Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies

Composition des 3 types de foie gras : oie, canard mulard et canard de Barbarie

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Modifications des lipoprotéines de basse densité (LDL) par radiolyse γ de l'eau : reconnaissance par les récepteurs APO B/E et «scavenger», et cytotoxicité vis-à-vis de fibroblastes humains en culture

Le but de ce travail était d'étudier la reconnaissance par le récepteur B/E de fibroblastes humains et le récepteur "scavenger" de macrophages, de LDL d'origine humaine oxydées par radiolyse γ de l'eau (O2°-/OH°). Leur cytotoxicité vis-à-vis de fibroblastes humains en culture a également été testée. Nous avons montré que les LDL oxydées (doses comprises entre 600 et 1800 Gy) étaient encore partiellement reconnues par le récepteur apo B/E des fibroblastes MRC5. Ces LDL oxydées étaient cytotoxiques vis-à-vis de fibroblastes humains en culture et cet effet était dépendant de la dose d'irradiation. En revanche, la reconnaissance par le récepteur "scavenger" des macrophages ne semblait pas dépendante de la dose d'irradiation, dans nos conditions expérimentales. La peroxydation des LDL par les radicaux générés par radiolyse γ de l'eau semblerait se distinguer de celle induite par le cuivre et pourrait constituer un modèle expérimental intéressant pour l'introduction de lipides peroxydés dans le milieu intracellulaire

behavior of chromium coated m5tm claddings under loca conditions

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