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Objectives: Polo-like kinase1 (PLK1) belongs to the family of serine/threonine kinases and plays an important role in centrosome maturation, bipolar spindle formation, and cytokinesis during mitosis. We found in this study that PLK1 was aberrantly highly expressed in a variety of human leukemia cell lines (n=20), as well as, freshly isolated leukemia cells from individuals with acute myelogenous leukemia (n=50) and acute lymphoblastic leukemia (n=15) compared with bone marrow mononuclear cells from healthy volunteers (n=13) (acute myelogenous leukemia, P=0.016; acute lymphoblastic leukemia, P=0.008), as measured by real-time RT–PCR. Downregulation of PLK1 by a small interfering RNA in NB4 acute myelogenous leukemia cells inhibited their proliferation. GW843682X is a novel selective PLK1 inhibitor. The compound-induced growth inhibition, caused accumulation of cells in the G2/M phase of the cell cycle and mediated apoptosis of human leukemia cells. Pre-treatment of cells with the caspase inhibitor Z-VAD-FMK attenuated the action of GW843682X in leukemia cells, indicating the involvement of the caspase pathway in the PLK1 inhibitor-mediated apoptosis. Furthermore, we found that the PLK1 inhibitor synergistically potentiated the growth inhibition and apoptosis of leukemia cells when combined with tubulin-depolymerizing agent vincristine. Taken together, targeting PLK1 may be a promising treatment strategy for individuals with leukemia. [ABSTRACT FROM AUTHOR]

Fludarabine is a purine analog that has demonstrated significant activity in B-cell malignancies, including CLL. Fludarabine also possesses an immunosuppressive effect and is being used to prevent GVHD in hematopoietic stem cell transplantation. However, the molecular mechanism by which fludarabine inhibits immunoreaction remains to be fully elucidated. This study found that fludarabine inhibited tumor necrosis factor α (TNF-α)-stimulated degradation of IκBα, resulting in blockade of nuclear translocation of nuclear factor κB (NF-κB) in Jurkat T cells, as measured by western blot analysis and immunocytochemistry. The ability of fludarabine to inhibit NF-κB was further confirmed by electrophoretic mobility shift assay. We also found that fludarabine induced growth arrest and apoptosis of alloreactive and TNF-α-stimulated PBMCs. In addition, fludarabine inhibited TNF-α-stimulated production of IL-2 and IFN-γ, which play important roles in the onset of GVHD, in Jurkat cells. Taken together, fludarabine is useful for management of immune diseases, including GVHD, through inactivation of NF-κB.Bone Marrow Transplantation (2008) 41, 303–309; doi:10.1038/sj.bmt.1705901; published online 12 November 2007 [ABSTRACT FROM AUTHOR]

Summary:We conducted a nationwide survey to define incidence of deep fungal infections and fungal prophylaxis practices after HSCT. In all, 63 institutions responded. Total number of in-patient transplantations was 935: 367 autologous, 414 allogeneic myeloablative, and 154 allogeneic reduced-intensity (RIST) (n=154). Number of patients who were cared for in a clean room at transplant was 261 (71%) in autologous, 409 (99%) in conventional and 93 (66%) in RIST, respectively. All patients received prophylactic antifungal agents; 89% fluconazole. Number of patients who received the dosage recommended in the CDC guidelines (400?mg/day) was 135 (42%) in conventional transplant and 34 (30%) in RIST (P=0.037). Number of patients who received fluconazole until engraftment and beyond day 75 in conventional transplant vs RIST was, respectively, 324 (100%) vs 109 (97%), and 39 (12%) vs 18 (16%), with no significant difference between the two groups. A total of 37 patients (4.0%) were diagnosed with deep fungal infections; autologous transplantation (0.03%), conventional transplantation (6.0%) and RIST (7.1%). Wide variations in antifungal prophylaxis practice according to the type of transplant and the institutions, and deep fungal infection remain significant problems in RIST.Bone Marrow Transplantation (2004) 33, 1173-1179. doi:10.1038/sj.bmt.1704526 Published online 19 April 2004 [ABSTRACT FROM AUTHOR]

Cardiac toxicities in 39 consecutive patients with breast cancer receiving high-dose chemotherapy (HDC) with stem cell transplantation were reviewed. All 39 patients received various anthracycline-containing regimens in adjuvant settings and/or for metastatic disease before HDC. As a cytoreductive regimen, all received cyclophosphamide 2000 mg/m2 and thiotepa 200 mg/m2 for 3 consecutive days. No immediate fatal toxicities were observed, but one patient developed chronic congestive heart failure and two had transient left ventricular dysfunction. Pericardial effusion was observed in another three patients. ST-T abnormalities during HDC were observed in two patients and arrhythmias were observed in nine, four of which occurred during stem cell infusion (SCI). There were three atrial arrhythmias, two ventricular arrhythmias, and four atrioventricular (AV)-block episodes. Two patients developed advanced and complete AV-block with an asystolic pause. Notably, three patients experienced AV-block with uncontrolled vomiting. No relationship was observed between the cumulative dose of anthracycline and cardiac toxicities during HDC. These results suggest that abnormalities in the conduction system during HDC may be more frequent than previously reported. Vagal reflex secondary to emesis may play an important role in the development of AV-block. Bone Marrow Transplantation (2000) 25, 185–189. [ABSTRACT FROM AUTHOR]

Bone marrow transplant-associated thrombotic microangiopathy (BMT-TM), usually associated with thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and renal insufficiency, has been reported to occur approximately 5-6 months after BMT. We report a case of relapsed malignant lymphoma complicated by BMT-TM of hyperacute onset, which has never been described in the literature. Our patient, a 52-year-old male, developed MAHA with gross haematuria, thrombocytopenia, lactate dehydrogenase elevation and renal insufficiency 2 days after autologous PBSC transplantation following high-dose chemotherapy. Supportive treatment, ie glucocorticoid, fresh frozen plasma and haemodiafiltration were given, and thereafter the BMTTM gradually improved. In heavily pretreated patients, caution should be exercised for possible occurrence of the BMT-TM of hyperacute onset. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a case of a 68-year-old man diagnosed with engraftment syndrome (ES) after hematopoietic stem cell transplantation (HSCT) and treated with recombinant human soluble thrombomodulin (rTM).

A letter to the editor is presented in response to the article "Successful treatment of sinusoidal obstructive syndrome after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin" in the August 31, 2009 issue.

A letter to the editor is presented in response to the article "Successful treatment of transplantation-associated thrombotic microangiopathy with recombinant human soluble trombomodulin" in the September 21, 2009 issue.

A letter to the editor about the ability of the ZD6474 selective inhibitor of tyrosine kinases coding to induce growth arrest and apoptosis of human leukemia cells is presented.