Pic Of The Day
Posted by rob on May 27, 2005 under Uncategorized | 
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A woman rests on a cow-shaped bench in Hanover during the 30th Church Day organized by the German Protestants.
Longer Treatment Durations and the Launch of Novel Treatments Will Grow the Drug Market for Chronic Myelogenous Leukemia
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Decision Resources, Inc., one of the world’s leading research and advisory firms focusing on pharmaceutical and health care issues, finds that longer treatment durations and the launch of novel treatments will grow the drug market for chronic myelogenous leukemia almost 12% annually between 2004 and 2009. Novel agents such as those from Bristol-Myers Squibb and Novartis will increase patient drug consumption by offering a viable, and likely durable, second-line pharmacological approach to the treatment of chronic myelogenous leukemia.
High sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic ev | CMLHope.Com
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Mutations in the kinase domain (KD) of BCR-ABL are the leading cause of acquired imatinib resistance. In some cases, identical mutations were detected at relapse and in pre-therapeutic specimens, consistent with selection of resistant clones in the presence of drug. However, the incidence of KD mutations in imatinib-naive patients, irrespective of response to therapy, is unknown. We studied mutation frequency in 66 CML patients, using cDNA sequencing and allele specific oligonucleotide (ASO) – PCR assays for 8 common mutations. Thirteen patients were positive by ASO-PCR only, 1 by ASO-PCR and sequencing in 1 patient and 1 by sequencing only (overall frequency 22.7%). T315I was most frequent (12% of patients). Eleven of the 14 ASO-PCR-positive patients had follow-up samples available for sequencing. Wild type sequence was detected in 6/11, two different mutations in 1/11 and identical mutations in 4/11 patients, two of whom had achieved major cytogenetic response. In multivariate analysis mutation detection was associated with clonal cytogenetic evolution, exposure to 6-Thioguanine and a low platelet count, but not with response to imatinib, event-free and overall survival. KD mutants present at low levels do not invariably lead to relapse and additional factors are required to induce a fully drug resistant phenotype.
High sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic ev | CMLHope.Com
Response to imatinib mesylate in a patient with idiopathic hypereosinophilic syndrome associated with cyclic eosinophil oscillations.
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Imashuku S, Kakazu N, Ueda I, Morimoto A, Harada H, Teramura T, Tamura S, Fukushima-Nakase Y, Kuroda H
Int J Hematol. 2005 May ; 81(4): 310-4
A 26-year-old man with idiopathic hypereosinophilic syndrome (HES) was treated with imatinib mesylate following a 5-year history of prednisolone therapy. The patient had hypereosinophilia (absolute eosinophil counts >1500/3L) occurring in cyclic oscillations as well as histologically diagnosed eosinophilic vasculitis, bursitis, and periodic soft-tissue swellings. Laboratory data revealed high levels of serum tryptase and increased numbers of mast cells in the bone marrow, but serum interleukin 5 levels were within the normal range. The disease initially responded well to 100 mg/day of imatinib mesylate but recurred 8 weeks later.Thereafter, a daily 200-mg dose was temporarily effective. Despite the response to imatinib, the FIP1L1-PDGFRA fusion gene was not detected by fluorescence in situ hybridization analysis. Additional molecular and cytogenetic studies showed neither translocations of platelet-derived growth factor receptor (PDGFR) genes nor mutations in the c-KIT or the PDGFR genes.Although imatinib mesylate is a choice of treatment for patients with HES, its precise molecular mechanism in individual cases remains to be clarified.
Dysplastic definitive hematopoiesis in AML1/Evi-1 knock-in embryos.
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Maki K, Yamagata T, Asai T, Yamazaki I, Oda H, Hirai H, Mitani K
Blood. 2005 May 24;
The AML1/Evi-1 chimeric gene is created by the t(3;21)(q26;q22) chromosomal translocation seen in patients with leukemic transformation of myelodysplastic syndrome or blastic crisis of chronic myelogenous leukemia. We knocked-in the AML1/Evi-1 chimeric gene into mouse AML1 genomic locus to explore its effect in developmental hematopoiesis in vivo. AML1/Evi-1/+ embryo showed defective hematopoiesis in the fetal liver, and died around E13.5 due to hemorrhage in the central nervous system. The peripheral blood had yolk sac-derived nucleated erythroblasts but lacked erythrocytes of the definitive origin. While E12.5 fetal liver contained progenitors for macrophage only, E13.5 fetal liver contained multi-lineage progenitors capable of differentiating into dysplastic myelocyte and megakaryocyte. No erythroid progenitor was detected in E12.5 or E13.5 fetal liver. Hematopoietic progenitor from E13.5 AML1/Evi-1/+ fetal liver was highly self-renewal compared to that from wild-type liver. Maintained expression of PU.1 gene and decreased expression of LMO2 and SCL genes may explain the aberrant hematopoiesis in AML1/Evi-1/+ fetal liver.
Dysplastic definitive hematopoiesis in AML1/Evi-1 knock-in embryos.
Methyl protodioscin induces G(2)/M arrest and apoptosis in K562 cells with the hyperpolarization of mitochondria.
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Liu MJ, Yue PY, Wang Z, Wong RN
Cancer Lett. 2005 Jun 28; 224(2): 229-41
Methyl protodioscin is a furostanol bisglycoside with antitumor properties. The present study investigated its effects on human chronic myelogenous leukemia K562 cells. Cell cycle analysis showed that methyl protodioscin caused distinct G(2)/M arrest, with the appearance of polyploidy population. The levels of cyclin B1 decreased, whereas Cdc2 kept at a steady level. Subsequent apoptosis after G(2)/M blockage was demonstrated through DNA fragmentation and the annexin V staining assay. Methyl protodioscin induced a biphasic alteration (i.e. an early hyperpolarization, followed by depolarization) in mitochondrial membrane potential of K562 cells. The transient decline of intracellular Ca(2+) concentration was observed at early stage. The generation of reactive oxygen species was also detected. The anti-apoptotic Bcl-x(L) transiently increased and then decreased. And the pro-apoptotic Bax was markedly up-regulated. Taken together, these data demonstrated that methyl protodioscin inhibits K562 cell proliferation via G(2)/M arrest and apoptosis, with mitochondrial hyperpolarization and the disruption of Ca(2+) homeostasis playing important roles.
Extramedullary Blast Crisis Derived from 2 Different Clones in the Central Nervous System and Neck during Complete Cytogenetic Remission of Chronic My
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Matsuda M, Morita Y, Shimada T, Miyatake J, Hirase C, Tanaka M, Tatsumi Y, Maeda Y, Kanamaru A
Int J Hematol. 2005 May ; 81(4): 307-9
We describe a patient with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who developed an extramedullary blast crisis in the central nervous system (CNS) and then a subcutaneous tumor of the neck during treatment with imatinib mesylate.Administered 400 mg of imatinib mesylate after the diagnosis of chronic-phase CML, the patient achieved a complete cytogenetic remission 4 months later. However, he developed a mixed myeloid/B-cell blast crisis with additional karyotype abnormalities only in the CNS during a complete cytogenetic remission in the bone marrow. Several doses of intrathecal chemotherapy and whole-brain irradiation were effective in treating the blast crisis in the CNS. After 7 months of complete cytogenetic remission, the patient experienced a subcutaneous tumor in the right neck. A biopsy of the tumor revealed a mixed myeloid/T-cell blast crisis.The cytogenetic analysis showed that the blast crisis clone in the neck tumor was different from that of the CNS. An increased dose of imatinib mesylate was ineffective in treating the neck tumor. Irradiation to the right neck was therefore undertaken.This case suggests that the development of a clone resistant to imatinib mesylate is not always detected in the bone marrow and that multiple Ph-positive clones have the potential to become transformed into a blast crisis.