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PubMed1979

Pyrimidine dimer excision in a Bacillus subtilis Uvr- mutant.

A technique which allows the measurement of small numbers of pyrimidine dimers in the deoxyribonucleic acid (DNA) of cells of Bacillus subtilis irradiated with ultraviolet light has been used to show that a strain mutant at the uvr-1 locus is able to excise pyrimidine dimers. Excision repair in this strain was slow, but incision may not be rate limiting because single-strand breaks in DNA accumulate under some conditions. Excision repair probably accounted for a liquid-holding recovery previously reported to occur in this strain. Recombinational exchange of pyrimidine dimers into newly replicated DNA was readily detected in uvr-1 cells, but this exchange did not account for more than a minor fraction of the dimers removed from parental DNA. Excision repair in the uvr-1 strain was inhibited by a drug which complexes DNA polymerase III with DNA gaps. This inhibition may be limited to a number of sites equal to the number of DNA polymerase III molecules, and it is inferred that large gaps are produced by excision of dimers. Because the uvr-1 mutation specifically interferes with excision of dimers at incision sites, it is concluded that the uvr-1 gene product may be an exonuclease which is essential for efficient dimer excision.

Bacillus subtilis↗

PubMed1984

Regeneration of insertionally inactivated streptococcal DNA fragments after excision of transposon Tn916 in Escherichia coli: strategy for targeting and cloning of genes from gram-positive bacteria.

The conjugative transposon Tn916 (15 kilobases), originally identified in Streptococcus faecalis DS16, has been cloned as an intact element on the pBR322-derived vector pGL101 in Escherichia coli. The EcoRI F' (EcoRI F::Tn916) fragment of pAM211 (pAD1::Tn916) was cloned into the single EcoRI site of pGL101 to form the chimera, pAM120, by selecting for the expression of Tn916-encoded tetracycline resistance (Tcr). Interestingly, in the absence of continued selection for Tcr, Tn916 excised from pAM120 at high frequency. This excision event resulted in a plasmid species consisting of the pGL101 vector and a 2.7-kilobase restriction fragment comigrating with the EcoRI F fragment of pAD1 during agarose gel electrophoresis. Filter blot hybridization experiments showed the 2.7-kilobase fragment generated as a result of Tn916 excision to be homologous with the EcoRI F fragment of pAD1. Analogous results were obtained with another chimera, pAM170, generated by ligating the EcoRI D' (EcoRI D::Tn916) fragment of pAM210 (pAD1::Tn916) to EcoRI-digested pGL101. Comparison of the AluI and RsaI cleavage patterns of the EcoRI F fragment isolated after Tn916 excision with those from an EcoRI F fragment derived from pAD1 failed to detect any difference in the two fragments: data in support of a precise Tn916 excision event in E. coli. Subcloning experiments showed that an intact transposon was required for Tn916 excision and located the Tcr determinant near the single HindIII site on Tn916. Although excision occurred with high frequency in E. coli, Tn916 insertion into the E. coli chromosome was a much rarer event. Tcr transformants were not obtained when pAM120 DNA was used to transform a polA1 strain, E. coli C2368.

Chromosomes, Bacterial↗

PubMed2004

Effects of the Delta67 complex of mutations in human immunodeficiency virus type 1 reverse transcriptase on nucleoside analog excision.

Long-term use of combination therapy against human immunodeficiency virus type (HIV-1) provides strong selective pressure on the virus, and HIV-1 variants that are resistant to multiple inhibitors have been isolated. HIV-1 variants containing amino acid substitutions within the coding region of HIV-1 reverse transcriptase (RT), such as the 3'-azido-3'-deoxythymidine (AZT)-resistant variant AZT-R (M41L/D67N/K70R/T215Y/K219Q) and a variant containing an insertion in the fingers domain (S69SGR70/T215Y), are resistant to the nucleoside RT inhibitor (NRTI) AZT because of an increase in the level of excision of AZT monophosphate (AZTMP) from the primer. While rare, variants have also been isolated which contain deletions in the RT coding region. One such virus, described by Imamichi et al. (J. Virol 74:10958-10964, 2000; J. Virol. 74:1023-1028, 2000; J. Virol. 75:3988-3992, 2001), contains numerous amino acid substitutions and a deletion of codon 67, which we have designated the Delta67 complex of mutations. We have expressed and purified HIV-1 RT containing these mutations. We compared the polymerase and pyrophosphorolysis (excision) activity of an RT with the Delta67 complex of mutations to wild-type RT and the two other AZT-resistant variants described above. All of the AZT-resistant variants we tested excise AZTMP and 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA [tenofovir]) from the end of a primer more efficiently than wild-type RT. Although the variant RTs excised d4TMP less efficiently than AZTMP and PMPA, they were able to excise d4TMP more efficiently than wild-type RT. HIV-1 RT containing the Delta67 complex of mutations was not able to excise as broad a range of NRTIs as the fingers insertion variant SSGR/T215Y, but it was able to polymerize efficiently with low concentrations of deoxynucleoside triphosphates and seems to be able to excise AZTMP and PMPA at lower ATP concentrations than AZT-R or SSGR/T215Y, suggesting that a virus containing the Delta67 complex of mutations would replicate reasonably well in quiescent cells, even in the presence of AZT.

Amino Acid Substitution↗

PubMed1997

Recognition and repair of compound DNA lesions (base damage and mismatch) by human mismatch repair and excision repair systems.

Nucleotide excision repair and the long-patch mismatch repair systems correct abnormal DNA structures arising from DNA damage and replication errors, respectively. DNA synthesis past a damaged base (translesion replication) often causes misincorporation at the lesion site. In addition, mismatches are hot spots for DNA damage because of increased susceptibility of unpaired bases to chemical modification. We call such a DNA lesion, that is, a base damage superimposed on a mismatch, a compound lesion. To learn about the processing of compound lesions by human cells, synthetic compound lesions containing UV photoproducts or cisplatin 1,2-d(GpG) intrastrand cross-link and mismatch were tested for binding to the human mismatch recognition complex hMutS alpha and for excision by the human excision nuclease. No functional overlap between excision repair and mismatch repair was observed. The presence of a thymine dimer or a cisplatin diadduct in the context of a G-T mismatch reduced the affinity of hMutS alpha for the mismatch. In contrast, the damaged bases in these compound lesions were excised three- to fourfold faster than simple lesions by the human excision nuclease, regardless of the presence of hMutS alpha in the reaction. These results provide a new perspective on how excision repair, a cellular defense system for maintaining genomic integrity, can fix mutations under certain circumstances.

Adaptor Proteins, Signal Transducing↗

PubMed1986

Analysis of the essential and excision repair functions of the RAD3 gene of Saccharomyces cerevisiae by mutagenesis.

The RAD3 gene of Saccharomyces cerevisiae, which is involved in excision repair of DNA and is essential for cell viability, was mutagenized by site-specific and random mutagenesis. Site-specific mutagenesis was targeted to two regions near the 5' and 3' ends of the coding region, selected on the basis of amino acid sequence homology with known nucleotide binding and with known specific DNA-binding proteins, respectively. Two mutations in the putative nucleotide-binding region and one in the putative DNA-binding region inactivate the excision repair function of the gene, but not the essential function. A gene encoding two tandem mutations in the putative DNA-binding region is defective in both excision repair and essential functions of RAD3. Seven plasmids were isolated following random mutagenesis with hydroxylamine. Mutations in six of these plasmids were identified by gap repair of mutant plasmids from the chromosome of strains with previously mapped rad3 mutations, followed by DNA sequencing. Three of these contain missense mutations which inactivate only the excision repair function. The other three carry nonsense mutations which inactivate both the excision repair and essential functions. Collectively our results indicate that the RAD3 excision repair function is more sensitive to inactivation than is the essential function. Overexpression of wild-type Rad3 protein and a number of rad3 mutant proteins did not affect the UV resistance of wild-type yeast cells. However, overexpression of Rad3-2 protein rendered wild-type cells partially UV sensitive, indicating that excess Rad3-2 protein is dominant to the wild-type form. These and other results suggest that Rad3-2 protein retains its affinity for damaged DNA or other substrates, but is not catalytically active in excision repair.

Amino Acid Sequence↗

PubMed2005

Eyelid basal cell carcinoma: non-Mohs excision, repair, and outcome.

AIM: To analyse the outcome of basal cell carcinoma (BCC) excision in a subregional (non-Mohs) oculoplastic service. METHODS: A single surgeon retrospective series, medical record review of 223 consecutive cases with histologically confirmed eyelid BCC (between 1987 and 2004). Tumour recurrence rate was derived from the 69 patients with a minimum 5 year follow up. RESULTS: Of the total 223 patients, the surviving 162 were included in this study. The follow up for the whole cohort ranged from 2 months to 120 months. All cases underwent excisional biopsy. 4 mm excision margins were taken in 83% of cases. The pathology revealed 84% complete primary excision. Of those reported incompletely excised 53% contained no tumour at re-excision. 70% of lid defects were treated by primary direct closure. Following confirmed histological clearance the remainder underwent delayed direct closure (2%), full thickness skin or tarsal grafts (13%), local skin and muscle flaps (11%), and spontaneous granulation (laissez faire) (4%). No major complications were noted. There were no recurrences for non-infiltrative BCCs. The overall 5 year and over recurrence rate including previously recurrent BCCs was 4.35%, only one of which was in the primary BCC group (1.6%). All recurrences were in infiltrative BCCs. CONCLUSIONS: Non-infiltrative BCC excision with 4 mm margins gave a zero recurrence rate. Long term follow up of such patients may be unnecessary. Infiltrative BCCs should be followed up indefinitely. Previous recurrence and infiltrative histology have predictive value for recurrence. We achieved one of the lowest recurrence rates reported in non-Mohs surgical excision. Direct closure was applicable in 72% of cases.

Adult↗

PubMed1998

Clinicopathological correlation of primary and recurrent choroidal neovascularisation following surgical excision in age related macular degeneration.

AIMS/BACKGROUND: Fluorescein angiography and histopathological findings were correlated in two patients with recurrent choroidal neovascular membranes (CNVs) in an attempt to gain insight into the possible causes of recurrent CNVs and into the healing response after CNV excision. METHODS: Two patients with recurrent CNVs underwent repeat excision, and the excised tissue was studied with light and electron microscopy. RESULTS: Incomplete CNV excision probably led to the recurrences. The portion initially excised appears to have been anterior to the RPE in case 1. In both cases, recurrent CNVs contained RPE-like like cells suggesting that native RPE can repopulate the dissection bed. The tissue excised at the second operation contained areas with hyperplastic RPE and fragments of Bruch's membrane (external to the RPE basement membrane) in a matrix of fibrillar collagen and fibrocytes, suggesting that initial removal of the CNV can be followed by an abnormal anatomical arrangement of RPE and scarring of Bruch's membrane. CONCLUSIONS: Abnormal resurfacing of the dissection bed by RPE and fibroblasts may underlie, in part, the limited visual outcome often seen after surgical excision of CNVs in age related macular degeneration.

Aged↗

PubMed1989

Mutational specificity and the influence of excision repair: insights into the mechanisms of error-avoidance and error-fixation.

The excision repair process controlled by the uvrABC gene in Escherichia coli is the major pathway for the repair of a diverse series of DNA damages. To achieve a better understanding of the mechanics of this repair pathway and its impact upon mutagenesis, we have applied a recently developed technology by which the nature of mutation is determined at the DNA sequence level. A comparison of the classes and distribution of mutation in excision-repair-proficient and excision-repair-deficient strains of E. coli reveals that the absence of excision repair can alter both the nature of the mutations recovered as well as their distribution. This can occur in one of several ways. For example, under some circumstances the action of the UvrABC pathway can lead to interruptions of DNA strand continuity and an enhancement of both frameshift and deletion events. Such an effect is seen following damage by psoralen plus near UV (PUVA) treatment that produces crosslinks in the DNA. In comparison, several other treatments produce similar distributions within the classes of mutations recovered but demonstrate an alteration in site specificity. Such is the case following UV irradiation. In this case, the data indicate that while the premutagenic lesions may be the same, mutation fixation in the presence and absence of excision repair may involve different mechanisms. Similarly, evidence from the repair of damage by ethylating agents indicates that while the nature of the mutations recovered is not altered, the preferred location of these events is altered in the absence of excision repair. These results indicate that local DNA sequence can affect on the efficiency of excision repair.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylating Agents↗

PubMed1999

Variations in the maize Ac transposase transcript level and the Ds excision frequency in transgenic wheat callus lines

To investigate the excision of a maize transposable element in wheat cells, plasmid DNAs containing a Dissociation (Ds) element located between a rice actin 1 gene promoter and a beta-glucuronidase (GUS) gene (gus) were introduced into wheat callus lines by microprojectile bombardment, and transient GUS expression was assayed. The gus-expressing cells after Ds excision were detected only when the Activator (Ac) transposase gene was co-transformed. To further examine a relationship between the amount of Ac mRNA and the Ds excision frequency, the Ds-containing plasmids were introduced into 15 independent transgenic callus lines transformed with the Ac transposase gene. Ten lines expressed the Ac transposase gene under the control of either the cauliflower mosaic virus 35S promoter or the Ac native promoter. The gus gene expression that indicated the Ds excision was observed only in the transgenic callus lines stably expressing the Ac transposase gene. The number of blue spots reflecting the frequency of Ds excision was variable among them. Northern-blot analysis also showed a large variability in the amount of Ac transposase transcripts among the lines. It was however noted that the excision frequency was decreased at a high level of the Ac transposase transcripts, supporting the hypothesis that Ds excision is inhibited above a certain level of the Ac transposase as observed in maize and transgenic tobacco.

Journal Article↗

PubMed1987

Regional lymph node metastasis created by partial excision of carcinomas induced in hamster cheek pouch with 9,10-dimethyl-1,2-benzanthracene.

The feasibility of using the hamster cheek pouch/dimethyl-benzanthracene (DMBA) system as an experimental model of lymphatic metastasis was investigated. Forty male Syrian golden hamsters treated with DMBA were divided into two equal groups--one with surgical excision of their tumors and a control group without tumor excision. In the excision group, the animals received three applications/week to the left cheek pouch of 0.3% DMBA in acetone for 14 weeks. Following a three-week observation period, the tumors in the pouch were excised at their base, and the animals were killed after four weeks of further observation. In the control group, the animals were treated for 14 weeks in a manner similar to that used for the excision group, left for seven weeks without treatment, and then killed. Cheek pouches with tumors and cervical lymph nodes were processed for histological examination. All of the animals, both with and without metastasis, had borne squamous cell carcinomas (SCC) in their treated cheek pouches. Histologically, seven out of 16 animals in the excision group showed metastatic deposits of SCC confined to the left cervical lymph nodes, while in the control group, metastasis was not found in any of the 19 animals with SCC in their cheek pouches. The results demonstrate that surgical excision of the hamster cheek pouch carcinoma is efficient in producing unequivocal lymph node metastasis.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2001

First intron excision of GnRH pre-mRNA during postnatal development of normal mice and adult hypogonadal mice.

Previously, we demonstrated that excision of the GnRH first intron (intron A) was largely attenuated in non-GnRH-producing tissues but accelerated in GnRH neurons. In the present study, we examined the splicing rate of GnRH pre-mRNA in developing normal mice and adult hypogonadal mice. The preoptic area and cerebral cortex were removed from mice at ages 1-7 wk. GnRH pre-mRNA splicing was examined by competitive RT-PCR using a variety of primer sets. The ratio of mature mRNA to intron A-containing RNA species in the preoptic area was lowest in 1- and 2-wk-old mice, significantly augmented in 3-wk-old mice, and further increased until adulthood. In contrast, the ratio of mRNA to intron A-containing RNA in the cerebral cortex was extremely low, drastically decreased in 3-wk-old mice, and remained at low levels until adulthood. These data indicate a preoptic area-specific increase in intron A excision during development. Intron B or C excision in the preoptic area was not significantly changed during development. To elucidate the possible involvement of the exonic splicing enhancers located in GnRH exons 3 and 4 in the developmental increase in intron A excision, we examined the splicing rate of GnRH pre-mRNA in hypogonadal mice whose GnRH exons 3 and 4 were truncated. The intron A excision in the preoptic area of hypogonadal mice was significantly lower than that of normal mice but similar to that in other tissues, such as cerebral cortex and olfactory bulb. To support the functional relevance of intron A-containing RNA species, we examined the translation efficiency of intron A-containing RNA. Insertion of intron A sequence into the upstream portion of the luciferase open reading frame significantly decreased translation efficiency. The present study demonstrates that intron A excision in the preoptic area is developmentally regulated in normal mice but largely attenuated in hypogonadal mice, indicating the functional importance of intron A excision in GnRH pre-mRNA splicing.

Animals↗

PubMed2006

Prognostic effect of re-excision in adult soft tissue sarcoma of the extremity.

BACKGROUND: We explored the outcome of patients with primary adult soft tissue sarcoma (STS) of the extremities undergoing re-excision after previous unplanned surgery. METHODS: A total of 597 consecutive adult patients with primary extremity STS were treated with conservative surgery at our institution over a 20-year time span. A total of 318 patients were referred after unplanned excisions, and the remaining 279 underwent primary resection at our center. The two groups significantly differed in tumor size and depth. The assessed end points were sarcoma-specific mortality, local recurrence, and distant metastasis. Univariable and multivariable analyses, adjusted for other prognostic factors, were performed in the competing risks framework. RESULTS: The adjusted 10-year cumulative incidences in re-excised and primarily operated patients were, respectively, 18.7% and 16.4% (P = .535) for local relapse, 17.6% and 20.2% (P = .541) for metastasis, and 20.4% and 22.4% (P = .645) for mortality. Among patients who underwent re-excision, evidence of microscopic residual disease on pathologic examination had a significant prognostic effect on multivariable analysis for distant metastases (P = .002). A trend for survival was detected as well. CONCLUSIONS: At a referral center with a liberal policy of re-excisions in adult primary STS of the extremities, the outcome of patients who underwent re-excision was similar to that of patients who had primary resections. Evidence of microscopic residual disease at re-excision was a marker of clinical aggressiveness.

Adult↗

PubMed2006

Lobular neoplasia in breast core needle biopsy specimens is associated with a low risk of ductal carcinoma in situ or invasive carcinoma on subsequent excision.

To address the significance of lobular neoplasia (LN) in breast core needle biopsy specimens, we prospectively obtained LN cases and correlated results of subsequent tissue sampling. LN was diagnosed by core needle biopsy in 467 women; in 101 (21.6%), invasive carcinoma (IC) or ductal carcinoma in situ (DCIS) was diagnosed concurrently. Two patients (0.4%) had previous diagnoses of IC or DCIS, and 17 (3.6%) had a concurrent diagnosis of contralateral IC or DCIS. Of 366 patients without a concurrent diagnosis of IC or DCIS, subsequent tissue diagnoses were available for 156 cases (42.6%). Of 60 cases of LN and atypical ductal hyperplasia on the biopsy, 5 had IC and 10 had DCIS on the excision (total, 25%). Of 4 women with LN and a mucocele-like lesion on the biopsy, none had IC or DCIS on excision. Of 92 with LN alone on the biopsy, 7 had IC (6) or DCIS (1) on excision. Two cases were in sites away from the biopsy site, 3 in subsequent excisions of the biopsy site, and 2 after previous excision of the biopsy site without finding IC or DCIS. Although LN is associated with a high overall rate of IC and DCIS (30%), excision of the biopsy site for women with LN alone on core needle biopsy has a very low rate of IC and DCIS in our center. Women in whom biopsy sites are excised are still at risk for subsequent DCIS and IC.

Biopsy, Needle↗

PubMed1983

Xenon-enhanced CT CBF measurements in cerebral AVM's before and after excision. Contribution to pathogenesis and treatment.

Unlike neurological deficits resulting from intracranial hemorrhage in patients with cerebral arteriovenous malformation (AVM), which have well defined etiology, the pathogenesis and treatment of progressive and/or fluctuating non-hemorrhagic neurological and psychological deficits require clarification. Values for local cerebral blood flow (LCBF) and local partition coefficients (L lambda) were measured by the method using stable xenon (Xe)-computerized tomography (CT-CBF) scanning, and were compared to 133Xe inhalation values using external probes in 16 patients with cerebral AVM's. Values were measured by both methods before and after total excision of AVM's in five cases. Neurological and mental status assessments were compared with LCBF results. Clinical improvement was most evident after total excision of AVM's. Other procedures, such as clipping of vessels, partial excision, and ventriculoperitoneal shunting for hydrocephalus, were associated with frequent complications. Embolization carried risks of cerebral infarction and was not efficacious unless combined with excision. Medical treatment resulted in poor or unsuccessful seizure control, with neurological deterioration despite anticonvulsant therapy. Compared with age-matched normal individuals, LCBF values in patients with AVM's were significantly reduced, particularly adjacent to the AVM's. Mean L lambda values for gray and white matter were normal. After excision, LCBF values in gray and white matter increased significantly up to normal. Due to overestimation of CBF by shunt flow with the 133Xe method of measurement, no correlation was found with results of the CT-CBF method before AVM excision, but significant correlation of the two methods resulted after excision. If accurate LCBF values are obtained by high resolution, direct measurement of tracer clearance from brain tissue, progressive and/or fluctuating neuropsychological deficits correlate with the degree of cerebral steal.

Adolescent↗

PubMed1999

Predictors of local recurrence following excision alone for ductal carcinoma in situ.

BACKGROUND: The treatment of ductal carcinoma in situ (DCIS) remains controversial, particularly in regard to the selection of patients who may be appropriately treated with wide excision alone. To help identify such patients, the authors assessed prognostic factors for local recurrence in patients with DCIS treated with excision alone. METHODS: The study population consisted of 59 patients diagnosed with DCIS between 1985 and 1990. All had been treated with excision alone, had their histologic slides available for re-review by a study pathologist, and had negative margins of excision on review. The median age at diagnosis was 54 years, and the median follow-up time was 95.5 months. Ninety-six percent presented with mammographic findings only; all patients had a reexcision. The size of the DCIS was assessed by the total number of low-power fields (LPF) in which DCIS was present (median LPF = 5). RESULTS: Ten patients experienced a local recurrence (LR) at 5-132 months (median, 37 months) after excision. The actuarial 5-year LR rate was 10%. Four of the recurrences were invasive carcinomas, and 6 were DCIS. No patients have developed metastatic disease or have died of disease. Lesion size >5 LPF was the only significant prognostic factor for local recurrence on univariate analysis (3% vs. 17% for < or = 5 vs. > or = 5 LPF, P = 0.02) and in proportional hazards models. Although patients with nuclear Grade 3 lesions had a higher LR rate than those with nuclear Grade 1 and 2 lesions (18% vs. 6% and 5%, respectively) and patients with close margins (< or = 1 mm) had a higher LR rate than patients with negative margins (>1 mm) (25% vs. 8%), these differences did not reach statistical significance. Among the 19 cases with margins negative by more than 1 mm, lesion size < or = 5 LPF, and nuclear Grade 1 or 2, there were no LRs; by contrast, the remaining 40 patients had a 5-year actuarial LR rate of 15% (P = 0.08). CONCLUSIONS: Lesion size was the only statistically significant prognostic factor for local recurrence in this series of patients with DCIS treated with excision alone. Other factors, such as margin status and nuclear grade, may also be useful in the identification of patients with DCIS who can be managed with excision alone. However, the most reliable and reproducible method of assessing these factors and the best way to combine them have not been determined.

Adult↗

PubMed1999

[Rectal carcinoma. Optimizing therapy by local excision].

The results of local excision and radical surgery in patients with T1-carcinomas of the rectum were compared. In a retrospective study (1.1.1985-1.7.1997) the results obtained in 107 patients with T1-rectal carcinoma ("low risk" T1: n = 83, "high risk" T1: n = 24) undergoing local excision or radical surgical therapy were compared. The complication rate in patients undergoing local excision was 3.3% (2/60) and ranged at 19% (9/47) in the group treated with radical surgery. Two out of 47 patients (4.2%) died after radical resection; there were no deaths after local excision. With regard to the actuarial 5-year survival rate, in the group with "low risk" T1 carcinoma no difference was observed between patients treated with local excision (79%) or radical resection (81%) (p = 0.72). In patients with "high risk" T1 carcinoma lymph node metastases were identified in 4 out of 11 patients undergoing radical resection (36%). 4 out of 13 patients with "high risk" T1 carcinoma treated by local excision developed recurrences, while none of the patients undergoing primary radical surgery had a recurrence. This underlines the necessity of radical surgery in "high risk" T1-carcinomas. Local excision for the treatment of "low risk" T1-carcinoma is associated with a significantly lower complication rate than the performance of a radical surgical therapy. There is no difference in five-year-survival between local and radical surgical therapy in patients with "low risk" T1 carcinoma.

Follow-Up Studies↗

PubMedDate not supplied

[Evaluation of the diagnosis of pigmented tumors of the skin and factors leading to a decision to excise. Dermatologists of the Postgraduate Association of Haute-Normandie].

INTRODUCTION: The necessity of excising melanomas characterized by a slight thickness at an early stage, leads dermatologists to remove pigmented lesions which do not correspond to melanomas. The aims of this study were: a) to prospectively assess the accuracy of melanoma diagnosis, b) to quantify the number of excisions performed according to the degree of melanoma suspicion, c) to determine the specific clinical sign or signs of relevant diagnostic value. PATIENTS AND METHODS: This study was conducted prospectively from January 1996 to August 1997 by dermatologists in private practice and dermatologists from a University Hospital staff. When it was decided to excise a pigmented lesion, a form was filled out choosing the most appropriate clinical diagnosis, the degree of melanoma suspicion, and clinical signs which lead to surgery. Based on histological findings as the reference, the sensitivity, specificity, accuracy of melanoma diagnosis and the kappa test that evaluates the concordance between clinical and histological diagnosis, were performed. The diagnostic value of clinical signs was assessed by variance analysis. RESULTS: Of the 353 excised lesions, 38 (10.7 p. 100) were identified as melanoma on histologic examination. The sensitivity, the specificity and diagnostic accuracy were: 79 p. 100, 94 p. 100 and 53 p. 100 respectively. The kappa test concordance between clinical and histological diagnosis was 0.66. Two hundred and two lesions (57 p. 100) were excised even though the clinical suspicion of melanoma was poorly considered. Only one of these 202 lesions was identified histologically as a true melanoma. Thirty seven (24.5 p. 100) of the 151 remaining excised lesions with an "average" or "strong" suspicion were true melanomas. The clinical signs considered, alone or associated, had a poor predictive positive value (< 38 p. 100). An analytical approach performed with a logistic model permitted the identification of two associated signs suggesting a best diagnostic value. DISCUSSION: This is the only study, to our knowledge, reported in the literature which prospectively assesses the sensitivity, specificity and concordance between clinical and histological diagnosis of melanoma. Results were considered from average to good. The originality of this study was to assess the number of pigmented lesions excised according to the degree of melanoma suspicion, suggesting the possibility of reducing the number of nevi removed when the melanoma risk was considered clinically poor. Finally, this study emphasizes the limits of clinical semiology and the need for future diagnostic methods in the assessment of melanoma.

Adult↗

PubMed2001

Excision repair of adozelesin-N3 adenine adduct by 3-methyladenine-DNA glycosylases and UvrABC nuclease.

Adozelesin is a synthetic analog of the antitumor antibiotic CC-1065, which alkylates the N3 of adenine in the minor groove in a sequence-selective manner. Since the cytotoxic potency of a DNA alkylating agent can be modulated by DNA excision repair system, we investigated whether nucleotide excision repair (NER) and base excision repair (BER) enzymes are able to excise the bulky DNA adduct induced by adozelesin. The UvrABC nuclease and 3-methyladenine-DNA glycosylase, that exhibit a broad spectrum of substrate specificity, were selected as typical NER and BER enzymes, respectively. The adozelesin-DNA adduct was first formed in the radiolabeled restriction DNA fragment and its excision by purified repair enzymes was monitored on a DNA sequencing gel. The treatment of the DNA adduct with a purified UvrABC nuclease and sequencing gel analysis of cleaved DNA showed that UvrABC nuclease was able to incise the adozelesin adduct. The incision site corresponded to the general nuclease incision site. Excision of this adduct by 3-methyladenine-DNA glycosylases was determined following the treatment of the DNA adduct with a homogeneous recombinant bacterial, rat and human 3-methyladenine-DNA glycosylases. Abasic sites generated by DNA glycosyalses were cleaved by the associated lyase activity of the E. coli formamidopyrimidine-DNA glycosylase (Fpg). Resolution of cleaved DNA on a sequencing gel showed that the DNA glycosylase from different sources could not release the N3-adenine adducts. A cytotoxicity assay using E. coli repair mutant strains showed that E. coli mutant strains defective in the uvrA gene were more sensitive to cell killing by adozelesin than E. coli mutant strain defective in the alkA gene or the wild type. These results suggest that the NER pathway seems to be the major excision repair system in protecting cells from the cytotoxicity of adozelesin.

Alkylation↗