BCR-ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients.

Tumor necrosis factor-related apoptosis-inducing ligand-TNFSF10 (TRAIL), a member of the TNF-α family and a death receptor ligand, was shown to selectively kill tumor cells. Not surprisingly, TRAIL is downregulated in a variety of tumor cells, including BCR-ABL-positive leukemia. Although we know much about the molecular basis of TRAIL-mediated cell killing, the mechanism responsible for TRAIL inhibition in tumors remains elusive because (a) TRAIL can be regulated by retinoic acid (RA); (b) the tumor antigen preferentially expressed antigen of melanoma (PRAME) was shown to inhibit transcription of RA receptor target genes through the polycomb protein, enhancer of zeste homolog 2 (EZH2); and (c) we have found that TRAIL is inversely correlated with BCR-ABL in chronic myeloid leukemia (CML) patients. Thus, we decided to investigate the association of PRAME, EZH2 and TRAIL in BCR-ABL-positive leukemia. Here, we demonstrate that PRAME, but not EZH2, is upregulated in BCR-ABL cells and is associated with the progression of disease in CML patients. There is a positive correlation between PRAME and BCR-ABL and an inverse correlation between PRAME and TRAIL in these patients. Importantly, knocking down PRAME or EZH2 by RNA interference in a BCR-ABL-positive cell line restores TRAIL expression. Moreover, there is an enrichment of EZH2 binding on the promoter region of TRAIL in a CML cell line. This binding is lost after PRAME knockdown. Finally, knocking down PRAME or EZH2, and consequently induction of TRAIL expression, enhances Imatinib sensibility. Taken together, our data reveal a novel regulatory mechanism responsible for lowering TRAIL expression and provide the basis of alternative targets for combined therapeutic strategies for CML.

Comparison between hybrid MOPPABV and ABVD chemotherapy protocols for Hodgkin's lymphoma in public hospitals of the largest South American city: a retrospective 14-year study.

The behavior of Hodgkin's lymphoma (HL) is different in developing countries, perhaps due to differences in epidemiology and population access to health care. We performed a retrospective study comparing the efficacy of mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPPABV) versus adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy protocols as first-line therapy for HL in a Brazilian population. A hundred and eighty-six HL patients were retrospectively analyzed regarding their first-line treatment with MOPPABV and ABVD at two public hospitals in São Paulo, Brazil. Eligible patients were either previously untreated or at first relapse after being treated with only radiotherapy with confirmed HL diagnosis. At a median follow-up of 9 years, complete remission is 89.5 and 85.9 (P = 0.3), overall survival 93.8% and 89.6% (P = 0.68), disease-free survival 85.6% and 81.6% (P = 0.41), and relapse ratios 20.9% and 26.4% (P = 0.17) for ABVD and MOPPABV, respectively. Extended-field radiation therapy postchemotherapy was mostly used in the MOPPABV group. There were three cases of secondary neoplasm (colon adenocarcinoma, myeloid chronic leukemia, and non-Hodgkin's lymphoma), all associated with MOPPABV. ABVD and MOPPABV protocols as first-line treatment for HL resulted in similar therapeutic outcomes and did not influence overall survival, disease-free survival, and relapse ratio. MOPPABV was related to a higher risk of secondary malignancy and, therefore, ABVD should be considered a better option for HL therapy. These findings corroborate recent data in literature.

Epidemiology of bacteremia and factors associated with multi-drug-resistant gram-negative bacteremia in hematopoietic stem cell transplant recipients.

The incidence of Gram-negative bacteremia has increased in hematopoietic stem cell transplant (HSCT) recipients. We prospectively collected data from 13 Brazilian HSCT centers to characterize the epidemiology of bacteremia occurring early post transplant, and to identify factors associated with infection due to multi-drug-resistant (MDR) Gram-negative isolates. MDR was defined as an isolate with resistance to at least two of the following: third- or fourth-generation cephalosporins, carbapenems or piperacillin-tazobactam. Among 411 HSCT, fever occurred in 333, and 91 developed bacteremia (118 isolates): 47% owing to Gram-positive, 37% owing to Gram-negative, and 16% caused by Gram-positive and Gram-negative bacteria. Pseudomonas aeruginosa (22%), Klebsiella pneumoniae (19%) and Escherichia coli (17%) accounted for the majority of Gram-negative isolates, and 37% were MDR. These isolates were recovered from 20 patients, representing 5% of all 411 HSCT and 22% of the episodes with bacteremia. By multivariate analysis, treatment with third-generation cephalosporins (odds ratio (OR) 10.65, 95% confidence interval (CI) 3.75-30.27) and being at one of the hospitals (OR 9.47, 95% CI 2.60-34.40) were associated with infection due to MDR Gram-negative isolates. These findings may have important clinical implications in the decision of giving prophylaxis and selecting the empiric antibiotic regimen.