Cancerous stem cells: deviant stem cells with cancer-causing misbehavior

Stem cells maintain homeostasis in adult tissues via self-renewal and generation of terminally differentiated cells. Alterations in this intricate balance can result in disease. It has become increasingly evident that cancer can be initiated at the level of stem cells. Therefore, understanding what causes stem cells to become cancerous may lead to new therapeutic approaches. Multiple signaling pathways ultimately affect stem cell survival and proliferation, thus maintaining homeostasis in the gut. Changes in these pathways could perturb normal stem cell behavior, leading to cancerous stem cells. In addition, cancerous stem cells show resistance to current therapies and may lead to a dangerous selection process resulting in recurrence and metastasis. Genomic instability, the driving force of mutation and resistance, may give cancerous stem cells an adaptive advantage, especially when subjected to cancer therapies. Targeting the unique characteristics of cancerous stem cells to promote either terminal differentiation or destruction would effectively eradicate cancer and improve patient care and survival

Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation.

Exposure to high levels of ionizing radiation (IR) leads to debilitating and dose-limiting gastrointestinal (GI) toxicity. Using three-dimensional mouse crypt culture, we demonstrated that p53 target PUMA mediates radiation-induced apoptosis via a cell-intrinsic mechanism, and identified the GSK-3 inhibitor CHIR99021 as a potent radioprotector. CHIR99021 treatment improved Lgr5+ cell survival and crypt regeneration after radiation in culture and mice. CHIR99021 treatment specifically blocked apoptosis and PUMA induction and K120 acetylation of p53 mediated by acetyl-transferase Tip60, while it had no effect on p53 stabilization, phosphorylation or p21 induction. CHIR99021 also protected human intestinal cultures from radiation by PUMA but not p21 suppression. These results demonstrate that p53 posttranslational modifications play a key role in the pathological and apoptotic response of the intestinal stem cells to radiation and can be targeted pharmacologically

Selective Depletion of Eosinophils or Neutrophils in Mice Impacts the Efficiency of Apoptotic Cell Clearance in the Thymus

Developing thymocytes undergo a rigorous selection process to ensure that the mature T cell population expresses a T cell receptor (TCR) repertoire that can functionally interact with major histocompatibility complexes (MHC). Over 90% of thymocytes fail this selection process and die. A small number of macrophages within the thymus are responsible for clearing the large number of dying thymocytes that must be continuously cleared. We studied the capacity of thymic macrophages to clear apoptotic cells under acute circumstances. This was done by synchronously inducing cell death in the thymus and then monitoring the clearance of apoptotic thymocytes. Interestingly, acute cell death was shown to recruit large numbers of CD11b+ cells into the thymus. In the absence of a minor CSF-1 dependent population of macrophages, the recruitment of these CD11b+ cells into the thymus was greatly reduced and the clearance of apoptotic cells was disrupted. To assess a possible role for the CD11b+ cells in the clearance of apoptotic cells, we analyzed mice deficient for eosinophils and mice with defective trafficking of neutrophils. Failure to attract either eosinophils or neutrophils to the thymus resulted in the impaired clearance of apoptotic cells. These results suggested that there is crosstalk between cells of the innate immune system that is necessary for maximizing the efficiency of apoptotic cell removal

Les pouvoirs de saisie des services d'inspection du travail: L'arrêt rendu le 4 Décembre 2008 par la cour du travail de Gand (section de Bruges)

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Establishment and Characterization of 5-Fluorouracil-Resistant Human Colorectal Cancer Stem-Like Cells: Tumor Dynamics under Selection Pressure

5-Fluorouracil (5-FU) remains the gold standard of first-line treatment for colorectal cancer (CRC). Although it may initially debulk the tumor mass, relapses frequently occur, indicating the existence of cancer cells that are therapy-resistant and are capable of refueling tumor growth. To identify mechanisms of drug resistance, CRC stem-like cells were subjected to long-term 5-FU selection using either intermittent treatment regimen with the IC50 drug dose or continuous treatment regimen with escalating drug doses. Parental cancer cells were cultivated in parallel. Real-time PCR arrays and bioinformatic tools were used to investigate gene expression changes. We found the first method selected for cancer cells with more aggressive features. We therefore transplanted these cancer cells or parental cells in mice, and again, found that not only did the 5-FU-selected cancer cells generate more aggressive tumors with respect to their parental counterpart, but they also showed a different gene expression pattern as compared to what we had observed in vitro, with ID1 the top upregulated gene. We propose ID1 as a stemness marker pervasively expressed in secondary lesions emerging after completion of chemotherapy

Mesure des résistances électriques élevées à l'aide d'une chambre d'ionisation utilisée comme source de courant

The accurate measurement of high electric resistances is very difficult when their values are above 1012 ohms, and, if a classic method is used, for instance ammeter and voltmeter. We describe a method using an ionization chamber, acting like a current source, put into series with the unknown resistance ; we calculate the value of this resistance from the voltage between its terminals, measured with an electrometer. The ionization chamber is filled with air or argon ; its electrodes are two parallel plates, which spacing can be varied. Constant ionization current supplied by the system is provided by a thin layer of uranium dioxide, deposited on one side of a plate. If the filling pressure is modified, the ionization current can be continuously varied ; its maxima value is 2.7 × 10—11 ampere, under atmospheric pressure. Our method allows measurement with great accuracy of resistances which have small values as compared to the internal resistance p of the chamber (p = ΔV/Ai). Under atmospheric pressure, p is of the order of 1015 ohms ; with air, under a pressure of 2 cm of mercury, p will be 1016 ohms. The upper [limit of resistances which can be measured accurately, with this ionization chamber, is 10 14 ohms.Il devient très difficile de mesurer, avec une bonne précision, les résistances électriques élevées, lorsque leurs valeurs dépassent 1012 ohms, et que l'on fait appel à une méthode classique, comme celle de l'ampèremètre et du voltmètre. Nous décrivons une méthode utilisant une chambre d'ionisation, fonctionnant comme une source de courant, et placée en série avec la résistance inconnue : la valeur de cette résistance se déduit de la tension entre ses bornes, mesurée par un montage électrométrique. La chambre d'ionisation est remplie d'air ou d'argon ; ses électrodes sont deux plateaux parallèles, dont il est possible de faire varier la distance. Le courant d'ionisation constant, débité par l'appareil, est créé par une couche mince de bioxyde d'uranium, déposée sur l'un des plateaux. En modifiant la pression de remplissage, il est possible de faire varier de façon continue le courant d'ionisation ; sa valeur maximum est de 2,7 .10—11 ampère, sous la pression atmosphérique. Notre méthode permet de mesurer, avec une précision excellente, les résistances de faibles valeurs par rapport à la résistance interne p de la chambre (p = ΔV/Δ i). Sous la pression atmosphérique, p est de l'ordre de 1015 ohms ; pour un remplissage d'air sous la pression de 2 cm de mercure, p atteint 1016 ohms. Finalement, avec la chambre d'ionisation décrite, la limite supérieure des résistances mesurables avec précision est de 1014 ohms

Technique de mesure des résistances électriques élevées au moyen d'une chambre d'ionisation

An ionization chamber acting like a current source allows accurate measurements of high electric resistances [1], [2]. The working up of this technic is explained here. In the simplest method, the voltage applied to the whole circuit is maintained constant. The measures are limited to resistances, the values of which are small as compared to the internal resistance of the chamber : with an internal resistance of 10^16 ohms, the limit is near 4.10^14 ohms. To keep up constant the voltage between the electrodes of the chamber, by a method of compensation, is more interesting ; an important reduction of the current crossing the chamber is not to be feared ; the only practical limit lies in the maximum voltage that the resistance under measure can support, this maximum voltage being imposed by the current supplied by the source. The method has been used to study various thin dielectrics sheets, more particularly micas.Une chambre d'ionisation, utilisée comme source de courant, permet la mesure précise de résistances électriques élevées [1], [2]. On précise ici la mise en œuvre de cette technique. La méthode la plus simple consiste à maintenir constante la tension appliquée à l'ensemble du circuit ; les résistances ne sont mesurables que si elles sont faibles par rapport à la résistance interne de la chambre : pour une résistance interne de 10^16 ohms, la limite est voisine de 4.10^14 ohms. Il est plus intéressant de maintenir constante, par compensation, la tension entre les électrodes de la chambre : on n'a plus à craindre une diminution importante de l'intensité du courant d'ionisation et la seule limite pratique réside dans la valeur maximale de la tension que peut supporter la résistance à mesurer, valeur imposée par l'intensité du courant débité par la source. Cette méthode a été appliquée à l'étude de divers isolants en feuilles minces, notamment des micas

Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas

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