Chemoprevention of mammary carcinogenesis in the rat: combined use of raloxifene and 9-cis-retinoic acid.
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Animals↗
Biomedical subjects
A B Roberts
Publications and source records attributed to A B Roberts.
Human albumin solder supplemented with TGF-beta 1 accelerates healing following laser welded wound closure.
BACKGROUND AND OBJECTIVE: We examined the possibility that human albumin solder can be used as a vehicle for site specific delivery of growth factors for the purpose of accelerating tissue repair following laser welded wound closure. Certain human recombinant growth factors have been shown to accelerate wound healing in model systems. Pilot in vitro studies have established that several growth factors, including TGF-beta 1, maintain bioactivity following exposure to temperatures achieved during laser tissue welding. Using a temperature controlled laser delivery system (TCL) to precisely maintain welding temperatures, it is now possible to avoid thermal denaturation of exogenous bioactive molecules such as growth factors. STUDY DESIGN/MATERIALS AND METHODS: HB-EGF, bFGF, and TGF-beta 1 were tested in vitro for maintenance of bioactivity after exposure to 80 degrees C. In vivo experiments using porcine skin determined the efficacy of solders augmented with growth factors. Incisions were repaired using human albumin alone or supplemented with HB-EGF (2 micrograms), bFGF (10 micrograms), or TGF-beta 1 (1 microgram). Wounds were excised at 3, 5, and 7 days post-operatively. Tensile strength, total collagen content, and histology were performed. RESULTS: At 3 days, tensile strength (TS) of TGF-beta 1 wounds were 36% (P < 0.05) and 20% (n.s.) stronger than laser alone and suture closures, respectively. By 5 days the TS of the TGF-beta 1 group increased by 50% (P < 0.05) and 59% (P < 0.02) over laser alone and suture groups, respectively. At 7 days the TGF-beta 1 group was 50% (P < 0.05) and 79% (P < 0.01) stronger than laser solder alone or suture, respectively. The HB-EGF and bFGF groups were equivalent to the laser solder group at all time points. Total collagen TGF-beta 1 Accelerates Healing Following Laser Welding content at 7 days increased in the TGF-beta 1 group by 7% (n.s.) over the suture group and 21% (P < 0.05) in the laser group. CONCLUSION: Human albumin solder supplemented with TGF-beta 1 increases the early post-operative strength of laser welded wounds. This novel application of laser tissue soldering augmented with a growth factor has the potential to bring about immediate fluid tight seals while providing site specific delivery of biological modifiers. This may lead to an overall improvement in post-operative convalescence, wound infections, and hospital costs.
Albumins↗
Transforming growth factor-beta1-deficient mice: identification of isoform-specific activities in vivo.
A remarkable range of activities has been ascribed to the family of proteins known as transforming growth factor-beta (TGF-beta). Each plays an important role in development and homeostasis, influencing mesenchymal-epithelial interactions, regulating cellular differentiation, and maintaining control of cell proliferation. Although in vitro comparisons of activity demonstrate a high degree of functional similarity, recent studies of mice with a targeted deletion of the TGF-beta1 gene reveal that true isoform-specific activities do exist in vivo and that the three mammalian isoforms are not functionally redundant. This approach has defined a unique role for TGF-beta1 in the establishment and maintenance of normal immune function, shed new light on the relevance of endogenous TGF-beta1 to the normal wound healing process, and expanded the list of known mechanisms of TGF-beta1 activity to include endocrine functions. Thus, the TGF-beta1-deficient mouse allows the definition of isoform-specific activities, providing an invaluable window through which to view the principal functions of TGF-beta1 in vivo.
Animals↗
Control of nitric oxide production by endogenous TGF-beta1 and systemic nitric oxide in retinal pigment epithelial cells and peritoneal macrophages.
Both in vivo and in vitro experiments demonstrate that transforming growth factor-beta1 (TGF-beta1) suppresses expression of the inducible form of nitric oxide synthase (iNOS). In this study, we examined the effects of exogenous and endogenous TGF-beta1 on retinal pigment epithelial (RPE) cells and resident peritoneal macrophages ex vivo using cells from TGF-beta1 null (TGF-beta1-/-) mice or age-matched wild-type (TGF-beta1+/+) or heterozygous (TGF-beta1+/-) littermates. RPE cells from both TGF-beta1-/- mice and TGF-beta1+/+ littermates produced NO and were immunocytochemically positive for iNOS protein only following treatment with interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS); however, RPE cells from TGF-beta1-/- mice produced 40% more NO than cells from TGF-beta1+/+ mice. In contrast, resident peritoneal macrophages from both TGF-beta1+/+ and TGF-beta1-/- mice expressed iNOS protein without stimulation and in the absence of detectable production of NO. The expression of iNOS was increased by treatment with IFN-gamma, resulting in detectable levels of NO. Macrophages from TGF-beta1+/+ mice appeared to produce NO in a manner inversely proportional to the serum content of NO2- and NO3- of the mice from which the cells were obtained; no such correlation existed in TGF-beta1+/- or TGF-beta1-/- mice. Treatment of RPE cells or macrophages from both TGF-beta1+/+ and TGF-beta1-/- mice with exogenous TGF-beta1 decreased both iNOS protein and NO production. These findings demonstrate a novel role of endogenous TGF-beta1 in coupling systemic NO production to the production of NO by macrophages, and demonstrate that endogenous and exogenous TGF-beta1 can act differently to suppress NO production.
Animals↗
Tumor suppressor activity of the TGF-beta pathway in human cancers.
The TGF-betas are a family of cytokines with antiproliferative activity on many cell types. Recent findings demonstrate that the TGF-beta receptor complex functions as a tumor suppressor gene in human malignancy. Somatic mutations of the type II subunit of the TGF-beta receptor (RII) have been demonstrated in several different tumor types. RII frameshift mutations within a short coding region polyadenine repeat are particularly characteristic of colon and gastric cancers that also demonstrate the phenotype of microsatellite instability (RER cancers). These and other mutations as in the type I receptor (RI) are associated with both loss of cell surface TGF beta receptors and with resistance of the cancer cells to TGF-beta-induced growth inhibition. Restoration of receptor expression by gene transfection reverses the transformed phenotype in cancer cells that lacked functional RII or RI. These receptors and, by implication, TGF-beta as well as its complete signalling pathway, are thus new and novel additions to the family of human tumor suppressor genes.
Cell Division↗
Popliteal artery injury after total knee arthroplasty.
Total knee arthroplasty (TKA) is a commonly performed orthopedic procedure. The incidence of vascular complications after TKA is low. However, these complications may be debilitating, limb-threatening, and potentially avoidable. Our first patient, who had no preexisting vascular occlusive disease, developed an ischemic extremity after TKA. The second patient underwent TKA and was diagnosed with a severely ischemic limb 48 hours postoperatively. Both patients underwent above-knee to below-knee popliteal artery saphenous vein bypass grafting. Although limb salvage was obtained in both cases, one had a significantly neuropathic foot. In conclusion, long-term morbidity can be avoided by early identification and treatment of ischemia by bypass grafting.
Aged↗
Graft surveillance and angioplasty prolongs dialysis graft patency.
BACKGROUND: In the United States of America, vascular access complications are the most frequent cause of death among patients with end-stage renal disease on hemodialysis. The majority of American patients with end-stage renal disease have prosthetic grafts for access. The most common complication of prosthetic graft fistulas is thrombosis. To prolong graft life and decrease the frequency of operations, a university-based dialysis unit adopted a policy of graft surveillance by measuring venous resistance, followed by fistulagram and percutaneous dilatation of identified stenoses. The purpose of this retrospective study is to determine if this policy affected graft patency and graft life. STUDY DESIGN: This retrospective review compares outcomes for two years before adoption of this policy (control group, 210 patients) with the outcomes for three years after adoption (study group, 260 patients). Fifty (24 percent) of the control group and 71 (27 percent) of the study group were defined as "complicated" patients because they underwent more than one intervention over any 12-month period. RESULTS: The 50 complicated patients in the control group underwent 104 operations for thrombosis over two years, 1.04 thrombotic episodes and operations per patient year. Seventy new grafts were placed with a mean primary patency of 3.9 months. Mean graft survival time was 6.3 months. The 71 complicated patients in the study group underwent 111 fistulagrams, 80 angioplasties, and 110 operations over three years, for 0.52 thrombotic episodes per patient year (p < .001). Forty-five new grafts were placed with a primary patency of 11.5 months (p < .001). Mean graft survival time was 15.8 months (p < .001). CONCLUSIONS: This retrospective study demonstrates the effectiveness of a policy of graft surveillance and percutaneous treatment of graft stenosis in prolonging primary surgical patency and graft survival.
Angioplasty, Balloon↗
Characterization of the promoter region of the human transforming growth factor-beta type II receptor gene.
Diminished cellular responsiveness to transforming growth factor-beta (TGF-beta) is frequently correlated with decreased transcription of the type II receptor for TGF-beta (TGF-beta RII). We have cloned and characterized the human TGF-beta RII promoter and, using S1 nuclease mapping and 5' rapid amplification of cDNA ends polymerase chain reaction, have identified five alternative transcription start sites within the region -33 to +57. DNA transfection experiments and electrophoretic mobility shift assays have revealed the existence of five distinct regulatory regions including two positive regulatory elements and two negative regulatory elements in addition to the core promoter region. The first positive regulatory element (-219 to -172) interacts with two distinct nuclear protein complexes, at least one of which appears to be a previously unidentified transcription factor. The second positive regulatory element (+1 to +35) also interacts with two separate protein complexes, both of which appear to be novel transcription factors. Deletion of either positive regulatory element markedly decreased expression of the target gene, suggesting that both positive regulatory elements are necessary for basal expression levels of TGF-beta RII.
Base Sequence↗
Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions.
Aberrant expression of transforming growth factor beta 1 (TGF-beta 1) has been implicated in a number of disease processes, particularly those involving fibrotic and inflammatory lesions. To determine the in vivo effects of overexpression of TGF-beta 1 on the function and structure of hepatic as well as extrahepatic tissues, transgenic mice were generated containing a fusion gene (Alb/TGF-beta 1) consisting of modified porcine TGF-beta 1 cDNA under the control of the regulatory elements of the mouse albumin gene. Five transgenic lines were developed, all of which expressed the Alb/TGF-beta 1 transgene selectively in hepatocytes. The transgenic line 25 expressing the highest level of the transgene in the liver also had high (> 10-fold over control) plasma levels of TGF-beta 1. Hepatic fibrosis and apoptotic death of hepatocytes developed in all the transgenic lines but was more pronounced in line 25. The fibrotic process was characterized by deposition of collagen around individual hepatocytes and within the space of Disse in a radiating linear pattern. Several extrahepatic lesions developed in line 25, including glomerulonephritis and renal failure, arteritis and myocarditis, as well as atrophic changes in pancreas and testis. The results from this transgenic model strongly support the proposed etiological role for TGF-beta 1 in a variety of fibrotic and inflammatory disorders. The transgenic model may also provide an appropriate paradigm for testing therapeutic interventions aimed at neutralizing the detrimental effects of this important cytokine.
Animals↗
Specific and sensitive quantitation of transforming growth factor beta 3 by sandwich enzyme-linked immunosorbent assay.
Transforming growth factors beta (TGF-beta) consist of a highly homologous family of 25 kDa dimers involved in a diverse array of biological functions. Progress in understanding the biology of the third isoform (TGF-beta 3) of this family has been limited by the absence of a quantitative assay for TGF-beta 3. Here we report the development of a sensitive and specific sandwich enzyme-linked immunosorbent assay (SELISA), which is based on an anti-TGF-beta mouse monoclonal IgG as the capture antibody and chicken anti-recombinant-hTGF-beta 3 IgY as the secondary antibody. This assay can quantitate TGF-beta 3 in complex biological fluids, with a detection limit of 2 pg and no cross-reactivity or interference with as high as 1000-fold molar excesses of either TGF-beta s 1, 2 or 1.2. This TGF-beta 3 SELISA is the first reported assay for the direct and sensitive quantitation of TGF-beta 3 in complex biological fluids.
Animals↗
Pulmonary hypoplasia and fetal breathing in preterm premature rupture of membranes.
Forty-eight patients with premature rupture of membranes prior to 24 weeks gestation (PPROM) were studied to investigate whether there was any difference in fetal breathing movements in those fetuses that did or did not develop pulmonary hypoplasia. The diagnosis of pulmonary hypoplasia was made on the basis of ultrasound measurement of fetal lung length. A control group of fetuses with intact membranes and normal pregnancies at the same gestation was also studied. The group that developed pulmonary hypoplasia had significantly less breathing movements than those that did not develop pulmonary hypoplasia and controls. This reduction in breathing movements may contribute to the development of pulmonary hypoplasia.
Female↗
Fetal Doppler and behavioral responses during hypoglycemia induced with the insulin clamp technique in pregnant diabetic women.
OBJECTIVE: This study was undertaken to assess human fetal behavior and fetal blood flow after insulin-induced symptomatic maternal hypoglycemia of sufficient magnitude to elicit counterregulatory hormones and a symptomatic response. STUDY DESIGN: Plasma glucose was lowered from approximately 95 mg/dl to 45 mg/dl in decrements of 10 mg/dl every 40 minutes with the insulin clamp technique. In 10 insulin-dependent diabetic women in the third trimester, the fetus was studied by monitoring fetal heart rate and recording fetal body and breathing movements and by performing Doppler waveform analysis with real-time ultrasonography. Maternal levels of glucagon, cortisol, epinephrine, and growth hormone were measured at each plasma glucose level. RESULTS: The mean number of fetal limb and body movements at the start of the study was 25 +/- 16 per 15 minutes, which increased to a mean of 38 +/- 28 at a glucose level of 60 mg/dl and then declined to a mean of 23 +/- 10 at a glucose level of approximately 45 mg/dl. These changes, however, did not achieve statistical significance. In addition, no significant reductions in fetal breathing movements or heart rate were observed, although maternal epinephrine and growth hormone levels were significantly (p < 0.001) increased. No consistent changes in Doppler velocity waveforms were observed. CONCLUSION: These data suggest that fetal well-being remains unaltered in spite of moderate maternal hypoglycemia in diabetic women.
Blood Glucose↗
Correlation of venography, venous pressure, and hemoaccess function.
We analyzed the anatomic features of both grafts and fistulas and correlated these features with access function. We also attempted to determine venous pressures predicting access dysfunction (critical venous pressures) at various blood flow rates (BFRs). Therefore, accesses of 46 chronic hemodialysis patients were studied by venography in a prospective fashion. We defined the incidences of various lesions and the effects of venous collaterals on graft function, and determined critical venous pressures at various BFRs. Eighty-three percent of the accesses had outflow obstruction. Five types of anatomic lesions were identified. The incidences were venous stenosis of the draining vein immediately proximal to the venous anastomosis, 36.4%; central vein, 23.6%; venous anastomosis, 25.5%; arterial anastomosis, 10.9%; and intragraft hyperplasia, 3.6%. Twelve patients had multiple lesions. When the homogenous polytetrafluoroethylene arm graft population was studied for the effect of venous collaterals, we found that venous collaterals conferred protection but did not prevent graft failure. Venous pressure measurements were good predictors of access failure at the lower BFRs. Venous pressures increased with increasing BFRs. A critical venous pressure of 145 mm Hg was found for a BFR of 250 mL/min. At a BFR of 300 mL/min, the critical venous pressure was 170 mm Hg. A critical venous pressure could not be found for a BFR of 400 mL/min.
Arteriovenous Shunt, Surgical↗
Thin-walled polytetrafluoroethylene graft failure is a cause of axillary pullout syndrome.
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Arteries↗
Cervico-isthmic pregnancy with placenta percreta ending in a livebirth.
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Adult↗
Transforming growth factor-beta s in mammary tumorigenesis: promoters or antipromoters?
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Animals↗
The E1A oncogene induces resistance to the effects of 1,25-dihydroxyvitamin D3 on inhibition of growth of mouse keratinocytes.
1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] inhibited DNA synthesis in transformed mouse keratinocytes (Pam212) in a time- and dose-dependent manner as measured by [3H]thymidine incorporation. To investigate the mechanism through which 1,25-(OH)2D3 acts, we examined its effects on Pam212 cells further transformed with the E1A oncogene. Here, we show that transformation of the cells with the E1A oncogene induced resistance to the effects of 1,25-(OH)2D3 on inhibition of growth of Pam212 cells. While 1,25-(OH)2D3 treatment increased the level of expression of vitamin D receptor mRNA 20-fold in parental cells, the E1A-transformed cells failed to express vitamin D receptor mRNA even after treatment with 1,25-(OH)2D3. Transfection of the E1A-transformed cell line with an expression construct encoding the vitamin D receptor restored receptor expression as well as the inhibition of growth by 1,25-(OH)2D3. These results suggest that one of the mechanisms for acquisition of 1,25-(OH)2D3 resistance induced by E1A may involve loss of vitamin D receptor inducibility by 1,25-(OH)2D3.
Adenovirus E1A Proteins↗
[Ser77]transforming growth factor-beta 1. Selective biological activity and receptor binding in mink lung epithelial cells.
Transforming growth factor-beta 1 (TGF-beta 1) is a homodimeric protein stabilized by a single disulfide bridge between Cys77 on the respective monomers and two paired complementary hydrophobic interfaces between the two subunits. A TGF-beta 1 mutant with Cys77 replaced by serine has been expressed in stably transfected Chinese hamster ovary cells and purified to homogeneity. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis confirms that the sole interchain disulfide bond in TGF-beta 1 has been eliminated. It is 20% as potent as native TGF-beta 1 in the induction of plasminogen activator inhibitor-1 promoter expression in mink lung epithelial cells (Mv1Lu), although it is less than 1% as potent as native TGF-beta 1 in inhibition of growth in the same cell line. The mutant acts as a full agonist in both bioassays. [Ser77]TGF-beta 1 binds to soluble type II receptors and competes with native TGF-beta 1 in sandwich-enzyme-linked immunosorbent assays; however, in Mv1Lu cells, the mutant shows preferential cross-linking to type I rather than type II receptors. [Ser77]TGF-beta 1 is a useful tool for understanding the different ligand-receptor complexes and numerous biological activities of this multifunctional cytokine.
Animals↗