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R T Curnow

Publications and source records attributed to R T Curnow.

34 records · Page 2Linked to original sources
PubMed1979

Association of glycogen synthase phosphatase and phosphorylase phosphatase activities with membranes of hepatic smooth endoplasmic reticulum.

A detailed investigation was conducted to determine the precise subcellular localization of the rate-limiting enzymes of hepatic glycogen metabolism (glycogen synthase and phosphorylase) and their regulatory enzymes (synthase phosphatase and phosphorylase phosphatase). Rat liver was homogenized and fractionated to produce soluble, rough and smooth microsomal fractions. Enzyme assays of the fractions were performed, and the results showed that glycogen synthase and phosphorylase were located in the soluble fraction of the livers. Synthase phosphatase and phosphorylase phosphatase activities were also present in soluble fractions, but were clearly identified in both rough and smooth microsomal fractions. It is suggested that the location of smooth endoplasmic reticulum (SER) within the cytosome forms a microenvironment within hepatocytes that establishes conditions necessary for glycogen synthesis (and degradation). Thus the location of SER in the cell determines regions of the hepatocyte that are rich in glycogen particles. Furthermore, the demonstration of the association of synthase phosphatase and phosphorylase phosphatase with membranes of SER may account for the close morphological association of SER with glycogen particles (i.e., disposition of SER membranes brings the membrane-bound regulatory enzymes in close contact with their substrates).

Animals↗
PubMed1978

Effect of starvation on hepatic glycogen metabolism and glucose homeostasis.

The effects of starvation on the hepatic glycogen synthase and phosphporylase systems were sequentially assessed in fed and 24-120-hr-fasted rats. Enzymic changes before and after glucose were correlated with simultaneous measurements of hepatic cyclic AMP and glycogen concentrations and glucose, insulin, and glucagon concentrations in the portal vein plasma. Fasting caused parallel changes in plasma glucose and hepatic glycogen concentrations with decreases by 24 hr and subsequent increases, which correlated with increases in hepatic synthase l and decreases in phosphorylase activites. Hepatic cyclic AMP levels increased as 24-48 hr, decreased below fed levels at 96 hr, and increased again at 120 hr. Fasting caused progressive impairment of glucose disposal, decreased basal and postglucose insulin concentrations, and decreased basal glucagon levels at 48-72 hr. Hepatic synthase l increments following glucose were exaggerated in 48-120-hr-fasted rats, although consistent phosphorylase decrements were seen only in fed rats. There was no clearcut relationship between synthase activation and phosphorylase inactivation following glucose in fed or fasted rats.

Animals↗
PubMed1978

Altered mechanism of glucagon-mediated hepatic glycogenolysis during long-term starvation in the rat.

The effect of long-term starvation on glucagon-mediated hepatic glycogenolysis was investigated in the rat in vivo. Following glucagon (50 microgram/kg i.v.) fed rats showed rapid phosphorylase activation but no change in synthase-I activities. In contrast, rats fasted 72 hr (long-term fasting) showed rapid synthase inactivation but no significant phosphorylase activation. Rats fasted 24 hr (short-term fasting) demonstrated coordinated inactivation of synthase and activation of phosphorylase. Hepatic cyclic AMP responses were greater in fasted rats. Hepatic glycogen concentrations in rats fasted 72 hr were approximately 30% of fed levels. After glucagon, comparable decrements in hepatic glycogen and increments in plasma glucose concentrations were seen in fed and 72-hr groups. The diminished responsiveness of the hepatic phosphorylase system in rats fasted 72 hr was not attributable to altered cyclic AMP-dependent protein kinase or phosphorylase kinase activities. However, the diminished responsiveness could be ascribed to diminished total phosphorylase with nearly complete activation in the basal state. In fed and fasted rats, synthase decrements after glucagon correlated closely with basal levels of synthase-I. Thus, it is proposed that the enzymatic mechanism of glucagon-mediated hepatic glycogenolysis differs in fed and fasted rats. It is also proposed that partial hepatic glycogen reaccumulation during long-term fasting could be physiologically important for glucose homeostasis.

Animals↗
PubMed1976

Altered hepatic glycogen metabolism and glucoregulatory hormones during sepsis.

Levels of glucose, insulin, and glucagon in portal vein plasma and of liver glycogen and cyclic AMP and activities of glycogen synthase and phosphorylase in liver were assayed in control (CONT) rats and rats infected (INF) with Diplococcus pneumoniae. In INF rats compared with CONT rats, insulin and glucagon levels were higher (8,12,24 h). Activity of synthase I was lower (8, 12, 24 h) and of phosphorylase higher (12 and 24 h) in INF rats. Cyclic AMP levels were higher in INF rats at 12 and 24 h. Total synthase activity was lower in INF rats at 24 h. Glucose given intravenously increased glycogen less in INF than in CONT rats and activated synthase and inactivated phosphorylase in all animals except at 24 h in INF rats. However, in situ perfusion of the livers at 24 h with glucose in buffer decreased phosphorylase activities in all animals and increased synthase I activities in CONT but not INF rats.

Animals↗
PubMed1976

Virus-induced pancreatic disease by Venezuelan encephalitis virus. Alterations in glucose tolerance and insulin release.

Viral infections have been implicated in the induction of diabetes mellitus in man and laboratory animals. Since virus-specific immunofluorescence (FA) is detectable in hamster pancreas during the acute phase of Venezuelan encephalitis (VE), experiments were designed to correlate pathologic and virologic events with metabolic studies in VE-infected hamsters. Golden Syrian hamsters were inoculated s.c. in groups of four to 12 with 100,000 plaque-forming units (PFU) of the vaccine strain (TC-83) of VE or 1,000 PFU of the virulent Trinidad strain of VE. Ultrastructurally, during Trinidad infection, mature virions were associated with the cell surfaces and within pancreatic beta cells in contrast to absence of virus-related changes in TC-83-infected hamsters. Virus-specific-FA was noted in islet cells and acinar cells of Trinidad-infected hamsters. VE growth curves demonstrated viral replication in pancreas with both strains. Although ultrastructural and FA changes were much more prominent in Trinidad-infected hamsters in contrast to TC-83-infected hamsters during the first few days of illness, the rapid lethality of the Trinidad-infected group necessitated performing all metabolic studies in TC-83-strain-infected hamsters. Accordingly, for the metabolic studies, glucose tolerance tests (GTT) using 2 mg. or 5 gm./kg. glucose i.p. were performed in groups of hamsters acutely infected two days earlier with the TC-83 vaccine strain and in 24-day and 90-day convalescent hamsters after TC-83 vaccine strain. Samples were obtained for glucose and immunoreactive insulin (IRI) determinations. Glucose intolerance occurred in hamsters in each of the infected groups given 5 gm./kg. glucose except for the 90-day convalescent TC-83 group. Severely decreased IRI responses occurred in the 24-day and 90-day convalescent TC-83 hamsters following both 2- and 5-gm./kg. glucose. Pancreatic IRI content in 24-day convalescent TC-83 hamsters was within normal limits, suggesting a defect in IRI release from the beta cells at this stage of convalescence.

Animals↗
PubMed1975

Control of hepatic glycogen metabolism in the rhesus monkey: effect of glucose, insulin, and glucagon administration.

The effects of intravenous glucose, insulin and glucagon admininistration on the hepatic glycogen synthase and glycogen phosphorylase systems were assessed in the anesthetized rhesus monkey. Results were correlated with measurements of hepatic cyclic AMP (cAMP) concentrations and plasma glucose, insulin, and glucagon concentrations. Both glucose and insulin administration promoted significant inactivation of phosphorylase by 1 min, which was followed by more gradual activation of synthase. Neither glucose nor insulin caused significant changes in hepatic cAMP. Marked hyperglucagonemia resulting from insulin-induced hypoglycemia did not cause increases IN in hepatic cAMP, suggesting that the elevated insulin levels possibly inhibited glucagon action on the hepatic adenylate cyclase-cAMP system. Glucagon administration caused large increases in hepatic cAMP and activation of phosphorylase within 1 min, followed by more gradual inactivation of synthase when it had been previously activated by glucose. Concomitant glucose infusion, with resulting increased plasma insulin concentrations, markedly diminished the duration of hepatic cAMP elevations following glucagon adminstration, again suggesting an insulin inhibition of glucagon action on the hepatic adenylate-cAMP system.

Animals↗
PubMed1975

A protein from polymorphonuclear leukocytes (LEM) which affects the rate of hepatic amino acid transport and synthesis of acute-phase globulins.

A proteinaceous secretion from phagocytizing polymorphonuclear leukocytes, termed "leukocytic endogenous mediator" (LEM), has been shown to have marked effects on hepatic amino acid transport and RNA and protein synthesis. A single injection of LEM results in a marked accumulation of labeled nonmetabolizable model amino acids in the liver of normal rats. The LEM-stimulated uptake of amino acids by liver was observed in adrenalectomized, hypophysectomized, thyroidectomized, or diabetic rats and could not be duplicated by pharmacological doses of a large variety of hormones. In addition, LEM stimulated an increased uptake of alpha-aminoisobutyric acid by isolated livers during their perfusion in vitro. LEM also stimulated an increased incorporation of orotic acid into hepatic RNA of intact rats, especially into the bound ribosomal fraction. This increased synthesis of RNA preceded an enhanced hepatic production of a number of the acute-phase plasma globulins. LEM did not stimulate the adenylate cyclase-cAMP system in liver and was not found to utilize this system as a second messenger. Thus, the effects of LEM in stimulating hepatic amino acid transport appear to be direct, without mediation by other hormones, and to be independent of cAMP. On the other hand, the ability of LEM to stimulate RNA and acute phase globulin synthesis in liver may require the presence of physiological quantities of hormones such as adrenal corticoids.

Adenylyl Cyclases↗
PubMedDate not supplied

Clinical experience with CD64-directed immunotherapy. An overview.

The class I IgG receptor (Fc gamma RI or CD64 receptor), which is present on key cytotoxic effector cells, has been shown to initiate the destruction of tumor cells in vitro and has been hypothesized to play a role in the destruction of antibody-coated cells such as platelets in idiopathic thrombocytopenia purpura (ITP). This overview summarizes the clinical experience with CD64-directed immunotherapy in cancer patients with the bispecific antibodies MDX-447 [humanized Fab anti-CD64 x humanized Fab anti-(epidermal growth factor receptor, EGFR)] and MDX-H210 (humanized Fab anti-DC64 x Fab anti-HER2/neu), and with the anti-CD64 monoclonal antibody (mAB) MDX-33 (H22) in the modulation of monocyte CD64 in vivo. In an ongoing phase I/II open-label trial with progressive dose escalation (1-15 mg/m2), patients with treatment refractory EGFR-positive cancers (renal cell carcinoma (RCC), head and neck, bladder, ovarian, prostate cancer and skin cancer) are treated weekly with intravenous MDX-447, with and without granulocyte-colony-stimulating factor (G-CSF). MDX-447 has been found to be immunologically active at all doses, binding to circulating monocytes and neutrophils (when given with G-CSF), causing monocytopenia and stimulating increases in circulating plasma cytokines. MDX-447 is well tolerated, the primary toxicities being fever, chills, blood pressure lability, and pain/ myalgias. Of 36 patients evaluable for response, 9 have experienced stable disease of 3-6 month's duration. The optimal dose and the maximal tolerated dose (MTD) have yet to be defined; dose escalation continues to define better the dose, toxicity, and the potential therapeutic role of this bispecific antibody. Three MDX-H210 phase II trials are currently in progress, all using the intravenous dose of 15 mg/m2 given with granulocyte/macrophage (GM-CSF). These consist of one trial each in the treatment of RCC patients, patients with prostate cancer, and colorectal cancer patients, all of whom have failed standard therapy. At the time of writing, 11 patients have been treated in these phase II trials. Four patients have demonstrated antitumor effects. Patients demonstrating responses include 2 with RCC and 2 with prostate cancer. One RCC patient has had a 54% reduction in size of a hepatic metastatic lesion and the other has had a 49% decrease in the size of a lung metastasis with simultaneous clearing of other non-measurable lung lesions. Regarding the two patients with prostate cancer, one has had a 90% reduction in serum prostate-specific antigen (PSA; 118-11 ng/ml), which has persisted for several months; the other patient with prostate has had a 70% reduction of serum PSA (872 ng/ml to 208 ng/ml) within the first month of treatment. Both patients have also demonstrated symptomatic improvement. In a completed phase I and in ongoing phase I/II clinical trials, patients with treatment-refractory HER2/neu positive cancers (breast, ovarian, colorectal, prostate) have been treated with MDX-H210, which has been given alone and in conjunction with G-CSF, GM-CSF, and interferon gamma (IFN gamma). These trials have been open-label, progressive dose-escalation (0.35-135 mg/m2) studies in which single, and more often, multiple weekly doses have been administered. MDX-H210 has been well tolerated, with untoward effects being primarily mild-to-moderate flu-like symptoms. The MTD has not yet been defined. MDX-H210 is immunologically active, binding to circulating monocytes, causing monocytopenia, as well as stimulating increases in plasma cytokine levels. Furthermore, some patients have evidence of active antitumor immunity following treatment with MDX-210. Antitumor effects have been seen in response to MDX-H210 administration; these include 1 partial, 2 minor, and 1 mixed tumor response; 15 protocol-defined stable disease responses have occurred. (ABSTRACT TRUNCATED)

Antibodies, Bispecific↗