Ligand substitution of receptor targeted DNA complexes affects gene transfer into hepatoma cells.
(33/174666)
We have targeted the serpin enzyme complex receptor for gene transfer in human hepatoma cell lines using peptides < 30 amino acids in length which contain the five amino acid recognition sequence for this receptor, coupled to poly K of average chain length 100 K, using the heterobifunctional coupling reagent sulfo-LC SPDP. The number of sulfo-LC SPDP modified poly-L-lysine residues, as well as the degree of peptide substitution was assessed by nuclear magnetic resonance spectroscopy. Conjugates were prepared in which 3.5%, 7.8% or 26% of the lysine residues contained the sulfo-LC SPDP moiety. Each of these conjugates was then coupled with ligand peptides so that one in 370, one in 1039, or one in 5882 lysines were substituted with receptor ligand. Electron microscopy and atomic force microscopy were used to assess complex structure and size. HuH7 human hepatoma cells were transfected with complexes of these conjugates with the plasmid pGL3 and luciferase expression measured 2 to 16 days after treatment. All the protein conjugates in which 26% of the K residues were modified with sulfo-LC SPDP were poor gene transfer reagents. Complexes containing less substituted poly K, averaged 17 +/- 0.5 nm in diameter and gave peak transgene expression of 3-4 x 10(6) ILU/mg which persisted (> 7 x 10(5) ILU) at 16 days. Of these, more substituted polymers condensed DNA into complexes averaging 20 +/- 0.7 nm in diameter and gave five-fold less luciferase than complexes containing less substituted conjugates. As few as eight to 11 ligands per complex are optimal for DNA delivery via the SEC receptor. The extent of substitution of receptor-mediated gene transfer complexes affects the size of the complexes, as well as the intensity and duration of transgene expression. These observations may permit tailoring of complex construction for the usage required. (+info)
Avoidable mortality in Europe 1955-1994: a plea for prevention.
(34/174666)
OBJECTIVE: To analyse trends of avoidable mortality in Europe, emphasising causes of death amenable to primary prevention through reduction of exposures, secondary prevention through early detection and treatment, and tertiary prevention through improved treatment and medical care. DESIGN: Descriptive study of mortality from avoidable causes for the years 1955 through 1994, for ages 5-64 at time of death. Using the World Health Organisation Mortality Database, five year death rates were standardised to the world population. SETTING: 21 countries of Europe in four regions (northern, central, and southern Europe, Nordic countries). PARTICIPANTS: All causes of deaths for men and women, aged 5-64, at time of death. MAIN RESULTS: Between 1955-59 and 1990-94, the reduction in mortality was somewhat greater for avoidable causes than for all causes: 45.8% v 45.1% (women) and 39.3% v 32.6% among men. Reductions in mortality were greater for causes amenable to improved medical care: 77.9% among women and 76.3% among men. The smallest reduction in mortality was seen in women for causes amenable to secondary prevention (11.0%), and in men for causes amendable to primary prevention including tobacco related conditions (16.6%). From a geographical point of view, there were slight differences in trends between European regions, but overall the patterns were similar. CONCLUSIONS: The greatest reduction of avoidable mortality in Europe from 1955-94 came from causes amenable to improved treatment and medical care for both sexes. Further reductions of avoidable mortality can be achieved through implementation of primary and secondary prevention activities, such as tobacco control, reduction of occupational exposures, and universal access to breast and cervical cancer screening programmes. (+info)
Is hospital care involved in inequalities in coronary heart disease mortality? Results from the French WHO-MONICA Project in men aged 30-64.
(35/174666)
OBJECTIVES: The goal of the study was to assess whether possible disparities in coronary heart disease (CHD) management between occupational categories (OC) in men might be observed and contribute to the increasing inequalities in CHD morbidity and mortality reported in France. METHODS: The data from the three registers of the French MONICA Collaborative Centres (MCC-Lille, MCC-Strasbourg, and MCC-Toulouse) were analysed during two period: 1985-87 and 1989-91. Acute myocardial infarctions and coronary deaths concerning men, aged 30-64 years, were included. Non-professionally active and retired men were excluded. Results were adjusted for age and MCC, using a logistic regression analysis. RESULTS: 605 and 695 events were analysed for 1985-87 and 1989-91, respectively. Out of hospital cardiac arrests, with or without cardiac resuscitation, and 28 day case fatality rates were lower among upper executives in both periods. A coronarography before the acute event had been performed more frequently in men of this category and the proportion of events that could be hospitalised was higher among them. In both periods, the management of acute myocardial infarctions in hospital and prescriptions on discharge were similar among occupational categories. CONCLUSIONS: For patients who could be admitted to hospital, the management was found to be similar among OCs, as was the 28 day case fatality rate among the hospitalised patients. In contrast, lower prognosis and higher probability of being hospitalised after the event among some categories suggest that pre-hospital care and the patient's conditions before the event are the primary factors involved. (+info)
Herpes virus induced proteasome-dependent degradation of the nuclear bodies-associated PML and Sp100 proteins.
(36/174666)
The PML protein is associated to nuclear bodies (NBs) whose functions are as yet unknown. PML and two other NBs-associated proteins, Sp100 And ISG20 are directly induced by interferons (IFN). PML and Sp100 proteins are covalently linked to SUMO-1, and ubiquitin-like peptide. PML NBs are disorganized in acute promyelocytic leukemia and during several DNA virus infections. In particular, the HSV-1 ICP0 protein is known to delocalize PML from NBs. Thus, NBs could play an important role in oncogenesis, IFN response and viral infections. Here, we show that HSV-1 induced PML protein degradation without altering its mRNA level. This degradation was time- and multiplicity of infection-dependent. Sp100 protein was also degraded, while another SUMO-1 conjugated protein, RanGAP1 and the IFN-induced protein kinase PKR were not. The proteasome inhibitor MG132 abrogated the HSV-1-induced PML and Sp100 degradation and partially restored their NB-localization. HSV-1 induced PML and Sp100 degradation constitutes a new example of viral inactivation of IFN target gene products. (+info)
Expression and differential regulation of connective tissue growth factor in pancreatic cancer cells.
(37/174666)
CTGF is an immediate early growth responsive gene that has been shown to be a downstream mediator of TGFbeta actions in fibroblasts and vascular endothelial cells. In the present study hCTGF was isolated as immediate early target gene of EGF/TGFalpha in human pancreatic cancer cells by suppression hybridization. CTGF transcripts were found in 13/15 pancreatic cancer cell lines incubated with 10% serum. In 3/7 pancreatic cancer cell lines EGF/TGFalpha induced a significant rise of CTGF transcript levels peaking 1-2 h after the start of treatment. TGFbeta increased CTGF transcript levels in 2/7 pancreatic cancer cell lines after 4 h of treatment and this elevation was sustained after 24 h. Only treatment with TGFbeta was accompanied by a parallel induction of collagen type I transcription. 15/19 human pancreatic cancer tissues were shown to overexpress high levels of CTGF transcripts. CTGF transcript levels in pancreatic cancer tissues and nude mouse xenograft tumors showed a good correlation to the degree of fibrosis. In situ hybridization and the nude mouse experiments revealed that in pancreatic cancer tissues, fibroblasts are the predominant site of CTGF transcription, whereas the tumor cells appear to contribute to a lesser extent. We conclude that CTGF may be of paramount importance for the development of the characteristic desmoplastic reaction in pancreatic cancer tissues. (+info)
Prolonged eosinophil accumulation in allergic lung interstitium of ICAM-2 deficient mice results in extended hyperresponsiveness.
(38/174666)
ICAM-2-deficient mice exhibit prolonged accumulation of eosinophils in lung interstitium concomitant with a delayed increase in eosinophil numbers in the airway lumen during the development of allergic lung inflammation. The ICAM-2-dependent increased and prolonged accumulation of eosinophils in lung interstitium results in prolonged, heightened airway hyperresponsiveness. These findings reveal an essential role for ICAM-2 in the development of the inflammatory and respiratory components of allergic lung disease. This phenotype is caused by the lack of ICAM-2 expression on non-hematopoietic cells. ICAM-2 deficiency on endothelial cells causes reduced eosinophil transmigration in vitro. ICAM-2 is not essential for lymphocyte homing or the development of leukocytes, with the exception of megakaryocyte progenitors, which are significantly reduced. (+info)
Intrahepatic recurrence after curative resection of hepatocellular carcinoma: long-term results of treatment and prognostic factors.
(39/174666)
OBJECTIVE: This study aimed to evaluate the long-term results of treatment and prognostic factors in patients with intrahepatic recurrence after curative resection of hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: Recent studies have demonstrated the usefulness of re-resection, transarterial oily chemoembolization (TOCE), or percutaneous ethanol injection therapy (PEIT) in selected patients with intrahepatic recurrent HCC. The overall results of a treatment strategy combining these modalities have not been fully evaluated, and the prognostic factors determining survival in these patients remain to be clarified. METHODS: Two hundred and forty-four patients who underwent curative resection for HCC were followed for intrahepatic recurrence, which was treated aggressively with a strategy including different modalities. Survival results after recurrence and from initial hepatectomy were analyzed, and prognostic factors were determined by univariate and multivariate analysis using 27 clinicopathologic variables. RESULTS: One hundred and five patients (43%) with intrahepatic recurrence were treated with re-resection (11), TOCE (71), PEIT (6), systemic chemotherapy (8) or conservatively (9). The overall 1-year, 3-year, and 5-year survival rates from the time of recurrence were 65.5%, 34.9%, and 19.7%, respectively, and from the time of initial hepatectomy were 78.4%, 47.2%, and 30.9%, respectively. The re-resection group had the best survival, followed by the TOCE group. Multivariate analysis revealed Child's B or C grading, serum albumin < or = 40 g/l, multiple recurrent tumors, recurrence < or = 1 year after hepatectomy, and concurrent extrahepatic recurrence to be independent adverse prognostic factors. CONCLUSIONS: Aggressive treatment with a multimodality strategy could result in prolonged survival in patients with intrahepatic recurrence after curative resection for HCC. Prognosis was determined by the liver function status, interval to recurrence, number of recurrent tumors, any concurrent extrahepatic recurrence, and type of treatment. (+info)
Delayed gastric emptying after Billroth I pylorus-preserving pancreatoduodenectomy: effect of postoperative time and cisapride.
(40/174666)
OBJECTIVE: To study the recovery course of gastric emptying after Billroth I pylorus-preserving pancreatoduodenectomy (PPPD) and therapeutic effects of cisapride. METHODS: To examine gastric emptying, acetaminophen was given, admixed in a pasty liquid meal, to 16 patients undergoing PPPD before surgery and at 1, 3, 6, 9, and 12 months after surgery. Cisapride was given orally to 10 patients before they received the acetaminophen regimen. Electrogastrography was performed at 2 weeks to 1 month after surgery in eight patients and at 6 to 12 months after surgery in seven patients. RESULTS: Gastric emptying was delayed but returned to the preoperative level by 6 months after surgery. Pretreatment with cisapride accelerated gastric emptying during months 1 to 6 but not during months 6 to 12 after surgery. Electrogastrography frequently showed tachygastria 2 weeks to 1 month after surgery, but seldom 6 to 12 months after surgery. CONCLUSIONS: After Billroth I PPPD, gastric emptying is delayed but recovers by 6 months after surgery. Tachygastria may play a part in the pathogenesis of delayed gastric emptying, but it can be treated with cisapride. (+info)