Biomedical subjects
Publications and source records attributed to R J Coffey.
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Transforming growth factor beta is a known inhibitor of the proliferation and differentiation of early haematopoietic progenitors but has no effect on mature erythroid cells in vitro. Mice injected with rhTGF beta 1 exhibited severe and progressive suppression of erythropoiesis manifested by a decline of reticulocyte count, marrow erythroblasts and marrow and spleen CFU-E, which could be prevented by administration of erythropoietin. This suppression of erythropoiesis was associated with the appearance of tumour necrosis factor in the blood, development of pronounced cachexia and depression of serum erythropoietin levels. TGF beta induces TNF in vivo that leads to cachexia, decrease of serum erythropoietin levels and suppression of erythropoietin dependent erythropoiesis.
Transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF) are thought to be important in gastric epithelial proliferation and repair. It was therefore of interest to determine if TGF-alpha and EGF promoted the growth of an in vitro primary culture system of guinea pig gastric mucous epithelial cells (MEC). MEC were isolated from guinea pig stomachs and cultured in 24-well Primaria plates with DMEM with or without 10% fetal calf serum (FCS). Growth of MEC was determined by changes in [3H]thymidine uptake, cell counts, protein, and DNA. The sources of peptides were human recombinant TGF-alpha (recTGF-alpha) and human recombinant EGF (recEGF). Both recTGF-alpha and recEGF were used at equipotent doses as determined by competing activity in a 125I-labeled TGF-alpha radioreceptor binding assay using A-431 cells. Basal growth (no peptides) of MEC in 10% FCS was dependent on the initial plating density. Under serum-free conditions, [3H]thymidine uptake increased up to 17-fold at 24 h with recTGF-alpha (0.1-10.0 nM) compared with only a 4-fold increase using rec-EGF (0.1-10.0 nM) at this same time period. Under serum-free conditions, recTGF-alpha (0.01-10.0 nM) increased cell counts up to 4.9-fold over control cultures, whereas similar does of recEGF produced a 2.5-fold increase in cell counts. Administration of recEGF 1 ng/ml) resulted in a 1.9-fold increase in the 4.8-kb TGF-alpha mRNA transcript, and TGF-alpha protein immunoreactivity was found in both 24-h conditioned media and cell lysates.(ABSTRACT TRUNCATED AT 250 WORDS)
By sheer weight of numbers, patients with malignant glial neoplasms of the astrocytoma series (glioblastoma multiforme, anaplastic astrocytoma, astrocytoma grade 3 or grade 4, depending upon the grading system), and to a lesser extent, patients with high-grade ependymomas, oligodendrogliomas or other primary brain tumors, have represented a significant proportion of individuals referred for consideration of radiosurgery. Although most such tumors are either too large, too poorly defined on imaging studies, or too infiltrative to consider for treatment, hundreds of highly selected patients with smaller, apparently well-circumscribed tumors have been treated using radiosurgery over the past few years. To better define the role of radiosurgery in the treatment of patients with malignant primary brain tumors, the first 30-month experience with the 60Co Gamma Unit at the Mayo Clinic was reviewed.
Changes in the concentration of transforming growth factor-alpha (TGF alpha) protein were measured in regenerating liver. TGF alpha stimulates both DNA and protein synthesis in various liver-derived cells, and its mRNA levels increase in liver after partial hepatectomy (PH), suggesting that it may be an important autocrine regulator of liver regeneration. Using a sheep antiserum raised against mature rat TGF alpha, we developed a sensitive TGF alpha RIA. TGF alpha was extracted from livers in a detergent-containing buffer with protease inhibitors. Liver extracts, to a volume of 10 microliters/tube, produced a displacement curve of [125I]TGF alpha that was parallel to the pure standard. The TGF alpha content of normal liver was 57.04 +/- 26.25 pg/mg protein, 5.24 +/- 2.61 ng/mg DNA, and 10.33 +/- 4.47 ng/g liver (n = 5; mean +/- SD). Between 13-17 h after operation, TGF alpha concentrations in the livers of PH animals increased over those in sham-operated (SH) controls (P < 0.05) and remained twice those in SH controls for more than 96 h, returning to control values by 8 days. In unoperated liver, gel chromatography showed all TGF alpha immunoactivity to be in fractions corresponding to known TGF alpha precursors (15-30 kilodaltons). Mature 5.6-kilodalton TGF alpha was not detected until 48 h after PH and was still present at 96 h. These data support a role for TGF alpha in the response to PH in the rat. However, the presence of TGF alpha precursors in normal liver, the short (< 4-h) interval between the increase in TGF alpha concentrations and the onset of hepatocyte DNA synthesis, the sustained elevation of TGF alpha levels after DNA synthesis has ceased, and the lack of detectable processing to the mature form until DNA synthesis has subsided all suggest that the membrane-anchored precursor and the mature forms of TGF alpha may have different functions, cellular sources, or target cells in regenerating liver.
Two young adult siblings independently developed similar neurological complaints that included headaches, photophobia, nausea, and intermittent lancinating facial pains. Magnetic resonance imaging revealed fourth ventricular lesions that required surgery in both patients. A pathological review revealed subependymomas with virtually identical histological features. The clinical features and common pathological findings of both patients suggest that familial subependymomas may have a maldevelopmental origin with genetic implications.
Hemangiopericytomas of the meninges, classified previously as angioblastic meningiomas, have a propensity to recur either locally or at distant sites within the nervous system after surgical resection. Visceral metastases also develop much more commonly in these lesions than in other types of histologically benign meningiomas. The radiosurgical gamma knife was used to treat five patients with 11 meningeal hemangiopericytomas (seven new, two recurrent, and two residual tumors) after surgical resection of an initially solitary intracranial lesion. Three patients had undergone multiple craniotomies and radiation therapy before referral, and two patients underwent a second radiosurgical procedure for lesions that appeared between 5 and 13 months after the first treatment session. Dramatic tumor shrinkage occurred in most patients within 6 to 10 months after treatment. The only treatment-related morbidity in this series was a partial visual-field defect in one patient with a large falx-tentorial junction hemangiopericytoma who had previously undergone radiation therapy. Radiosurgery appears to cause dramatic early shrinkage of small and medium-sized intracranial hemangiopericytomas that have recurred or developed after previous surgery and/or radiation therapy.
Cytokeratins 8 and 18 (Endo A and B) are among the earliest expressed embryonic genes and the major components of the cytoskeleton in simple epithelia of the adult. Recent data indicate that these cytokeratins are aberrantly expressed in several epithelial tumor types and that expression in cultured mouse keratinocytes is linked to activation of the rasHa oncogene. Furthermore, up-regulation of K8/K18 in keratinocytes is associated with reciprocal suppression of K1. We now show that the aberrant expression of K8 and K18 and suppression of K1 in cultured keratinocytes transduced with the v-rasHa gene are mediated by a factor secreted into the culture medium. Furthermore, transforming growth factor alpha (TGF-alpha) and epidermal growth factor elicit an identical pattern of K8/K18 expression and K1 suppression in normal keratinocytes. The factor in medium from v-rasHa keratinocytes is TGF-alpha, as a specific blocking antibody for rat and mouse TGF-alpha prevents the expression of K8 and restores expression of K1. The tyrosine kinase inhibitor genistein also prevents K8 induction in v-rasHa keratinocytes and in normal keratinocytes treated with TGF-alpha- or v-rasHa-conditioned medium. However, simply stimulating proliferation of keratinocytes by cholera toxin does not result in expression of K8 or suppression of K1. Finally, tumor grafts from neoplastic epidermal cells overexpressing TGF-alpha via retroviral transduction of human TGF-alpha complementary DNA in vitro show coordinate expression of K8 and human TGF-alpha. These studies indicate that K8 expression in keratinocytes, and derivative neoplastic cells, in vivo and in vitro is regulated by epidermal growth factor receptor ligands. Since the expression of cytokines and K8/K18 in early embryogenesis is often coincident, cytokines may be the physiological mediators of K8/K18 expression in embryonic cells.
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In the studies reported here, we demonstrate that transforming growth factor alpha (TGF-alpha) or epidermal growth factor (EGF) is required for the establishment of small colonies of human keratinocytes at clonal densities, but once small (10-15 cells) colonies have formed, the continued growth of these colonies can proceed in the absence of exogenous TGF-alpha or EGF. Equivalent receptor-binding concentrations of TGF-alpha and EGF were equipotent in stimulating colony formation. We also demonstrate that the growth of keratinocytes at high densities proceeds in the absence of exogenous peptide growth factors or hormones. The expression of TGF-alpha mRNA and protein is regulated by both cell density and the presence of exogenous growth factors. The addition of an antibody which blocks the mitogenic effect of mature TGF-alpha had no effect on the autocrine/paracrine growth of these cells at either density. However, monoclonal antibodies which antagonize ligand activation of the EGF receptor inhibit the autonomous proliferation of keratinocytes at high density and abrogate the exogenous TGF-alpha/EGF-independent expansion of colonies at clonal density. The results of these experiments are among the first evidence to demonstrate that normal human epithelial cells in culture exhibit autocrine/paracrine-mediated proliferation. Exogenous growth factors initiate colonies of human keratinocytes that become self-perpetuating in culture. Keratinocytes regulate production of the mitogenic ligand, TGF-alpha, through a density-dependent mechanism, and cell density stringently controls proliferation.
Amphiregulin (AR) is a heparin-regulated, epidermal growth factor-like growth factor capable of stimulating the proliferation of non-tumorigenic cells while inhibiting cell proliferation in some human tumor cell lines in vitro. In the present study, we have investigated AR mRNA expression in normal, hyperproliferative, and neoplastic human epithelium. Our results demonstrate that, compared with the adjacent uninvolved epithelium, AR mRNA expression is markedly elevated in epidermal biopsies derived from three human psoriatic lesions as well as in biopsies derived from five human colon carcinomas and three human stomach carcinomas. Moreover, analysis of a colon carcinoma by in situ hybridization revealed that AR mRNA is localized to the epithelium.
Transforming growth factor alpha and beta 1 (TGF alpha and TGF beta 1) are representative members of two distinct and expanding families of polypeptide growth factors. TGF alpha is an epithelial cell mitogen, whereas TGF beta 1 inhibits epithelial cell growth; the role of these factors in contributing to the transformed phenotype is uncertain. Steady state mRNA expression for these growth factors and their receptors in a panel of human colon cancers and adjacent normal mucosa is presented. Based in part on results from transgenic mice in which TGF alpha is selectively overproduced in the mammary gland, a possible role for TGF alpha as a tumor promoter in the process of transformation is discussed.
Transforming growth factor alpha (TGF-alpha) production recently has been found in normal mammalian gastric mucosa. Inasmuch as TGF-alpha and epidermal growth factor (EGF) both stimulate epithelial cell migration and proliferation and suppress gastric acid secretion, the authors of the current study proposed that these growth factors may participate in tissue repair after acute gastric mucosal injury. Consequently, TGF-alpha and EGF production were examined after orogastric administration of either acidified taurocholate or 0.6 mol/L HCl to rats. TGF-alpha messenger RNA (mRNA) expression increased in a dose- and time-dependent manner after administration of taurocholate, whereas EGF mRNA expression was not detected. Radioimmunoassay of gastric mucosal scrapings obtained 6 hours after gastric injury induced by 0.6 mol/L HCl showed a 2.1-fold increase in immunoreactive TGF-alpha but no increase in immunoreactive EGF. In addition, there was a 68-fold increase in immunoreactive TGF-alpha in gastric juice within 30 minutes of gastric instillation of HCl and, again, no increase in immunoreactive EGF. There is a rapid appearance of TGF-alpha in the gastric juice within 30 minutes of injury, which is followed by increased expression of TGF-alpha mRNA and protein in the gastric mucosa. These studies suggest that locally produced TGF-alpha may participate in gastric mucosal repair following acute gastric injury to rats.
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Staff members from the University of Michigan Medical Center (UMMC), 1990 winner of the Commitment to Quality Award, describe how they integrated its quality assurance (QA) program into its total quality management (TQM) strategy. The QA program has changed in recent years to establish quality as a central priority, to educate staff in the importance of quality, and to disseminate information more effectively. While these initiatives were underway, UMMC began to embrace TQM as an operating philosophy. Recognizing both the strengths and weaknesses of QA, staff members have worked to apply TQM principles (eg, focus on processes) to QA while using the ongoing monitoring of QA to identify opportunities for improvement within the organization's TQM management system.
This study was designed to determine whether transforming growth factor alpha (TGF alpha) protects rat gastric mucosa against ethanol- and aspirin-induced injury. Systemic administration of TGF alpha dose-dependently decreased 100% ethanol-induced gastric mucosal injury; a dose of 50 micrograms/kg delivered intraperitoneally 15 min before ethanol decreased macroscopic mucosal injury by > 90%. At the microscopic level, TGF alpha prevented deep gastric necrotic lesions and reduced disruption of surface epithelium. Pretreatment with orogastric TGF alpha (200 micrograms/kg) only partially (40%) decreased macroscopic ethanol damage. Intraperitoneal administration of TGF alpha at a dose of 10 micrograms/kg, which does not significantly inhibit gastric acid secretion, decreased aspirin-induced macroscopic damage by > 80%. TGF alpha protection does not seem to be mediated by prostaglandin, glutathione, or ornithine decarboxylase-related events, as evidenced by lack of influence of the inhibition of their production. Pretreatment with the sulfhydryl blocking agent N-ethylmaleimide partially abolished (40%) the protective effect of TGF alpha. In addition, systemic administration of TGF alpha resulted in a two-fold increase in tyrosine phosphorylation of phospholipase C-gamma 1 and in a time- and dose-dependent increase in levels of immunoreactive insoluble gastric mucin; these events occurred in a time frame consistent with their participation in the protective effect of TGF alpha.
A critical path defines the optimal sequencing and timing of interventions by physicians, nurses, and other staff for a particular diagnosis or procedure. Critical paths are developed through collaborative efforts of physicians, nurses, pharmacists, and others to improve the quality and value of patient care. They are designed to minimize delays and resource utilization and to maximize quality of care. Critical paths have been shown to reduce variation in the care provided, facilitate expected outcomes, reduce delays, reduce length of stay, and improve cost-effectiveness. The approach and goals of critical paths are consistent with those of total quality management (TQM) and can be an important part of an organization's TQM process.