IntroductionCervical cancer causes 15% of deaths from cancer in women worldwide. Epidemiological data indicate the sexually transmitted high oncogenic risk human papillomaviruses (HPV) 16 and 18 as aetiological agents. 1,2 In particular, the expression of the viral E6 and E7 oncoproteins appears to contribute to malignant progression. Consequently, great efforts have been directed towards designing therapeutic vaccines against HPV-induced cervical carcinoma by using the HPV16/18 E6 and E7 proteins as tumour-associated antigens. 3,4 However, the time when a vaccine will have an impact on the prevalence of papillomavirus-induced dysplasia and cancer seems to be still some way off. 5 For example, a successful papillomavirus vaccine strategy should evoke CTL able to recognize antigenic fragments of internal viral proteins. Therefore, a reason for the failure of the immune system to control HPV infection may also reside in the scarce antigenicity, that is, scarce 'non-self ' character, of the viral peptides exhibited by the MHC groove.The ability of the immune system to distinguish between self and non-self molecules is an important property in maintaining tissue/organism integrity. Breakage of this selftolerance is one of the main bases for autoimmune diseases. 6,7 However, the tolerance mechanisms used to prevent autoimmune destruction could be the main basis through which tumour-associated-antigens escape from functional antigenspecific immune recognition. To gain a better understanding of the recognition of HPV protein antigens by the immune system, we have analysed the sharing of amino acid (aa) motifs between human 'self ' molecular determinants and the HPV16 E7 oncoprotein by similarity sequence studies. Materials and MethodsThe analysed HPV16 E7 oncoprotein sequence was as reported by Seedorf et al. 8 (Medline accession no. K02718). As controls, we analysed the sequences of the following proteins: (i) small t antigen (SWISS-PROT accession no. P03081) from simian virus 40 (SV40); (ii) the non-structural protein NS2A (Medline U89339) from yellow fever virus (YFV); and (iii) three fragments from the haemagglutininneuramidase (HN) protein (EMBL accession no. X79092) from Newcastle disease virus (NDV). The three polypeptide fragments from the haemagglutinin-neuramidase protein were approximately 33 aa long each, for a total of 100 aa, and were spaced at almost regular intervals along the entire protein sequence. The fragments were: aa 176-208, fragment 1; aa 337-369, fragment 2; and aa 467-499, fragment 3. Sequence similarity analyses were conducted by using the MEDLINE, FASTA, BLAST, PIR, SWISS-PROT and PRINTS sequence analysis programs. 9-11 The SYFPEITHI program (http://www.uni-tuebingen.de/uni/kxi/) was used as database of HLA ligands and peptide motifs. 12 ResultsMolecular mimicry is defined as similar motifs/structures shared by molecules from dissimilar genes or by their protein products. 13 To investigate the molecular mimicry between HPV16 E7 oncoprotein sequence and human proteoma, a systematic study of...

Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma. [Mol Cancer Ther 2007;6(12):3256-62]

Soluble FGF-2, VEGF and PDGF-beta levels decline after radiotherapy in NHLs, and may have predictive significance for response to treatment and recurrence.

Summary Transforming growth factor 11 (TGF-p1l) is a potent modulator of cell proliferation in vitro, and recent studies have demonstrated its overexpression in several different tumours; nevertheless, the molecular mechanisms of TGF-11 action on cell growth and differentiation have not been fully elucidated. To clarify the role of TGF-1 and its receptor in human endometrial proliferation and differentiation, TGF-01 expression at both the mRNA and protein levels has been evaluated by using Northern blotting and immunohistochemistry, in both normal (atrophic, proliferative and secretory) and neoplastic (adenocarcinoma) endometrial samples. This study demonstrates that TGF-1l mRNA expression is dramatically reduced in endometrial carcinomas with respect to non-neoplastic tissues, whereas the immunohistochemical expression of TGF-11 is enhanced in the epithelial component of endometrial carcinomas compared with non-neoplastic tissues. These data suggest that TGF-f1 acts as a paracrine regulator of endometrial cell proliferation and that it may contribute to the carcinogenic mechanisms of endometrial carcinoma.Keywords: transforming growth factor 131; RNA expression; uterus; adenocarcinoma; immunohistochemistry; Northern blotting Epithelial and stromal endometrial cells undergo sequential proliferation, differentiation and shedding throughout the menstrual cycle, and it is well known that these changes are driven by coincident variations of oestrogen and progesterone seric levels. It has been recently demonstrated that endometrial cells synthesize cytokines and growth factors that may be derived from constituent epithelial, mesenchymal or inflammatory cells and which modulate endometrial proliferation and differentiation (Smith, 1994).Such an interactive system, which involves different cell types, steroid hormones, cytokines and growth factors, should probably rely on a complex network of intercellular and intracellular signalling in which cytokines and growth factors play a paracrine, autocrine or endocrine role. In this regard, several cytokines and growth factors, such as transforming growth factor a and 1, insulin-like growth factors, epidermal growth factor, tumour necrosis factor a, colony stimulating factor 1 and interleukins 1 and 6, have been shown to play a role in the regulation of endometrial growth and differentiation and to interact with steroid hormones (Tabibzadeh, 1991;Giudice, 1994). Although unbalanced oestrogen stimulation of the endometrium, without the differentiative effects of progesterone, is one of the main aetiologic factors of endometrial hyperplasia and carcinoma (Gurpide, 1991), the molecular basis of proliferating diseases is mostly unknown.Recent evidence strongly suggest that most human cancers result from sequential gene damage and subsequent alterations of

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