The accurate execution of DNA replication requires a strict control of the replication licensing factors hCdt1 and hCdc6. The role of these key replication molecules in carcinogenesis has not been clarified. To examine how early during cancer development deregulation of these factors occurs, we investigated their status in epithelial lesions covering progressive stages of hyperplasia, dysplasia, and full malignancy, mostly from the same patients.

Knowing the status of molecules involved in cell cycle control in cancer is vital for therapeutic approaches aiming at their restoration. The p27 KIP1 and p57 KIP2 cyclin-dependent kinase inhibitors are nodal factors controlling normal cell cycle. Their expression in normal lung raises the question whether they have a mutual exclusive or redundant role in nonsmall cell lung cancer (NSCLC). A comparative comprehensive analysis was performed in a series of 70 NSCLCs. The majority of cases showed significantly reduced expression of both members compared to normal counterparts. Low KIP protein levels correlated with increased proliferation, which seems to be histological subtype preponderant. At mechanistic level, degradation by SKP2 was demonstrated, in vivo and in vitro, by siRNA-methodology, to be the most important downregulating mechanism of both KIPs in NSCLC. Decreased p57 ), suggested that inhibition of the SKP2-degradation mechanism restores p27 KIP1 and p57 KIP2 expression. Double siRNA treatments demonstrated that each KIP is independently capable of restraining cell growth. An additional demethylation step is required for complete reconstitution of p57 KIP2 expression in NSCLC. ' 2006 Wiley-Liss, Inc.

Response Human memory but not naïve ␥␦ T cells from TST-positive individuals respond to M tuberculosis antigenWe thank Casetti et al for their interest in our recent work, "CD4 ϩ CD25 ϩ Treg cells inhibit human memory ␥␦ T cells to produce IFN-␥ in response to M tuberculosis antigen ESAT-6." 1 In our article, we showed that stimulation of peripheral blood mononuclear cells (PBMCs) from tuberculin skin test (TST)-positive individuals with ESAT-6 resulted in not only the production of cytokines but also the activation and division of memory ␥␦ T cells. These responding ␥␦ T cells displayed the phenotype of memory but not naive ␥␦ T cells. Most interestingly, CD4 ϩ CD25 ϩ Treg cells could inhibit IFN-␥ production by ␥␦ T cells. Casetti et al observed that CD4 ϩ but not ␥␦ T cells from 4 patients with active tuberculosis (TB) disease and 4 subjects with latent TB infection (LTBI) responded to ESAT-6 to express IFN-␥. In accordance with their and others' observations, 2 in our unpublished data from a few active TB patients, we also found that CD4 ϩ T cells, in addition to ␥␦ T cells, produced IFN-␥ in response to ESAT-6. Of note, the cells from different individuals with TB infection had distinct quality of response. The discrepancies between their and our results on the response of ␥␦ T cells to ESAT-6 might be influenced by many factors. The concern might be that the source of ESAT-6 we purchased from suppliers was different from that Casetti et al used. The various preparations of recombinant antigens, including cloning, sequences, expression, and purification process from different companies, might have different biologic activities. Moreover, differences in the classical and nonclassical major histocompatibility class (MHC) molecules, the affinity to antigenic epitopes, and the distinct biologic features between eastern and western peoples might lead to distinct reactivity to the same antigen. Clearly, it has been reported that ␥␦ T cells from bovines could react to ESAT-6 by IFN-␥ production and proliferation. 3 In addition, several antigenic epitopes/proteins recognized by human ␥␦ T cells have been identified via CDR3␦ peptide-based immunobiochemical strategy. 4 These peptides not only bind to ␥␦ T cells but also activate ␥␦ T cells. Moreover, in human chronic human herpesvirus 8 (HHV-8) infection, purified viral proteins resulted in ␥␦ V␦1 T cell activation. 5 Taken together, we agree with Casetti et al that human ␥␦ T cells recognize nonpeptidic phosphoantigens, metabolites of the isoprenoid pathway. 6,7 However, the mechanism by which human ␥␦ T cells recognized protein antigens remains unclear currently and needs further investigation. Li Li and Chang-You Wu Approval was obtained from the Zhongshan School of Medicine, Sun Yat-Sen University institutional review board for these studies. Informed consent was obtained in accordance with the Declaration of Helsinki. Conflict-of-interest disclosure: The authors declare no competing financial interests.Correspondence : Changyou Wu, MD, PhD, Department of Immuno...

The aim of this review is to present the advances in our understanding of the progression of tumorigenesis in neuroendocrine lung tumors. Current information on established and putative diagnostic and prognostic markers of neuroendocrine tumors are evaluated, with a special reference to

<div>Abstract<p>The accurate execution of DNA replication requires a strict control of the replication licensing factors hCdt1 and hCdc6. The role of these key replication molecules in carcinogenesis has not been clarified. To examine how early during cancer development deregulation of these factors occurs, we investigated their status in epithelial lesions covering progressive stages of hyperplasia, dysplasia, and full malignancy, mostly from the same patients. Abnormal accumulation of both proteins occurred early from the stage of dysplasia. A frequent cause of unregulated hCdc6 and hCdt1 expression was gene amplification, suggesting that these components can play a role per se in cancer development. Overexpression of hCdt1 and hCdc6 promoted rereplication and generated a DNA damage response, which activated the antitumor barriers of senescence and apoptosis. Generating an inducible hCdt1 cellular system, we observed that continuous stimulus by deregulated hCdt1 led to abrogation of the antitumor barriers and resulted in the selection of clones with more aggressive properties. In addition, stable expression of hCdc6 and hCdt1 in premalignant papilloma cells led to transformation of the cells that produced tumors upon injection into nude mice depicting the oncogenic potential of their deregulation. [Cancer Res 2007;67(22):10899–909]</p></div>