Posted by rob on September 30, 2011 under Uncategorized | 
Summary Inference regarding the inclusion or exclusion of random effects in linear mixed models is challenging because the variance components are located on the boundary of their parameter space under the usual null hypothesis. As a result, the asymptotic null distribution of the Wald, score, and likelihood ratio tests will not have the typical ?2 distribution. Although it has been proved that the correct asymptotic distribution is a mixture of ?2 distributions, the appropriate mixture distribution is rather cumbersome and nonintuitive when the null and alternative hypotheses differ by more than one random effect. As alternatives, we present two permutation tests, one that is based on the best linear unbiased predictors and one that is based on the restricted likelihood ratio test stati…
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Authors: Kapadia RK, Steeves JH
PMID: 21930739 [PubMed - as supplied by publisher] (Source: cmaj)
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US Kanade, SD Birare, P Gadgil, SY SwamiIndian Journal of Dermatology 2011 56(4):451-452 (Source: Indian Journal of Dermatology)
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Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-Abl, a chimeric protein with deregulated tyrosine kinase activity. The protein-tyrosine phosphatase 1B (PTP1B) is up-regulated in Bcr-Abl-expressing cells, suggesting a regulatory link between the two proteins. To investigate the interplay between these two proteins, we inhibited the activity of PTP1B in Bcr-Abl-expressing TonB.210 cells by either pharmacological or siRNA means and examined the effects of such inhibition on Bcr-Abl expression and function. Herein we describe a novel mechanism by which the phosphatase activity of PTP1B is required for Bcr-Abl protein stability. Inhibition of PTP1B elicits tyrosine phosphorylation of Bcr-Abl that triggers the degr…
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NK cells are dysfunctional in human chronic myelogenous leukemia before and on imatinib treatment and in BCR–ABL-positive mice
Leukemia advance online publication, September 9, 2011.
doi:10.1038/leu.2011.239
Authors: C I-U Chen, S Koschmieder, L Kerstiens, M Schemionek, B Altvater, S Pscherer, J Gerss, H T Maecker, W E Berdel, H Juergens, P P Lee
& C Rossig (Source: Leukemia)
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Authors: Razga F, Racil Z, Machova Polakova K, Buresova L, Klamova H, Zackova D, Dvorakova D, Polivkova V, Cetkovsky P, Mayer J
PMID: 21901397 [PubMed - in process] (Source: International Journal of Hematology)
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In conclusion, this case is unusual at three levels: first, extramedullary nodal BC as a presenting manifestation of CML is rare and the blasts are of precursor T lymphoblastic lineage, rather than the more common B?cell lineage; second, this case suggests that extramedullary lymphoid nodal BC of CML can exist independently without the bone marrow developing into BC; and third, FISH analysis on the single neoplastic cell is an accurate way to confirm that the neoplasm is either extramedullary localized blasts of CML or genetically distinct neoplasm. Diagn. Cytopathol. 2011;. © 2011 Wiley?Liss, Inc. (Source: Diagnostic Cytopathology)
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The p210Bcr/Abl and p190Bcr/Abl fusion oncoproteins are known to cause chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Bcr/Abl phosphorylates several proteins that can lead to leukemogenesis. Crk?associated substrate lymphocyte type (Cas?L)/human enhancer of filamentation?1 (HEF1)/neural precursor cell expressed, developmentally down?regulated 9 (NEDD9) is an adapter protein at focal adhesions known to be associated with solid tumor metastasis. Crk?associated substrate lymphocyte type has also been reported to be tyrosine phosphorylated by p190Bcr/Abl. We demonstrated that Cas?L was expressed in murine granulocytes, as well as in lymphocytes, and that Cas?L?deficient (Cas?L?/?) granulocytes had increased migratory activity and decreased adhe…
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AbstractThe p210Bcr/Abl and p190Bcr/Abl fusion oncoproteins are known to cause chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL). Bcr/Abl phosphorylates several proteins that can lead to leukemogenesis. The lymphocyte?type Cas family protein Cas?L (Crk?associated substrate lymphocyte type)/HEF1/NEDD9 is an adapter protein at focal adhesions known to be associated with solid tumor metastasis, and Cas?L has been reported to be tyrosine?phosphorylated by p190Bcr/Abl. We demonstrated that Cas?L was expressed in murine granulocytes as well as in lymphocytes and that Cas?L?deficient granulocytes had increased migratory activity and decreased adhesiveness. To examine whether Cas?L was involved in leukemogenesis by p210Bcr/Abl, we generated Cas?L?defic…
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Chronic myeloid leukemia in chronic phase (CML-CP) cells that harbor oncogenic BCR-ABL1 and normal ABL1 allele often become resistant to the ABL1 kinase inhibitor imatinib. Here, we report that loss of the remaining normal ABL1 allele in these tumors, which results from cryptic interstitial deletion in 9q34 in patients who did not achieve a complete cytogenetic remission (CCyR) during treatment, engenders a novel unexpected mechanism of imatinib resistance. BCR-ABL1–positive Abl1?/? leukemia cells were refractory to imatinib as indicated by persistent BCR-ABL1–mediated tyrosine phosphorylation, lack of BCR-ABL1 protein degradation, increased cell survival, and clonogenic activity. Expression of ABL1 kinase, but not a kinase-dead mutant, restored the antileukemic effects of imatinib…
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Conclusion
Uniform definitions of PFS and EFS are needed to compare the long-term efficacy and potential use of different TKIs in CML. (Source: Journal of Clinical Oncology)
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Authors: Demarquet M, Labussière-Wallet H, Nicolas-Virelizier E, Nicolini FE
Second-generation tyrosine kinase inhibitors (TKI 2) represent a recent important improvement in the treatment of Philadelphia positive leukemias. These agents are a suitable major option if resistance or significant imatinib intolerance occurs in chronic and accelerated phase CML. They are now introduced as first line therapy in chronic phase CML where they induce cytogenetic and molecular response rates never seen to date, which is promising for long-term survival. We propose here an analysis of the main current data available for the use of TKI 2 in CML.
PMID: 21816704 [PubMed - as supplied by publisher] (Source: Bulletin du Cancer)
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On a sweltering August evening in 2009 Pat Elliott noticed that her feet seemed swollen. Because she had been standing for hours while teaching a workshop in Phoenix, she was not surprised. “I thought it was the heat,” she says. But her feet hurt, too, so Elliott decided to play it safe and called her doctor, who suggested she come in for some tests. Days later the marketing professional learned that she had developed an uncommon form of blood cancer called chronic myelogenous leukemia (CML).Elliott’s cancer is the result of a genetic change that arose in one or more stem cells in her bone marrow. (Normally these stem cells give rise to various blood cells in the body.) The defect caused the stem cells and their progeny to produce an abnormal enzyme known as Bcr-Abl. This…
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We describe such a patient where both CML and CLL responded to imatinib. To our knowledge this is the first description of a patient with CLL who has been treated with imatinib alone. (Source: Leukemia Research)
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Ethyl acetate extract and its major constituent, isorhamnetin 3-O-rutinoside, from Nitraria retusa leaves, promote apoptosis of human myelogenous erythroleukaemia cells.
Cell Prolif. 2011 Oct;44(5):453-61
Authors: Boubaker J, Bhouri W, Ben Sghaier M, Ghedira K, Dijoux Franca MG, Chekir-Ghedira L
Abstract
Objective:? Fractionation of ethyl acetate extract (EA) obtained from Nitraria retusa leaves was assessed using different methods of chromatography, and isorhamnetin3-O-rutinoside (I3-O-R) was isolated from this extract. Its structure was determined using data obtained from (1) H and (13) C NMR spectra, as well as by various correlation experiments (COSY, HMQC and HMBC). Both EA extract and I3-O-R were investigated for their ability to induce apoptosis in human chronic myelogenous erythroleukaemia cells (K562). Materials and methods:? Apoptosis of cells from the K562 line was detected by DNA fragmentation, PARP cleavage and by evaluating activities of caspases 3 and 8. Results:? Apoptosis, revealed by DNA fragmentation and PARP cleavage, was observed after 48-h incubation of these human myelogenous erythroleukaemia cells (K562), with the tested products. Likewise, caspase 3 and caspase 8 activities were induced in the presence of the EA extract and I3-O-R after 48?h of incubation. Conclusion:? Our results strongly suggest the involvement of the extrinsic pathway of apoptosis in cells treated by both the original EA extract and its major component, I3-O-R.
PMID: 21951288 [PubMed - in process]
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Case of insulin edema occurring during intensive insulin therapy after bone marrow transplantation.
J Dermatol. 2011 Sep 27;
Authors: Sugiyama A, Takeuchi S, Fukagawa S, Moroi Y, Yoshimoto G, Miyamoto T, Akashi K, Furue M
Abstract
A 50-year-old female patient, who had had a long-term history of myelodysplastic syndrome and type II diabetes mellitus, had developed acute myelogenous leukemia and received allogeneic bone marrow transplantation (BMT). She was being treated with tacrolimus, methotrexate and prednisolone for prophylaxis and treatment of graft-versus-host disease, and with intensive insulin therapy for better glycemic control. The patient suddenly developed marked leg edema at 27?days after starting intensive insulin therapy (on day 40 after BMT) without coexistence or exacerbation of apparent causes such as renal failure, cardiac dysfunction or leg thrombosis around the onset of leg edema. Interestingly, the leg edema regressed soon after daytime hyperglycemia and intensive insulin therapy were performed. Histopathological examination revealed slight dermal edema and small bullae with little inflammatory infiltration but no signs of autoimmune blistering diseases or vasculitis. These findings indicate that the present case may be considered a form of so-called insulin edema occurring during intensive insulin therapy after BMT.
PMID: 21951268 [PubMed - as supplied by publisher]
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Permutation Tests for Random Effects in Linear Mixed Models.
Biometrics. 2011 Sep 27;
Authors: Lee OE, Braun TM
Abstract
Summary Inference regarding the inclusion or exclusion of random effects in linear mixed models is challenging because the variance components are located on the boundary of their parameter space under the usual null hypothesis. As a result, the asymptotic null distribution of the Wald, score, and likelihood ratio tests will not have the typical ?(2) distribution. Although it has been proved that the correct asymptotic distribution is a mixture of ?(2) distributions, the appropriate mixture distribution is rather cumbersome and nonintuitive when the null and alternative hypotheses differ by more than one random effect. As alternatives, we present two permutation tests, one that is based on the best linear unbiased predictors and one that is based on the restricted likelihood ratio test statistic. Both methods involve weighted residuals, with the weights determined by the among- and within-subject variance components. The null permutation distributions of our statistics are computed by permuting the residuals both within and among subjects and are valid both asymptotically and in small samples. We examine the size and power of our tests via simulation under a variety of settings and apply our test to a published data set of chronic myelogenous leukemia patients.
PMID: 21950470 [PubMed - as supplied by publisher]
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Molecular mechanism study of chemosensitization of doxorubicin-resistant human myelogenous leukemia cells induced by a composite polymer micelle.
Int J Pharm. 2011 Sep 16;
Authors: Han M, Diao YY, Jiang HL, Ying XY, Chen DW, Liang WQ, Gao JQ
Abstract
The present study was aimed to overcome the multidrug resistance (MDR) of tumor cells which accounts for the failure of clinical chemotherapy. A novel doxorubicin (DOX)-loaded composite micelle consisting of polyethylene glycol (PEG)-polycaprolactone (PCL)/Pluronic P105 has been developed and was proved to inhibit the drug resistance of human myelogenous leukemia (K562/ADR) cells. The modulation mechanism that DOX-loaded the composite micelle inhibited MDR was for the first time investigated at cell levels. Results indicated that the cytotoxicity in K562/ADR cells treated by DOX-loaded PEG-PCL/P105 composite micelle was about 4 times higher than DOX solution at 12?g/mL of DOX. Confocal images showed that the DOX-loaded composite micelles gradually entered into cytoplasm and nucleus, and stayed in intracellular much longer than DOX solution. All the micelles (PEG-PCL micelle, P105 micelle and PEG-PCL/P105 composite micelle) did not change Pgp expression on the surface of K562/ADR cells. However, further study revealed that micelle containing of P105 (P105 or PEG-PCL/P105 composite micelle) significantly decreased ATP level, and consequently restricted the activity of Pgp by down-regulation of mitochondrial membrane potential. On the other hand, the PEG-PCL micelle had no effect on both mitochondrial membrane potential and ATP level of the K562/ADR cells, but its access to K562/ADR cells through endocytic pathway avoided the recognition of Pgp. The PEG-PCL/P105 composite micelle was designed based on the combination of P105-mediated down regulation of mitochondrial membrane potential the malignant cells and PEG-PCL-mediated internalization effect. Therefore, the novel composite micelle is a promising drug delivery system for anticancer drug to overcome MDR.
PMID: 21945184 [PubMed - as supplied by publisher]
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Treatment of Higher-Risk Myelodysplastic Syndrome.
Semin Oncol. 2011 Oct;38(5):673-681
Authors: Garcia-Manero G
Abstract
The myelodysplastic syndromes (MDS) are divided into lower-risk and higher-risk categories. This differentiation is important for treatment selection. Over the last decade, we have witnessed significant improvements in the treatment of patients with higher-risk MDS that have resulted in improved survival with the hypomethylating agent 5-azacytidine This has resulted in a shift from the use of acute myelogenous leukemia (AML)-like therapies, which were traditionally offered to this group of patients in the past, to the hypomethylating agents, which have become the standard of care. Despite these advances, new therapies or combinations are needed to improve response and survival rates. This review will summarize results from current available therapies and discuss potential needs and ongoing research in the area of treatment of higher-risk MDS.
PMID: 21943674 [PubMed - as supplied by publisher]
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Incomplete Chromatin Condensation in Enlarged Rat Myelocytic Leukemia Cells.
DNA Cell Biol. 2011 Sep 23;
Authors: Trencsenyi G, Nagy G, Bako F, Kertai P, Banfalvi G
Abstract
The distinguishable morphologic features of nuclei of acute myelogenous leukemia cells with enlarged size and finely distributed nuclear chromatin indicate incomplete chromosome condensation that can be related to elevated gene expression. To confirm this, interphase chromosome structures were studied in exponentially growing rat myelomonocytic leukemia 1 cells isolated at the University of Debrecen (My1/De cells). This cell line was established from primary rat leukemia chemically induced by 7,12-dimethylbenz[a]anthracene treatment. The enlarged nuclei of My1/De cells allowed improved fluorescent visualization of chromosomal structures. Increased resolution revealed major interphase intermediates consisting of (1) veil-like chromatin, (2) chromatin ribbon, (3) chromatin funnel, (4) chromatin bodies, (5) elongated prechromosomes, (6) seal-ring, spiral shaped, and circular chromosomal subunits, (7) elongated, bent, u- and v-shaped prechromosomes, and (8) metaphase chromosomes. Results confirmed the existence of the chromatin funnel, the first visible interphase chromosome generated by the supercoiling of the chromatin ribbon. Other intermediates not seen previously included the spiral subunits that are involved in the chromonemic folding of metaphase chromosomes. The existence of spiral subunits favors the helical coil model of chromosome condensation. Incomplete chromatin condensation in leukemia cells throughout the cell cycle is an indication of euchromatization contributing to enhanced gene expression and is regarded as a leukemic factor.
PMID: 21942442 [PubMed - as supplied by publisher]
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