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Biomedical subjects

R Rubin

Publications and source records attributed to R Rubin.

At least 55 records · Page 3Linked to original sources
PubMed1998

Interferon-alpha2b therapy is efficacious in Asian-Americans with chronic hepatitis B infection: a prospective controlled trial.

Chronic hepatitis B virus infection is endemic in Asian communities in the United States. The purpose of the current study was to compare the antiviral efficacy of interferon-alpha2b in a group of adult Asian patients chronically infected with hepatitis B with active replication compared to a control group of Caucasian patients treated with the same regimen. Patients with entry aminotransferase (ALT) levels greater than three times the upper limit of normal received interferon-alpha2b, 5 million units, subcutaneously daily for 16 weeks. Patients with pretreatment ALT levels 1.5-3 times the upper limit of normal received prednisone for a total of six weeks prior to interferon starting at 60 mg daily with reduction in dosage by 20 mg every two weeks with a two-week period between finishing prednisone and starting interferon-alpha2b. Eight (62%) of the 13 Asians and six (60%) of the 10 Caucasians cleared HBeAg and HBV DNA from serum (NS). By the end of one year of follow-up after therapy, four (67%) of six Caucasian responders but none of the Asian responders had cleared hepatitis B surface antigen from serum (P < 0.05). Loss of serum markers of active replication appeared less durable in the Asian responders compared to the Caucasians with reappearance of serum HBeAg in two (25%) of eight of the former but only one (17%) of the latter group. Three other Asian patients subsequently redeveloped HBeAg in serum. It is concluded that adult Asian-Americans have an identical initial response rate to antiviral therapy with interferon-alpha2b; however, the response may be less durable and does not usually lead to loss of HBsAg.

Adult↗
PubMed1998

Ethanol induces apoptosis in cerebellar granule neurons by inhibiting insulin-like growth factor 1 signaling.

The ability of ethanol to interfere with insulin-like growth factor 1 (IGF-1)-mediated cell survival was examined in primary cultured cerebellar granule neurons. Cells underwent apoptosis when switched from medium containing 25 mM K+ to one containing 5 mM K+. IGF-1 protected granule neurons from apoptosis in medium containing 5 mM K+. Ethanol inhibited IGF-1-mediated neuronal survival but did not inhibit IGF-1 receptor binding or the neurotrophic action of elevated K+, and failed to potentiate cell death in the presence of 5 mM K+. Inhibition of neuronal survival by ethanol was not reversed by increasing the concentration of IGF-1. Significant inhibition by ethanol (15-20%) was observed at 1 mM and was half-maximal at 45 mM. The inhibition of IGF-1 protection by ethanol corresponded to a marked reduction in the phosphorylation of insulin receptor substrate 1, the binding of phosphatidylinositol 3-kinase (PI 3-kinase), and a block of IGF-1-stimulated PI 3-kinase activity. The neurotrophic response of IGF-1 was also inhibited by the PI 3-kinase inhibitor LY294002, the protein kinase C inhibitor chelerythrine chloride, and the protein kinase A inhibitor KT5720, but unaffected by the mitogen-activated protein kinase kinase inhibitor PD 98059. These data demonstrate that ethanol promotes cell death in cerebellar granule neurons by inhibiting the antiapoptotic action of IGF-1.

Animals↗
PubMed1998

Triage of women with ASCUS and LSIL on Pap smear reports: management by repeat Pap smear, HPV DNA testing, or colposcopy?

BACKGROUND: The purpose of this study was to determine the efficacy of a repeat Papanicolaou (Pap) smear and the Hybrid Capture tube-based (HCT) HPV DNA test for detecting cervical intraepithelial neoplasia (CIN) grade 2 or 3 in women with recent atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) Pap smear reports. METHODS: Women with a recent Pap smear report of ASCUS (n = 169) or LSIL (n = 110) had a repeat Pap smear, sampling of the cervix for HCT HPV DNA assay and a colposcopy examination. Data were evaluated using three different triage thresholds for colposcopy examination: a repeat Pap smear of persistent ASCUS or more severe dysplasia, a finding of persistent LSIL or more severe dysplasia, and a carcinogenic HPV test result. RESULTS: The sensitivity, specificity, and positive and negative predictive values for detecting CIN 2/3 were 70%, 45%, 7%, and 96% for a repeat Pap smear using an ASCUS-positive threshold and 20%, 86%, 8%, and 94% for a repeat Pap smear using an LSIL-positive threshold, respectively, when women with an initial ASCUS Pap smear were considered. HPV testing for carcinogenic viruses alone or in combination with a repeat Pap smear (using ASCUS as a positive threshold) yielded results of 50%, 67%, 9%, and 96%, respectively, and 70%, 37%, 7%, and 95%, respectively, for detecting CIN 2/3. In women with an initial LSIL Pap smear, respective values for detecting CIN 2/3 by a repeat Pap smear with an ASCUS threshold were 92%, 26%, 14%, and 96%, and for an LSIL threshold 23%, 64%, 8%, and 86%, respectively. Hybrid Capture HPV testing alone or in combination with a repeat Pap smear yielded 69%, 43%, 14%, and 91%, respectively, and 100%, 21%, 14%, and 100%, respectively. CONCLUSIONS: A Pap smear triage threshold restricted to LSIL or more severe dysplasia for women with prior ASCUS or LSIL Pap smear results was clearly ineffective for detecting high-grade cervical precancerous lesions. In contrast, when the repeat Pap smear triage threshold was expanded to include persistent ASCUS as abnormal, 83% of the women with CIN 2/3 were detected. Detection of carcinogenic HPV DNA using the HCT test was almost as sensitive for detecting CIN 2/3 as a solitary repeat Pap smear using an ASCUS or more severe positive threshold. Combining the HPV test with a repeat Pap smear did not significantly improve the sensitivity of cytology for detecting high-grade CIN. This study suggests that women with ASCUS and particularly LSIL Pap smears should be referred for a colposcopy examination until better triage methods become available.

Adult↗
PubMed1997

AAC-11, a novel cDNA that inhibits apoptosis after growth factor withdrawal.

Many growth factors and cytokines act as cellular survival factors by preventing programmed cell death (apoptosis). However, the specific genes and corresponding proteins that mediate survival are poorly defined. To identify potential survival genes, a cDNA library was prepared from murine fibroblasts and screened by a functional expression cloning approach. A 1023-bp cDNA, AAC-11, was identified that encodes a protein of approximately 25 kDa. The AAC-11 gene shows strong species conservation and is ubiquitously expressed in embryonic and adult tissues with multiple transcripts, as well as in various human tumor cell lines. The predicted protein contains a leucine zipper domain but lacks a DNA-binding domain. BALB/c3T3 fibroblasts that were stably transfected with AAC-11 cDNA were viable in serum-free medium for up to 12 weeks. The protective action of AAC-11 was abolished by mutation of leucines to arginines within the leucine zipper domain. We also isolated a longer AAC-11 cDNA that codes for up to an additional 290 amino-terminal amino acids but did not protect against apoptosis. The cDNA for human AAC-11 was identified and exhibits strong homology with the murine species and retains the leucine zipper domain. Western immunoblots of BALB/c3T3 cells using rabbit anti-AAC-11 polyclonal serum revealed a major native 55-kDa AAC-11 protein and a minor 25-kDa protein corresponding to the long and short forms of AAC-11 cDNA, respectively. In summary, we report a cDNA whose expression supports cell viability after withdrawal of growth factors. The corresponding native protein may function as a novel inhibitor of apoptosis.

Alternative Splicing↗
PubMed1997

Structure-activity relationships in a series of orally active gamma-hydroxy butenolide endothelin antagonists.

The design of potent and selective non-peptide antagonists of endothelin-1 (ET-1) and its related isopeptides are important tools defining the role of ET in human diseases. In this report we will describe the detailed structure-activity relationship (SAR) studies that led to the discovery of a potent series of butenolide ETA selective antagonists. Starting from a micromolar screening hit, PD012527, use of Topliss decision tree analysis led to the discovery of the nanomolar ET(A) selective antagonist PD155080. Further structural modifications around the butenolide ring led directly to the subnanomolar ETA selective antagonist PD156707, IC50's = 0.3 (ET(A)) and 780 nM (ET(B)). This series of compounds exhibited functional activity exemplified by PD156707. This derivative inhibited the ETA receptor mediated release of arachidonic acid from rabbit renal artery vascular smooth muscle cells with an IC50 = 1.1 nM and also inhibited the ET-1 induced contraction of rabbit femoral artery rings (ETA mediated) with a pA2 = 7.6. PD156707 also displayed in vivo functional activity inhibiting the hemodynamic responses due to exogenous administration of ET-1 in rats in a dose dependent fashion. Evidence for the pH dependence of the open and closed tautomerization forms of PD156707 was demonstrated by an NMR study. X-ray crystallographic analysis of the closed butenolide form of PD156707 shows the benzylic group located on the same side of the butenolide ring as the gamma-hydroxyl and the remaining two phenyl groups on the butenolide ring essentially orthogonal to the butenolide ring. Pharmacokinetic parameters for PD156707 in dogs are also presented.

Administration, Oral↗
PubMed1997

Ethanol promotes cell death by inhibition of the insulin-like growth factor I receptor.

The mechanism by which chronic alcohol abuse induces widespread cell and tissue damage is unknown. Insulin-like growth factor I (IGF-I) is an important inhibitor of apoptosis in many cell types, in addition to its ability to stimulate proliferation. We have demonstrated previously (J. Biol. Chem. 268:21777-21782, 1993; Lab. Invest. 71:657-662, 1994) that ethanol in low concentrations inhibits the tyrosine autophosphorylation of the IGF-I receptor (IGF-IR) and IGF-I-mediated cell proliferation. We now demonstrate that ethanol reverses the antiapoptotic action of the IGF-IR in a tumor necrosis factor-alpha (TNF-alpha) model of apoptosis. In serum-depleted medium, IGF-I markedly protected BALB/c3T3 cells from TNF-alpha-induced apoptosis. Ethanol reversed the protective action of IGF-I, but did not enhance TNF-alpha killing in the absence of IGF-I. Half-maximal effective concentrations of ethanol were 5 to 10 mM. In the presence of 5 to 10% fetal bovine serum, TNF-alpha was cytotoxic for 3T3 cells only in the presence of ethanol. Mouse embryo fibroblasts with targeted knockout of the IGF-IR were completely insensitive to ethanol, in contrast with the ethanol-induced potentiation of apoptosis in wild-type cells. These results indicate that ethanol directly interacts with cellular factors that inhibit apoptosis and could provide a novel mechanism for ethanol-induced cytotoxicity in general.

Animals↗
PubMed1996

Rating the HMOs.

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Community Participation↗
PubMed1996

The war on cancer.

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Disease Progression↗
PubMed1996

Activation of the insulin-like growth factor-I receptor inhibits tumor necrosis factor-induced cell death.

The effect of insulin-like growth factor (IGF) on tumor necrosis factor (TNF)-induced cell killing was determined for mouse BALB/c3T3 fibroblasts in vitro. Cells maintained in 0.5% fetal bovine serum (FBS) were killed by TNF within 6 h in a concentration-dependent manner, an effect that was prevented by IGF-I. TNF-induced cytotoxicity of 3T3 cells that overexpress the human IGF-I receptor (p6 cells) was prevented by IGF-I alone in the absence of serum. TNF-induced cell death was associated with the morphologic features of apoptosis and the release of low-molecular-weight DNA, both of which were prevented by IGF-I. Neither epidermal growth factor (EGF) nor platelet-derived growth factor (PDGF) protected p6 cells from TNF-induced apoptosis. The specific protective action of the IGF-I receptor was demonstrated further by the marked sensitivity to TNF of embryo fibroblasts derived from mice with targeted disruption of the IGF-I receptor (R-cells) but not of fibroblasts derived from wild-type littermates or R-cells transfected with the cDNA for the human IGF-I receptor. Cycloheximide or actinomycin D markedly reduced the protection offered by IGF-I. IGF-I protection of BALB/c3T3 cells persisted for up to 5 days in the presence of PDGF and EGF, whereas IGF-I lost its effectiveness after 2 days in the absence of growth factors. IGF-I did not prevent TNF-induced release of arachidonic acid. The results demonstrate a specific role for the IGF-I receptor in the protection against TNF cytotoxicity. This action of the IGF-I receptor is mediated by protective cytosolic proteins that exhibit a high rate of turnover and whose levels are regulated principally by factors within serum other than IGF-I.

3T3 Cells↗
PubMed1996

Inhibition of rat C6 glioblastoma tumor growth by expression of insulin-like growth factor I receptor antisense mRNA.

The expression of insulin-like growth factor I receptor (IGF-IR) antisense mRNA inhibits the growth of C6 rat glioblastoma cells both in vitro and in vivo [Cancer Res (1994) 54:2218]. Moreover, the injection of C6 cells expressing an antisense mRNA to the IGF-IR into syngeneic rats prevents subsequent wild-type tumorigenesis and induces regression of established tumors. For the study of immune function in syngeneic rats, C6 cells expressing either IGF-IR sense or IGF-IR antisense mRNA were injected and splenic lymphocyte function analyzed in vitro after 2 weeks. Cytotoxic, CD8+ lymphocytes from animals injected with IGF-IR antisense cells, but not from those treated with IGF-IR sense cells, proliferated in vitro in response to wild-type C6 cells. Wild-type C6 cells or IGF-IR-sense-RNA-expressing cells rapidly formed tumors upon subcutaneous injection into athymic nude mice. IGF-IR antisense cells were weakly tumorigenic, exhibiting a six- to tenfold increase in tumor latency. Injection of IGF-IR antisense C6 cells mildly delayed the development of wild-type tumors, and did not induce the regression of established wild-type C6 tumors in athymic nude mice. Thus, these findings demonstrate the stimulation of a cellular immune response in rats following the injection of IGF-IR antisense cells. However, studies of athymic nude mice indicate that expression of IGF-IR antisense mRNA also inhibits C6 cells tumorigenicity by additional mechanisms.

Animals↗
PubMed1996

Ethanol-induced inhibition of cell proliferation is modulated by insulin-like growth factor-I receptor levels.

Ethanol inhibits the tyrosine autophosphorylation of the insulin-like growth factor (IGF)-I receptor, an action that correlates with the inhibition of IGF-I-stimulated cell proliferation [J. Biol. Chem. 268:21777-21782 (1993)]. In the current study, the IGF-I-dependent proliferation of mouse BALB/c3T3 cells was completely inhibited by ethanol, but the growth of BALB/c3T3 cells that overexpress the IGF-I receptor (p6 cells) was only partially inhibited by ethanol BALB/ c3T3 cells that simultaneously overexpress both the IGF-I receptor and IGF-I were insensitive to growth inhibition by ethanol. In p6 cells, increasing concentrations of IGF-I overcame the inhibition of IGF-I receptor tyrosine autophosphorylation in the presence of ethanol. The importance of the IGF-I receptor as a specific target for ethanol was further investigated in C6 rat giloblastoma cells that respond mitogenically to both epidermal growth factor (EGF) and IGF-I. The mitogenic response of C6 cells to EGF was abrogated in cells expressing antisense mRNA to the IGF-I receptor. Thus, EGF action in these cells is dependent on activation of an IGF-I/IGF-I receptor autocrine pathway. Indeed, EGF stimulated an increase in IGF-I receptor levels by more than 100%. Ethanol completely inhibited the proliferation of C6 cells in response to either EGF or IGF-I. However, ethanol did not directly interfere with EGF receptor function, because EGF-induced cell proliferation was unaffected by ethanol when added exclusively during a 1-hr exposure to EGF. Ethanol did not interfere with the EGF-induced increase in IGF-I receptor expression. The addition of both EGF and IGF-I overcame the inhibitory action of ethanol. In conclusion, the potency of ethanol as an inhibitor of IGF-I-mediated cell proliferation correlates with the level of IGF-I receptors. In contrast to its effect on the IGF-I-receptor, ethanol has no direct effect on EGF receptor activation.

Animals↗