Many leukemia patients suffer from dysregulation of their immune system, making them more susceptible to infections and leading to general weakening (cachexia). Both adaptive and innate immunity are affected. The fruit flyDrosophila melanogasterhas an innate immune system, including cells of the myeloid lineage (hemocytes). To studyDrosophilaimmunity and physiology during leukemia, we established three models by driving expression of a dominant-active version of the Ras oncogene (RasV12) alone or combined with knockdowns of tumor suppressors inDrosophilahemocytes. Our results show that phagocytosis, hemocyte migration to wound sites, wound sealing, and survival upon bacterial infection of leukemic lines are similar to wild type. We find that in all leukemic models the two major immune pathways (Toll and Imd) are dysregulated. Toll-dependent signaling is activated to comparable extents as after wounding wild-type larvae, leading to a proinflammatory status. In contrast, Imd signaling is suppressed. Finally, we notice that adult tissue formation is blocked and degradation of cell masses during metamorphosis of leukemic lines, which is akin to the state of cancer-dependent cachexia. To further analyze the immune competence of leukemic lines, we used a natural infection model that involves insect-pathogenic nematodes. We identified two leukemic lines that were sensitive to nematode infections. Further characterization demonstrates that despite the absence of behavioral abnormalities at the larval stage, leukemic larvae show reduced locomotion in the presence of nematodes. Taken together, this work establishes newDrosophilamodels to study the physiological, immunological, and behavioral consequences of various forms of leukemia.
- MeSH
- Drosophila MeSH
- fenotyp * MeSH
- hemocyty imunologie MeSH
- kachexie * genetika imunologie MeSH
- larva genetika imunologie MeSH
- leukemie * genetika imunologie MeSH
- modely nemocí na zvířatech MeSH
- přirozená imunita * MeSH
- proteiny Drosophily genetika imunologie MeSH
- protoonkogenní proteiny p21(ras) genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Panitumumab prokázal účinnost v klinických studiích v 1., 2., ale i 3. linii léčby metastatického kolorektálního karcinomu. Analýza biomarkerů v těchto studiích ukazuje, že účinnost léčby je závislá nejen na stavu onkogenu KRAS, ale na stavu celé rodiny onkogenů RAS. Pacienti s nemutovaným (wild type) RAS dosahovali ve studiích nejlepších výsledků, naopak pacienti s mutací RAS by v dnešní době neměli být léčeni inhibitory EGFR, protože by to jednoznačně vedlo k poškození pacienta.
Panitumumab has shown efficacy in clinical studies of first-, second-, but also third lines of therapy of metastatic colorectal carcinoma. Biomarker analysis in these studies indicates that treatment efficacy depends not only on the oncogene KRAS status, but also on the status of the whole RAS oncogene family. Patients with non-mutant (wild type) RAS attained best results in the studies , while patients with mutant RAS should not be treated with EGFR inhibitors today as this would clearly result in damage to the patients.
- MeSH
- algoritmy MeSH
- analýza přežití MeSH
- cílená molekulární terapie metody normy využití MeSH
- erbB receptory * antagonisté a inhibitory aplikace a dávkování farmakokinetika terapeutické užití MeSH
- hodnocení léčiv MeSH
- humanizované monoklonální protilátky aplikace a dávkování farmakokinetika terapeutické užití MeSH
- klinické zkoušky, fáze III jako téma MeSH
- kolorektální nádory * farmakoterapie patofyziologie MeSH
- lidé MeSH
- metastázy nádorů * farmakoterapie MeSH
- monoklonální protilátky aplikace a dávkování farmakokinetika terapeutické užití MeSH
- panitumumab MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- protoonkogenní proteiny p21(ras) genetika imunologie účinky léků MeSH
- Check Tag
- lidé MeSH
