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Biomedical subjects

R Rubin

Publications and source records attributed to R Rubin.

At least 91 records · Page 5Linked to original sources
PubMed1994

Growth regulation of human glioblastoma T98G cells by insulin-like growth factor-1 and its receptor.

The interaction of insulin-like growth factors (IGFs) with the IGF-1 receptor is an important step in the control of cell proliferation and development. In particular, IGF-1 and IGF-2 are key regulators of central nervous system development, and may modulate the growth of glial tumors. We have investigated the growth factor regulation of the human glioblastoma cell line T98G. These cells growth arrested in serum-free medium at 34 degrees C, despite their secretion of substantial amounts of bioactive IGF-1. To be stimulated to divide, growth-arrested cells required the addition of platelet-derived growth factor (PDGF) or its equivalent, 1% serum. Cell proliferation in serum-free medium could also be obtained by shifting the cells to a temperature of 39.6 degrees C. Treatment of growth-arrested cells with PDGF or temperature shift was accompanied by a transient increase in the expression of the mRNA for the IGF-1 receptor. Transfection with a plasmid constitutively expressing the full cDNA for the human IGF-1 receptor allowed autonomous growth in serum-free medium at 34 degrees C. By contrast, growth induction by growth factors or temperature shift was abrogated by transfection of the cells with a plasmid expressing a 300 bp segment of mRNA antisense to the IGF-1 receptor mRNA. Cloning in soft agar was also inhibited by expression of antisense IGF-1 receptor mRNA. These results demonstrate that the IGF-1 receptor is strictly required for the growth of T98G glioblastoma cells. Moreover, the autocrine interaction of IGF-1 with its receptor regulates both autonomous and anchorage-independent growth of these cells.

Base Sequence↗
PubMed1994

Alcohol and platelet function.

Epidemiological studies have shown that moderate consumption of alcoholic beverages is inversely related to the incidence of the complications of coronary artery disease. The protective effect of ethanol may be partially attributable to an inhibitory effect of ethanol on platelets. This article summarizes the experimental observations that ethanol inhibits platelet responses to specific physiological agonists. In alcoholics, various platelet defects have been observed, but these may be influenced by metabolic factors rather than the presence of ethanol alone. The acute effects of ethanol on platelet functions both in vivo and ex vivo will be reviewed. Evidence will be presented demonstrating that ethanol added acutely in vitro inhibits phospholipase A2 in stimulated platelets. The interaction of ethanol with other signal transduction pathways will also be discussed.

Alcohol Drinking↗
PubMed1994

Effect of a null mutation of the insulin-like growth factor I receptor gene on growth and transformation of mouse embryo fibroblasts.

Fibroblast cell lines, designated R- and W cells, were generated, respectively, from mouse embryos homozygous for a targeted disruption of the Igf1r gene, encoding the type 1 insulin-like growth factor receptor, and from their wild-type littermates. W cells grow normally in serum-free medium supplemented with various combinations of purified growth factors, while pre- and postcrisis R- cells cannot grow, as they are arrested before entering the S phase. R- cells are able to grow in 10% serum, albeit more slowly than W cells, and with all phases of the cell cycle being elongated. An activated Ha-ras expressed from a stably transfected plasmid is unable to overcome the inability of R- cells to grow in serum-free medium supplemented with purified clones. Nevertheless, even in the presence of serum, R- cells stably transfected with Ha-ras, alone or in combination with simian virus 40 large T antigen, fail to form colonies in soft agar. Reintroduction into R- cells (or their derivatives) of a plasmid expressing the human insulin-like growth factor I receptor RNA and protein restores their ability to grow with purified growth factors or in soft agar. The signaling pathways participating in cell growth and transformation are discussed on the basis of these results.

Animals↗
PubMed1994

A functional insulin-like growth factor I receptor is required for the mitogenic and transforming activities of the epidermal growth factor receptor.

When wild-type mouse embryo cells are stably transfected with a plasmid constitutively overexpressing the epidermal growth factor (EGF) receptor (EGFR), the resulting cells can grow in serum-free medium supplemented solely with EGF. Supplementation with EGF also induces in these cells the transformed phenotype (growth in soft agar). However, when the same EGFR expression plasmid is introduced and overexpressed in cells derived from littermate embryos in which the insulin-like growth factor I (IGF-I) receptor genes have been disrupted by homologous recombination, the resulting cells are unable to grow or to be transformed by the addition of EGF. Reintroduction into these cells (null for the IGF-I receptor) of a wild-type (but not of a mutant) IGF-I receptor restores EGF-mediated growth and transformation. Our results indicate that at least in mouse embryo fibroblasts, the EGFR requires the presence of a functional IGF-I receptor for its mitogenic and transforming activities.

Animals↗
PubMed1994

Combined antihypertensive and lipid-lowering therapy in experimental glomerulonephritis.

We examined the interrelation between systemic hypertension, hyperlipidemia, and progressive renal injury in experimental glomerulonephritis. Induction of nephrotoxic serum nephritis in Sprague-Dawley rats led to systemic hypertension and hyperlipidemia. Four groups of rats were studied over a 16-week period: (1) untreated nephritic rats; (2) nephritic rats treated with hydralazine, reserpine, and lasix (AH); (3) nephritic rats treated with lovastatin (4 mg/kg) (Lova); and (4) nephritic rats treated with combined antihypertensive/lipid-lowering therapy (AH/Lova). Systolic blood pressure rose progressively in untreated rats (152 +/- 4 mm Hg at 16 weeks). Blood pressure was reduced by antihypertensive therapy (P < .001) (108 +/- 2 mm Hg in the AH group and 111 +/- 3 mm Hg in the AH/Lova group) but remained elevated in animals treated with lovastatin alone (P > .05) (156 +/- 3 mm Hg in the Lova group). Serum cholesterol rose progressively in untreated rats (3.70 +/- 0.85 mmol/L [143 +/- 33 mg/dL] at 16 weeks). The rise in serum cholesterol was prevented by lovastatin therapy (P < .001) (2.22 +/- 0.41 mmol/L [86 +/- 16 mg/dL] in the Lova group and 2.09 +/- 0.52 mmol/L [81 +/- 2 mg/dL] in the AH/Lova group) but not antihypertensive therapy (P > .05) (2.92 +/- 0.65 mmol/L [113 +/- 25 mg/dL] in the AH group). Proteinuria was reduced by antihypertensive therapy (P < .001) and lipid-lowering therapy (P < .05) (16-week values: 1.069 +/- 0.167 g/d in untreated rats, 0.663 +/- 0.164 g/d in the Lova group, 0.392 +/- 0.051 g/d in the AH group, and 0.176 +/- 0.035 g/d in the AH/Lova group).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Noninvasive, real-time monitoring of renal function during critical care.

The inadequacy of the current techniques to monitor renal function has been the most important limitation for determining the appropriateness of a particular form of therapy in acute renal failure. The objective of this study was to determine the advantage offered by a new method of accurate, noninvasive, and real-time monitoring of renal function during the critical care of patients. A radiation detector attached to a miniature data logger was used to monitor the clearance of the glomerular filtration agent 99mTc-diethylene triamine pentaacetic acid from the extracellular space in 20 patients admitted into an intensive care unit. The rate constant for this clearance was calculated online from 5-min epoch lengths of activity versus time. Changes in this constant were compared with changes in plasma creatinine and timed urine output. The results showed that the ambulatory renal monitor could accurately measure rapid changes in renal function during the critical care of patients who are at risk of acute renal failure with a resolution time of 5 to 10 min. The sensitivity and specificity of the technique are also superior to plasma creatinine and urine output because it can detect minimal and transient changes in renal function that otherwise may have gone undetected by these parameters. This unique approach should allow for the immediate institution and/or adjustment of the appropriate therapeutic procedure to preserve or improve the renal function.

Acute Kidney Injury↗
PubMed1994

Ethanol inhibits insulin-like growth factor-1-mediated signalling and proliferation of C6 rat glioblastoma cells.

BACKGROUND: Alcohol consumption during pregnancy often results in disorders of fetal development (Fetal Alcohol Syndrome). The brain appears to be particularly vulnerable, and alcohol abuse during pregnancy is probably the most common cause of acquired mental retardation. We therefore studied the in vitro effects of ethanol on insulin-like growth factor-1 (IGF-1)-mediated proliferation of rat C6 glioblastoma cells. EXPERIMENTAL DESIGN: The proliferation of C6 rat glioblastoma cells was measured in serum-free medium supplemented with specific growth factors in the presence or absence of ethanol. The effect of ethanol on IGF-1 receptor and insulin receptor substrate 1 (IRS-1) tyrosine phosphorylation was determined by immunoprecipitation and Western blotting, as was the phosphatidylinositol 3-kinase content within IRS-1 immunoprecipitates. RESULTS: C6 cells grew slowly in serum-free medium and proliferated in response to IGF-1. Ethanol, at physiologically tolerated concentrations, markedly inhibited the growth of C6 cells in response to IGF-1, but had no effect on the proliferative rate in the presence of platelet-derived growth factor or 1% fetal bovine serum. Inhibition of cell proliferation was evident when ethanol was only present during a 1-hour pulse of IGF-1. Cell growth in the presence of IGF-2 was also prevented by ethanol. The inhibition of IGF-1-mediated cell proliferation was accompanied by abrogation of IGF-1 receptor tyrosine autophosphorylation. Ethanol also interfered with the IGF-1-induced tyrosine phosphorylation of IRS-1, and the association of phosphatidylinositol-3 kinase with IRS-1. CONCLUSIONS: The data indicate that physiologically relevant concentrations of ethanol inhibit the responses of glial cells to IGF-1, including IGF-1 receptor autophosphorylation, IRS-1 and phosphatidylinositol-3 kinase activation, and cell growth.

Amino Acid Sequence↗
PubMed1994

Hepatic fibrosis associated with hereditary cystinosis: a novel form of noncirrhotic portal hypertension.

Hepatomegaly is a common feature of hereditary nephropathic cystinosis but is rarely associated with symptoms of liver disease. Aside from cystine crystal deposit within Kupffer cells, the cause of liver enlargement is unknown. We report the case of a patient with nephropathic cystinosis who died at the age of 24 yr after multiple renal transplants. In addition to classical systemic signs of advanced cystinosis, the patient had evidence of portal hypertension. At autopsy, the liver was enlarged for body size (1520 g) and very firm. Massive crystal accumulation within Kuppfer cells was accompanied by intense sinusoidal deposition of collagen types I, III, and IV, with associated hepatocyte atrophy. There was no inflammation or regenerative nodules. Numerous enlarged and fat-laden Ito cells were present in association with the collagen. This case illustrates a novel form of noncirrhotic portal hypertension associated with cystinosis. Analysis of future cases may serve to highlight the role of Kupffer and Ito cells in the pathogenesis of hepatic fibrosis.

Adult↗
PubMed1994

Sulfasalazine-induced fulminant hepatic failure and necrotizing pancreatitis.

We report the simultaneous development of fulminant hepatic failure and necrotizing pancreatitis in a patient treated with sulfasalazine. The patient had recent onset of ulcerative colitis. A diffuse skin rash and fulminant hepatic failure developed 2-3 wk after initiation of sulfasalazine therapy. An exploratory laparotomy revealed severe necrotizing pancreatitis with phlegmon, in addition to confluent hepatic necrosis. Electron microscopy of the liver was consistent with drug injury. The patient died after 2 months of hospitalization. This is the first reported case of the concurrent development of these complications associated with sulfasalazine hypersensitivity. These potential adverse effects of sulfasalazine should be considered when using this agent.

Adult↗
PubMed1993

Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor.

Fibroblast cell lines were established from mouse embryos homozygous for a targeted disruption of the Igf1r gene, encoding the type 1 receptor for insulin-like growth factor I (IGF-I) and from their wild-type littermates. The cells from the wild-type embryos (W cells) grow in serum-free medium supplemented with platelet-derived growth factor, epidermal growth factor, and IGF-I, whereas the cells from Igf1r(-/-) embryos (R- cells) do not, although they grow at a reduced rate in 10% fetal calf serum. The simian virus 40 (SV40) large T antigen, expressed from a transfected plasmid, can transform W cells, which form foci in monolayer cultures and colonies in soft agar (anchorage-independent growth). In contrast, the SV40 large tumor antigen, although normally expressed from the transfected template, is unable to transform R- cells, which remain contact-inhibited and fail to grow in soft agar. The transformed phenotype is restored if the R- cells carrying the SV40 large tumor antigen are stably transfected with a plasmid expressing the human IGF-I receptor. These results demonstrate that signaling via the IGF-I receptor is an indispensable component of the SV40 transformation pathway. This conclusion is further supported from the results of antisense RNA experiments with tumor cell lines showing that interference with the function of the IGF-I receptor has a profound effect on anchorage-independent growth, even under conditions that only modestly affect growth in monolayers.

Animals↗
PubMed1993

Ethanol inhibits the autophosphorylation of the insulin-like growth factor 1 (IGF-1) receptor and IGF-1-mediated proliferation of 3T3 cells.

The effect of ethanol on cell proliferation was studied in Balb/c 3T3 cells and in stably transfected 3T3 cells constitutively overexpressing the human insulin-like growth factor 1 (IGF-1) receptor (p6 cells). Ethanol inhibited growth of both cell lines when they were cultured in serum-free medium supplemented with individual growth factors, i.e. platelet-derived growth factor and IGF-1 for 3T3 cells, and IGF-1 only for p6 cells. Increases in cell number were prevented in both cell lines even when ethanol was present exclusively during the period of IGF-1 stimulation. The inhibitory effect of ethanol was concentration-dependent, with a 30% inhibition observed at 10 mM ethanol. IGF-1 receptor tyrosine autophosphorylation was completely prevented by ethanol both in intact cells and in immunopurified IGF-1 receptor preparations. The binding of IGF-1 to its receptor on intact cells was unaffected by ethanol. Ethanol also inhibited the stimulation of IGF-1 receptor autophosphorylation and the corresponding growth of p6 cells induced by IGF-2. Transcription of c-myc, c-fos, and c-jun in response to IGF-1 was inhibited by ethanol. These findings demonstrate that ethanol at low concentrations markedly inhibits IGF-1 receptor autophosphorylation and IGF-1-mediated cell growth.

3T3 Cells↗
PubMed1993

Rejection-independent cholangitis and cirrhosis following orthotopic liver transplantation.

The histologic diagnosis of extrahepatic biliary obstruction in the setting of orthotopic liver transplantation (OLT) may be complicated by nonobstructive factors, such as rejection, preservation injury, drug effects, and infection. Indeed, biopsy specimens from OLT patients frequently exhibit early posttransplant cholestasis, which is likely the result of several of these factors acting in concert. We reviewed the clinicopathologic features of 14 OLT patients whose biopsy specimens displayed prominent cholangitis with "obstructive"-type features. Cholangiograms, Doppler ultrasound examinations, and bacterial cultures were obtained in conjunction with all biopsy specimens. Despite histologic evidence of biliary obstruction, cholangiography revealed obstruction in only one case, leaks in four cases, and nine normal studies. Ten patients had severe systemic bacterial or cytomegalovirus infections. Biliary infection was documented in two cases. Hepatic artery occlusion was diagnosed in one case. The cholangitic pattern persisted in patients with unremitting infections, and two patients developed secondary biliary cirrhosis despite having consistently normal cholangiograms. Features of acute rejection or viral hepatitis were not observed on any biopsy specimen. The presence of this clinicopathologic spectrum was associated with a poor prognosis. Nine patients died and only four patients who responded to antibiotics survived. These findings demonstrate a striking cholangitic response to systemic infections in OLT grafts. The diagnosis of biliary obstruction in OLT liver biopsy specimens cannot be rendered without cholangiographic verification.

Adult↗
PubMed1993

Clinicopathologic features of late hepatic dysfunction in orthotopic liver transplants.

Orthotopic liver transplantation (OLT) has been used with increasing frequency as a definitive treatment for end-stage liver disease. Whereas the spectrum of pathology in the early posttransplant period is well documented, the clinicopathologic features of patients with late hepatic dysfunction are less clearly defined. In a series of 100 OLTs we identified 12 patients with progressive liver dysfunction 4 months after transplantation. Four patients succumbed rapidly to fulminant hepatitis 4 to 6 months following transplantation, three of whom had recurrent hepatitis B infection. One patient lost two successive grafts owing to hepatitis C. Liver biopsies were diagnostic for hepatitis in all cases. The outcome of the remaining eight patients with late hepatic dysfunction was grim. Their clinical courses were notable for intractable and progressive cholestasis. Five patients died and two others required retransplantation. Only one patient responded to increased immunosuppression with FK506. Ductopenia was a common feature of liver biopsies in these cases, but severe ductopenia (vanishing bile duct syndrome) was seen in the liver biopsies of only four patients. In contrast, occlusive arteriopathy and secondary ischemic changes were ubiquitous. In summary, the liver biopsy is a useful adjunct in the diagnosis of late OLT dysfunction, particularly in distinguishing recurrent viral hepatitis from chronic graft rejection. Centrilobular ischemic changes occur frequently in chronic rejection, whereas ductopenia may be difficult to document consistently.

Adolescent↗
PubMed1993

Idiopathic hemochromatosis: MR imaging findings in cirrhotic and precirrhotic patients.

The authors reviewed T2-weighted and T2*-weighted abdominal magnetic resonance (MR) images in 19 pathology-proved cases of hepatic iron overload to compare patterns of iron distribution among cirrhotic and precirrhotic patients with idiopathic hemochromatosis (IH), as well as nontransfusional hepatic siderosis of other causes. Fifteen patients had clinical and laboratory evidence of IH. Four patients without IH had cirrhosis with moderate siderosis. In the MR images of all 19 patients, the liver had low signal intensity. The pancreas of 10 of 11 cirrhotic patients with IH had low signal intensity. All four precirrhotic patients with IH and all four cirrhotic patients without IH had pancreas with normal signal intensity at MR. Thus, pancreatic signal intensity was decreased only in cirrhotic patients with IH in this limited series. Conversely, pancreatic signal intensity is often normal in precirrhotic patients with IH prior to the development of cirrhosis, a stage at which definitive diagnosis by means of quantitative liver biopsy is important because early phlebotomy may prevent morbidity and mortality from IH. In cirrhotic patients with MR evidence of increased hepatic iron, the cause of cirrhosis is less likely to be IH if pancreatic signal intensity is normal.

Adult↗