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Biomedical subjects

S Markowitz

Publications and source records attributed to S Markowitz.

At least 55 records · Page 3Linked to original sources
PubMed1994

Paradoxical inhibition of solid tumor cell growth by bcl2.

The BCL2 gene product has been demonstrated to prevent apoptosis and provide a selective growth advantage to many cell types. We report an unexpected effect of bcl2 expression on the in vitro growth of several solid tumor cell lines. Expression of bcl2 in these cell lines resulted in growth inhibition similar to that seen with p53. In contrast, a COOH-terminal deletion mutant of bcl2 was unable to suppress growth. Thus, the bcl2 protein may exert distinct biological effects in different cell types.

Base Sequence↗
PubMed1993

Amplification of cyclin genes in colorectal carcinomas.

The genetic status of cyclin genes was examined in a panel of 47 colorectal carcinoma cell lines. Cyclin D2 was found to be amplified in one tumor and cyclin E in another. In each of the two cases, the amplified cyclin gene was overexpressed at the protein or mRNA level. Cyclin D1, previously shown to be amplified in breast and other tumors, was not amplified in these cancers. These data suggest that a variety of cyclin genes can play a role in human tumorigenesis and that cyclins D2 and E are particularly important in a subset of colorectal neoplasms.

Carcinoma↗
PubMed1993

The APC gene product in normal and tumor cells.

The APC gene has been found to be mutated during the development of sporadic colorectal tumors as well as in the germ line of familial adenomatous polyposis patients. To facilitate the characterization of both normal and mutant APC protein, a series of monoclonal and polyclonal antibodies specific for the APC protein was produced. When lymphoblastoid cell lines derived from seven familial adenomatous polyposis patients with known mutations were analyzed by Western blot, an approximately 300-kDa protein corresponding to the predicted size of full-length APC was detected in all 7 cell lines. In addition, truncated APC proteins corresponding to the product of the known mutated alleles could be detected in 4 of the 7 lines. Similar analysis of 23 colon carcinoma and 9 adenoma cell lines revealed truncated proteins in 24 (75%) of the cell lines. Moreover, 26 (81%) of the colon tumor lines were totally devoid of the normal, full-length protein. In contrast, Western blot analysis of 40 cell lines derived from sporadic tumors of other organs detected only full-length APC. Immunohistochemical analysis of APC in normal colonic mucosa revealed cytoplasmic staining with more intense staining in the basolateral margins of the epithelial cell. This staining was markedly increased in the upper portions of the crypts, suggesting an increased level of expression with maturation. These studies provide some initial clues to the function of the cytoplasmic protein APC and demonstrate the feasibility of identifying APC mutations by direct analysis of the APC protein.

Adenoma↗
PubMed1993

Eastern equine encephalomyelitis with hematuria and bladder dysfunction.

We have described a patient with eastern equine encephalomyelitis acquired in central Virginia, an area in which EEE is not ordinarily considered endemic. The unusual presenting features of our patient's encephalomyelitis were bladder dysfunction and hematuria as well as prominent mood and affect disturbances, which are usually seen in association with St. Louis encephalitis. The diagnosis of arboviral encephalomyelitis was considered because of the severe CNS manifestations and spinal cord involvement, and was facilitated by the detection of specific IgM antibodies in both the CSF and serum. A high index of suspicion is required to make the diagnosis of EEE, especially in nonendemic areas.

Adult↗
PubMed1992

The influence of inhibitory afferents on the development of postsynaptic dendritic arbors.

The growth and maintenance of dendritic form is dependent on normally functioning excitatory afferents. We have now examined the development of dendritic arbors in the gerbil lateral superior olive (LSO), following contralateral cochlear removal at postnatal day 7, a manipulation that substantially eliminates driven inhibitory transmission. Previous studies have demonstrated that the morphology of LSO dendritic arbors varies with tonotopic position and becomes more restricted with age. The presumed decrease of inhibitory transmission in the contralateral LSO resulted in a hypertrophic response. Quantification of Golgi-impregnated neurons revealed that dendrites had a significantly greater number of branch points, and their arbors were more spread out along the frequency axis compared to normal. This was especially apparent in the high frequency projection region where the glycine receptor density is known to be 4-fold higher than in the low frequency projection region. A measure of LSO nucleus size, cross-sectional area, was identical to control values, indicating no overt signs of degenerative phenomena. Cochlear ablation resulted in a significant atrophy of the ipsilateral LSO, with significant effects on dendritic structure. We conclude that decreased inhibitory transmission during development does not lead to a net degenerative response. Rather, the postsynaptic neurons exhibit a hypertrophic phenotype that may be due to the persistence of an immature state. These results indicate that activity-dependent morphogenetic events are a consequence of both excitatory and inhibitory synaptic transmission.

Afferent Pathways↗
PubMed1992

Reevaluating the carcinogenicity of ortho-toluidine: a new conclusion and its implications.

The aromatic amine ortho-toluidine has been recognized by IARC as an animal carcinogen for the past decade. Three recent epidemiological studies of worker populations have now implicated this chemical as a human bladder carcinogen. In a study by E. Ward, A. Carpenter, S. Markowitz, D. Roberts, and W. Halperin ((1991), J. Natl. Cancer Inst. 83, 501-506), workers definitely exposed to ortho-toluidine for at least 10 years experienced a Standardized Incidence Ratio (SIR) of 27.2 (90% CI = 11.8-53.7). The other major exposure was to aniline, which significant epidemiological studies have failed to confirm as a human carcinogen. In retrospect, studies by G. F. Rubino, G. Scansetti, G. Piolatto ((1982) Environ. Res. 27, 241-254) and M. J. Stasik ((1988) Int. Arch. Occup. Environ. Health 60, 21-24) also support the hypothesis that ortho-toluidine is a human bladder carcinogen. Animal studies of both ortho-toluidine and its possible confounders in these epidemiological investigations further confirm this hypothesis. When evaluated in a suitably comprehensive way, according to the traditional standards for assessing causality outlined by A. B. Hill ((1977) A Short Textbook of Medical Statistics, pp. 288-294, Lippincott, Philadelphia) the evidence that ortho-toluidine causes human bladder cancer has become much more conclusive. In this case, animal tests have proven a good predictor of human carcinogenicity.

Animals↗
PubMed1992

Effect of occupational and recreational activity on the risk of colorectal cancer among males: a case-control study.

Epidemiological studies have consistently demonstrated that either occupational or recreational physical activity is protective against colon cancer. However, it is unclear whether recreational activity is similarly protective among those who engage in high or low occupational activity. We therefore compared 440 male cases of colorectal cancer with 1164 male hospital patients. Occupational activity was defined according to job title, while recreational activity was assessed by questionnaire for three different periods of life. Occupational activity was protective with respect to colorectal cancer irrespective of whether one engaged in recreational activity at any different period of life. In contrast, recreational activity, performed at 20-44 years of age appeared to decrease colon cancer risk by 10-25% irrespective of the intensity of job activity. The present results suggest that, although we observed a larger effect with occupational activity than with recreational activity, middle-aged men may reduce their risk of colorectal cancer if they exercise when they are not working. These findings need to be confirmed in other populations.

Adolescent↗
PubMed1992

Serum growth factors and oncoproteins in firefighters.

Firefighters are potentially at increased risk for cancer and non-malignant respiratory disease due to their toxic exposures on the job. Growth factors and oncogene proteins are thought to play a role in the development of various malignancies and pulmonary fibrotic diseases. Therefore, a cohort of firefighters and matched controls have been screened for the presence of nine different growth factors and oncoproteins using an immunoblotting assay. Fourteen of the firefighters were found to be positive for beta-transforming growth factor (beta-TGF) related proteins compared to no positives in the controls (P = 0.0017). These results suggest that beta-TGF may be a possible biomarker for monitoring firefighters and other exposed workers for the potential development of cancer or non-malignant respiratory disease.

Amino Acid Sequence↗
PubMed1992

Lung cancer and occupation: results of a multicentre case-control study.

The objective of the current study was to estimate the risk of lung cancer attributable to occupational factors and not due to tobacco. At 24 hospitals in nine metropolitan areas in the United States, 1793 male lung cancer cases were matched for race, age, hospital, year of interview, and cigarette smoking (never smoker, ex-smoker, smoker (1-19 and > or = 20 cigarettes per day)) to two types of controls (cancer and non-cancer hospital patients). Information on usual occupation, exposure to specific potential carcinogens, and cigarette smoking was obtained by interview. Risk of lung cancer was increased significantly for electricians; sheetmetal workers and tinsmiths; bookbinders and related printing trade workers; cranemen, derrickmen, and hoistmen; moulders, heat treaters, annealers and other heated metal workers; and construction labourers. All of these occupations are potentially exposed to known carcinogens. Odds ratios (ORs) were increased for exposure to coal dust (adjusted OR = 1.5; 95% confidence interval (95% CI) 1.1-2.1). After stratification, this association was statistically significant only after 10 or more years of exposure. Lung cancer was also related to exposure to asbestos (adjusted OR = 1.8; 95% CI 1.5-2.2). The ORs increased with increasing duration of exposure to asbestos for all smoking categories except for current smokers of 1-19 cigarettes per day. The statistical power to detect ORs among occupations that were previously reported to be at increased risk of lung cancer but that failed to show an OR of at least 1.5 in the current study was small. The cumulative population attributable risk (PAR) of lung cancer due to occupation was 9.2%. It is concluded that occupational factors play an important part in the development of lung cancer independently of cigarette smoking. Because occupations at high risk of lung cancer were under-represented, the cumulative PAR of the present study is likely to be an underestimate of the true contribution of occupation to risk of lung cancer.

Case-Control Studies↗
PubMed1991

Excess number of bladder cancers in workers exposed to ortho-toluidine and aniline.

A retrospective cohort study of the incidence of bladder cancer was conducted in response to a union request for an evaluation of a possible excess number of cases of bladder cancer at a chemical plant in western New York State. Workers at the plant were exposed to two potential bladder carcinogens--ortho-toluidine (o-toluidine) and aniline. Incidence rates of bladder cancer among workers at the plant were compared with those of the population of New York State (excluding New York City). Among all 1749 workers at the plant, 13 cases of bladder cancer were observed versus 3.61 expected [standardized incidence ratio (SIR) = 3.60; 90% confidence interval (CI) = 2.13-5.73]. Among the 708 workers who worked in areas in which o-toluidine and aniline were used, 7 cases were observed versus 1.08 expected (SIR = 6.48; 90% CI = 3.04-12.2). Among the 288 maintenance, shipping, and janitorial workers thought to have been possibly exposed, 4 cases were observed versus 1.09 expected (SIR = 3.66; 90% CI = 1.25-8.37). Among the remaining 753 workers who were probably not exposed, 2 bladder cancers were observed versus 1.43 expected (SIR = 1.39; 90% CI = 0.25-4.39). Increased risk of bladder cancer was strongly associated with increased duration of employment in the department where o-toluidine and aniline were used (P less than .001). Among workers with 10 or more years of employment in the department, the SIR was 27.2 (90% CI = 11.8-53.7). o-Toluidine is an animal carcinogen more potent than aniline and is known to produce bladder tumors in rats; hence, it is more likely that o-toluidine is responsible for the observed excess number of cases of bladder cancer, although aniline may have played a role.

Adult↗
PubMed1991

Lectinophagocytosis of encapsulated Klebsiella pneumoniae mediated by surface lectins of guinea pig alveolar macrophages and human monocyte-derived macrophages.

Macrophages express a mannose/N-acetylglucosamine-specific lectin which serves as a receptor for nonopsonic phagocytosis of mannose-coated particles. We have examined the binding to guinea pig alveolar macrophages in a serum-free medium of 16 Klebsiella pneumoniae serotypes and of the capsular polysaccharides isolated from 7 of these serotypes. Only five polysaccharides containing the repeating sequence Man alpha 2/3Man or L-Rha alpha 2/3-L-Rha bound to the macrophages. Of the 11 bacterial serotypes expressing such disaccharides in their capsular polysaccharides, 7 bound efficiently, 2 bound poorly, and 2 did not bind at all. No binding occurred with five serotypes lacking these disaccharides. Binding of the bacteria was inhibited by homologous and heterologous capsular polysaccharides that contain the disaccharide sequences, by mannan, and by (Man)25BSA (where BSA is bovine serum albumin). Man alpha 2/3Man-containing oligosaccharides were potent inhibitors compared with monosaccharides. Binding was dependent on Ca2+, modulated by cultivating the macrophages on mannan-coated surfaces, and increased in human monocyte-derived macrophages compared with monocytes. The bulk of the bacteria bound to the macrophages was internalized and killed. The data taken together suggest that Klebsiella pneumoniae cells undergo lectinophagocytosis mediated by capsular disaccharides recognized by the mannose/N-acetylglucosamine-specific lectin of macrophages. This may enhance clearance of the organisms from the serum-poor environment of the lung.

Animals↗
PubMed1990

p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis.

Coordinate loss of one copy of the p53 gene and mutation of the remaining copy occur in colorectal carcinomas and in many other human malignancies. However, the prevalence of p53 gene mutations in carcinomas which maintain both parental copies of p53 has not previously been evaluated. Moreover, it is not known whether p53 gene mutations are limited to malignant tumors or whether they can also occur in benign neoplasms. To answer these questions, a total of 58 colorectal tumors have been examined; in each tumor, allelic losses were assessed using restriction fragment length polymorphisms and p53 gene mutations were assessed by sequencing cloned polymerase chain reaction products. The following conclusions emerged: (a) p53 gene mutations occurred but were relatively rare in adenomas, regardless of size and whether the adenomas were derived from patients with familial adenomatous polyposis; (b) In carcinomas as well as in adenomas, p53 gene mutations were infrequently observed in tumors which contain both copies of chromosome 17p (17% of 30 tumors), while tumors which lost one copy of chromosome 17p usually had a mutation in the remaining p53 allele (86% of 28 tumors); (c) p53 gene mutations were found at similar frequencies in primary tumor samples and in cell lines derived from tumors. These and other data suggest that the rate limiting step in p53 inactivation is point mutation and that once a mutation occurs, loss of the remaining wild-type allele rapidly follows. Both mutations and allelic losses generally occur near the transition from benign to malignant growth, and the p53 gene may play a causal role in this progression.

Adenoma↗
PubMed1990

Suppression of human colorectal carcinoma cell growth by wild-type p53.

Mutations of the p53 gene occur commonly in colorectal carcinomas and the wild-type p53 allele is often concomitantly deleted. These findings suggest that the wild-type gene may act as a suppressor of colorectal carcinoma cell growth. To test this hypothesis, wild-type or mutant human p53 genes were transfected into human colorectal carcinoma cell lines. Cells transfected with the wild-type gene formed colonies five- to tenfold less efficiently than those transfected with a mutant p53 gene. In those colonies that did form after wild-type gene transfection, the p53 sequences were found to be deleted or rearranged, or both, and no exogenous p53 messenger RNA expression was observed. In contrast, transfection with the wild-type gene had no apparent effect on the growth of epithelial cells derived from a benign colorectal tumor that had only wild-type p53 alleles. Immunocytochemical techniques demonstrated that carcinoma cells expressing the wild-type gene did not progress through the cell cycle, as evidenced by their failure to incorporate thymidine into DNA. These studies show that the wild-type gene can specifically suppress the growth of human colorectal carcinoma cells in vitro and that an in vivo-derived mutation resulting in a single conservative amino acid substitution in the p53 gene product abrogates this suppressive ability.

Cell Division↗
PubMed1989

The development of neurogenic plasma extravasation in the rat dura mater does not depend upon the degranulation of mast cells.

Mast cells were visualized in stretch preparations of the rat dura mater and were found mostly in relation to small and large blood vessels. The overall number of dural mast cells was unaffected by electrical trigeminal or chemical deafferentation. As in other tissues, mast cell degranulation increased at sites of local injury (electrode penetration) or after systemic treatment with compound 48/80. However, mast cells did not degranulate following electrical trigeminal stimulation, or after injection of drugs (capsaicin or substance P) which promote plasma extravasation in the dura. Furthermore, pretreatment with a mast cell stabilizer (sodium dicromoglycate) or with large doses of H1 and H2 histamine receptor blockers (mepyramine and cimetidine), did not block electrically- or chemically-induced neurogenic plasma extravasation (NPE). Daily pretreatment with 48/80 however completely attenuated or abolished NPE. Taken together these data suggest that as assessed by the extrusion of metachromatic granules, mast cells are not essential to the development of neurogenic inflammation within the rat dura mater. However, these findings cannot exclude the possibility that mast cells may amplify or modulate this process.

Animals↗
PubMed1989

Current magnitude of occupational disease in the United States. Estimates from New York State.

The data from our study indicate that the magnitude of occupational disease in New York State is considerable, and that a detailed and comprehensive plan must be initiated and implemented if occupational disease is to be controlled. New York State contains slightly less than 10% of the nation's workforce. A direct linear extrapolation of findings in New York State cannot be made to derive estimates of the national burden of work-related illness. Nevertheless, a crude estimate of the national magnitude of occupational disease can be derived from the New York experience. Such extrapolation provides a crude estimate of 50,000-70,000 deaths each year from occupational disease and of 350,000 new cases of occupational illness. These numbers are distressingly similar to the annual estimates of 100,000 deaths and 400,000 cases of occupational illness developed almost 15 years ago by Ashford. Clearly substantial progress remains to be made.

Humans↗
PubMed1989

Expression of the ErbA-beta class of thyroid hormone receptors is selectively lost in human colon carcinoma.

Members of the erbA gene family are involved both in control of differentiation and in neoplasia. V-erbA, a retroviral oncogene, blocks avian erythroid differentiation. V-erbA-related transcripts are physiologically expressed in multiple normal tissues. They encode a family of transcriptional regulatory factors, some of which are thyroid hormone receptors. In man, two genes, erbA-alpha and erbA-beta, are transcriptionally active. We examined expression of erbA-related transcripts in normal and neoplastic colon. In normal colon mucosa, as well as in a colon polyp and in a colon polyp cell line, three characteristic erbA-related transcripts were consistently found. One transcript of 6 kb was erbA-beta related. Two transcripts of 2.7 and 5.2 kb were erbA-alpha related. In eight patients' colon carcinomas expression of the 6-kb erbA-beta transcript was absent or markedly diminished when compared with the same patients' noninvolved mucosa. In contrast, expression of the two erbA-alpha transcripts was the same in both colon carcinoma and noninvolved mucosa. No evidence was found of erbA-beta gene deletion in any of the tumors lacking erbA-beta expression. These data suggest that selective loss of normally present erbA-beta gene expression accompanies malignant transformation of the colonic epithelial cell.

Cell Line↗