Understanding autocrine growth regulation.
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Growth Substances↗
Biomedical subjects
R J Coffey
Publications and source records attributed to R J Coffey.
Development of mammary hyperplasia and neoplasia in MMTV-TGF alpha transgenic mice.
To study the role of transforming growth factor alpha (TGF alpha) in normal mammary development and mammary neoplasia in vivo, we have generated transgenic mice in which a human TGF alpha cDNA is expressed under the control of the MMTV enhancer/promoter. Overexpression of TGF alpha in the mammary epithelium, as confirmed by in situ hybridization and immunohistochemistry, is associated with hyperplasia of alveoli and terminal ducts in virgin female and pregnant transgenic mice. A range of morphologic abnormalities including lobular hyperplasia, cystic hyperplasia, adenoma, and adenocarcinoma is seen in mammary tissue of transgenic females. In contrast, no morphologic abnormalities are seen in transgenic males in spite of TGF alpha overexpression in salivary glands and reproductive organs. TGF alpha can therefore act as an oncogene in vivo and appears to predispose mammary epithelium to neoplasia and carcinoma.
Animals↗
Role of transforming growth factor beta 1 in induction of colon carcinoma differentiation by hexamethylene bisacetamide.
The differentiation agent hexamethylene bisacetamide (HMBA) increased expression of transforming growth factor beta 1 (TGF beta 1) mRNA in HT29 colon carcinoma cells. The increase was evident after 24 h and was maintained at levels 4-5-fold the control levels for at least 5-13 days. No increase in expression of TGF beta 2 or TGF alpha mRNA was observed. Both TGF beta 1 and HMBA induced loss of expression of a cell surface malignancy marker on HT29 cells, and both decreased cell growth in serum-free medium. Exogenously applied TGF beta 1 mimicked the growth-arresting effect of HMBA on three surgically resected moderately differentiated colon carcinomas in serum-free primary culture. Both TGF beta 1 and HMBA increased the tumor growth fraction in a second group of three more aggressive colon carcinomas, while neither agent had any measurable growth-modulating activity on two other colon carcinomas. The induction of TGF beta 1 mRNA by HMBA along with the parallel biological effects of HMBA and exogenously applied TGF beta 1 on resected carcinomas and on HT29 cells suggest that the effects of HMBA on colon carcinoma cells may be mediated in part by induction of TGF beta 1.
Acetamides↗
Stereotactic gamma knife radiosurgery. Initial North American experience in 207 patients.
The first North American gamma knife for stereotactic radiosurgery of brain tumors and arteriovenous malformations entered the therapeutic armamentarium at the University of Pittsburgh (Pa) on August 14, 1987. In this article, we report our initial testing and subsequent experience with this technique. In the first 16 months of operation, 207 patients were treated (113 had arteriovenous malformations, 78 had extra-axial skull base neoplasms, 9 had glial neoplasms, and 7 had metastatic tumors). The patients' lesions either were considered previously as "inoperable" or were residual lesions after attempted surgical resection, or the radiosurgery was performed after the patient declined surgical excision. Gamma radiosurgery was associated with no surgical mortality and no significant early morbidity, and the results were encouraging during the minimum follow-up period of 6 months. Compared with treatment by conventional intracranial surgery (craniotomy), both the average length of stay and hospital charges for radiosurgery were significantly lower. Our initial experience further suggests that stereotactic radiosurgery using the gamma knife is a therapeutically effective and economically sound alternative to microneurosurgical removal of selected intracranial tumors and vascular malformations.
Adolescent↗
Stereotactic radiosurgery of small intracranial tumors: neuropathological correlation in three patients.
The mechanism by which radiosurgery can stop the growth of some tumors is poorly understood, in part because postmortem neuropathological findings in patients have been reported only rarely. To define further the effects of radiosurgery, we present the correlation among clinical, neuroimaging, and neuropathological data in three patients with different intracranial tumors who died between 2 and 39 weeks after radiosurgery. The target volumes in two patients with malignant tumors showed sharply demarcated coagulative necrosis. In the third patient, who had a benign acoustic nerve tumor, neuropathological examination found intratumoral hemorrhage and cyst formation, but no necrosis. Radiosurgery appears to cause acute necrosis of malignant cells, although its effectiveness may be limited by the infiltrative nature of some tumors. In benign tumors, necrosis following radiosurgery is relatively delayed, and may not be required for growth arrest.
Adenocarcinoma↗
International perspective: neurological surgery in Nicaragua, 1989.
Despite the hardships of war, underdevelopment, and economic chaos, an active neurosurgical service and training program have been established at Lenín-Fonseca Hospital in Managua, Nicaragua. Using the few available diagnostic and ancillary facilities, a team of European, Latin American, and Soviet neurosurgeons cares for patients suffering from a variety of neurological conditions. Fortunately, the neurosurgical operating room is well equipped, most essential medications are available, and the physicians are well motivated. Over the past 10 years, the number of admissions to the neurosurgical service at Lenín-Fonseca Hospital has grown to over 2000 patients annually. The availability of resources for future improvements in facilities and manpower training depends upon continued international cooperation and the establishment of a peacetime economy.
Adult↗
Stereotactic radiosurgery of angiographically occult vascular malformations: indications and preliminary experience.
Stereotactic radiosurgery has been shown to treat successfully angiographically demonstrated arteriovenous malformations of the brain. Angiographic obliteration has represented cure and eliminated the risk of future hemorrhage. The role of radiosurgery in the treatment of angiographically occult vascular malformations (AOVMs) has been less well defined. In the initial 32 months of operation of the 201-source cobalt-60 gamma knife at the University of Pittsburgh, 24 patients meeting strict criteria for high-risk AOVMs were treated. Radiosurgery was used conservatively; each patient had sustained two or more hemorrhages and had a magnetic resonance imaging-defined AOVM located in a region of the brain where microsurgical removal was judged to pose an excessive risk. Venous angiomas were excluded by performance of high-resolution subtraction angiography in each patient. Fifteen malformations were in the medulla, pons, and/or mesencephalon, and 5 were located in the thalamus or basal ganglia. Follow-up ranged from 4 to 24 months. Nineteen patients either improved or remained clinically stable and did not hemorrhage again during the follow-up interval. One patient suffered another hemorrhage 7 months after radiosurgery. Five patients experienced temporary worsening of pre-existing neurological deficits that suggested delayed radiation injury. Magnetic resonance imaging demonstrated signal changes and edema surrounding the radiosurgical target. Dose-volume guidelines for avoiding complications were constructed. Our initial experience indicates that stereotactic radiosurgery can be performed safely in patients with small, well-circumscribed AOVMs located in deep, critical, or relatively inaccessible cerebral locations.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Expression of and response to growth regulatory peptides by two human pancreatic carcinoma cell lines.
Two human pancreatic adenocarcinoma cell lines (PANC 1 and MIA PACA 2) were examined for expression of growth factors that could potentially play a role either in growth regulation of the tumor cells, or in cells that comprise the stromal elements of tumors. Both cell lines expressed transforming growth factor-alpha (TGF alpha), basic fibroblast growth factor (bFGF), c-sis (PDGF B chain), TGF beta 1, and TGF beta 3 mRNA by Northern blot analysis. Only the PANC 1 cells, however, expressed the TGF beta 2 transcript. TGF beta-like competing activity was found in medium conditioned by either cell line, but TGF alpha-like [epidermal growth factor (EGF)-competing] activity was not detected in the medium from either cell line by radioreceptor assay. TGF alpha and EGF caused concentration-dependent stimulation of soft agar colony growth of the MIA PACA 2 cells, while only TGF alpha caused a significant but less dramatic stimulation of soft agar growth of the PANC 1 cells. Insulin stimulated the anchorage-independent growth of MIA PACA 2 but not PANC 1 cells. Likewise, bFGF also caused a concentration-dependent stimulation of MIA PACA 2 but not PANC 1 growth in soft agar, and PDGF had no effect on the growth of either cell line. TGF beta had no inhibitory or stimulatory effect on soft agar colony growth of either the PANC 1 or the MIA PACA 2 cells, although both cell lines exhibited high affinity, saturable TGF beta binding sites, and TGF beta 1 was capable of autoinduction of TGF beta 1 mRNA expression in PANC 1 cells. The ability to continue to respond to positive growth regulatory factors coupled with the loss of responsiveness to negative growth factors may be important in the pathogenicity of these aggressive tumors.
Adenocarcinoma↗
Pharmacokinetics of TGF beta with emphasis on effects in liver and gut.
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Animals↗
Image-guided stereotactic surgery: a 10-year evolutionary experience.
The recent revolution in medical imaging has demanded concurrent development of sophisticated and compatible stereotactic guiding devices in order to diagnose or treat mass lesions on the brain and disorders of cerebral physiology. Between July 1, 1979, and July 1, 1989, 1,006 patients underwent image-guided stereotactic surgery at the University of Pittsburgh. During this 10-year interval the first dedicated computed tomography stereotactic operating room and the first North American radiosurgical suite containing a 201 60Co source gamma knife were constructed. Early in our experience, 60.5% of the patients underwent diagnostic (biopsy) stereotactic surgery whereas, by 1988, 77.8% of the patients underwent therapeutic stereotactic surgery. At our institution, stereotactic surgery was performed last year in 257 patients, representing 19.9% of all neurosurgical operations. During the past 10 years, stereotactic surgery has developed an integral and definitive role in contemporary mainstream neurosurgery. Across the world stereotactic technology is now widely available. In the future increasing emphasis will be placed on therapy, image integration, computer software development, and new instrumentation designed to meet the evolving needs of neurological surgeons who demand safe, precise, and effective tools to explore the brain.
Biopsy↗
Stereotactic gamma radiosurgery for intracranial vascular malformations and tumors: report of the initial North American experience in 331 patients.
We reviewed the initial experience with 331 consecutive patients treated during the first 2 years of operation of the University of Pittsburgh Gamma Unit. Among 178 patients with vascular malformations, 161 had angiographically demonstrable arteriovenous malformations, and 17 had angiographically occult malformations. Patients with tumors included 123 with histologically benign, predominantly extra-axial neoplasms and 30 with malignant, predominantly intra-axial neoplasms. When the arteriovenous malformation nidus could be covered with at least the 50% isodose line and a dose to the margin greater than or equal to 20 Gy, 60% were obliterated within 1 year. Patients with benign tumors and well-circumscribed malignant tumors did not experience tumor growth within the radiosurgical treatment volume. The role of radiosurgery is expanding to include primary treatment of larger lesions than was formerly possible and adjunctive treatment of more complex arteriovenous malformation and tumors.
Adolescent↗
Expression and regulation of mRNA coding for acidic and basic fibroblast growth factor and transforming growth factor alpha in cells derived from human skin.
We investigated the regulation of mRNAs coding for acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), and transforming growth factor-alpha (TGF alpha) in cultures of human neonatal foreskin fibroblasts, keratinocytes, and melanocytes. Each cell type was propagated in an optimized serum-free medium. In rapidly growing fibroblasts, the addition of fetal bovine serum caused a modest induction of aFGF message within 2 h in conjunction with a concomitant elevation of bFGF transcripts. In these same cells, TGF alpha mRNA could not be detected in any experimental condition. In contrast, keratinocytes rapidly growing in the presence of epidermal growth factor (EGF) contained transcripts for TGF alpha that increased substantially when these cells were treated with serum. This observation suggests that factors present in serum can elevate the levels of TGF alpha mRNA beyond the levels already present in keratinocyte cultures growing in the presence of EGF. These same keratinocyte cultures had low to undetectable levels of bFGF or aFGF message, and the levels of these mRNAs were not affected by serum treatment. Treatment of keratinocytes proliferating in the presence of EGF with TGF beta for 48 h caused expression of bFGF mRNA in four of six independent cell strains. TGF beta-enhanced expression of bFGF mRNA occurred as early as 12-24 h after TGF beta exposure. TGF beta did not enhance the expression of mRNA for aFGF or TGF alpha in keratinocytes. Melanocytes failed to express detectable levels of mRNA coding for any of these growth factors in the presence of absence of TGF beta or serum.(ABSTRACT TRUNCATED AT 250 WORDS)
Blood↗
Employee involvement program changes and the total quality process: the University of Michigan Medical Center experience.
Employee involvement has increasingly been recognized as important for improving both quality and cost effectiveness. Given the especially crucial role played by employees in the health-care field, and the relatively high level of education and sophistication that characterizes this group, it is also recognized that initiating and sustaining meaningful employee involvement programs in a health-care setting represent unique challenges and opportunities. This article presents the operational evolution of a successful employee involvement program in a large, diversified academic medical center. The developed program includes quality-improving and revenue-enhancing suggestions as well as cost-containment ideas. Specific operational issues and program changes are examined within the context of the total quality process at the University of Michigan Medical Center. Finally, this article identifies three main types of incentives that can maximize the results obtained by employee involvement programs in health-care settings.
Academic Medical Centers↗
The role of stereotactic techniques in the management of craniopharyngiomas.
Despite the advances of microsurgery, endocrinology, radiation therapy, and neuroimaging over the last half-century, craniopharyngiomas continue to present neurosurgeons with a therapeutic dilemma. The tumor's histologic benignity belies its aggressive biologic behavior. Although total resection is theoretically curative, the cost in terms of functional disability can be high, especially in light of reports describing long-delayed tumor recurrences ("false cure"). As in other intracranial neoplasms, multimodality therapy is often necessary over the course of a patient's lifetime. Stereotactic techniques (intracystic irradiation, radiosurgery, cyst aspiration, biopsy) have a well-established role in selected cases. To maximize preservation of neurologic, visual, and hypothalamic-pituitary functions, the application of stereotactic, microsurgical, or external irradiation techniques in an individual patient must take into account all of the patient's prior treatments as well as the current status of his or her tumor. Our current recommendation for multimodality treatment of craniopharyngiomas is illustrated in Figure 5. Stereotactic surgery has a definitive role in the life-long management of some patients, and plays an important adjunctive role in many others.
Brachytherapy↗
Stereotactic radiosurgery using the 201 cobalt-60 source gamma knife.
Although Lars Leksell introduced the concept of stereotactic radiosurgery 40 years ago, the role of radiosurgery in the treatment of vascular malformations and benign or malignant intracranial tumors is only now being defined. Radiosurgery can be definitive therapy for small or medium-sized arteriovenous malformations and histologically benign tumors. For patients with more complex or recurrent tumors and for patients with vascular malformations that have not been eliminated by open surgery or endovascular embolization, radiosurgery has an adjunctive and often decisive therapeutic role. Selected malignant tumors, especially solitary metastases, have responded dramatically to radiosurgery, obviating the need for craniotomy and prolonged hospitalization in this group of patients.
Adolescent↗
Growth stimulation of human breast cancer cells with anti-transforming growth factor beta antibodies: evidence for negative autocrine regulation by transforming growth factor beta.
Exogenous TGF beta inhibits the proliferation of human breast cancer cells in vitro. These cells synthesize and secrete TGF beta into their medium predominantly in a latent form. With neutralizing antibodies against native, biologically active TGF beta (278ab and 282ab), we have examined whether HS578T and MDA-231 breast cancer cells utilize their endogenous TGF beta for growth regulation. Low levels of TGF beta activity were detectable in conditioned medium from confluent monolayers of both cell lines in the absence of acid or protease treatment as measured by radioreceptor assay. When added to subconfluent monolayers of the respective cell line, this untreated conditioned medium inhibited DNA synthesis and cell proliferation. This inhibition was blocked by anti-TGF beta antibodies, whereas nonimmune rabbit IgG had no effect. Similar to exogenous TGF beta 1, this conditioned medium induced a dose-dependent increase in steady-state TGF beta 1 mRNA levels when added to subconfluent HS578T cells; this increase was blocked by the 278ab. Consistent with the above, preincubation of either cell line with anti-TGF beta antibodies increased subsequent specific binding of 125I-TGF beta to cell surface receptors without changing binding affinity. Addition of 278ab to quiescent HS578T or MDA-231 cells induced a dose-dependent increase in [3H]thymidine incorporation. Both antibodies stimulated cell proliferation in serum-free medium and anchorage-independent growth of both cell lines. Finally, incubation of HS578T cells with 278ab under serum-free conditions decreased the basal level of TGF beta 1 message expression. These data indicate that cultured human breast cancer cells utilize endogenously produced TGF beta as an autocrine negative growth regulator.
Antibodies↗
Inhibition of parietal cell H+ secretion by transforming growth factor alpha: a possible autocrine regulatory mechanism.
Transforming growth factor-alpha (TGF alpha) and TGF alpha/epidermal growth factor receptor messenger ribonucleic acid have recently been demonstrated in isolated parietal cells. The aim of this study was to investigate the effects of TGF alpha on basal and stimulated secretion in vitro with the isolated rabbit parietal cell model. Acid secretion was assessed indirectly with cell uptake of carbon 14-labeled aminopyrine [( 14C]AP). TGF alpha (10(-11) to 10(-7) mol/L) had no effect on unstimulated [14C]AP uptake. TGF alpha dose dependently inhibited histamine (10(-5) to 10(-6) mol/L)-stimulated but not forskolin (10(-5) to 10(-7) mol/L)-stimulated [14C]AP uptake. This effect on histamine-stimulated activation was reversed by pertussis toxin (200 ng/ml) before incubation. TGF alpha had no effect on carbachol (10(-5) to 10(-6) mol/L)-stimulated [14C]AP uptake. Specific HCO3-buffer studies demonstrated that these observations were independent of extracellular buffer and possible TGF alpha effects on intracellular pH. Our data indicate that TGF alpha inhibits acid secretion by specifically uncoupling histamine/cyclic adenosine monophosphate transduction at the guanosine triphosphate-binding protein. TGF alpha, unlike epidermal growth factor, has no effect on carbachol stimulation, which suggests a qualitative difference between the biologic actions of TGF alpha and epidermal growth factor. Possible autocrine-paracrine modulation of histamine stimulation by TGF alpha invokes a novel regulatory mechanism of parietal cell secretion.
Aminopyrine↗
Induction of transforming growth factor-alpha expression in human keratinocytes by phorbol esters.
Exposure of cultured human epidermal keratinocytes to the protein kinase C (Ca2+- and phospholipid-dependent protein kinase)-activating phorbol esters 12-O-tetradecanoylphorbol-13-acetate (TPA) or 4-beta-phorbol-12,13-didecanoate markedly enhanced accumulation of transforming growth factor-alpha (TGF-alpha) mRNA and secretion of TGF-alpha protein. The nonactivating phorbol ester, 4-alpha-phorbol 12,13-didecanoate, had no effect. In the absence of exogenous growth factors, confluent cultures of keratinocytes express low or undetectable levels of TGF-alpha mRNA and protein. While TPA and epidermal growth factor treatment of keratinocyte cultures deprived of growth factors both induced TGF-alpha mRNA expression, maximum induction by TPA is 5-fold greater than epidermal growth factor. Furthermore, the addition of epidermal growth factor did not enhance TPA-mediated induction of TGF-alpha mRNA expression. Under these experimental conditions, TPA increased levels of secreted TGF-alpha protein by 20-fold at 24 h. Concentration dependence and kinetic studies of TGF-alpha expression showed that TPA (greater than or equal to 1 ng/ml) induced accumulation of TGF-alpha mRNA with an optimum concentration of 10 ng/ml. TGF-alpha mRNA expression increased within 1 h following TPA treatment (10 ng/ml) and peaked at 5 h. At 24 h, TPA-treated cultures still expressed elevated levels of TGF-alpha mRNA (1.7-fold). Protein secretion into the medium was enhanced 2-fold (5 h) to 3-fold (24 h) by TPA treatment of keratinocyte cultures containing growth factors. Prolonged pretreatment (24 h) of keratinocyte cultures with TPA caused marked desensitization of TGF-alpha mRNA expression to repeated stimulation by phorbol ester. The synthetic diacylglycerol, 1,2-sn-dioctanoylglycerol, enhanced levels of TGF-alpha transcription and secretion of TGF-alpha protein. The rate of TGF-alpha mRNA accumulation peaked and declined earlier for 1,2-sn-dioctanoylglycerol compared to TPA. 1,2-sn-Dioctanoylglycerol (50 micrograms/ml) increased production and secretion of TGF-alpha protein, but less than TPA treatment. An inhibitor of protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, also inhibited 1,2-sn-dioctanoylglycerol-mediated accumulation of TGF-alpha mRNA. Cycloheximide failed to inhibit TGF-alpha mRNA expression induced by TPA and, when added alone to keratinocyte cultures, significantly enhanced TGF-alpha mRNA accumulation. Actinomycin D abrogated transcriptional activation of TGF-alpha mRNA by TPA. These studies suggest that activation of protein kinase C by active phorbol esters or diacylglycerols is responsible, at least in part, for TGF-alpha gene expression.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗