A small molecule based on the pRb2/p130 spacer domain leads to inhibition of cdk2 activity, cell cycle arrest and tumor growth reduction in vivo.

One strategy in the development of anticancer therapeutics has been to arrest malignant proliferation through inhibition of the enzymatic activity of cyclin-dependent kinases (cdks), which are key regulatory molecules of the cell cycle. Over the past few years, numerous compounds with remarkable cdk inhibitory activity have been studied in cancer therapy, although it is very difficult to point out the best cdk to target. An excellent candidate appears to be cdk2, whose alteration is a pathogenic hallmark of tumorigenesis. The small molecule described in our study showed an inhibitory effect on the kinase activity of cdk2, a significant growth arrest observed in a colony formation assay and a reduction in the size of the tumor in nude mice, thus suggesting its potential role as a promising new type of mechanism-based antitumor drug, also for the treatment of hyperproliferative disorders.

IRTA1+ monocytoid B cells in reactive lymphadenitis show a unique topographic distribution and immunophenotype and a peculiar usage and mutational pattern of IgVH genes.

The origin and function of monocytoid B cells (MBCs) are poorly understood. Taking advantage of their strong expression of IRTA1 (a receptor that is also associated with MALT marginal zone B cells), we have comprehensively analysed MBCs in 25 cases of lymphadenitis of different aetiologies, shedding new light on the topographical distribution, immunophenotype and IgV(H) gene usage and mutational profile of this B cell subset. IRTA1(+) MBCs, although predominantly located in the subcapsular and intermediary sinuses, were also observed scattered within germinal centres (GCs) in all lymphadenitis cases examined. The molecular characterization of IgV(H) genes revealed that IRTA1(+) MBCs residing in different areas of the lymph node (subcapsular sinus, intermediary sinuses and GCs) can be clonally related (with intraclonal variation), and that those located in GCs are consistently more mutated and selected for expression of a functional antigen receptor than those located in the sinuses. Moreover, by contrast, IRTA1(+) MBCs in GCs express the memory B cell marker CD27. Finally, in toxoplasmic lymphadenitis, the IRTA1(+) MBC population shows a highly preferential usage of the V(H) genes 3-7 and 3-30 (without any obvious peculiarity in their CDR3s), possibly suggesting that a superantigen expressed by Toxoplasma gondii may be involved in the early activation of this B cell subset.

Rhodopsin maturation antagonized by dominant rhodopsin mutants.

ninaE(D1), a dominant allele of the major Drosophila rhodopsin gene, expresses a rhodopsin that is predominantly recovered in a 80-kD complex that likely represents rhodopsin dimers. By driving either ninaE(D1) or ninaE+ expression from a heat-shock promoter, we show that the 80-kD rhodopsin complex forms immediately after gene activation. In wild type, but not ninaE(D1), rhodopsin monomeric forms are detected at later times. The generation of monomeric forms of wild-type rhodopsin is suppressed in vitamin A-deprived flies or in flies heterozygous for the dominant rhodopsin mutation. We also show that ninaE(D1) expression does not affect the maturation of another Drosophila visual pigment, Rh3. These results are consistent with the view that the ninaE(D1) rhodopsin antagonizes an early posttranslation process that is specific for maturation of the ninaE-encoded rhodopsin.