New Interactors of the Truncated EBNA-LP Protein Identified by Mass Spectrometry in P3HR1 Burkitt's Lymphoma Cells.

The Epstein-Barr virus nuclear antigen leader protein (EBNA-LP) acts as a co-activator of EBNA-2, a transcriptional activator essential for Epstein-Barr virus (EBV)-induced B-cell transformation. Burkitt's lymphoma (BL) cells harboring a mutant EBV strain that lacks both the EBNA-2 gene and 3' exons of EBNA-LP express Y1Y2-truncated isoforms of EBNA-LP (tEBNA-LP) and better resist apoptosis than if infected with the wild-type virus. In such BL cells, tEBNA-LP interacts with the protein phosphatase 2A (PP2A) catalytic subunit (PP2A C), and this interaction likely plays a role in resistance to apoptosis. Here, 28 cellular and four viral proteins have been identified by mass spectrometry as further possible interactors of tEBNA-LP. Three interactions were confirmed by immunoprecipitation and Western blotting, namely with the A structural subunit of PP2A (PP2A A), the structure-specific recognition protein 1 (SSRP1, a component of the facilitate chromatin transcription (FACT) complex), and a new form of the transcription factor EC (TFEC). Thus, tEBNA-LP appears to be involved not only in cell resistance to apoptosis through its interaction with two PP2A subunits, but also in other processes where its ability to co-activate transcriptional regulators could be important.

Risk factors, clinical features, and outcome of Pseudomonas aeruginosa bacteremia in patients with hematologic malignancies: a case-control study.

BACKGROUND: We observed an increased rate of Pseudomonas aeruginosa bacteremia in our hematology unit in 2004-2007 without an identified environmental source. METHODS: We conducted a matched case-control study to investigate factors associated with P aeruginosa bacteremia in patients with hematologic malignancies. RESULTS: Forty-two episodes of P aeruginosa bacteremia were identified. At presentation, 26 patients (62%) had pneumonia and 9 patients (21%) were in shock. Twenty-five patients (60%) were aplastic. The clinical cure rate was 40%. Comparing the 42 cases with 84 matched controls identified the following independent risk factors for P aeruginosa bacteremia: hospitalization in the previous 3 months (odds ratio [OR], 12.84; 95% confidence interval [CI], 2.98-55.18), antibiotic therapy in the previous 3 months (OR, 5.34; 95% CI, 2.14-13.30), receipt of ceftriaxone in the previous 3 months (OR, 2.38; 95% CI, 1.08-5.27), receipt of aminoglycosides in the previous 3 months (OR, 6.65; 95% CI, 1.15-38.25) and receipt of fluoroquinolones in the previous 3 months (OR, 3.22; 95% CI, 1.48-7.00). CONCLUSIONS: Local antibiotic therapy algorithms were modified to decrease prescriptions of ceftriaxone and combination therapy with aminoglycosides and fluoroquinolones in an effort to decrease the risk of P aeruginosa bacteremia.

Balancing risk versus benefit in the treatment of Waldenström's Macroglobulinemia patients with nucleoside analogue-based therapy.

Nucleoside Analogues (NA) are considered as appropriate agents in the treatment of Waldenström's Macroglobulinemia (WM). There are sporadic reports on increased incidence of transformation to high grade non-Hodgkin lymphoma (transformation to NHL) and development of therapy related-myelodysplasia/acute leukemia (t-MDS/AML) among WM patients treated with NA. Several studies have been conducted in Europe and in the United States to retrospectively examine the incidence of such events in WM patients. The incidences of transformation to NHL and t-MDS/AML ranged from 4.7% to 8%, and from 1.4% to 8.9%, respectively, and demonstrated an increased incidence of these late events among WM patients treated with NA. The effect of these secondary malignancies needs to be better evaluated in prospective studies, especially in young patients. These NA treatment-associated risks should not by themselves be used to justify avoidance of NA therapy for WM patients but should be used in considering risk versus benefit for a particular patient given the expanding options of therapy for WM patients.

Bortezomib and Waldenstrom's macroglobulinemia.

Despite advances in therapy, Waldenstrom's macroglobulinemia (WM) remains incurable. Guidelines on therapeutic alternatives in WM recommended the use of alkylating agents, rituximab, nucleoside analogues and anthracyclins either in first line or at relapse and in combination in fit patients. While the overall response rates of combination regimens reached up to 80 - 90% in some studies, the complete response rate is low, no greater than 10 - 20%; and the disease-related median survival for symptomatic patients is approximately 6 years. As such, new therapeutic agents are needed for the treatment of WM. In ongoing efforts, advances were made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. Several preclinical studies have demonstrated that the NFkappaB pathway is a potential target for therapeutics in WM. Bortezomib (Velcade) is the first approved proteasome inhibitor for treating relapse/refractory multiple myeloma and, among other mechanisms of action, significantly inhibits the NFkB pathway. This report provides an update on biological studies and clinical efforts to develop bortezomib as a new treatment of Waldenstrom's macroglobulinemia.