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Aged↗
Biomedical subjects
R Rubin
Publications and source records attributed to R Rubin.
The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo.
The role of the insulin-like growth factor I receptor (IGF-IR) in programmed cell death has been investigated in vivo in a biodiffusion chamber, where the extent of cell death could be determined quantitatively. We found that a decrease in the number of IGF-IRs causes massive apoptosis in vivo in several transplantable tumors, either from humans or rodents. Conversely, an overexpressed IGF-IR protects cells from apoptosis in vivo. We also show that the same conditions that in vitro cause only partial growth arrest with a minimum of cell death, induce in vivo almost complete cell death. We conclude that the IGF-IR activated by its ligands plays a very important protective role in programmed cell death, and that its protective action is even more striking in vivo than in vitro.
3T3 Cells↗
Loss of the metastatic phenotype in murine carcinoma cells expressing an antisense RNA to the insulin-like growth factor receptor.
The ability of malignant cells to form metastases in secondary sites remains a major obstacle to the curative treatment of cancer. Previously, we identified type 1 insulin-like growth factor (IGF-1) as a paracrine mitogen for highly metastatic murine carcinoma, H-59 cells. Here the role of IGF-1 and its receptor (IGF-1R) in metastasis was further investigated using H-59 cells transfected with a plasmid vector expressing IGF-1R cDNA in the antisense orientation. The transfectants had a markedly reduced expression of IGF-1R and lost the ability to respond to IGF-1 in vitro. When injected in vivo, either directly into the microvasculature of the liver or lung (experimental metastasis) or s.c. to allow the growth of primary local tumors (spontaneous metastasis), these cells did not give rise to any metastases under conditions which allowed wild-type or control transfectants to form multiple hepatic and pulmonary metastases. The results demonstrate that the IGF-1R can play a critical role in the regulation of carcinoma metastasis.
Animals↗
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Computer Communication Networks↗
Insulin-like growth factor I (IGF-I) and the IGF-I receptor prevent etoposide-induced apoptosis.
The interaction of insulin-like growth factors (IGF) with the IGF-I receptor promotes cell proliferation and survival. We examined the role of the IGF-I receptor as a possible direct inhibitor of apoptosis induced by the topoisomerase I inhibitor etoposide. When exposed to this agent, BALB/c 3T3 cells that constitutively overexpress the human IGF-I receptor (p6 cells) arrested in S phase and subsequently underwent apoptosis as determined by the appearance of a pre-G1 apoptotic peak when studied by flow cytometry and the characteristic internucleosomal fragmentation of DNA. The addition of IGF-I markedly inhibited etoposide-induced apoptosis in a concentration-dependent manner. IGF-I was not mitogenic in the presence of etoposide. IGF-I was less effective in preventing apoptosis in parental BALB/c 3T3 cells and had no effect on etoposide-induced cell killing of mouse embryo fibroblasts that have a targeted disruption of the IGF-I receptor gene. These results demonstrate an important role for the IGF-I receptor as an inhibitor of apoptosis, independent of its mitogenic actions.
3T3 Cells↗
Use of magnetic resonance imaging and positron emission tomography in the assessment of synovial volume and glucose metabolism in patients with rheumatoid arthritis.
OBJECTIVE: To measure the anatomic and physiologic changes in the synovium of patients with active rheumatoid arthritis (RA) before and after the initiation of treatment with low-dose systemic glucocorticoids and methotrexate (MTX). METHODS: Two patients with RA with active synovitis involving the carpus were evaluated by imaging parameters at baseline and again after 14 weeks (of treatment with low-dose prednisone and MTX). Standard clinical parameters, laboratory measurements, and contrast-enhanced magnetic resonance imaging (MRI) (synovial volume estimate) and positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (18-FDG) (synovial metabolism estimate) were performed. RESULTS: Compared with baseline, standard clinical parameters (i.e., joint count, joint index, morning stiffness, global assessments of arthritis activity, and erythrocyte sedimentation rate) improved dramatically in both patients after treatment with low-dose prednisone and MTX. In concert with this trend, the synovial volume of the affected wrist was reduced by 60%, and 76% and the metabolism of 18-FDG was reduced by 66% and 69% in the 2 patients. CONCLUSION: These preliminary observations indicate that a volumetric estimate of inflamed synovium (using contrast-enhanced MRI) and quantification of synovial deoxyglucose metabolism (using PET) are technically feasible and, in the 2 reported cases, correlate well with standard outcome measures. These imaging modalities may provide new objective parameters to determine RA disease activity and effectiveness of antirheumatic medications; however, the potential clinical utility of these measures remains to be defined.
Arthritis, Rheumatoid↗
The radiologic and pathologic spectrum of biliary hamartomas.
OBJECTIVE: The purpose of our study was to correlate the spectrum of radiologic and pathologic findings in a series of patients with biliary hamartomas and known extrahepatic malignancy. MATERIALS AND METHODS: Biliary hamartomas were diagnosed in 18 patients with a primary malignant lesion who had liver biopsy for evaluation of possible metastatic disease. Prebiopsy imaging studies included CT in 16 patients and sonography in 11. Imaging studies were reviewed retrospectively and correlated with findings at surgery and on pathologic examination. The hamartomas were classified histologically by the degree of cystic dilatation of bile ducts within the lesion. RESULTS: Radiologically, biliary hamartomas presented a spectrum of findings including one or two circumscribed lesions (5-10 mm in diameter) in four patients; multiple (about five) lesions (approximately 5 mm each) in one patient; innumerable tiny, nearly uniform (2-5 mm) lesions in two patients; and innumerable lesions of varying size (2-15 mm) in three patients. Among the patients with innumerable lesions, the nodules were either uniformly or nonuniformly distributed throughout the liver. In all cases, the lesions were hypodense on contrast-enhanced CT scans and hypoechoic on sonograms. In eight patients, the lesions were not visible by imaging but biopsies were done at surgery when single or multiple tiny nodules were noted on the liver surface. The diagnosis was made by either wedge or core-needle biopsy; fine-needle aspirations were nondiagnostic. Pathologic examination revealed single or multiple hamartomas of varying sizes ranging from solid to largely cystic lesions; the degree of cystic dilatation did not correlate with imaging findings. Visibility on imaging correlated with larger lesion size; small surface lesions were usually occult. CONCLUSION: Biliary hamartomas cause single or multiple nonspecific hepatic lesions that may mimic metastases. This diagnosis should be considered in patients with a primary malignant tumor when single or multiple small hepatic lesions are seen, regardless of uniformity of size or distribution.
Adult↗
CHIN overview: when you've seen one, you've seen one.
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Community Networks↗
Insulin-like growth factor-I receptor. Its role in cell proliferation, apoptosis, and tumorigenicity.
From the point of view of cell growth, the IGF-IR activated by its ligands has three important functions: (a) it is required for optimal growth both in vivo and in vitro, although some growth occurs even in its absence; (b) it is obligatory for the establishment and maintenance of the transformed phenotype and for tumorigenesis for several types of cells; and (c) it protects cells from apoptosis, both in vivo and in vitro. The IGF-I receptor does seem to occupy a central role in these processes. Whereas an overexpressed IGF-I receptor is mitogenic for IGF-I alone and is fully transforming and protects cells from apoptosis, the same cannot be said for overexpressed EGF and PDGF receptors (205, 206). These two receptors can neither induce growth or transform most cells lacking IGF-I receptors. The reversal of the transformed phenotype and the induction of apoptosis that occur when the levels of IGF-I receptors are artificially decreased also point out the essential role of the receptor in these three processes. An important distinction in this regard is that it is not so much an overexpressed IGF-I receptor that is important in transformation but the lack of it that does not allow the transformed phenotype. This distinction is extremely important if we wish to use the IGF-IR as an approach to therapeutic interventions. Returning to more basic questions, a mutational analysis of the IGF-I receptor has shown that specific domains are involved in its mitogenicity or its ability to facilitate transformation and that these two processes can be separated at the level of the receptor itself. This finding raises a crucial question: Is the transforming activity using a pathway that is separate from the mitogenic signaling pathway? Alternatively, is it simply a question of a quantitative effect? The answer to this question could be a very important contribution to the mechanism of transformation. Little is known about the mechanism(s) by which the IGF-I receptor protects cells from apoptosis; here again, some fundamental questions can be raised. Are there specific domains in the receptor for its antiapoptotic activity? Is this activity tied to mitogenesis and/or transformation? Which elements in the signal transduction pathway are involved in these three different functions of the IGF-I receptor? Although many problems are still unresolved, the last few years have seen a very rapid rise in the importance of the IGF-I receptor in both normal and abnormal growth.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis.
One hundred fifty-one patients with primary biliary cirrhosis (PBC) grouped into four strata based on entry serum bilirubin ( < 2 mg/dL vs. 2 md/dL or greater) and liver histology (stages I, II vs. stages III, IV-Ludwig criteria) were randomized within each stratum to ursodiol or placebo given in a single dose of 10 to 12 mg/kg at bedtime for 2 years. Placebo- (n = 74) and ursodiol- treated (n = 77) patients were well matched at baseline for demographic and prognostic factors. Ursodiol induced major improvements in biochemical tests of the liver in strata 1 and 2 (entry bilirubin < 2), but had less effect on laboratory tests in patients with entry serum bilirubin of > or +2 (strata 3 and 4). Histology was favorably affected by ursodiol in patients in strata 1 and 2 but not in strata 3 and 4. Ursodiol enrichment in fasting bile obtained at the conclusion of the trail was approximately 40% and comparable in all strata. Thus, differences in ursodiol enrichment of the bile acid pool do not explain better responses of laboratory tests and histology found in patients with less advanced PBC. Patients treated will ursodiol tended to develop a treatment failure less frequently that those who received placebo, particularly in strata 1 and 2 (ursodiol 42%, placebo 60%, P = .078). Development of severe symptoms (fatigue/pruritus) and doubling of serum bilirubin were reduced significantly in ursodiol-treated patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Histopathological heterogeneity in fulminant hepatic failure.
The clinicopathological features of 38 patients admitted consecutively for fulminant hepatic failure were studied. Histopathological material was reviewed in all patients. Both percutaneous and whole livers (either explanted or autopsy specimens) were available in 16 patients: whole livers only in 12 patients and biopsy specimens only in 10 patients. All patients were negative for antibodies to hepatitis C, whereas 24% had hepatitis B infection and 10% had adverse drug reactions. Livers from 75% of patients showed confluent hepatic necrosis. However, there was considerable variability in the extent of necrosis, and biopsy specimens from about 50% of the most severely affected livers showed only minimal bridging necrosis. In patients with massive hepatic necrosis, percutaneous liver biopsy specimens were frequently misleading because of regional inhomogeneities. Interestingly, five patients (13%) had established cirrhosis at the time of diagnosis. The best clinical predictors of survival were age and the maximal grade of encephalopathy. By contrast, neither the severity of confluent hepatic necrosis nor the etiology predicted the decision to transplant or the outcome. There were no differences in the histopathology corresponding to different etiologies. In summary, the approach to the patient with fulminant hepatic failure should be guided principally on clinical grounds, and further classification should be based on pathological and etiologic considerations. However, histological classification and prognosis based on percutaneous biopsy specimens alone may be misleading.
Adolescent↗
Growth inhibition of human melanoma cells in nude mice by antisense strategies to the type 1 insulin-like growth factor receptor.
The growth of human melanoma cells FO-1 in nude mice is strongly inhibited or even abrogated when the cells are stably transfected with a plasmid expressing an antisense RNA to the insulin-like growth factor 1 receptor (IGF-1R) RNA, which causes a marked reduction in the number of IGF-1 receptors. When a tumor arises after a long delay in nude mice, it can be shown that the tumor cells have lost the expression plasmid and that the number of IGF-1 receptors has returned to wild-type levels. The antisense effect is even more remarkable, since the growth of FO-1 melanoma cells in monolayers is not affected by the expression of the antisense RNA. Inhibition of tumorigenesis was also evident when FO-1 melanoma cells were treated with antisense oligodeoxynucleotides to the IGF-1R RNA prior to injection into nude mice. These results confirm in human cells that the IGF-1R plays a dominant role in transformation and tumorigenesis and that its effect on tumorigenesis is more profound than its effect on mitogenesis.
Animals↗
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Female↗
Leupeptin inhibits phospholipases D and C activation in rat hepatocytes.
The relationship between phospholipase D and C activation was studied in intact rat hepatocytes and rat liver plasma membranes. In intact hepatocytes, in the presence of ethanol, vasopressin, phorbol ester, and calcium independently stimulated phosphatidylethanol (PETH) formation, a specific marker of phospholipase D activity. Leupeptin (10-1500 microM) inhibited PETH formation induced by vasopressin, but was ineffective in response to phorbol ester or calcium. Leupeptin also inhibited the formation of inositol phosphates in intact cells in response to vasopressin. In liver plasma membranes, GTP[S] induced the production of phosphatidic acid and, in the presence of ethanol, PETH. Plasma membrane-associated phospholipase D did not require calcium and was insensitive to protein kinase C inhibitors. Leupeptin inhibited PETH formation in response to GTP[S]. The inhibition by leupeptin could be overcome by increasing the concentration of GTP[S]. In plasma membranes, the inhibitory effects of leupeptin on phospholipase D occurred at doses that far exceed those required to maximally inhibit proteolysis. These data highlight a central role for phospholipase C in the activation of phospholipase D, and a minor role for a direct G-protein activation. The findings also demonstrate a novel use of leupeptin as an inhibitor of phospholipases D and C, perhaps at the level of a G protein.
Animals↗
America's best hospitals.
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Attitude of Health Personnel↗
Best hospitals. Raising questions of care.
What should you do if finances--or geography or health plan rules--put a high-ranked hospital out of reach? Good question. Here are some answers, along with other hypothetical questions related to hospital choice, access and cost. The responses, developed with the help of medical and consumer experts, are real.
Consumer Advocacy↗
Rat glioblastoma cells expressing an antisense RNA to the insulin-like growth factor-1 (IGF-1) receptor are nontumorigenic and induce regression of wild-type tumors.
Insulin-like growth factor-1 (IGF-1) and IGF-2 are critical regulators of cell proliferation. The growth-promoting action of both ligands is mediated by the type 1 IGF receptor (IGF-1R). We have investigated the role of the IGF-1R in the growth and tumorigenicity of rat C6 glioblastoma cells. For this purpose, antisense RNA to IGF-1R RNA was introduced into cells by either the addition of oligodeoxynucleotides or by transfection with plasmids that express antisense RNA to IGF-1R RNA. At low cell density, C6 cells grew slowly in serum-free medium and proliferated with the sole addition of IGF-1 or IGF-2. Both antisense IGF-1R oligodeoxynucleotides and stable transfection with a plasmid expressing an antisense IGF-1R RNA inhibited IGF-1-mediated growth in monolayers and clonogenicity in soft agar. Sense oligodeoxynucleotides and sense-expressing plasmid had no effect on either parameter. In stable antisense transfectants, tyrosine-phosphorylated IGF-1 receptors were not detectable, although they were easily detected in wild-type cells. When wild-type C6 cells were injected s.c. into syngeneic immunocompetent rats, tumors developed within 1 week. In contrast, stably transfected C6 cells overexpressing antisense IGF-1R RNA were nontumorigenic. Moreover, when C6 IGF-1R antisense cells were injected, subsequent tumor formation by wild-type C6 cells was completely prevented. Finally, injection of C6 IGF-1R antisense cells into rats carrying an established wild-type C6 tumor caused complete regression of the tumors. The results demonstrate the critical importance of the IGF-1R in glioblastoma cell growth, clonogenicity, and tumorigenicity. Although the mechanism is presently unknown, the fact that the injection of C6 cells expressing an antisense RNA to IGF-1R RNA leads to regression of already established wild-type C6 tumors suggests the possibility of practical applications.
Animals↗
The role of cytosolic Ca2+, protein kinase C, and protein kinase A in hormonal stimulation of phospholipase D in rat hepatocytes.
Ca(2+)-dependent and protein kinase C-dependent mechanisms of phospholipase D (PLD) activation were studied in rat hepatocytes by measuring phosphatidylethanol (Peth) formation in the presence of ethanol. Stimulation of Peth formation by 12-O-tetradecanoyl-phorbol 13-acetate (TPA), vasopressin, or A23187 was inhibited by multiple protein kinase C inhibitors or by protein kinase C down-regulation, indicating that this enzyme is involved in the action of all these agents. A controlled elevation of the cytosolic Ca2+ concentration ([Ca2+]cyt) over the range of 0.1-2.0 microM activated Peth formation in the absence of other agonists. Staurosporin potentiated Ca(2+)-induced Peth formation by shifting the [Ca2+]cyt dose-response curve to the left. Other protein kinase C inhibitors (calphostin C, bisindolylmaleimide) inhibited Ca(2+)-mediated Peth formation, but this inhibition was reduced in staurosporin-treated cells. Okadaic acid potentiated PLD activation by TPA, but suppressed PLD activation by elevated [Ca2+]cyt. Desensitization of TPA-induced PLD activity did not affect PLD activation by Ca2+. These data indicate that [Ca2+]cyt and protein kinase C control distinct pathways of PLD activation, but the Ca(2+)-mediated pathway is suppressed by a staurosporin-sensitive protein kinase. Both mechanisms contribute to vasopressin-induced Peth formation in intact hepatocytes. Activation of protein kinase A enhanced vasopressin-induced Peth formation, but not TPA-stimulated or Ca(2+)-stimulated stimulated Peth formation. Protein kinase A acted by enhancing hormonal Ca2+ mobilization, rather than by directly activating PLD, and thereby shifted the balance of Ca(2+)-dependent and protein kinase C-dependent activation mechanisms of PLD in intact cells.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗