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Constitutively activated mutants of the non-receptor tyrosine kinases (TK) ABM (Abelson murine leukemia viral (v-abl) homolog (1) protein) and JAK2 (JAnus Kinase 2 or Just Another Kinase 2) play a central role in the pathogenesis of clinically and morphologically distinct chronic myeloproliferative disorders but are also found in some cases of de novo acute leukemia and lymphoma. Ligand-independent activation occurs as a consequence of point mutations or insertions/deletions within functionally relevant regulatory domains (JAK2) or the creation of TK fusion proteins by balanced reciprocal translocations, insertions or episomal amplification (ABL1 and JAK2). Specific abnormalities are correlated with clinical phenotype, although some are broad and encompass several World Health Organization-defined entities. TKs are excellent drug targets as exemplified by the activity of imatinib in BCR-ABL1-positive disease, particularly chronic myeloid leukemia. Resistance to imatinib is seen in a minority of cases and is often associated with the appearance of secondary point mutations within the TK domain of BCR-ABL1. These mutations are highly variable in their sensitivity to increased doses of imatinib or alternative TK inhibitors such as nilotinib or dasatinib. Selective and nonselective inhibitors of JAK2 are currently being developed, and encouraging data from pre-clinical experiments and initial phase-l studies regarding efficacy and potential toxicity of these compounds have already been reported. [ABSTRACT FROM AUTHOR]

Background: The very high cure rate of 1-week quadruple therapy offers an opportunity to study a shorter treatment duration. This is needed to construct a time–response curve for the regimen. Methods: Fifty-two patients with endoscopically proven H. pylori infection received lansoprazole 30 mg b.d., tripotassium dicitrato bismuthate 120 mg q.d.s., tetracycline 500 mg q.d.s. and metronidazole 500 mg q.d.s., following 3 days of lansoprazole pre-treatment. A second endoscopy was performed at least 6 weeks later. A patient was cured if histology, CLO-test, and culture of antrum and corpus were negative. Results: We achieved an intention-to-treat cure rate of 30/50 (60%, 95% CI: 46–73%) and a per protocol cure rate of 30/48 (63%, 95% CI: 48–75%). Cure rate in metronidazole-sensitive strains was 24/37 (65%, 95% CI: 48–79%) and 2/5 (40%) in resistant strains. All patients that failed the regimen had a metronidazole-resistant strain post-treatment. Compliance was excellent and moderate or severe side-effects occurred in only 4% of patients. Conclusion: A 2-day ‘weekend’ quadruple therapy cures only 60% of patients and cannot be recommended, but these findings provide an insight into the mode of action of quadruple therapy. [ABSTRACT FROM AUTHOR]