Posted by rob on September 30, 2009 under Uncategorized | 
Autophagy is an important event for megakaryocytic differentiation of the chronic myelogenous leukemia K562 cell line.
Autophagy. 2009 Nov 24;5(8)
Authors: Colosetti P, Puissant A, Robert G, Luciano F, Jacquel A, Gounon P, Cassuto JP, Auberger P
Autophagy is a highly conserved catabolic process for the elimination and recycling of organelles and macromolecules, characterized by the formation of double-membrane vesicles called autophagosomes. To date, the function of autophagy in cell differentiation is poorly documented. Here, we investigated the possibility that megakaryocytic differentiation of the Chronic Myelogenous Leukemia (CML) cell line K562, a process known to be accompanied by accumulation of vacuoles inside the cells, might involve autophagy. Using various complementary approaches, we show that the combination of the phorbol ester PMA and the p38(MAPK) inhibitor SB202190 (SB), which engaged a majority of K562 cells towards the megakaryocytic lineage, also triggered vacuolization and autophagy. The combination of PMA + SB appears to induce both increase in autophagic fluxes and an autophagic degradation blockage. Induction of autophagy was accompanied also by increased expression of Beclin 1 and p62/SQSTM1 and was found to precede the onset of megakaryocytic differentiation. Moreover, knockdown of LC3 and Beclin 1 by specific siRNAs impaired PMA + SB-mediated vacuolization, LC3-II accumulation and megakaryocytic differentiation, as well. To the best of our knowledge, this is the first description that induction of autophagy is involved in megakaryocytic differentiation of K562 CML cells.
PMID: 19786835 [PubMed - as supplied by publisher]
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Impact of Antifungal Prophylaxis on Colonization and Azole Susceptibility of Candida species.
Antimicrob Agents Chemother. 2009 Sep 28;
Authors: Mann PA, McNicholas PM, Chau AS, Patel R, Mendrick C, Ullmann AJ, Cornely OA, Patino H, Black TA
Two large studies compared posaconazole vs. fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and development of resistance in yeasts, identification and susceptibility testing were performed on yeasts cultured at regular intervals from mouth/throat/stool samples. Prior to therapy 34-50% of subjects were colonized with yeasts. For all three drugs, the number of positive Candida albicans cultures decreased during drug therapy. In contrast, the proportion of subjects with positive C. glabrata cultures increased by two- and four-fold in the posaconazole and itraconazole arms, respectively. Likewise, in the fluconazole arm the proportion of subjects with positive C. krusei cultures increased two-fold. C. glabrata was the species that most frequently exhibited decreases in susceptibility and this trend did not differ significantly between the prophylactic regimens. For the subset of subjects with colonizing C. glabrata isolated at baseline and end of treatment approximately, 40% of isolates exhibited a >four-fold increase in MIC while on therapy. Molecular typing of C. albicans and C. glabrata isolates confirmed that the majority of the baseline and end of treatment isolates were closely related to suggesting that they were persistent colonizers and not newly acquired. Overall breakthrough infections by Candida species were very rare ( approximately 1%) and C. glabrata was the colonizing species most frequently associated with breakthrough infections.
PMID: 19786600 [PubMed - as supplied by publisher]
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Hematopoietic Stem Cell Origin of Human Fibroblasts: Cell Culture Studies of Female Recipients of Gender Mismatch Stem Cell Transplantation and Patients with Chronic Myelogenous Leukemia.
Exp Hematol. 2009 Sep 25;
Authors: Shirai K, Sera Y, Bulkeley W, Mehrotra M, Moussa O, Larue AC, Watson DK, Stuart RK, Lazarchick J, Ogawa M
OBJECTIVES: Our series of studies using transplantation of single hematopoietic stem cells (HSCs) demonstrated that mouse fibroblasts/myofibroblasts are derived from HSCs. In order to determine the origin of human fibroblasts, we established a method for culturing fibroblasts from human peripheral blood (PB) mononuclear cells and studied fibroblasts from gender mismatch HSC transplant recipients and patients with untreated Philadelphia chromosome-positive chronic myelogenous leukemia (CML). METHODS: We cultured PB cells from three female subjects who showed near complete hematopoietic reconstitution from transplantation of granulocyte-colony stimulating factor (G-CSF)-mobilized male PB cells and examined the resulting fibroblasts using fluorescent in situ hybridization (FISH) for Y chromosome. Because the mobilized PB cells may contain mesenchymal stem cells (MSCs), we could not determine the HSC or MSC origin of the fibroblasts seen in culture. To further document the HSC origin of human fibroblasts, we next examined fibroblasts from two patients with untreated CML, a known clonal disorder of HSCs. RESULTS: All cultured fibroblasts from female recipients of male cells showed the presence of Y-chromosome, indicating the donor origin of fibroblasts. Cultured fibroblasts from the CML patients revealed the presence of BCR-ABL translocation. This demonstration provided strong evidence for the HSC origin of human fibroblasts, because CML is a clonal disorder of the HSC. CONCLUSIONS: These studies strongly suggest that human fibroblasts are derived from HSCs. In addition, the results suggest that fibrosis seen in patients with CML may be a part of the clonal process.
PMID: 19786066 [PubMed - as supplied by publisher]
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A new technique to remove a “stuck” totally implantable venous access catheter.
J Pediatr Surg. 2009 Jul;44(7):1465-7
Authors: Huang SC, Tsai MS, Lai HS
Removal of a totally implantable venous access device (port) is usually a simple procedure; however, if a catheter has been in place for a very long period, it may adhere firmly to the vessel wall. We report a new technique to facilitate removal of a stuck catheter. A 16-year-old girl was admitted for removal of her port, which had been inserted for chemotherapy 11 years earlier. After her disease was controlled, the catheter could not be pulled out during surgery. To remove the catheter, we inserted a guidewire to straighten the catheter and then applied a “push-in” force to detach the adherence from the central vein. The catheter was then removed successfully. We believe that this is a new and simple method for removing a “stuck” catheter.
PMID: 19573682 [PubMed - indexed for MEDLINE]
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Chronic myeloid leukemia (CML) with P190 BCR-ABL: analysis of characteristics, outcomes, and prognostic significance.
Blood. 2009 Sep 10;114(11):2232-5
Authors: Verma D, Kantarjian HM, Jones D, Luthra R, Borthakur G, Verstovsek S, Rios MB, Cortes J
The most common BCR-ABL transcripts in chronic myeloid leukemia (CML) are e13a2(b2a2) and e14a2(b3a2). Other transcripts such as e1a2 are rare and their outcome with tyrosine kinase inhibitors (TKI) therapy is undefined. We analyzed 1292 CML patients and identified 14 with only e1a2 transcripts, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Of the CP, 4 achieved complete hematologic response (CHR); 2, complete cytogenetic response (CCyR); 2, partial cytogenetic response (PCyR), and 1 did not respond to imatinib. Five patients progressed to myeloid BP (3), lymphoid BP (1), or AP (1). The AP patient received various TKIs sequentially and achieved only CHR. BP patients received hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone) plus imatinib/dasatinib or idarubicin plus cytarabine (Ara-C); 2 did not respond, 1 had CCyR, and 1 short-lasting complete molecular response (CMR). Overall, cytogenetic responses lasted 3 to 18 months; only 2 achieved major molecular response (MMR) on TKI. P190(BCR-ABL) CML is rare and is associated with an inferior outcome to therapy with TKI. These patients need to be identified as high-risk patients.
PMID: 19531657 [PubMed - indexed for MEDLINE]
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