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At least 685 records · Page 38Linked to original sources
PubMed2003

Mechanisms of altered protein turnover in chronic diseases: a review of human kinetic studies.

PURPOSE OF REVIEW: Changes in hormone secretion, tissue perfusion, oxygen availability, energy-protein intake, free amino acid pattern, hydration state, acid-base balance as well as activation of the systemic inflammatory response may affect protein synthesis and degradation. The overall purpose of this review is to describe how these factors may interact to change protein turnover in the different directions seen in kinetic studies in humans. RECENT FINDINGS: Evidence indicates that, in vivo, changes of protein synthesis and degradation are strictly related. When protein synthesis is primarily suppressed, protein degradation is found to be unchanged or even slightly decreased. When protein degradation is primarily accelerated, the rate of synthesis is unchanged or even increased. Chronic disease states can, therefore, be characterized either by decreased or accelerated protein turnover. Apparent discrepancies among various studies in chronic uraemia, liver cirrhosis, chronic obstructive pulmonary disease and cancer may stem from the fact that the pathogenesis of protein metabolism abnormalities is multifactorial. When the effects of inflammatory mediators and stress hormones start overwhelming factors that tend to decrease protein synthesis and turnover (decreased protein-energy intake, physical activity, tissue oxygen delivery, leucine levels, etc.), the rate of protein degradation and turnover may increase. SUMMARY: Low-protein turnover conditions are usually associated with the adequate sparing of body proteins, whereas in high-protein turnover conditions protein loss may proceed at a faster rate. Nonetheless, impaired recovery from acute complications and the reduced renewal of damaged and toxic proteins are potential undesired consequences of low-protein turnover.

Chronic Disease↗
PubMed2004

The human tumour suppressor gene SLC5A8 expresses a Na+-monocarboxylate cotransporter.

The orphan cotransport protein expressed by the SLC5A8 gene has been shown to play a role in controlling the growth of colon cancers, and the silencing of this gene is a common and early event in human colon neoplasia. We expressed this protein in Xenopus laevis oocytes and have found that it transports small monocarboxylic acids. The electrogenic activity of the cotransporter, which we have named SMCT (sodium monocarboxylate transporter), was dependent on external Na(+) and was compatible with a 3 : 1 stoichiometry between Na(+) and monocarboxylates. A portion of the SMCT-mediated current was also Cl(-) dependent, but Cl(-) was not cotransported. SMCT transports a variety of monocarboxylates (similar to unrelated monocarboxylate transport proteins) and most transported monocarboxylates demonstrated K(m) values near 100 microm, apart from acetate and d-lactate, for which the protein showed less affinity. SMCT was strongly inhibited by 1 mm probenecid or ibuprofen. In the absence of external substrate, a Na(+)-independent leak current was also observed to pass through SMCT. SMCT activity was strongly inhibited after prolonged exposure to high external concentrations of monocarboxylates. The transport of monocarboxylates in anionic form was confirmed by the observation of a concomitant alkalinization of the cytosol. SMCT, being expressed in colon and kidney, represents a novel means by which Na(+), short-chain fatty acids and other monocarboxylates are transported in these tissues. The significance of a Na(+)-monocarboxylate transporter to colon cancer presumably stems from the transport of butyrate, which is well known for having anti-proliferative and apoptosis-inducing activity in colon epithelial cells.

Animals↗
PubMed2004

Direct assessment of drug penetration into tissue using a novel application of three-dimensional cell culture.

The failure of many anticancer drugs to control growth of solid cancers may stem in part from inadequate delivery to tumor regions distant from vasculature. Although the identification of new anticancer drug targets has led to the development of many new drug candidates, there is a lack of methodology for identifying drugs that adequately penetrate tumor tissue. We have developed a novel multilayered cell culture-based assay, which detects the penetration of anticancer drugs based on their effect within tissue. Drug exposures are made over 1 hour to one side of a disk of tissue approximately 150-microm thick, with the other side temporarily closed off, and penetration is then assessed 1-3 days later via bromodeoxyuridine-based detection of S-phase cells. Using this assay, the tissue distribution of a selection of anthracycline analogues was assessed. At clinically relevant exposures, none of the agents were able to affect cells on the far side of the culture at levels approaching that seen on the near (exposed) side. Doxorubicin and epirubicin exhibited approximately 10-fold decreases in the drug exposure seen by the cells on the far side relative to those on the near side of the cultures, whereas for daunorubicin and mitoxantrone, approximately 30-fold and >30-fold decreases were observed respectively. Results were consistent with the observed gradients in drug-derived fluorescence of doxorubicin, epirubicin, and daunorubicin. This model could be applied as a simple anticancer drug development screen to discover drugs that exhibit desirable penetration properties.

Anthracyclines↗
PubMed2005

Hyperbolastic growth models: theory and application.

BACKGROUND: Mathematical models describing growth kinetics are very important for predicting many biological phenomena such as tumor volume, speed of disease progression, and determination of an optimal radiation and/or chemotherapy schedule. Growth models such as logistic, Gompertz, Richards, and Weibull have been extensively studied and applied to a wide range of medical and biological studies. We introduce a class of three and four parameter models called "hyperbolastic models" for accurately predicting and analyzing self-limited growth behavior that occurs e.g. in tumors. To illustrate the application and utility of these models and to gain a more complete understanding of them, we apply them to two sets of data considered in previously published literature. RESULTS: The results indicate that volumetric tumor growth follows the principle of hyperbolastic growth model type III, and in both applications at least one of the newly proposed models provides a better fit to the data than the classical models used for comparison. CONCLUSION: We have developed a new family of growth models that predict the volumetric growth behavior of multicellular tumor spheroids with a high degree of accuracy. We strongly believe that the family of hyperbolastic models can be a valuable predictive tool in many areas of biomedical and epidemiological research such as cancer or stem cell growth and infectious disease outbreaks.

Cell Proliferation↗
PubMed2006

Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients.

INTRODUCTION: The diagnosis of invasive pulmonary aspergillosis, according to the criteria as defined by the European Organisation for the Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG), is difficult to establish in critically ill patients. The aim of this study is to address the clinical significance of isolation of Aspergillus spp. from lower respiratory tract samples in critically ill patients on the basis of medical and radiological files using an adapted diagnostic algorithm to discriminate proven and probable invasive pulmonary aspergillosis from Aspergillus colonisation. METHODS: Using a historical cohort (January 1997 to December 2003), all critically ill patients with respiratory tract samples positive for Aspergillus were studied. In comparison to the EORTC/MSG criteria, a different appreciation was given to radiological features and microbiological data, including semiquantitative cultures and direct microscopic examination of broncho-alveolar lavage samples. RESULTS: Over a 7 year period, 172 patients were identified with a positive culture. Of these, 83 patients were classified as invasive aspergillosis. In 50 of these patients (60%), no high risk predisposing conditions (neutropenia, hematologic cancer and stem cell or bone marrow transplantation) were found. Typical radiological imaging (halo and air-crescent sign) occurred in only 5% of patients. In 26 patients, histological examination either by ante-mortem lung biopsy (n = 10) or necropsy (n = 16) was performed, allowing a rough estimation of the predictive value of the diagnostic algorithm. In all patients with histology, all cases of clinical probable pulmonary aspergillosis were confirmed (n = 17). Conversely, all cases classified as colonisation had negative histology (n = 9). CONCLUSION: A respiratory tract sample positive for Aspergillus spp. in the critically ill should always prompt further diagnostic assessment, even in the absence of the typical hematological and immunological host risk factors. In a minority of patients, the value of the clinical diagnostic algorithm was confirmed by histological findings, supporting its predictive value. The proposed diagnostic algorithm needs prospective validation.

Aged↗
PubMed2005

Atomic force microscopy measurements of protein-ligand interactions on living cells.

Cell adhesion receptors are expressed on the surface of cells and can mediate binding to other cells and to the extracellular matrix. Here, we describe in detail the use of atomic force microscopy (AFM)-based force spectroscopy for studying cell detachment forces on living leukocytes. With this technique it is now possible to measure force with resolution down to the level of individual molecules. AFM force spectroscopy is particularly well suited for research in cell adhesion, which has relevance in both the medical and life sciences including immunology, cancer and stem cell research, and human pharmacology. Along with its limitations, we herein, describe how the rupture force of a single complex formed between the integrin receptor leukocyte function-associated antigen (LFA)-1, expressed on the surface of a living leukocyte, and immobilized intercellular adhesion molecule-1 (ICAM-1) was measured. With only minor modifications this protocol can be used to study other adhesion receptors on almost any mammalian cell or bacterial system. This protocol is also suitable for studying single-molecule de-adhesion events in cell-free systems as well as between two living cells.

Cell Adhesion↗
PubMed2001

Tunneled femoral central venous catheters in children with cancer.

OBJECTIVE: We discuss the feasibility of long-term femoral venous access by means of a cuffed subcutaneously tunneled central venous catheter (Broviac catheter) in selected pediatric cancer and stem cell transplant patients in whom access via the veins of the upper part of the torso is difficult or contraindicated and in whom alternative routes must be used. PATIENTS AND METHODS: We report on our experience with 9 patients (3 of whom underwent stem cell transplantation) who received femoral Broviac catheters between December 1990 and November 1999. Results. Time in place ranged from 4 to 155 days with a median of 58 days (mean: 71.2 days). Three catheters had to be removed: 1 because of infection of the subcutaneous tunnel and 2 because of catheter obstruction. The remaining 6 catheters functioned well without problems as long as they were needed; 1 of them got accidentally dislodged while the patient was off treatment. No episodes of catheter-related septicemia, thrombosis, kinking, or drug extravasation were noted; there were no catheter-related infectious complications in the transplant patients. CONCLUSIONS: Our experience indicates that in those instances in which customary access to the superior vena cava is precluded, long-term venous access by way of the femoral vein is a feasible and safe alternative in children, even in the setting of stem cell transplantation.

Adolescent↗
PubMed2000

[Germ-line mutations of the BRCA1 gene in northeastern France].

Thirty-seven breast/ovarian or breast-only cancer families selected on a regional basis have been analyzed for mutations at BRCA1. By combining direct sequence analysis and protein truncation test, mutations were detected in 14 families (38%). We found seven different mutations, two of which have not been described before. Mutations at BRCA1 were present in 60% of breast/ovarian and 32% of breast-only cancer families. Mutations were frequent in families with at least one breast cancer case before age 40 (44%) and/or one bilateral breast cancer case (54%). Two mutations, namely 3600del11 and G1710X, are frequent in the population native from northeastern France. Oriented BRCA1 analysis should facilitate carrier detection in breast and/or ovarian cancer families stemming from this French area.

Adult↗
PubMed2005

Gene therapy in the treatment of Fanconi anemia, a progressive bone marrow failure syndrome.

Fanconi anemia (FA) is a genetic disease characterized by progressive, fatal bone marrow failure, congenital anomalies and predisposition to cancer. Although stem cell transplantation is therapeutic, human leukocyte antigen-identical sibling donors are available to a minority of patients. In murine models and human cells in vitro, gene transfer corrects the FA cellular phenotype of chromosomal breakage in response to DNA-damaging agents, suggesting therapeutic use of gene transfer is possible. However, disease-specific characteristics make application of viral vector technology difficult. Multiple studies are currently underway to develop a gene therapy approach for treating this disease, including phase I trials.

Clinical Trials as Topic↗