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PubMed1998

Substrate specificity of the Ogg1 protein of Saccharomyces cerevisiae: excision of guanine lesions produced in DNA by ionizing radiation- or hydrogen peroxide/metal ion-generated free radicals.

We have investigated the substrate specificity of the Ogg1 protein of Saccharomyces cerevisiae (yOgg1 protein) for excision of modified DNA bases from oxidatively damaged DNA substrates using gas chromatography/isotope dilution mass spectrometry. Four DNA substrates prepared by treatment with H2O2/Fe(III)-EDTA/ascorbic acid, H2O2/Cu(II) and gamma-irradiation under N2O or air were used. The results showed that 8-hydroxyguanine (8-OH-Gua) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) were efficiently excised from DNA exposed to ionizing radiation in the presence of N2O or air. On the other hand, 8-OH-Gua and FapyGua were not excised from H2O2/Fe(III)-EDTA/ascorbic acid-treated and H2O2/Cu(II)-treated DNA respectively. Fourteen other lesions, including the adenine lesions 8-hydroxyadenine and 4,6-diamino-5-formamidopyrimidine, were not excised from any of the DNA substrates. Kinetics of excision significantly depended on the nature of the damaged DNA substrates. The findings suggest that, in addition to 8-OH-Gua, FapyGua may also be a primary substrate of yOgg1 in cells. The results also show significant differences between the substrate specificities of yOgg1 protein and its functional analog Fpg protein in Escherichia coli.

DNA Damage↗

PubMed2000

The 26S proteasome negatively regulates the level of overall genomic nucleotide excision repair.

Regulation of protein expression can be achieved through destruction of proteins by the 26S: proteasome. Cellular processes that are regulated by proteolysis include cell cycle progression, stress responses and differentiation. Several nucleotide excision repair proteins in yeast and humans, such as Rad23, Rad4 and XPB, have been shown to co-purify with Cim3 and Cim5, AAA ATPases of the 19S: proteasome regulatory subunit. However, it has not been determined if nucleotide excision repair is regulated through protein destruction. We measured nucleotide excision repair in yeast mutants that are defective in proteasome function and found that the repair of the transcribed and non-transcribed strands of an RNA polymerase II-transcribed reporter gene was increased in the absence of proteasome function. Additionally, overexpression of the Rad4 repair protein, which is bound to the repair/proteolytic factor Rad23, conferred higher rates of nucleotide excision repair. Based on our data we suggest that a protein (or proteins) involved in nucleotide excision repair or in regulation of repair is degraded by the 26S proteasome. We propose that decreased proteasome function enables increased DNA repair, due to the transient accumulation of a specific repair factor, perhaps Rad4.

DNA Adducts↗

PubMed2004

N-terminus of the rat adenine glycosylase MYH affects excision rates and processing of MYH-generated abasic sites.

Repair of most modified and mispaired bases in the genome is initiated by DNA glycosylases, which bind to their respective targets and cleave the N-glycosyl bond to initiate base excision repair (BER). The mammalian homolog of the Escherichia coli MutY DNA glycosylase (MYH) cleaves adenine residues paired with either oxidized or non-modified guanines. MYH is crucial for the avoidance of mutations resulting from oxidative DNA damage. Multiple N-terminal splice variants of MYH exist in mammalian cells and it is likely that different variants result in the production of enzymes with altered properties. To investigate whether modifications in the N-terminus are consequential to MYH function, we overexpressed intact and N-terminal-deletion rat MYH proteins and examined their activities. We found that deletion of 75 amino acids, which perturbs the catalytic core that is conserved with E.coli MutY, abolished excision activity. In contrast, deletions limited to the extended mammalian N-terminal domain, differentially influenced steady-state excision rates. Notably, deletion of 50 amino acids resulted in an enzyme with a significantly lower K(m) favoring formation of excision products with 3'-OH termini. Our findings suggest that MYH isoforms divergent in the N-terminus influence excision rates and processing of abasic sites.

Adenine↗

PubMed2005

A functional analysis of the DNA glycosylase activity of mouse MUTYH protein excising 2-hydroxyadenine opposite guanine in DNA.

2-hydroxy-2-deoxyadenosine triphosphate (2-OH-dATP), generated by the oxidation of dATP, can be misincorporated by DNA polymerases opposite guanine in template DNA during DNA replication, thus causing spontaneous mutagenesis. We demonstrated that mouse MUTYH (mMUTYH) has a DNA glycosylase activity excising not only adenine opposite 8-oxoguanine (8-oxoG) but also 2-hydroxyadenine (2-OH-A) opposite guanine, using purified recombinant thioredoxin-mMUTYH fusion protein. mMUTYH formed a stable complex with duplex oligonucleotides containing an adenine:8-oxoG pair, but the binding of mMUTYH to oligonucleotides containing a 2-OH-A:guanine pair was barely detectable, thus suggesting that mMUTYH recognizes and interacts with these two substrates in a different manner which may reflect the difference in the base excision repair process for each substrate. Mutant mMUTYH with G365D amino acid substitution, corresponding to a G382D germline mutation of human MUTYH found in familial adenomatous polyposis patients, almost completely retained its DNA glycosylase activity excising adenine opposite 8-oxoG; however, it possessed 1.5% of the wild-type activity excising 2-OH-A opposite guanine. Our results imply that the reduced repair capacity of the mutant hMUTYH(G382D), which inefficiently excises 2-OH-A opposite guanine, results in an increased occurrence of somatic G:C to T:A transversion mutations in the APC gene as well as tumorigenesis in the colon.

Amino Acid Substitution↗

PubMed2000

Sarcomas arising in dermatofibrosarcoma protuberans: a reappraisal of biologic behavior in eighteen cases treated by wide local excision with extended clinical follow up.

There is a prevailing view that sarcomas arising in dermatofibrosarcoma protuberans (DFSP) have a higher risk of metastasis than ordinary DFSP, but these data are based on cases with variable and often suboptimal treatment. There has not been a large study of sarcomas arising in DFSP in which all cases were treated by wide local excision, thereby arguably altering outcome. Clinicopathologic features of 18 cases of sarcomas arising in DFSP treated by wide local excision and having follow up of at least 5 years were analyzed. An estimate of the proportion of sarcoma and DFSP was made. The number of mitotic figures and degree of CD34 immunoreactivity were assessed in each case. The cohort included 13 females and 5 males (age, 23-87 yrs; median, 47 yrs). The tumors involved the trunk (7), scalp (4), extremities (4), and inguinal region (3), and ranged from 1.5 to 7 cm (median, 4 cm). Sarcoma occurred de novo in 15 cases and in a recurrence in three. Sarcomas resembled fibrosarcoma (17) or malignant fibrous histiocytoma (1) and occupied between 20% and 80% of the tumor (median, 60%). Mitotic activity ranged from 2 to 16 per 10 high-power field (HPF; median 7 per 10 HPF) in the sarcomatous component and 0 to 3 per 10 HPF (median, 1 per 10 HPF) in the DFSP component. All tumors expressed CD34 in the DFSP component but only nine (50%) in the sarcomatous component. All patients were treated by wide local excision with negative margins; three additionally received radiation. Four patients (22%) developed recurrences, but none developed metastasis during the follow-up period of 62 months to 17 years (median, 81.5 mos). In contrast to earlier studies, we demonstrate that patients with sarcomas arising in DFSP do not have an increased risk of distant metastasis within a 5-year follow-up period, provided they are treated by wide local excision with negative margins. This probably reflects the fact that wide local excision results in eradication of local tumor, thereby eliminating the source for subsequent dissemination. However, we cannot completely exclude the possibility that tumors in which clear margins are achieved represent a less aggressive subset, as has been suggested for high-grade extremity sarcomas. Previous studies showing increased metastasis for sarcomas arising in DFSP should be re-evaluated to determine if, with treatment stratification, metastatic rate varies.

Adult↗

PubMed1996

An evaluation of excision with application of autografts or porcine xenografts within 24 hours of burn injury.

An evaluation of feasibility and safety of excising burn wounds within 24 hours of injury was carried out. Over a 2-year period, 124 patients were admitted and taken to the operating room within 24 hours of initial burn injury. All cases were from one surgeon's practice. There were 99 males and 28 females. Age ranged from 8 months to 93 years. Burn size ranged from 0.5% to 70%, with a mean of 17.59%. Time from injury to surgery varied from 2 hours 10 minutes to 23 hours 40 minutes, with a mean of 14.42 hours. All patients admitted within 24 hours of injury were considered for immediate excision. Patients admitted too late in their course to receive excision within 24 hours were not included in the evaluation. Second-degree burns were treated with tangential debridement and porcine xenografts. If third-degree burns were obviously present, electrocautery excision was carried out followed by cadaver grafting or autografting as appropriate. Blood loss ranged from 0 to 2000 cc (mean, 215.08 cc) for the first surgery. The mean number of operations per patient was 1.72. Very large burns underwent staged procedures. There were five deaths (4.0%) in the group. There were no operative deaths. Twenty-three patients required readmission for further treatment, usually including surgery. It appears that excision within 24 hours of injury is safe. There is the obvious benefit of a reduced hospital stay by decreasing the time to surgery and the theoretical advantage obtained by early removal of sources of infection.

Adolescent↗

PubMed2002

Arteriovenous malformation involving the thumb and hand: radical excision and reconstruction of multiple components.

Arteriovenous malformation of the fingers is not an uncommon presentation in daily practice. The lesions may or may not become clinically evident from birth to adulthood. Treatment of the arteriovenous malformation includes conservative treatment, selective embolization, partial excision, and radical excision. However, recurrence, repeat operations, and even deformity requiring amputation are common problems. The excision is difficult because it is easy to damage the nutrient vessels of the digit, and ischemia or necrosis develop subsequently. Embolization and partial excision are prone to recurrence as well. Radical excision and flap reconstruction are beneficial for some patients, as demonstrated by the authors. In the treatment of digital arteriovenous malformation, it is always important to maintain a balance of cure, function, and aesthetic result.

Adult↗

PubMed1989

A comparison of conservative versus early excision. Therapies in severely burned patients.

Early excision and grafting of small burn wounds is a generally accepted treatment. Early excision of burn injuries greater than 30% total body surface area (TBSA) in adults, however, has not been universally accepted. In this study, 85 patients whose ages ranged from 17 to 55 years with greater than 30% total body surface area (TBSA) burns were randomly assigned to either early excision or topical antimicrobial therapy and skin grafting after spontaneous eschar separation. Mortality from burns without inhalation injury was significantly decreased by early excision from 45% to 9% in patients who were 17 to 30 years of age (p less than 0.025). No differences in mortality could be demonstrated between therapies in adult patients older than 30 years of age or with a concomitant inhalation injury. Children (n = 259) with similar large burns treated by early excision showed a significant increase in mortality with increasing burn size and with concomitant inhalation injury (p less than 0.05). The mean length of hospital stay of survivors was less than one day per per cent of TBSA burn in both children and adults.

Adolescent↗

PubMed2000

Local excision of rectal cancer without adjuvant therapy: a word of caution.

OBJECTIVE: To evaluate the results of local excision alone for the treatment of rectal cancer, applying strict selection criteria. BACKGROUND DATA: Several retrospective studies have demonstrated that tumor control in properly selected patients with rectal cancer treated locally is comparable to that observed after radical surgery. Although there is a consensus regarding the need for patient selection for local excision, the specific criteria vary among centers. METHODS: The authors reviewed 82 patients with T1 (n = 55) and T2 (n = 27) rectal cancer treated with transanal excision only during a 10-year period. At pathologic examination, all tumors were localized to the rectal wall, had negative excision margins, were well or moderately differentiated, and had no blood or lymphatic vessel invasion, nor a mucinous component. End points were local and distant tumor recurrence and patient survival. RESULTS: Ten of the 55 patients with T1 tumors (18%) and 10 of the 27 patients with T2 tumors (37%) had recurrence at 54 months of follow-up. Average time to recurrence was 18 months in both groups. Seventeen of the 20 patients with local recurrence underwent salvage surgery. The survival rate was 98% for patients with T1 tumors and 89% for patients with T2 tumors. Preoperative staging by endorectal ultrasound did not influence local recurrence or tumor-specific survival. CONCLUSION: Local excision of early rectal cancer, even in the ideal candidate, is followed by a much higher recurrence rate than previously reported. Although most patients in whom local recurrence develops can be salvaged by radical resection, the long-term outcome remains unknown.

Aged↗

PubMed2002

The intraoperative use of mitomycin-C in excision of ocular surface neoplasia with or without limbal autograft transplantation.

PURPOSE: To evaluate the efficacy of intraoperative mitomycin-C in excision of ocular surface neoplasia for prevention of recurrence. METHODS: Seven patients (eight eyes), three men and four women, aged 56 to 87 years (mean, 73.8 years), with lesions suspicious for corneal or conjunctival neoplasia, were operated on between October 1998 and March 2000. During excision of the lesion, mitomycin-C 0.02% was applied intraoperatively for 5 minutes. In two cases, excision was combined with conjunctival limbal autograft transplantation. All excised lesions were sent for histopathologic evaluation. RESULTS: During the follow-up period ranging from 6 to 28 months (mean, 16 months) one patient (one eye) died of an unrelated cause. Histopathologic study showed four cases of squamous cell carcinoma, one case of carcinoma in situ, two cases of dysplasia, and one case of actinic keratosis. Of the eight eyes, no clinical recurrence of the lesion occurred in seven eyes, whereas one eye with squamous cell carcinoma showed mild recurrence 5 months after surgery and was successfully treated with topical mitomycin-C. Up to the last follow-up of this case 10 months later, the lesion did not recur. CONCLUSION: The excision of conjunctival and corneal epithelial neoplasia combined with the intraoperative use of mitomycin-C seems to reduce the recurrence rate. The combined use of mitomycin-C and conjunctival limbal autograft transplantation in two cases did not alter the surgical outcome. More cases and a longer follow-up are needed to establish the efficacy of such an approach.

Aged↗

PubMedDate not supplied

The optimal time for excision of scald burns in toddlers.

During the past decade, morbidity and mortality have been shown to be decreased by early excision and grafting in treatment of moderate and large burns. Because of the lack of data on the efficacy of such treatment in scald burns, a retrospective study was done of children under age 4 who were admitted to a burn unit within three days of scald injury. Four groups were examined according to day of first surgical procedure: (1) sooner than five days; (2) 6-10 days; (3) 11-20 days; and (4) later than 20 days. The four groups (similar in age, weight, and percent of TBSA burn) were also analyzed for differences in percent of excised area, blood loss, and length of hospital stay. The amount of excised area in group 1 was significantly larger than in groups 2 and 3, and group 1 also had a significantly greater blood loss. Only in group 4 was the length of stay significantly increased. If excision could be delayed until after day 5, the area excised and the blood loss might be decreased without prolonging hospital stay.

Burns↗

PubMedDate not supplied

Partial excision of residual burn lesions.

Most burn victims have unattractive residual lesions, which may include hypertrophic donor sites, unsightly skin grafts, hypertrophic scars, and mature scars with altered pigmentation or texture. Some of these lesions can be treated by total excision in one or more stages or they can be reconstructed utilizing grafts, flaps, Z-plasties, or tissue expansion. But frequently these procedures are either not indicated or not elected by the patient. In such a situation, the only surgical option is partial excision, with the goal of making the lesion less conspicuous and more easily concealed by clothing. Whether or not such partial excisions are worthwhile is the obvious question. We could not find an answer in the literature and therefore decided to review our own experience. Between 6/30/81 and 3/12/86, 92 such procedures were performed and followed in 25 patients. Partial excision of hypertrophic donor sites, unsightly skin grafts, and hypertrophic scars did yield improved appearance in most patients. However, partial excision of mature scars, ie, areas of altered pigmentation or texture, did not have the same success. We continue to treat the first three types of lesions in this fashion but no longer include the latter.

Adolescent↗

PubMedDate not supplied

Lack of immediate effects of wound excision on the hyperdynamic circulation of burned patients.

The high cardiac output (CO) observed during the chronic phase in burned patients has been ascribed, among other factors, to the elevated blood flow in the burn wound. The hemodynamic effects of wound excision to fascia have been studied in eight patients with second- and third-degree burns ranging from 42% to 70% total body surface area (TBSA) undergoing debridement and skin-grafting procedures. The study was performed on the 4th to the 51st postburn day when all patients were in a hyperdynamic state. Serial hemodynamic measurements, including arterial and mixed-venous blood O2 saturation and content, were made before induction of anesthesia, during surgery both before and after wound excision, and in the recovery room a few hours after surgery. During anesthesia, the elevated CO decreased probably as a consequence of decreased metabolic requirements, but no further hemodynamic change was observed following wound excision. The size of burn wound excised to fascia averaged 24% TBSA and ranged from one-third to more than one-half of the initial burn. With discontinuation of anesthesia, CO rose rapidly above preoperative values, apparently to meet a similar increase in oxygen consumption. The excision of large areas of burned tissue did not attenuate the hyperdynamic circulation in burned patients, at least during and immediately after surgery. The data suggest that the elevated blood flow in the burn wound does not play a significant role in the pathogenesis of the hyperdynamic state.

Adult↗

PubMedDate not supplied

Tourniquet and subcutaneous epinephrine reduce blood loss during burn excision and immediate autografting.

Blood loss has been reduced using both tourniquets and epinephrine-injected subeschar during burn wound excision. This study quantified and compared blood loss in extremities distal to an inflated tourniquet with that after subeschar infusion of 1:1,000,000 epinephrine in saline into the trunk or proximal extremities. Tangential excision of eschar to viable dermis or fat was followed by immediate application of meshed autograft. Blood loss was calculated by determining the difference of preoperative and postoperative hemoglobin values and the volume of whole blood administered between these. With tourniquets for limbs, 2.07 +/- 0.34% of circulating blood volume per 1% body surface excised was lost; whereas after epinephrine injection 3.42 +/- 0.39% of blood volume per 1% body surface excised was lost (P < 0.05). Both methods effectively reduced blood loss when compared with excision followed by delayed autograft application. Where there was a choice the tourniquet was more effective.

Adolescent↗

PubMed1982

The beneficial effect of early excision on clinical response and thymic activity after burn injury.

Catabolic response and immunodepression were studied in guinea pigs with scald burns that were excised on day 1 postburn and those that were scald burned but unexcised. Weight gain returned to normal by day 6 in the excised group but remained depressed in burned but unexcised animals whose wounds were untreated, or in unexcised animals whose wounds were treated by topical silver sulfadiazine. Thymic DNA synthesis returned to normal by day 6 in the excised group but remained depressed in the unexcised group. Plasma and thymic-free cortisol returned to normal by day 6 in the excised group but remained markedly elevated in the burned, unexcised animals. These studies indicate early excision and early wound closure reduce the catabolic response and immunodepression of guinea pigs following burn injury.

Anesthetics↗

PubMed2002

Fractures of the olecranon: an in vitro study of elbow joint stresses after tension-band wire fixation versus proximal fracture fragment excision.

BACKGROUND: Displaced fractures of the olecranon usually require operative treatment, by either open reduction with internal fixation (ORIF) or excision of the proximal fragment. However, the relative merits of these treatment options have not been fully delineated. One treatment outcome measure of joint function is residual intra-articular stress. The purpose of this study was to evaluate the effect of these two types of olecranon fracture treatment on humeroulnar joint stress. METHODS: Eight matched pairs of fresh frozen cadaveric upper extremities were thawed; stripped of skin, muscular, and neurovascular tissue; and potted in polymethylmethacrylate. The intra-articular humeroulnar joint peak pressures were measured at 90 degrees of elbow flexion using pressure-sensitive film after application of a 0.15 kg-m torque through the remaining triceps muscle attachment. First, pretreatment (normal) pressures were obtained from the major contact regions of the humeroulnar joint. A 50% olecranon osteotomy was then performed simulating a fracture, and the elbows from each of the paired specimens were randomly assigned to one or the other of two treatment groups: ORIF (using a tension-band wiring technique) and proximal fragment excision. Joint pressures were remeasured. A two-tailed paired t test was used for statistical analysis. RESULTS: After osteotomy, the peak pressures were higher, overall, in the excision group. Comparing each posttreatment experimental group to its pretreatment (normal) counterpart revealed that the peak pressures in the distal medial and distal lateral articular subzones were significantly higher for the fragment excision group (p = 0.005 and p= 0.0008, respectively), but were not significantly different in the ORIF group (p = 0.545 and p= 0.153, respectively). CONCLUSION: The findings of this study indicate that ORIF restores the normal biomechanics of the elbow joint and proximal fragment excision results in abnormally elevated joint stresses. These elevated joint stresses may, over time, contribute to the development of elbow pain and osteoarthrosis. Therefore, ORIF should continue to be regarded as the treatment of choice for displaced fractures of the olecranon involving large proximal fracture fragments similar in size to those in this study.

Biomechanical Phenomena↗

PubMed1996

Extended followup of the influence of wide excision of the neurovascular bundle(s) on prognosis in men with clinically localized prostate cancer and extensive capsular perforation.

PURPOSE: The effect of wide excision of the neurovascular bundles on disease-free survival was determined in men with clinically localized prostate cancer and pathological evidence of extensive capsular perforation in the region of the neurovascular bundle. MATERIALS AND METHODS: We previously analyzed 107 men with clinically localized prostate cancer and pathological evidence of extensive capsular perforation in the region of the neurovascular bundles. Wide excision of the neurovascular bundle on the sides of palpable induration resulted in negative surgical margins in 58% of patients compared to only 45% in whom the neurovascular bundles were left intact (p = 0.03). At a mean followup of 20 months, median interval to disease recurrence as defined by a measurable PSA level was 33 months in patients whose neurovascular bundle(s) were widely excised versus 22 months in those whose neurovascular bundle(s) were left intact (p = 0.03). However, by 43 months 75% of the patients in both groups had a detectable prostate specific antigen and the Kaplan-Meier curves had converged, suggesting that wide excision of the neurovascular bundle(s) did not confer a sustained survival advantage. RESULTS: With an additional followup of 28 months, the probability of having an undetectable prostate specific antigen level at 5 years was 47% in patients with negative versus 6% with positive surgical margins (p < 0.001). CONCLUSIONS: Our extended followup suggests that some patients with extensive capsular perforation can be rendered free of disease with wide excision of the neurovascular bundle(s).

Actuarial Analysis↗

PubMed1989

The "sponge deformity" after tangential excision and grafting of burns.

Sequential excision and grafting of burns have resulted in several new problems. We have termed one of these the "sponge deformity," i.e., a grafted area where, in multiple small areas, the bed heals underneath the graft with or without slough of the overlying graft. If the graft sloughs, a pockmark forms. If the graft does not slough, an overlying bridge forms. In our experience, this deformity is very troublesome to patients because it is difficult to wash, catches on objects, bleeds, and looks quite unsightly. Between February of 1981 and June of 1986, we treated 16 patients with this deformity. All 16 patients were treated by simple excision of the bridges and pockmark edges with a curved iris scissors. In all patients, the wounds healed well and the resultant surfaces were considerably smoother. This retrospective review of the patients suggests that the deformity usually occurs around the periphery of the excised area where the excision was shallower and when thicker grafts are used. Perhaps the bed underneath the graft epithelializes from residual epithelial elements prior to vascularization of the autograft. If this is true, it might be possible to prevent the deformity by excising the wound deeper, by applying thinner grafts, or by applying allograft or xenograft, expecting that the area will heal promptly and not require autografting.

Adolescent↗