PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosaassociated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification. (Blood. 2011;118(20):5517-5527) IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common type of adult non-Hodgkin lymphoma (NHL), accounting for approximately 40% of all NHL cases. 1 Rather than being a simple entity, it encompasses a constellation of different disorders with varying clinical presentations, molecular pathogenesis, and responses to therapy. 1 Expression-profile studies have revealed the existence of several DLBCL categories, 2 reflecting their origin from discrete B-cell differentiation stages, or the coregulated expression of transcriptional signatures that reflect features of the cell of origin, molecular pathogenesis, or the microenvironment. 1,3,4 Three main subtypes can be distinguished on the basis of the cell-of-origin classification: GCB-DLBCL that express germinal center (GC) genes, activated B-like DLBCL (ABC-DLBCL) with a signature including plasma cell and NF-B-expressed genes, and primary mediastinal DLBCL. 5,6 The standard first-line therapy for treating DLBCL patients is a combination of chemotherapeutical agents (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]) with the rituximab (R) chimeric CD20 monoclonal antibody. 7 Despite this therapy, the disease remains fatal in 30% to 40% of patients. 8 Novel therapeutic opportunities have been proposed based on molecular profiles, suggesting essential regulatory pathways in lymphomas (NF-B pathway, B-cell receptor signaling, B-cell lymphoma 2, B-cell lymphoma 6, and tumor microenvironment) as candidate targets. 9 Although there is a considerable amount of information about the molecular pathogenesis of DLBCL, relatively little progress has been made in developing therapies using compounds that target mutated genes or deregulated pathways. The improved knowledge about the molecular pathogenesis ...

Neoadjuvant MTX-il reduced the presurgical size of cSCC lesions and could simplify their subsequent surgery.

Darbepoetin-␣ treatment enhances glomerular regenerative process in the Thy-1 glomerulonephritis model. Am J Physiol Renal Physiol 299: F1278-F1287, 2010. First published September 8, 2010 doi:10.1152/ajprenal.00343.2009.-Recent studies have demonstrated that erythropoietin (EPO) and its analogs induce cytoprotective effects on many nonerythroid cells. In this study, we examined whether darbepoetin-␣ might prevent glomerular lesions in the Thy-1.1 model of glomerulonephritis (Thy-1-GN). GN was induced in Wistar rats by a single injection of monoclonal anti-Thy-1.1 antibody. Rats were killed at 24 h, 72 h, 7 days, 10 days, or 15 days after antibody injection. Kidneys were removed for histological analysis, and proteinuria was measured. Because at day 7 the maximal degree of renal damage and proteinuria was found, the effect of darbepoetin-␣ was tested at day 7 and two different protocols of administration were used; After anti-Thy-1.1 injection, rats received two doses of darbepoetin-␣ or vehicle at days 0 and 4 or at days 4 and 6. At day 7, proteinuria, plasma creatinine concentration, and renal morphology analysis were performed. Also, ␣-actin, desmin, caspase-3, and Ki67 protein expression were evaluated by immunohistochemistry. Our results showed that in both protocols of administration, darbepoetin-␣ treatment decreased proteinuria in Thy-1-GN rats and this effect correlated with the improvement in renal morphology. Glomerular lesions, ␣-actin, and caspase-3 protein expression, observed in most glomeruli of Thy-1-GN rats, were significantly reduced in darbepoetin-␣-treated rats, while cell proliferation was significantly enhanced. The results indicate that darbepoetin-␣ treatment promotes glomerular recovery. erythropoietin analog; cytoprotective effects; glomerular regeneration ERYTHROPOIETIN (EPO) has been described as a hematopoietic cytokine required for the proliferation and differentiation of erythroid progenitor cells regulating the level of circulating red blood cells (4). However, it has been reported that EPO receptors (EPORs) are also expressed in nonerythroid cells (neurons, endothelial cells, cardiomyocytes, renal tubular cells, podocytes, and mesangial cells) which can respond to EPO treatment (17,18,22,24,27).Therefore, it seems that the therapeutic benefits of EPO treatment on nonhematopoietic tissues are not only the result of the correction of anemia-related tissue hypoxia, suggesting that there are further molecular pathways involved (5,7,9,23,25,26).

but she was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Sézary syndrome is a primary cutaneous T-cell lymphoma characterized by the triad of erythroderma, lymphadenopathy and circulating atypical cells. The emergence of new molecular targets has enabled the development of drugs such as alemtuzumab, an anti-CD52 monoclonal antibody, which has shown promising results in the treatment of this entity. We report the case of a 70-year-old male with refractory Sézary syndrome in whom treatment with alemtuzumab achieved an 80% skin lesion clearance with complete haematologic and radiologic response. The treatment was discontinued after 4 months due to adverse effects, with the patient showing a sustained response without disease progression after 13 months of follow-up.