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Biomedical subjects

L Grossman

Publications and source records attributed to L Grossman.

At least 37 records · Page 2Linked to original sources
PubMed1997

Epidemiology of ultraviolet-DNA repair capacity and human cancer.

The following conclusions are derived from an epidemiological study. Reduced repair of ultraviolet (UV)-induced DNA damage contributes directly to basal cell carcinoma (BCC) in individuals with prior sunlight overexposure. A family history of BCC is a predictor of low DNA repair. Repair of UV-damaged DNA declines at a fixed rate of approximately 1% per annum in noncancerous controls. The DNA repair differences between young BCC cases and their controls disappear as they age. Hence, BCC, in terms of DNA repair, is a premature aging disease. The persistence of photochemical damage because of reduced repair results in point mutations in the p53 gene and allelic loss of the nevoid BCC gene (Gorlin's syndrome) located on chromosome 9q. The fact that environmental vulnerability is gender oriented implicates hormones in regulating DNA repair. Xeroderma pigmentosum appears to be a valid paradigm for the role of DNA repair in BCC in the general population.

Aging↗
PubMed1996

The topodynamics of incision of UV-irradiated covalently closed DNA by the Escherichia coli Uvr(A)BC endonuclease.

The Escherichia coli Uvr(A)BC endonuclease (Uvr(A)BC) initiates nucleotide excision repair of a large variety of DNA damages. The damage recognition and incision steps by the Uvr(A)BC is a complex process utilizing an ATP-dependent DNA helix-tracking activity associated with the UvrA2B1 complex. The latter activity leads to the generation of highly positively supercoiled DNA in the presence of E. coli topoisomerase I in vitro. Such highly positively supercoiled DNA, containing ultraviolet irradiation-induced photoproducts (uvDNA), is resistant to the incision by Uvr(A)BC, whereas the negatively supercoiled and relaxed forms of the uvDNA are effectively incised. The E. coli gyrase can contribute to the above reaction by abolishing the accumulation of highly positively supercoiled uvDNA thereby restoring Uvr(A)BC-catalyzed incision. Eukaryotic (calf thymus) topoisomerase I is able to substitute for gyrase in restoring this Uvr(A)BC-mediated incision reaction. The inability of Uvr(A)BC to incise highly positively supercoiled uvDNA results from the failure of the formation of UvrAB-dependent obligatory intermediates associated with the DNA conformational change. In contrast to Uvr(A)BC, the Micrococcus luteus UV endonuclease efficiently incises uvDNA regardless of its topological state. The in vitro topodynamic system proposed in this study may provide a simple model for studying a topological aspect of nucleotide excision repair and its interaction with other DNA topology-related processes in E. coli.

Adenosine Triphosphatases↗
PubMed1996

The effect of donor age on the processing of UV-damaged DNA by cultured human cells: reduced DNA repair capacity and increased DNA mutability.

Aging in humans carries an increased risk of skin cancer, a disorder linked to somatic mutations in sun damaged skin. DNA repair plays a major role in protection against sun damage. We found an age-related decline in post-UV DNA repair capacity (measured by the ability to repair a UV-treated plasmid (pCMVcat)) of-0.6% per year (p = 0.0001) in cultured primary skin fibroblasts from normal donors from the first to the tenth decade of life. There was a corresponding age-related increase in post-UV mutability (measured as mutations introduced into a transfected, UV-treated plasmid (pSP189)) of +0.6% per year (p = 0.001) in lymphoblastoid cell lines from normal donors of the same age range. This study indicates that aging in humans is associated with decreasing ability to process new UV-induced DNA damage and this age-related reduction in DNA repair capacity and increase in DNA mutability is reflected in cultured skin and blood cells.

Adolescent↗
PubMed1996

RNA polymerase signals UvrAB landing sites.

Transcription when coupled to nucleotide excision repair specifies the location in active genes where preferential DNA repair is to take place. During DNA damage-induced recruitment of RNA polymerase (RNAP), there is a physical association of the beta subunit of Escherichia coli RNAP and the UvrA component of the repair apparatus (G. C. Lin and L. Grossman, submitted for publication). This molecular affinity is reflected in the ability of the RNAP to increase, in a promoter-dependent manner, DNA supercoiling by the UvrAB complex. In the presence of the RNAP, the UvrAB complex is able to bind to promoter regions and to translocate in a 5' to 3' direction along the non-transcribed strand. As a consequence of this helicase-catalyzed translocation, preferential incision of DNA damaged sites occurs downstream on the transcribed strand. Because of the helicase directionality, the initial binding of the UvrAB complex to the transcribed strand would inevitably lead to its collision with the RNAP. These results imply that the RNAP-induced DNA structure in the vicinity of the transcription start site signals a landing or entry site for the UvrAB complex on DNA.

Adenosine Triphosphatases↗
PubMed1996

The binding of UvrAB proteins to bubble and loop regions in duplex DNA.

Based on the binding of the UvrAB complex to a promoter region in transcription open complexes (Ahn, B., and Grossman, L. (1996) J. Biol. Chem. 271, 21453-21461) and the requirement of a single-stranded region for UvrAB helicase activity, we examined the binding of UvrAB proteins to synthetic bubble or loop regions in duplex DNA and the role of these regions in translocation of the UvrAB complex as well as incision of DNA damage. We found that the UvrAB complex was able to bind to bubble and loop regions with an affinity similar to that for damaged DNA in the absence of RNAP. The preferential recognition and incision of damaged sites by the UvrAB complex was observed downstream of the bubble or loop region in the strand complementary to the strand along which the UvrAB complex translocates. These results imply that the bubble region generated in duplex DNA by RNAP serves as a preferred entry site for the translocation of the UvrAB complex, and that preferential binding and unidirectional translocation of the UvrAB complex predetermine where incision is to occur.

Adenosine Triphosphatases↗
PubMed1996

The effect of epigastric vessel ligation on the vascular territories of the pig rectus muscle.

In a pig model, unilateral ligation of the inferior epigastric vessels caused an initial decrease in normal vascularity, followed by an increase toward normal vascularity, in the inferior portion of the rectus muscle over 42 days. Ligation appeared to dilate the choke vessels between the superior and inferior arterial territories. The results indicate that by ligation of the inferior epigastric vessels, the vascular territory, which is normally tenuous, can undergo a transposition without vascular compromise.

Animals↗
PubMed1996

Measurement of DNA repair deficiency in workers exposed to benzene.

We hypothesize that chronic exposure to environmental toxicants can induce genetic damage causing DNA repair deficiencies and leading to the postulated mutator phenotype of carcinogenesis. To test our hypothesis, a host cell reactivation (HCR) assay was used in which pCMVcat plasmids were damaged with UV light (175, 350 J/m2 UV light), inactivating the chloramphenicol acetyltransferase reporter gene, and then transfected into lymphocytes. Transfected lymphocytes were therefore challenged to repair the damaged plasmids, reactivating the reporter gene. Xeroderma pigmentosum (XP) and Gaucher cell lines were used as positive and negative controls for the HCR assay. The Gaucher cell line repaired normally but XP cell lines demonstrated lower repair activity. Additionally, the repair activity of the XP heterozygous cell line showed intermediate repair compared to the homozygous XP and Gaucher cells. We used HCR to measure the effects of benzene exposure on 12 exposed and 8 nonexposed workers from a local benzene plant. Plasmids 175 J/m2 and 350 J/m2 were repaired with a mean frequency of 66% and 58%, respectively, in control workers compared to 71% and 62% in exposed workers. Conversely, more of the exposed workers were grouped into the reduced repair category than controls. These differences in repair capacity between exposed and control workers were, however, not statistically significant. The lack of significant differences between the exposed and control groups may be due to extremely low exposure to benzene (< 0.3 ppm), small population size, or a lack of benzene genotoxicity at these concentrations. These results are consistent with a parallel hprt gene mutation assay.

Adult↗
PubMed1996

'Psychic reality' and reality testing in the analysis of perverse defences.

The author considers that a large group of clinical phenomena, of which perversion is the most dramatic example, is characterised by the effort to disavow troubling perceptions of reality. In these cases, patients are sometimes characterised--erroneously, in his view-as living in a different 'psychic reality'. He suggests that patients who use perverse defences are able to distinguish fantasy from reality, but they are motivated to refrain from testing cherished fantasies against their own view of reality. Such patients are difficult to work with, because they dismiss painful realities in treatment as readily as any other unwanted perceptions. The author suggests that treatment must focus on the various disavowals of the patient's own perceptions of reality, to the extent that the analyst must be prepared to be a spokesperson for reality. Treatment in which the patient's 'psychic reality' is viewed as a 'kind' of reality rather than addressed as a fantasy can thus collude with perverse defences.

Adult↗
PubMed1996

The analyst's influence.

Analytic work involves a variety of influences the analyst brings to bear on the patient. Our emphasis on the centrality of interpretation tends to neglect consideration of the many ways in which the analyst influences the patient other than by the content of interpretation. The author considers the kinds of influence necessary to establish and maintain an analytic process and a therapeutic alliance. The nature and the role of the analyst's authority are discussed, along with the issue of how the analyst influences the patient to question the analyst's authority.

Communication↗
PubMed1995

DNA repair capacity for ultraviolet light-induced damage is reduced in peripheral lymphocytes from patients with basal cell carcinoma.

Sunlight exposure and certain host factors such as red hair and fair skin are established risk factors for non-melanoma skin cancers. Because deficient DNA repair capacity has contributed to the development of skin cancers in a rare genetic disease, xeroderma pigmentosum, we explored this deficiency as an etiologic factor in a recent population study. We used a new DNA repair assay, the host-cell reactivation, in a clinic-based case-control study to test the hypothesis that reduced DNA repair is the underlying molecular mechanism for the development of sunlight-induced basal cell carcinoma. The peripheral lymphocytes from 88 patients with primary BCC and 135 cancer-free controls were tested for their capacity to repair ultraviolet light-induced DNA damage in a reporter gene, chloramphenicol acetyl transferase. All subjects were between the ages of 20 and 60 years and were frequency matched by age (+/- 5) and sex. Among those who reported frequent sunbathing, poor tanning ability, a history of multiple sunburns, exposure to chemicals, or multiple medical irradiations, the BCC patients had significantly lower DNA repair capacity than controls (p < 0.05). DNA repair capacity was also found substantially lower in the basal cell carcinoma patients who had red hair and light skin (type I). Compared to controls, basal cell carcinoma cases with selected risk factors had a relative decrease in DNA repair capacity of 10-28%. These findings provided evidence that reduced DNA repair capacity is one of the underlying molecular mechanisms for sunlight-induced skin carcinogenesis in the general population.

Adult↗
PubMed1995

DNA repair and epidemiology of basal cell carcinoma.

In a molecular epidemiological study of DNA repair, host reactivation assay was used to measure the DNA repair capacity of cryopreserved lymphocytes from 88 primary basal cell carcinoma (BCC) patients and 135 cancer-free controls. In this study population, reduced repair of ultraviolet radiation-induced DNA damage contributed to the risk of sunlight-induced BCC. A family history of BCC is associated with low DNA repair. Repair of ultraviolet radiation-damaged DNA declines at a rate of approximately 1%/year in noncancerous controls. Reduced DNA repair is more likely seen in young BCC patients, indicating that BCC is a premature aging disease of the skin. The persistence of photochemical damage because of reduced repair results in point mutations in the p53 gene and allelic loss of the nevoid BCC gene located on chromosome 9q. Xeroderma pigmentosum appears to be a valid paradigm for the role of DNA repair in BCC in the general population.

Adult↗
PubMed1994

The use of monoclonal antibodies for studying intermediates in DNA repair by the Escherichia coli Uvr(A)BC endonuclease.

The Escherichia coli Uvr(A)BC endonuclease acts in a progression of several distinct steps accompanied by changes in the conformation of macromolecular constituents, the overall architecture of the complex, and its stoichiometry. In order to probe these structural changes, we generated monoclonal antibodies (mAbs) to Uvr proteins. The anti-UvrA mAb, A2D1, recognizing the N-terminal zinc-finger region of UvrA, and the anti-UvrB mAb, B2E2, having an epitope within the 43 C-terminal amino acids of UvrB, were purified and further characterized. It was found that A2D1 mAb interacts in solution both with UvrA-UvrB and UvrA-DNA complexes in the presence of the requisite ATP. This implies that the N-terminal zinc-finger of UvrA doesn't play a direct role in its interactions with UvrB and DNA. On the other hand, A2D1 does inhibit formation of the UvrB-damaged DNA preincision complex, apparently by preventing UvrB delivery by UvrA. The interaction of B2E2 with UvrA-UvrB and nucleoprotein complexes, including UvrB, suggests that the highly hydrophobic C-terminal domain of UvrB (i) doesn't participate in its interaction with UvrA, (ii) is accessible to this mAb in an intermediate UvrA-UvrB DNA helix-tracking complex, and (iii) seems to be directly involved in the formation of the preincision complex. These conclusions are supported by the finding that the neutralizing effect of A2D1 and B2E2 on the Uvr(A)BC endonuclease is significantly decreased if the preincision complex is preformed prior to mAbs addition.

Antibodies, Monoclonal↗
PubMed1994

DNA repair and susceptibility to basal cell carcinoma: a case-control study.

This study investigated the role of DNA repair in susceptibility to sunlight-induced basal cell carcinoma using a host cell reactivation assay in peripheral lymphocytes. The study included Maryland basal cell carcinoma patients and cancer-free dermatologic controls who had had noncancerous skin disorders diagnosed between 1987 and 1990. Logistic regression models were used to assess the independent effect of the selected variables stratified by DNA repair level, with adjustment for age and family history. Skin type, lifetime number of severe sunburns, and actinic elastosis were also selected as risk factors for basal cell carcinoma. Cryopreserved lymphocytes from 88 cases and 135 controls were used for the DNA repair assay. When data were stratified by DNA repair level and adjusted for age and family history of skin cancer, significantly increased odds ratios associated with lighter skin (odds ratio (OR) = 3.2, 95% confidence interval (CI) 1.5-7.3), six or more severe sunburns in a lifetime (OR = 4.2, 95% CI 1.6-10.7), and moderate or severe actinic elastosis (OR = 4.4, 95% CI 1.5-12.8) were observed in persons with low DNA repair but not in those with high DNA repair. These findings suggest that impaired DNA repair may be a susceptibility factor for sunlight-induced skin cancer in the general public, as it is in patients with xeroderma pigmentosum.

Adult↗