Over the past decade, there has been an exponential increase in our knowledge of how cytokines regulate signal transduction, cell cycle progression, differentiation and apoptosis. Research has focused on different biochemical and genetic aspects of these processes. Initially, cytokines were identified by clonogenic assays and purified by biochemical techniques. This soon led to the molecular cloning of the genes encoding the cytokines and their cognate receptors. Determining the structure and regulation of these genes in normal and malignant hematopoietic cells has furthered our understanding of neoplastic transformation. Furthermore, this has allowed the design of modified cytokines which are able to stimulate multiple receptors and be more effective in stimulating the repopulation of hematopoietic cells after myelosuppressive chemotherapy. The mechanisms by which cytokines transduce their regulatory signals have been evaluated by identifying the involvement of specific protein kinase cascades and their downstream transcription factor targets. The effects of cytokines on cell cycle regulatory molecules, which either promote or arrest cell cycle progression, have been more recently examined. In addition, the mechanisms by which cytokines regulate apoptotic proteins, which mediate survival vs death, are being elucidated. Identification and characterization of these complex, interconnected pathways has expanded our knowledge of leukemogenesis substantially. This information has the potential to guide the development of therapeutic drugs designed to target key intermediates in these pathways and effectively treat patients with leukemias and lymphomas. This review focuses on the current understanding of how hematopoietic cytokines such as IL-3, as well as its cognate receptor, are expressed and the mechanisms by which they transmit their growth regulatory signals. The effects of aberrant regulation of these molecules on signal transduction, cell cycle regulatory and apoptotic pathways in transformed hematopoietic cells are discussed. Finally, anti-neoplastic drugs that target crucial constituents in these pathways are evaluated.

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In this study, the abilities of constitutive and conditional forms of the three Raf kinases to abrogate the cytokine dependency of FDC-P1 cells were examined. The constitutively active forms (⌬) of all three Raf kinases were fused to the hormone-binding domain of the estrogen receptor (ER), rendering their activities conditionally dependent upon exogenous ␤-estradiol. The vast majority of ⌬Raf:ER-infected FDC-P1 cells remained cytokinedependent; however, cells were obtained at low frequency in which expression of ⌬Raf:ER abrogated cytokine dependency. Isoform specific differences between the Raf kinases were observed as cytokine-independent cells were obtained more frequently from ⌬A-Raf:ER than either ⌬Raf-1:ER or ⌬B-Raf:ER infected cells. To determine whether the regulatory phosphorylation sites in the Raf proteins were necessary for abrogation of cytokine dependency, they were changed by site-directed mutagenesis. Substitution with phenylalanine eliminated the transforming ability of the ⌬B-Raf:ER and ⌬Raf-1:ER kinases.

SUMMARY AimTo assess the relationship between the percentage of time intragastric pH >4.0 and healing of erosive oesophagitis. MethodsIn this proof-of-concept study, adults with endoscopically verified Los Angeles grade C or grade D erosive oesophagitis were randomly assigned to oral esomeprazole 10 or 40 mg once daily for 4 weeks. On day 5, patients underwent 24-h pH monitoring. At 4 weeks, erosive oesophagitis healing status was endoscopically assessed. Investigators scored gastro-oesophageal reflux disease symptoms on a 4-point scale [none to severe (0-3)] before and 4 weeks after treatment. The percentage of time intragastric pH was >4.0 and healing status were correlated and tested for significance using a Spearman rank correlation (r).Results 103 patients had evaluable data (mean age, 48.7 years; 65% men). Mean percentages of time with intragastric pH >4.0 on day 5 in patients with healed and unhealed erosive oesophagitis were 61% and 42%, respectively (P ¼ 0.0002), indicating that erosive oesophagitis healing rates were positively related to the percentage of time intragastric pH was >4.0. Greater intragastric acid control correlated with lower final daytime and night-time heartburn and acid regurgitation symptom scores (r ¼ )0.029, )0.029 and )0.021; P ¼ 0.003, 0.003 and 0.032, respectively). ConclusionA positive relationship between intragastric acid control and erosive oesophagitis healing was demonstrated.

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