Spontaneous Emergence of Multiple Drug Resistance in Tuberculosis before and during Therapy

The emergence of drug resistance in M. tuberculosis undermines the efficacy of tuberculosis (TB) treatment in individuals and of TB control programs in populations. Multiple drug resistance is often attributed to sequential functional monotherapy, and standard initial treatment regimens have therefore been designed to include simultaneous use of four different antibiotics. Despite the widespread use of combination therapy, highly resistant M. tb strains have emerged in many settings. Here we use a stochastic birth-death model to estimate the probability of the emergence of multidrug resistance during the growth of a population of initially drug sensitive TB bacilli within an infected host. We find that the probability of the emergence of resistance to the two principal anti-TB drugs before initiation of therapy ranges from 10−5 to 10−4; while rare, this is several orders of magnitude higher than previous estimates. This finding suggests that multidrug resistant M. tb may not be an entirely “man-made” phenomenon and may help explain how highly drug resistant forms of TB have independently emerged in many settings

Degradation of haloaromatic compounds

An ever increasing number of halogenated organic compounds has been produced by industry in the last few decades. These compounds are employed as biocides, for synthetic polymers, as solvents, and as synthetic intermediates. Production figures are often incomplete, and total production has frequently to be extrapolated from estimates for individual countries. Compounds of this type as a rule are highly persistent against biodegradation and belong, as "recalcitrant" chemicals, to the class of so-called xenobiotics. This term is used to characterise chemical substances which have no or limited structural analogy to natural compounds for which degradation pathways have evolved over billions of years. Xenobiotics frequently have some common features. e.g. high octanol/water partitioning coefficients and low water solubility which makes for a high accumulation ratio in the biosphere (bioaccumulation potential). Recalcitrant compounds therefore are found accumulated in mammals, especially in fat tissue, animal milk supplies and also in human milk. Highly sophisticated analytical techniques have been developed for the detection of organochlorines at the trace and ultratrace level

Cohort migration of carcinoma cells: Differentiated colorectal carcinoma cells move as coherent cell clusters or sheets

Active migration of tumor cells is usually assessed as single cell locomotion in vitro using Royden chamber-type assays. In vivo, however, carcinoma cells, malignant cells of epithelial origin, frequently invade the surrounding tissue as coherent clusters or nests of cells. We have called this type of movement "cohort migration". In our work, the invasion front of colon carcinomas consisted of compact tumor glands, partially resolved glands or markedly resolved glands with scattered tumor cell clusters or single cells lying ahead. In the former two types, which constituted about a half of all cases, cohort migration seems to be the predominant mechanism, whereas both cohort migration and single cell locomotion may be involved in the last one. In this light, it is very advantageous to investigate the mechanisms involved in the cohort migration. In this review, we present a two-dimensional motility assay as a cohort migration model, in which human colorectal carcinoma cells move outwards from the cell islands mainly as localized coherent sheets of cells when stimulated with 12-0-tetradecanoylphorbol- 13-acetate (TPA) or hepatocyte growth factorlscatter factor (HGFISF). Within the migrating cell sheets, wide intercellular gaps occur at the lower portion of the cells to allow the cells to extend leading lamellae forward while close cell-cell contacts remain at the upper portion of the cells. This localized modulation of cell-cell adhesion at the lower portion of the cells is associated with increased tyrosine phosphorylation of the Ecadherin- catenin complex in TPA-induced cohort migration and with reduced α-catenin complexed with E-cadherin in HGFISF-induced cohort migration. Furthermore, fibronectin deposited by migrating cells is essential for their movement, and on the gelatin-coated substrate even degradation and remodeling of the substrate by matrix metalloproteinases are also needed. Thus, in cohort migration it is likely that cells are released from cell-cell adhesion only at the lower portion of the cells via modulation of E-cadherin-catenin-based mechanism, and this change allows the cells to extend leading lamellae onto the extracellular matrix substrate remodeled by deposition of fibronectin and organized digestion

Endoscopic management and treatment of early gastric cancer

La présente étude comporte l'analyse rétrospective des résultats du traitement du cancer gastrique au début, respectivement par résection muqueuse endoscopique (RME) dans 106 cas et d'autre part, par traitement au laser dans 108 cas. Les auteurs ont examiné les critères déterminant le choix de la méthode optimale de traitement du cancer gastrique au début, y compris le choix d'un éventuel mode d'intervention chirurgicale. En fonction de l'examen histopathologique des tissus réséqués et de l'existence de métastases lymphatiques, les lésions ont été réparties en deux groupes: un groupe à «indication absolue» et un groupe à «indication relative». Les taux de résection complète après RME ont été respectivement de 69,7% (53/76) dans le groupe «indication absolue» et de 20% (6/30) dans le groupe «indication relative». Dans le groupe «indication absolue», les taux de cancers résiduels après traitement au laser étaient de 0% (0/24) et le taux de récidive tumorale après traitement au laser était de 4,2% (1/24). Le taux cumulé de curabilité, comportant la guérison de la lésion tumorale récidivante après traitement supplémentaire, était de 100% pour le même groupe (20/24). Dans le groupe «indication relative», le taux de cancers résiduels était de 17,4% (8/46), le taux de récidive était de 13,2% (5/38) et le taux cumulé de curabilité était de 97,4% (37/38). Ces résultats montrent que les réponses au traitement d'un cancer gastrique au début sont meilleures après application du laser qu'après résection par RME. Néanmoins, la RME présente l'avantage de fournir des échantillons tissulaires disponibles pour examen histopathologique. Cette caractéristique de la RME la rend recommandable en première intention pour le traitement d'un cancer au début classé dans le groupe «indication absolue», puisqu'il est possible après traitement, d'assurer sur base histopathologique la curabilité de la lésion. Un traitement par laser est indiqué en cas d'échec du traitement du cancer gastrique par RME ou dans les cas pour lesquels une RME est techniquement difficile à effectuer. Dans le groupe à «indication relative», sans élimination possible de métastases lymphatiques, certaines techniques opératoires permettent l'exérèse simultanée des ganglions lymphatiques et donc, sont recommandables en première intention. Le traitement endoscopique par laser est recommandé pour les patients de ce groupe lorsqu'ils refusent la chirurgie ou sont exposés à des risques inacceptables du fait de maladies intercurrentes ou de leur grand âg

Front-cell-specific expression of membrane-type 1 matrix metalloproteinase and gelatinase A during cohort migration of colon carcinoma cells induced by hepatocyte growth factor/scatter factor.

Migration of tumor cells is usually assessed as single cell locomotion in vitro using Boyden chamber type assays. In vivo, however, carcinoma cells frequently invade the surrounding tissue as coherent clusters or nests of cells. We have called this type of movement "cohort migration" and developed a two-dimensional in vitro cohort migration model, in which human rectal well-differentiated adenocarcinoma cells (L-10) migrate from piled-up cell islands as coherent sheets of cells when stimulated with hepatocyte growth factor/scatter factor. In this study, we examined whether there is a cohort migration-specific way of expression of matrix metalloproteinases (MMP) and whether degradation of extracellular matrix is necessary for this type of migration. Production of membrane-type 1-MMP (MT1-MMP) and gelatinase A (MMP-2) by L-10 cells was demonstrated by gelatin zymography, immunoblotting, and reverse transcription-PCR. When cohort migration was induced with hepatocyte growth factor/scatter factor, MT1-MMP and MMP-2 were immunolocalized predominantly in the leading edges of the front cells of migrating cell sheets, with the following cells being negative. In addition, during the cohort migration on gelatin-coated substratum, the gelatin matrix was degraded by the cells, in a very organized manner, causing radially arrayed lysis of gelatin matrix at the sites of leading edges. BB94, a synthetic inhibitor specific to MMPs, tissue inhibitor of metalloproteinases-1 and -2, and the COOH-terminal hemopexin-like domain of MMP-2 inhibited the migration on gelatin matrix. Thus, these data demonstrate that gelatin matrix is reorganized to suit cell migration via leading-edge-of-front-cell-specific localization of MT1-MMP and MMP-2 during cohort migration and suggest that the reorganization is essential for this type of migration

Cohort migration of carcinoma cells.Differentiated colorectal carcinoma cells move as coherent cell clusters or sheets

Active migration of tumor cells is usually assessed as single cell locomotion in vitro using Royden chamber-type assays. In vivo, however, carcinoma cells, malignant cells of epithelial origin, frequently invade the surrounding tissue as coherent clusters or nests of cells. We have called this type of movement "cohort migration". In our work, the invasion front of colon carcinomas consisted of compact tumor glands, partially resolved glands or markedly resolved glands with scattered tumor cell clusters or single cells lying ahead. In the former two types, which constituted about a half of all cases, cohort migration seems to be the predominant mechanism, whereas both cohort migration and single cell locomotion may be involved in the last one. In this light, it is very advantageous to investigate the mechanisms involved in the cohort migration. In this review, we present a two-dimensional motility assay as a cohort migration model, in which human colorectal carcinoma cells move outwards from the cell islands mainly as localized coherent sheets of cells when stimulated with 12-0-tetradecanoylphorbol- 13-acetate (TPA) or hepatocyte growth factorlscatter factor (HGFISF). Within the migrating cell sheets, wide intercellular gaps occur at the lower portion of the cells to allow the cells to extend leading lamellae forward while close cell-cell contacts remain at the upper portion of the cells. This localized modulation of cell-cell adhesion at the lower portion of the cells is associated with increased tyrosine phosphorylation of the Ecadherin- catenin complex in TPA-induced cohort migration and with reduced a-catenin complexed with E-cadherin in HGFISF-induced cohort migration. Furthermore, fibronectin deposited by migrating cells is essential for their movement, and on the gelatin-coated substrate even degradation and remodeling of the substrate by matrix metalloproteinases are also needed. Thus, in cohort migration it is likely that cells are released from cell-cell adhesion only at the lower portion Offprint requests to: Dr. Kazuki Nabeshima, Department of Pathology, Miyazaki Medical College, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. e-mail: [email protected] Histology and Histopathology of the cells via modulation of E-cadherin-catenin-based mechanism, and this change allows the cells to extend leading lamellae onto the extracellular matrix substrate remodeled by deposition of fibronectin and organized digestion