New Insights into the Pathogenesis of MDS and the rational therapeutic opportunities.

Myelodysplastic syndromes (MDS) include a heterogeneous group of acquired hematopoietic malignancies characterized by ineffective hematopoiesis, peripheral cytopenias, and a varying propensity for progression to acute myeloid leukemia. The clinical heterogeneity in MDS is a reflection of its molecular heterogeneity. Better understanding of aberrant epigenetics, dysregulation of immune responses, and del(5q) MDS has provided the rationale for well-established treatments in MDS.

Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma.

The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd.

Growth factor and signaling pathways and their relevance to prostate cancer therapeutics.

Treatments that target the androgen axis represent an effective strategy for patients with advanced prostate cancer, but the disease remains incurable and new therapeutic approaches are necessary. Significant advances have recently occurred in our understanding of the growth factor and signaling pathways that are active in prostate cancer. In conjunction with this, many new targeted therapies with sound preclinical rationale have entered clinical development and are being tested in men with castration-resistant prostate cancer.

Regulation of TRP channel TRPM2 by the tyrosine phosphatase PTPL1.

TRPM2, a member of the transient receptor potential (TRP) superfamily, is a Ca(2+)-permeable channel, which mediates susceptibility to cell death following activation by oxidative stress, TNFalpha, or beta-amyloid peptide. We determined that TRPM2 is rapidly tyrosine phosphorylated after stimulation with H(2)O(2) or TNFalpha. Inhibition of tyrosine phosphorylation with the tyrosine kinase inhibitors genistein or PP2 significantly reduced the increase in [Ca(2+)](i) observed after H(2)O(2) or TNFalpha treatment in TRPM2-expressing cells, suggesting that phosphorylation is important in TRPM2 activation.

Identification of an N-terminal TRPC2 splice variant which inhibits calcium influx.

TRPC2 is a member of the transient receptor potential (TRP) superfamily of Ca2+-permeable channels expressed in nonexcitable cells. TRPC2 is involved in a number of physiological processes including sensory activation of the vomeronasal organ, sustained Ca2+ entry in sperm, and regulation of calcium influx by erythropoietin. Here, a new splice variant of TRPC2, called "Similar to mouse TRPC2" (smTRPC2), was identified consisting of 213 amino acids, largely coincident with the N-terminus of TRPC2 clone 17.

Interaction of TRPC2 and TRPC6 in erythropoietin modulation of calcium influx.

Erythropoietin (Epo) modulates calcium influx through voltage-independent calcium-permeable channel(s). Here, we characterized the expression of transient receptor potential channels (TRPCs) in primary erythroid cells and examined their regulation. Erythroblasts were isolated from the spleens of phenylhydrazine-treated mice, and Epo stimulation resulted in a significant and dose-dependent increase in [Ca](i).