Thus, HPV usurps the DDR machinery for efficient HPV replication. As benzopyrene or cigarette smoke condensate are able to induce gamma-H2X phosphorylation and DDR, is plausible a cooperation between both carcinogenic agents. Recently, it was reported that tobacco smoke is able to induce early HPV transcription only when HPV persists as an episome. In consequence, the authors of this study suggest that tobacco has a prominent role in early stages of HPV-related carcinogenesis. We cannot deny this possibility because we compare the activation of the p97 promoter with non-tumor cell lines and in the study of Wei et al, cell lines established from CIN where HPV persists as an episome were used. Future studies using cells from precursor lesions of lung cancer are warranted. Considering the findings presented in this study and others, a model of tobacco smoke and HPV interaction is proposed. In this model, tobacco smoke and HPV are able to collaborate at different levels: first, tobacco smoke induces the activity of p97 promoter in a dose-dependent manner with an intact LCR and the expressed HPV-16 E6 and E7 oncogenes sensitize lung cells for tobacco smoke-dependent oxidative DNA damage. In addition, HPV-16 E6 and E7 oncogenes are able to collaborate with tobacco smoke for p97 promoter activation in the context of non-tumor lung cells. More studies are warranted to analyze the clinical consequences of these findings including other cells or tissues that are potentially exposed to both HPV and tobacco smoke. The constitutively active BCR-Abl tyrosine kinase is the product of the reciprocal translocation of chromosomes 9 and 22 and the GDC-0879 Raf inhibitor causative oncoprotein in over 95% of chronic myeloid leukemia cases. Imatinib, a small molecule ATPcompetitive inhibitor of BCR-Abl, is an effective front-line treatment for CML and has established the concept of targeted kinase inhibition as a viable strategy for cancer therapy. However, whereas the majority of newly diagnosed CML patients undergo remission, some patients are refractory to imatinib therapy and others who initially respond will eventually develop imatinib resistance. Multiple mechanisms of cellular resistance to imatinib have been described and include BCR-Abl-dependent mechanisms such as protein overexpression or expression of inhibitor-resistant mutations in the BCR-Abl kinase domain, such as the T315I ����gatekeeper mutation����. This mutation reduces the affinity of tyrosine kinase inhibitors while increasing the leukemogenic ICG-001 side effects signaling of BCR-Abl. Resistance also arises from BCRAbl- independent mechanisms such as alterations in drug import or export that affect intracellular imatinib levels, clonal evolution as the result of additional genetic abnormalities, and upregulation of alternative signaling pathways. Upregulation of kinases such as Akt or Src family kinases have been implicated in imatinib resistance whereby these kinases drive alternative cell survival and proliferation signaling.