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David T Efron

Publications and source records attributed to David T Efron.

6 recordsLinked to original sources
PubMed2003

Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior.

The growing understanding of the epigenetic changes associated with cancer, including aberrant promoter methylation of tumor suppressor genes that afford selective growth advantages to human neoplasms, suggests that the characterization of gene methylation patterns among gastrointestinal stromal tumors (GISTs) may be useful for predicting tumor behavior. Thirty-eight c-kit-positive gastric stromal tumors were subjected to methylation-specific polymerase chain reaction (MSP) to detect promoter methylation associated with 11 candidate tumor suppressor genes (p16/INK4a, APC, MGMT, hMLH1, p73, E-cadherin, RAR-beta, RASSF1A, RB, ER, and DAPK), established to have a role in tumorigenesis of several solid human organs. Aberrant methylation of any of the 11 candidate tumor suppressor genes was detected in 84% of all GISTs. In decreasing order of frequency, the six most commonly methylated genes were: MGMT (47%), p16 (45%), RASSF1A (40%), E-cadherin (37%), hMLH1 (34%), and APC (31%). For all of the GISTs, promoter methylation was less reliable than tumor mitotic rate in predicting 5-year tumor-free survival for the GISTs; however, E-cadherin methylation was a multivariate prognostic factor for early recurrence of GISTs (50% at 2 years; P=0.030). Among the mitotically active (>5 per 50 high-power field), histologically indistinguishable GISTs, E-cadherin methylation was an independent predictor of tumor-related mortality: 5-year disease-free survival was worse for the E-cadherin methylated GISTs (19%) compared to the E-cadherin unmethylated tumors (71%; P=0.010). Detection of methylation within selected genes may afford a reliable and accurate molecular marker system for predicting neoplastic behavior among GISTs. This study supports the methylation status of E-cadherin as a prognostic marker for early GIST recurrence and survival.

Adult↗
PubMed2002

Effect of supplemental ornithine on wound healing.

BACKGROUND: Supplemental arginine has been shown to enhance wound healing, in particular collagen synthesis. Ornithine is the main metabolite of arginine in the urea cycle and shares many of the biopharmacologic effects of arginine. The present study examines the effect of ornithine supplementation on wound healing and attempts to describe its possible mechanism. METHODS: Wild type (WT) and iNOS knockout (KO) mice were randomized to receive either normal chow and tap water or chow and water each supplemented with 0.5% ornithine (w/w). All animals underwent a midline dorsal skin incision with implantation of polyvinyl alcohol sponges into subcutaneous pockets. On postoperative day 14 the animals were sacrificed. The dorsal wound was harvested for breaking strength determination while the wound sponges were assayed for hydroxyproline content, total wound fluid amino acid, and nitrite/nitrate (NOx) concentration. RESULTS: Dietary ornithine supplementation enhanced wound breaking strength and collagen deposition in both WT and KO mice. This was accompanied by increased wound fluid proline and ornithine levels but not arginine, citrulline, or NOx levels. CONCLUSIONS: The results from this study demonstrate that ornithine supplementation enhances wound healing in both WT and KO mice. This suggests that ornithine's effect on wound healing is independent of the iNOS pathway.

Animals↗
PubMed2002

Characterization of incisional wound healing in inducible nitric oxide synthase knockout mice.

BACKGROUND: Excisional wound healing in inducible nitric oxide synthase knockout (iNOS-KO) mice has been previously shown to be impaired compared with their background strain controls. Incisional wounds were created in this experiment in both types of animals and paradoxically were found to heal with the same rapidity and breaking strength in both groups. METHODS: Dorsal 2.5 cm incisional wounds were created in iNOS-KO mice, as well as their parental strain controls (C57BL/6J). Standardized polyvinyl alcohol sponges were implanted in the wounds to allow for measurement of collagen deposition. Animals were harvested on postoperative days (PODs) 3, 5, 7, 10, 14, and 28, and their wounds subjected to tensiometric breaking strength analysis. Nonisotopic in situ hybridization quantitative analysis for iNOS, endothelial NOS (eNOS), basic fibroblast growth factor (bFGF), transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), and interleukin-4 (IL-4) expression in the wounds was performed. Hydroxyproline levels were quantitated in the harvested polyvinyl alcohol sponges. Data were analyzed with the Students t test. RESULTS: No significant differences were found in breaking strengths or levels of hydroxyproline (and thus collagen) in iNOS-KO versus wild-type wounds at all tested time points. Flawed iNOS expression levels in iNOS-KO animals were similar to (functional) iNOS expression in wild-types. eNOS and bFGF expression nearly doubled on POD 7 in iNOS-KO incisions (P =.002, and.002), respectively and remained 200% to 300% elevated thereafter. TGF-beta1 expression was increased approximately 50% to 100% in iNOS-KO wounds on PODs 5 and 7 (P =.006 and.01, respectively). VEGF and IL-4 expression was elevated by 25% to 100% in wild-type compared with iNOS-KO animals at all time points (P <.01). CONCLUSIONS: The overexpression of TGF-beta1 and eNOS may represent mechanisms in iNOS-KO mice to compensate for their loss of functional iNOS, resulting in incisional wound healing equivalent to controls. Their impaired expression of VEGF and IL-4, on the other hand, may partially explain the delayed excisional wound healing noted in these animals.

Animals↗
PubMedDate not supplied

Modulation of growth factor and cytokine expression by nitric oxide during rat colon anastomotic healing.

We have previously shown that inhibition of nitric oxide generated by inducible nitric oxide synthase (iNOS) results in impaired colon anastomotic healing. Therefore, we proceeded to assess whether disruption of iNOS activity alters the normal pattern of growth factor expression during anastomotic healing. Two groups of male Sprague-Dawley rats underwent distal colonic division and anastomosis, jugular venous catheterization and subcutaneous placement of polyvinyl alcohol sponges. The first group (n = 10) received q8 hour intravenous injections of 10 mg/kg L-N-iminoethyl-lysine (L-NIL, a selective inhibitor of iNOS), while the second group (n = 12) received equal volumes of saline. On postoperative day 5, animals were sacrificed and anastomotic bursting pressure was determined. Histologic sections of the anastomosis were subjected to in situ hybridization versus mRNA of the proteins listed below. Positive controls were reacted with a poly-thymidine (poly-T) probe versus ubiquitous mRNA poly-adenine tails. Positively stained cells were quantified using a calibrated optical grid encompassing 0.5 mm(2) area centered over the anastomosis. Results are reported as the number of positive cells per 1000 cells positive for poly-T. L-NIL treated animals demonstrated an 18% decrease in wound fluid NO(X) compared to controls (29.2 +/- 1.2 vs. 34.6 +/- 2.0 microM, mean +/- SEM; P = 0.035). This corresponded to a 17% decrease in anastomotic bursting pressure (153 +/- 4 vs. 182 +/- 8 mm Hg, mean +/- SEM; P < 0.05). L-NIL also markedly increased the number of cells expressing transforming growth factor-beta, tumor necrosis factor-alpha, vascular endothelial growth factor, and both inducible and endothelial forms of nitric oxide synthase. L-NIL had no effect on the expression of basic fibroblast growth factor. The data demonstrate that iNOS inhibition markedly disrupts the profile of cytokine and growth factor mRNA normally expressed during anastomotic healing. This provides in vivo evidence that NO modulates gene expression during anastomotic healing.

Anastomosis, Surgical↗
PubMedDate not supplied

Supplemental L-arginine enhances wound healing in diabetic rats.

L-arginine has been shown to enhance wound strength and collagen deposition in rodents and humans. Diabetes mellitus, which impairs wound healing, is accompanied by a reduction in nitric oxide at the wound site. The amino acid L-arginine is the only substrate for nitric oxide synthesis. We sought to determine whether supplemental L-arginine can restore the impaired wound healing of diabetic rats. Fifty-six male Lewis rats were used in this study, of which twenty-nine rats were rendered diabetic 7 days prior to surgery with intraperitoneal streptozotocin. Twenty-seven untreated rats served as controls. Animals underwent a dorsal skin incision with implantation of polyvinyl-alcohol sponges. Sixteen diabetic and 14 normal rats received 1 g/kg/day of L-arginine by injection, while the remainder received saline injections only. Animals were euthanized 10 days postwounding, and their wounds were analyzed for breaking strength. The wound sponges were assayed for total hydroxyproline and nitrite/nitrate content. Plasma and wound fluid concentrations of L-arginine, ornithine, and citrulline were determined. Wound sponge RNA was extracted and subjected to Northern blot analysis for procollagen I and III. Diabetic wounds had greatly decreased breaking strengths compared with controls. L-arginine significantly enhanced wound breaking strengths in both control (+23%) and diabetic animals (+44%), and also increased wound hydroxyproline levels in both diabetic (+40%) and control animals (+24%) as compared to their saline-treated counterparts. mRNA for procollagen I and III were elevated by L-arginine treatment in both diabetic rats and controls. Treatment with L-arginine significantly increased wound fluid nitrite/nitrate levels in diabetic animals. The data show that the impaired healing of diabetic wounds can be partially corrected by L-arginine supplementation, and that this effect is accompanied by enhanced wound nitric oxide synthesis.

Amino Acids↗