gene for human leukocyte antigen G (HLA-G), a nonclassical gene, is expressed at high levels in trophoblast. Unlike other MHC class I genes, the HLA-G gene lacks an interferon (IFN) response element. Moreover, we demonstrate here that IFN, which regulates classical MHC class I genes in other cell types, does not affect these genes in trophoblast, owing to inactivation of an IFNalpha signaling pathway. Trophoblast cells (JEG-3 and JAR) were found to be selectively refractory to IFN. Specifically, although IFNalpha induced the transcription factors STAT1, STAT2, and IFN regulatory factor-1, and a protective response against encephalomyocarditis virus, it failed to protect the cells from vesicular stomatitis virus, activate a transfected MHC class I gene promoter, and induce the transcription factor IFN-stimulated gene factor (ISGF)-3. The lack of ISGF3 DNA-binding activity apparently was due to diminished p48/ISGF3gamma subunit activity since ISGF3 DNA-binding activity and IFNalpha induction of MHC class I promoter activity were reconstituted by p48/ISGF3gamma supplementation. These data indicate that a specific IFN signaling pathway is inactive in JEG-3 trophoblast cells because of altered activity of p48/ISGF3gamma, and they suggest IFN insensitivity as a mechanism that may help promote feto-placental survival.

Choriocarcinoma↗
PubMed1999

Tetracycline and niacinamide: treatment alternatives in ocular cicatricial pemphigoid.

Cicatricial pemphigoid (CP) is one of the subepidermal autoimmune bullous dermatoses in which pathologic separation occurs between the epidermis and dermis. Ocular findings characteristic of CP include conjunctival cicatrization, subepithelial fibrosis, and symblepharon formation, which may progress to blindness. Ocular CP (OCP) is usually treated with steroids or immunosuppressive agents, which are problematic in and of themselves within the elderly population, which is most often afflicted with OCP. We describe the utility and effectiveness of therapy with tetracycline and niacinamide in elderly patients with OCP.

Administration, Oral↗
PubMed1998

Engraftment of severe combined immune deficient mice receiving allogeneic bone marrow via In utero or postnatal transfer.

Although in utero transplantation (IUT) has been shown to be effective in treating human severe combined immune deficiency (SCID), the relative merit of IUT as compared with postnatal bone marrow transplantation (BMT) for SCID is unknown. Therefore, comparative studies were undertaken in mice to determine the engraftment outcome in these two settings. Because T-cell depletion (TCD) reduces graft-versus-host disease (GVHD) severity but compromises alloengraftment, studies were performed with TCD or non-TCD BM and GVHD risk was assessed using a tissue scoring system and by the adoptive transfer of splenocytes from engrafted mice into secondary recipients. Non-SCID recipients received pre-BMT irradiation to simulate those circumstances in which conditioning is required for alloengraftment. IUT recipients of non-TCD and especially TCD BM cells in general had higher levels of donor T-cell and myeloid peripheral blood (PB) engraftment than nonconditioned SCID recipients. Increased TCD or non-TCD BM cell numbers in adult SCID recipients resulted in similar levels of PB engraftment as IUT recipients. However, under these conditions, mean GVHD scores were higher than in IUT recipients. The majority of adoptive transfer recipients of splenocytes from IUT recipients were GVHD-free, consistent with the in vitro evidence of tolerance to host alloantigens. Total body irradiation (TBI)-treated mice that had the highest engraftment had evidence of thymic damage as denoted by a higher proportion of thymic and splenic T cells with a memory phenotype as compared with IUT recipients. IUT mice had vigorous thymic reconstitution by 3 weeks of age. Our data indicate that IUT has a number of advantages as compared with postnatal BMT. Future studies examining the fine specificity of immunoreconstitution in IUT versus postnatal BMT are indicated.

Adoptive Transfer↗
PubMed1998

Rational design and combinatorial evaluation of enzyme inhibitor scaffolds: identification of novel inhibitors of matrix metalloproteinases.

The discovery of a novel series of heterocyclic matrix metalloproteinase (MMPs) inhibitors is described. Published crystal structures of peptidyl hydroxamates bound to MMPs were the basis for the rational design of diketopiperazine (DKP) inhibitors. Combinatorial libraries were prepared and evaluated for their ability to inhibit collagenase-1, stromelysin-1, and gelatinase-B substrate hydrolysis. Deconvolution of active pools resulted in the identification of potent inhibitors (IC50's < 100 nM) of collagenase-1 and gelatinase-B, with the most potent inhibitor exhibiting an IC50 of 30 nM against collagenase-1. A description of the combinatorial evaluation process, as well as initial SAR interpretation for this novel series, is provided.

Diketopiperazines↗
PubMed1998

Malignancy associated changes in bronchial epithelial cells and clinical application as a biomarker.

A total of 74 bronchial brushing specimens, 24 from patients with advanced stage cancer, eight from patients with CIS, 31 from patients with atypical metaplasia and 11 from normal subjects were examined for the existence of malignancy associated changes (MAC). Conventional fiberoptic bronchoscopy and fluorescence endoscopy was carried out on every case. Each case was classified according to the highest grade of abnormality diagnosed by bronchial biopsy of the suspect areas. During the endoscopy examination, a bronchial brushing specimen was obtained from a visually normal area very remote from the abnormal area as possible such as the opposite lung or another lobe. The bronchial brushing specimens were fixed, mounted and stained by a DNA specific method and approximately 1500 images of individual nuclei per case were captured by an automated high resolution image cytometry. For each of these images, more than 100 nuclear features such as size, shape and chromatin spatial organization were calculated. Discriminant function analysis revealed nuclear features which differentiated between normal bronchial cell nuclei from the normal subjects and ostensively normal nuclei (MAC cell nuclei) from the lung cancer patients. The best discrimination was achieved when the frequency of individual cells expressing MAC was 50% or greater. With this threshold, 75% of the patients with invasive cancer and CIS were correctly classified. Fifty percent of those with severe or moderate atypia and 35% with mild atypia were also MAC positive. The frequency of cells expressing MAC also increased as the degree of abnormality of the groups increased. MAC may be a useful criterium to determine biological behavior of the intra-epithelial (pre-invasive) neoplasia.

Aged↗
PubMed1998

Localization of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy.

BACKGROUND: In the treatment of lung cancer, the best outcome is achieved when the lesion is discovered in the intraepithelial (preinvasive) stage. However, intraepithelial neoplastic lesions are difficult to localize by conventional white-light bronchoscopy (WLB). OBJECTIVE: To determine if autofluorescence bronchoscopy, when used as an adjunct to WLB, could improve the bronchoscopist's ability to locate and remove biopsy specimens from areas suspicious of intraepithelial neoplasia as compared with WLB alone. METHOD: A multicenter clinical trial was conducted in seven institutions in the United States and Canada. WLB followed by fluorescence examination with the light-induced fluorescence endoscopy (LIFE) device was performed in 173 subjects known or suspected to have lung cancer. Biopsy specimens were taken from all areas suspicious of moderate dysplasia or worse on WLB and/or LIFE examination. In addition, random biopsy specimens were also taken from other parts of the bronchial tree. RESULTS: The relative sensitivity of WLB + LIFE vs WLB alone was 6.3 for intraepithelial neoplastic lesions and 2.71 when invasive carcinomas were also included. The positive predictive value was 0.33 and 0.39 and the negative predictive value was 0.89 and 0.83, respectively, for WLB+LIFE and WLB alone. CONCLUSION: Autofluorescence bronchoscopy, when used as an adjunct to standard WLB, enhances the bronchoscopist's ability to localize small neoplastic lesions, especially intraepithelial lesions that may have significant implication in the management of lung cancer in the future.

Adult↗
PubMed1997

Molecular damage in the bronchial epithelium of current and former smokers.

BACKGROUND: Most lung cancers are attributed to smoking. These cancers have been associated with multiple genetic alterations and with the presence of preneoplastic bronchial lesions. In view of such associations, we evaluated the status of specific chromosomal loci in histologically normal and abnormal bronchial biopsy specimens from current and former smokers and specimens from nonsmokers. METHODS: Multiple biopsy specimens were obtained from 18 current smokers, 24 former smokers, and 21 nonsmokers. Polymerase chain reaction-based assays involving 15 polymorphic microsatellite DNA markers were used to examine eight chromosomal regions for genetic changes (loss of heterozygosity [LOH] and microsatellite alterations). RESULTS: LOH and microsatellite alterations were observed in biopsy specimens from both current and former smokers, but no statistically significant differences were observed between the two groups. Among individuals with a history of smoking, 86% demonstrated LOH in one or more biopsy specimens, and 24% showed LOH in all biopsy specimens. About half of the histologically normal specimens from smokers showed LOH, but the frequency of LOH and the severity of histologic change did not correspond until the carcinoma in situ stage. A subset of biopsy specimens from smokers that exhibited either normal or preneoplastic histology showed LOH at multiple chromosomal sites, a phenomenon frequently observed in carcinoma in situ and invasive cancer. LOH on chromosomes 3p and 9p was more frequent than LOH on chromosomes 5q, 17p (17p13; TP53 gene), and 13q (13q14; retinoblastoma gene). Microsatellite alterations were detected in 64% of the smokers. No genetic alterations were detected in nonsmokers. CONCLUSIONS: Genetic changes similar to those found in lung cancers can be detected in the nonmalignant bronchial epithelium of current and former smokers and may persist for many years after smoking cessation.

Adult↗
PubMed1997

Telomerase expression in respiratory epithelium during the multistage pathogenesis of lung carcinomas.

To investigate the role of telomerase in the multistage pathogenesis of lung cancer, we examined 205 fresh and archival tissue samples obtained from 40 patients, 34 of whom had invasive lung carcinoma, 5 with carcinoma in situ (CIS) without invasion, and 1 without lung carcinoma. We analyzed samples for telomerase enzyme activity using the semiquantitative PCR-based telomeric repeat amplification protocol assay (131 samples) or by a radioactive in situ hybridization method for expression of the RNA component of human telomerase (hTR; 74 samples). A subset of samples was assayed by both methods, and the correlation was excellent (30 of 36; 83%). With the exception of a carcinoid tumor and a necrotic squamous cell carcinoma, all tumor cells were moderate to strongly positive for both hTR and telomerase activity, except for foci of keratinization in squamous cell carcinomas. Telomerase positivity, with weak enzyme activity and/or low hTR expression, was present in basal epithelial cells of large bronchi, both histologically normal (26%) and hyperplastic (71%), and in 23% of peripheral lung samples (in epithelium of small bronchi and bronchioles or lymphoid aggregates). More advanced epithelial changes (metaplasia, dysplasia, and CIS) were associated with telomerase dysregulation. Dysregulation in preneoplasia was manifested in three ways: almost all such lesions expressed hTR, although enzyme activity levels were several-fold lower than in the corresponding invasive tumors; cells throughout these multilayered processes expressed hTR; and intense, focal up-regulation of hTR occurred in CIS foci in the vicinity of invasive cancers. Alveolar cells and areas of atypical adenomatous hyperplasia (possible precursor lesions for peripheral adenocarcinomas) were negative. Our studies demonstrate that dysregulation of telomerase occurs early in the multistage pathogenesis of bronchogenic lung carcinomas and that intense focal localized hTR expression in CIS may indicate imminent invasion.

Carcinoma↗
PubMed1997

Molecular follow-up of a preinvasive bronchial lesion treated by 13-cis-retinoic acid.

We report the result of the follow-up molecular analysis of a bronchial carcinoma in situ treated by 13-cis-retinoic acid, which relapsed 9 months after cessation of drug therapy. Loss of heterozygosity at 3p21 and 9p22 genomic sequences were assessed by polymerase chain reaction (PCR) after microdissection of the dysplastic epithelia. Despite a transient regression of the lesion to a lower grade with treatment, molecular analysis showed the persistence of a 3p and 9p deletion in all the bronchial biopsies taken in the same area during a 1 year follow-up, preceding by 9 months the recurrence of the carcinoma in situ. Our findings suggest that molecular follow-up analysis can help to assess the persistence of a malignant clone within a bronchial epithelium that displays a more benign phenotype under retinoid treatment on follow-up. Molecular analysis may be of great importance to evaluate the effects of chemoprevention and to determine the duration of such intervention in responder patients.

Bronchial Neoplasms↗
PubMed1997

Sputum screening by quantitative microscopy: a reexamination of a portion of the National Cancer Institute Cooperative Early Lung Cancer Study.

OBJECTIVE: To investigate the hypothesis that image cytometry of sputum specimens can detect squamous carcinoma without requiring visually abnormal cells. DESIGN: The sensitivity and specificity of image cytometry were evaluated in a case-control study. MATERIAL AND METHODS: Seventy-three sputum slides from the Mayo portion of the National Cancer Institute Cooperative Early Lung Cancer Study were restained by a modified Feulgen method. We examined 40 slides from 9 patients in whom squamous carcinoma developed and 33 slides from 11 patients in whom no cancer developed during a follow-up of at least 5 years. Images of normal epithelial nuclei were collected by using an automated image cytometer. Discriminant analysis was used to determine differences in DNA distribution of normal nuclei in sputum specimens from noncancer patients versus normal nuclei in sputum samples from patients in whom carcinoma developed. RESULTS: By using features based on DNA distribution, 74% correct classification of nuclei was possible without human review of the material and without the use of visually abnormal nuclei. A receiver operating characteristic curve demonstrated sensitivities and specificities, including 40% sensitivity and 90% specificity. CONCLUSION: Although this study was limited to 20-year-old slides and squamous cell carcinoma, automated image cytometry detected a substantial proportion of patients with squamous cell cancer without using visually abnormal nuclei.

Aged↗