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Biomedical subjects

David J Gross

Publications and source records attributed to David J Gross.

12 recordsLinked to original sources
PubMed2006

The role of imatinib mesylate (Glivec) for treatment of patients with malignant endocrine tumors positive for c-kit or PDGF-R.

Imatinib mesylate (IM), a small molecule that is a selective inhibitor of the ABL, platelet derived growth factor receptor (PDGFR-R) and stem cell ligand receptor (c-kit) tyrosine kinases (TK). IM was also found to inhibit the TK activity of BCR/ABL fusion protein produced in chronic myelogenous leukemia, with marked clinical activity against the disease. Since both PDGF-R and c-kit both having a putative role in tumorigenesis, we investigated the efficacy and safety of the use of IM in patients with endocrine tumors unresponsive to conventional therapies that expressed c-kit and/or PDGF-R (within the framework of a comprehensive phase II multi-center study of IM in patients with solid tumors). IM was initiated at a dose of 400 mg/day, with possible dose escalation within 1 week to 600 mg/day and an option to raise the dose to 800 mg/day in the event of progression and in the absence of safety concerns for a period of up to 12 months. Between September 2002 and July 2003, 15 adult patients with disseminated endocrine tumors were recruited as follows: medullary thyroid carcinoma (MTC, n = 6); adrenocortical carcinoma (ACC, n = 4); malignant pheochromocytoma (pheo, n = 2); carcinoid (non-secreting, n = 2), neuroendocrine tumor (NET, n = 1). No objective responses were observed. MTC--disease progression in 4 patients, and treatment discontinuation in 2 patients due to adverse events; ACC--disease progression in 3 patients, and treatment discontinuation in 1 patient due to severe psychiatric adverse event; Pheo--disease progression in 2 patients; Carcinoid--stable disease in 1 patient (6.5 months), and disease progression in 1 patient; NET--disease progression in 1 patient. IM does not appear to be useful for treatment of malignant endocrine tumors, also causing significant toxicity in this patient population.

Adolescent↗
PubMed2005

Epidermal growth factor receptor downregulation in cultured bovine cumulus cells: reconstitution of calcium signaling and stimulated membrane permeabilization.

Cumulus cell-oocyte complexes (COCs), cultured in vitro, are competent for maturation and fertilization. Inclusion of epidermal growth factor (EGF) in the COC culture medium enhances in vitro maturation and subsequent embryonic development. It has been shown that isolated COCs exposed to EGF respond with a prolonged and pulsatile release of Ca2+ into the extra-cellular medium and that cumulus cells (CCs) of complexes exhibit both a slow rise in intracellular [Ca2+] ([Ca2+]i) and plasma membrane permeabilization in response to EGF. These unusual signaling responses were examined in isolated, cultured bovine CCs. Few individual CCs showed [Ca2+]i increases; the lack of response was found to be due to decrease of expression of endogenous EGF receptors after dissociation. CCs transfected with a human EGF receptor-GFP fusion protein showed robust, prolonged, EGF-stimulated [Ca2+]i elevations characteristic of CC responses in intact COCs. Many CCs that responded to EGF stimulation with a [Ca2+]i rise also released entrapped fura-2 dye at the peak of the [Ca2+]i response, suggesting that CC permeabilization and death follows activation of the EGF receptor. The [Ca2+]i elevation due to EGF stimulation and subsequent membrane permeabilization was shown to be mediated by the inositol triphosphate signaling pathway.

Animals↗
PubMed2005

Etoposide, doxorubicin and cisplatin plus mitotane in the treatment of advanced adrenocortical carcinoma: a large prospective phase II trial.

To investigate the activity of etoposide, doxorubicin, and cisplatin plus mitotane in the management of advanced adrenocortical carcinoma (ACC) patients, 72 patients with measurable disease not amenable to radical surgery were enrolled in a prospective, multicenter phase II trial. EDP schedule (etoposide 100 mg/m(2) on days 5-7, doxorubicin 20 mg/m(2) on days 1 and 8, and cisplatin 40 mg/m(2) on days 1 and 9) was administered intravenously every 4 weeks. Concomitantly, patients were given up to 4 g/day of oral mitotane. Five patients achieved a complete response and 30 a partial response, for an overall response rate of 48.6% (95% CI: 37.1-60.3). Median time to progression in responding patients was 18 months. The EDP regimen was well tolerated, leukopenia being the dose limiting toxicity. One toxic related death due to septic shock, however, was registered. Radical surgical resection of residual disease after chemotherapy was performed in 10 patients. The overall survival of patients attaining a disease free status (clinical complete responders+radically resected) was significantly higher than that of patients with partial response or no response (P<0.002). Androgen secretion was associated with long survival, while glucocorticoid secretion was associated with poor prognosis both in univariate and multivariate analysis. In conclusion, EDP plus mitotane is an active and manageable combination scheme for ACC patients. Surgical resection of residual disease subsequent to chemotherapy leads to a more favourable outcome. The natural history of the disease is significantly influenced by the secretory status of the tumor.

Adolescent↗
PubMed2004

Epidermal growth factor activates cytosolic [Ca2+] elevations and subsequent membrane permeabilization in mouse cumulus-oocyte complexes.

The role of epidermal growth factor (EGF) in the maturation of mammalian oocytes is well known but not well characterized. It is known that EGF enhances oocyte maturation in vitro and that EGF stimulation of cumulus-oocyte complexes (COCs) induces pulsatile Ca(2+) efflux from the cell complex. By use of quantitative Fura-2 imaging, EGF-stimulated changes in intracellular [Ca(2+)] in germinal vesicle stage murine COCs are shown to occur in a subpopulation of cumulus cells that interact cooperatively within individual COCs. Oocytes fail to respond to EGF stimulus. In many of the cumulus cells responding with a rise in intracellular [Ca(2+)], a concomitant permeabilization of the plasma membrane is found. Neither cumulus cells of control COCs nor those that show a rise in intracellular [Ca(2+)] in response to calcium ionophore treatment display a similar membrane permeabilization, although those cells responding with a prolonged [Ca(2+)] increase in response to thimerosal or thapsigargin do display plasma membrane permeabilization. Thus, EGF stimulation of mammalian COCs activates release of Ca(2+) from intracellular stores of cumulus cells, the depletion of which activates permeabilization of the plasma membrane. This membrane permeabilization leads to loss of cell contents and presumptive cumulus cell death. This catastrophic EGF-induced plasma membrane permeabilization of individual cumulus cells within a COC leads to pulsatile Ca(2+) efflux as previously seen, and may lead to improved cumulus cell expansion during COC maturation.

Animals↗
PubMed2004

Trends in manufacturer prices of brand name prescription drugs used by older Americans--first quarter 2004 update.

This Issue Brief reports on changes in manufacturers' prescription drug prices during the first three months of 2004 (January through March) for the brand name prescription drugs most widely used by Americans age 50 and over. This report is the first quarterly update in an ongoing study of changes in drug manufacturer prices-that is, manufacturers' prices charged for drugs they sold to wholesalers. A baseline study published in May 2004 by the AARP Public Policy Institute identified steady increases in the average annual manufacturer price from calendar year 2000 through calendar year 2003. This report's focus is on changes in the prices that brand name drug manufacturers charge to wholesalers for sales to retail pharmacies. The manufacturer's charge to wholesalers is the most substantial component of a prescription drug's retail price. When there is an increase in the manufacturer price to wholesalers for a brand name drug, this added cost is generally passed on as a similar percent change in the retail price to most prescription purchasers. The report presents three measures of price change (see methodological appendix). The first set of findings are annual rates of change in manufacturers' prices for widely used brand name drugs, using both rolling average and point-to-point estimates; information is presented on percentage change in manufacturer price and on potential dollar changes in consumer spending. The second set of findings are three-month percentage changes in prices (i.e., changes from December 31, 2003 through March 31, 2004); the distribution of percentage price changes is shown, as well as differences in average percentage price changes by manufacturer and by therapeutic category.

Aged↗
PubMed2003

Regulated EGF receptor binding to F-actin modulates receptor phosphorylation.

The epidermal growth factor receptor (EGFR) is known to bind to the F-actin cytoskeleton in intact cells, and this interaction has been suggested to sequester the EGFR signal transduction system to specific loci within the cell. In this study, the interaction of the EGFR with actin is examined in a reconstituted cell free system. Soluble protein components of the cytosol from A431 cells are shown to dramatically enhance binding of the EGFR to F-actin in a saturable, concentration-dependent fashion. Most of the intracellular C-terminal portion of the EGFR is found to be required for this interaction. Binding of the EGFR to F-actin strongly deactivates the receptor by diminishing EGFR autophosphorylation activity and enhancing tyrosine phosphatase activity toward the EGFR. These results suggest that a ternary or larger protein signaling complex forms on an F-actin cellular scaffold, providing a spatially restricted signal modulation site that can be regulated by cytoskeletal remodeling.

Actins↗
PubMed2003

Treatment with halofuginone results in marked growth inhibition of a von Hippel-Lindau pheochromocytoma in vivo.

Halofuginone has recently been shown to inhibit tumor progression of various types of cancers. The antitumoral effect was associated with decreased tumor angiogenesis rather than a direct cytostatic effect on the tumor cells. The antiangiogenic action of the drug could be related to its inhibition of collagen type I synthesis, inhibition of matrix metalloproteinases (MMPs), or via both mechanisms because both collagen synthesis and MMP activity have been shown to be involved in angiogenesis. Vascular endothelial growth factor (VEGF), in addition to its effect on endothelial cell proliferation, has been shown to be a potent inducer of MMP expression. Because von Hippel-Lindau (VHL)-associated tumors express high levels of VEGF, it was of interest to ascertain the potential usefulness of halofuginone for treatment of these tumors. Pheochromocytoma tissue fragments obtained at surgery from a VHL type 2a patient were propagated s.c. in male BALB/c nu/nu (nude) mice. For experiments, 2-3-mm tumor fragments were transplanted secondarily s.c. to nude mice. Two treatment groups received halofuginone in standard lab chow at 3 and 5 ppm; control animals received regular chow. All groups were followed for 6 weeks after transplantation. A marked and significant diminution of tumor size and weight was observed in the drug-treated animals (>90% reduction of mean tumor volume for both the 3 and 5 ppm groups). In vivo magnetic resonance imaging analysis of tumors in halofuginone-treated animals showed a significant reduction of vascular functionality. Immunohistochemical studies revealed decreased collagen type I levels and vascular density in treated tumors and gelatinase assays of tumor extracts revealed a reduction of MMP-2 and MMP-9 activity in halofuginone-treated cells. Taken together, our data indicate that therapy directed at blocking MMP activity (presumably related to excessive VEGF expression in VHL) and reduction of type I collagen deposition curtails angiogenesis and thereby presumably tumor growth in this model system.

Animals↗
PubMed2003

Linomide inhibits insulitis and modulates cytokine production in pancreatic islets in the nonobese diabetic mouse.

Linomide is an immunomodulator which has been shown to potently inhibit autoimmunity in several animal models for human autoimmune diseases, including type I diabetes in the nonobese diabetic (NOD) mouse. In this study, we investigate the basis for Linomide's protective effects in the NOD mouse by immunohistochemical and RT-PCR analysis of the phenotype and cytokine expression by cells infiltrating the islets of Langerhans in the pancreas. Linomide treatment was found to reduce the infiltration of T cells, B cells, dendritic cells (DC) and MHC class II(+) cells into the islets, but did not reduce macrophage (MPhi) infiltration. This was seen following Linomide treatment at 3-5, 4-8 and 14-24 weeks of age and thus appears to be independent of the stage of the autoreactive process and the extent of insulitis. The reduced insulitis may be due to reduced expression of adhesion molecules since decreased numbers of islet-associated blood vessels expressing CD106 and MAdCAM-1 were detected following Linomide treatment. Furthermore, short term Linomide treatment (3 or 7 days), which did not alter the number of infiltrating cells, was found to inhibit the production of TNF-alpha which is known to induce the expression of CD106 and MAdCAM-1. These results suggest that the reduced insulitis observed in Linomide-treated animals is secondary to a functional modulation of infiltrating cells.

Aging↗
PubMed2003

Insulin does not mediate glucose stimulation of proinsulin biosynthesis.

It has recently been suggested that insulin augments its own production by a physiologically important feed-forward autocrine loop. We studied the kinetics of glucose-regulated proinsulin gene expression and proinsulin biosynthesis in normal rat islets with emphasis on the potential role of insulin as a mediator of the glucose effect. There was a time-dependent increase in steady-state proinsulin mRNA in islets cultured at 16.7 mmol/l compared with 3.3 mmol/l glucose; no early (1-3 h) increase in proinsulin gene expression was observed. In contrast, there was a threefold increase in proinsulin biosynthesis within 1 h of glucose stimulation that was not affected by inhibition of glucose-stimulated proinsulin gene transcription with actinomycin D. In addition, inhibition of glucose-stimulated insulin secretion with diazoxide had no effect on glucose-stimulated proinsulin mRNA or biosynthesis. Furthermore, addition of different concentrations of insulin to islets cultured in low glucose failed to affect proinsulin biosynthesis. Taken together, our data suggest that the early glucose-dependent increase in proinsulin biosynthesis is mainly regulated at the translational level, rather than by changes in proinsulin gene expression. Moreover, we could not demonstrate any effect of insulin on islet proinsulin mRNA level or rate of proinsulin biosynthesis. Thus, if insulin has any effect on the proinsulin biosynthetic apparatus, it is a minor one. We conclude that the secreted insulin is not an important mediator of insulin production in response to glucose.

Animals↗
PubMed2002

Glucose-regulated proinsulin gene expression is required for adequate insulin production during chronic glucose exposure.

Psammomys obesus, an animal model of type 2 diabetes, shows rapid and marked depletion of pancreatic insulin content as hyperglycemia develops when fed a high-calorie diet. P. obesus islets do not increase proinsulin gene expression when exposed to high glucose, which may be related to absence of the conserved form of the transcription factor insulin promoter factor 1/pancreatic-duodenal homeobox 1. The present study assesses the importance of regulation of proinsulin gene expression by glucose for insulin production. Islets of diabetes-prone P. obesus and diabetes-resistant Wistar rats, cultured at various glucose concentrations for up to 24 h, were analyzed for proinsulin mRNA by quantitative RT-PCR, proinsulin biosynthesis by leucine incorporation into proinsulin, and insulin content and secretion by RIA. No increase in proinsulin mRNA was observed in P. obesus islets during 24-h exposure to increasing concentrations of glucose. In contrast, rat islets exposed to high glucose responded with a 2- to 3-fold stimulation of proinsulin mRNA. The failure of P. obesus islets to increase proinsulin mRNA was accompanied by a reduced proinsulin biosynthetic response: after 24 h, maximal proinsulin biosynthesis was blunted, associated with depletion of islet insulin content. Inhibition of glucose-stimulated proinsulin gene transcription in rat islets by actinomycin D did not affect the early proinsulin biosynthetic response, which, however, was reduced to the level of P. obesus islets after 24 h in culture. We conclude that stimulation of proinsulin gene transcription by glucose is necessary for maintaining proinsulin biosynthesis and hence conserving pancreatic insulin stores, under conditions of sustained secretory drive, but not for short-term regulation of proinsulin biosynthesis Our findings support the hypothesis that inadequate regulation of proinsulin gene expression by glucose contributes to the failure of P. obesus to cope with the increased demand for insulin associated with caloric excess, leading to depletion of insulin stores and diabetes.

Animals↗