Telomerase and the search for the end of cancer.

Many of the fundamental molecular mechanisms underlying tumor biology remain elusive and, thus, developing specific anticancer therapies remains a challenge. The recently discovered relationships identified among telomeres, telomerase, aging, and cancer have opened a new avenue in tumor biology research that may revolutionize anticancer therapy. This review summarizes the critical aspects of telomerase biology that underpin the development of novel telomerase-targeting therapies for malignant diseases, and special regard is given to the aspects of telomerase that make it such an appealing target, such as the widespread expression of telomerase in cancers. Despite significant progress, issues remain to be addressed before telomerase-based therapies are truly effective and we include critical discussion of the results obtained thus far.This is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.molmed.2012.11.00

Genetic variation and gastric cancer risk: a field synopsis and meta-analysis.

BACKGROUND: Data on genetic susceptibility to sporadic gastric carcinoma have been published at a growing pace, but to date no comprehensive overview and quantitative summary has been available. METHODS: We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing stomach cancer. To assess result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Meta-analysis was also conducted for subgroups, which were defined by ethnicity (Asian vs Caucasian), tumour histology (intestinal vs diffuse), tumour site (cardia vs non-cardia) and Helicobacter pylori infection status (positive vs negative). RESULTS: Literature search identified 824 eligible studies comprising 2 530 706 subjects (cases: 261 386 (10.3%)) and investigating 2841 polymorphisms involving 952 distinct genes. Overall, we performed 456 primary and subgroup meta-analyses on 156 variants involving 101 genes. We identified 11 variants significantly associated with disease risk and assessed to have a high level of summary evidence: MUC1 rs2070803 at 1q22 (diffuse carcinoma subgroup), MTX1 rs2075570 at 1q22 (diffuse), PSCA rs2294008 at 8q24.2 (non-cardia), PRKAA1 rs13361707 5p13 (non-cardia), PLCE1 rs2274223 10q23 (cardia), TGFBR2 rs3087465 3p22 (Asian), PKLR rs3762272 1q22 (diffuse), PSCA rs2976392 (intestinal), GSTP1 rs1695 11q13 (Asian), CASP8 rs3834129 2q33 (mixed) and TNF rs1799724 6p21.3 (mixed), with the first nine variants characterised by a low FPRP. We also identified polymorphisms with lower quality significant associations (n=110). CONCLUSIONS: We have identified several high-quality biomarkers of gastric cancer susceptibility. These data will form the backbone of an annually updated online resource that will be integral to the study of gastric carcinoma genetics and may inform future screening programmes.This is the author accepted manuscript. The final version is available from BMJ via http://dx.doi.org/10.1136/gutjnl-2015-30916

Survivin gene levels in the peripheral blood of patients with gastric cancer independently predict survival

<p>Abstract</p> <p>Background</p> <p>The detection of circulating tumor cells (CTC) is considered a promising tool for improving risk stratification in patients with solid tumors. We investigated on whether the expression of CTC related genes adds any prognostic power to the TNM staging system in patients with gastric carcinoma.</p> <p>Methods</p> <p>Seventy patients with TNM stage I to IV gastric carcinoma were retrospectively enrolled. Peripheral blood samples were tested by means of quantitative real time PCR (qrtPCR) for the expression of four CTC related genes: carcinoembryonic antigen (CEA), cytokeratin-19 (CK19), vascular endothelial growth factor (VEGF) and Survivin (BIRC5).</p> <p>Results</p> <p>Gene expression of Survivin, CK19, CEA and VEGF was higher than in normal controls in 98.6%, 97.1%, 42.9% and 38.6% of cases, respectively, suggesting a potential diagnostic value of both Survivin and CK19. At multivariable survival analysis, TNM staging and Survivin mRNA levels were retained as independent prognostic factors, demonstrating that Survivin expression in the peripheral blood adds prognostic information to the TNM system. In contrast with previously published data, the transcript abundance of CEA, CK19 and VEGF was not associated with patients' clinical outcome.</p> <p>Conclusions</p> <p>Gene expression levels of Survivin add significant prognostic value to the current TNM staging system. The validation of these findings in larger prospective and multicentric series might lead to the implementation of this biomarker in the routine clinical setting in order to optimize risk stratification and ultimately personalize the therapeutic management of these patients.</p

A technology platform for automatic high-level tennis game analysis

Sports video research is a popular topic that has been applied to many prominent sports for a large spectrum of applications. In this paper we introduce a technology platform which has been developed for the tennis context, able to extract action sequences and provide support to coaches for players performance analysis during training and official matches. The system consists of an hardware architecture, devised to acquire data in the tennis context and for the specific domain requirements, and a number of processing modules which are able to track both the ball and the players, to extract semantic information from their interactions and automatically annotate video sequences. The aim of this paper is to demonstrate that the proposed combination of hardware and software modules is able to extract 3D ball trajectories robust enough to evaluate ball changes of direction recognizing serves, strokes and bounces. Starting from these information, a finite state machine based decision process can be employed to evaluate the score of each action of the game. The entire platform has been tested in real experiments during both training sessions and matches, and results show that automatic annotation of key events along with 3D positions and scores can be used to support coaches in the extraction of valuable information about players intentions and behaviours

Telomerase reverse transcriptase locus polymorphisms and cancer risk: a field synopsis and meta-analysis.

BACKGROUND: Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. METHODS: A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as "strong," "moderate," and "weak" according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. RESULTS: Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. CONCLUSIONS: To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans.This work was in part supported by a grant from the Italian Association for Research on Cancer (AIRC Veneto Regional fund 2008-2011 to SM and DN).This is the author accepted manuscript. The final version is available from Oxford University Press via http://dx.doi.org/10.1093/jnci/djs22

Overexpression of squamous cell carcinoma antigen variants in hepatocellular carcinoma

Pathogenetic mechanisms of hepatocellular carcinoma (HCC) are stil unclear and new tools for diagnostic and therapeutic purposes are ongoing. We have assessed whether squamous cell carcinoma antigen (SCCA), a serpin overexpressed in neoplastic cells of epithelial origin, is also expressed in liver cancer. Squamous cell carcinoma antigen was evaluated by immunohistochemistry in 65 HCCs of different aetiology and in 20 normal livers. Proliferative activity was assessed using MIB-1 antibody. In 18 surgical samples, tumour and nontumour liver tissue was available for SCCA cDNA amplification and sequencing. Squamous cell carcinoma antigen was detected in 55 out of 65 (85%) tumour specimens, but in none of the 20 controls. In the majority of the cases, the positive signal was found in the cytoplasm of more than 50% of the hepatocytes. Low or undetectable SCCA (score less than or equal to1) was associated to lower MIB-1 labelling index, compared to cases with SCCA score greater than or equal to2 (mean +/-s.d.: 2%+/-2.4 vs 7.5%+/-10.3, P<0.05). Squamous cell carcinoma antigen mRNA could be directly sequenced in 14 out of 18 liver tumours but in none of the corresponding nontumour samples. From sequence alignment, a novel SCCA1 variant (G(351) to A) was identified in five cases, while SCCA1 was revealed in six cases and SCCA2 in three cases. In conclusion, SCCA variants are overexpressed in HCC, independently of tumour aetiology. A novel SCCA1 variant has been identified in one third of liver tumours

Induction of Endothelial Nitric Oxide Synthase Expression by Melanoma Sensitizes Endothelial Cells to Tumor Necrosis Factor-Driven Cytotoxicity

Purpose: The cascade of molecular events leading to tumor necrosis factor (TNF)-mediated tumor regression is still incompletely elucidated. We investigated the role of endothelial nitric oxide synthase in determining the tumor-selective activity of TNF. Experimental Design: Using quantitative real-time PCR, endothelial nitric oxide synthase gene levels were measured in melanoma metastases of the skin and normal skin biopsies obtained from 12 patients before undergoing TNF-based therapy. In vitro, the ability of melanoma cells supernatant to affect endothelial nitric oxide synthase transcription by endothelial cells and the influence of nitric oxide synthase inhibition on TNF cytotoxicity toward endothelial cells was evaluated. Results: Endothelial nitric oxide synthase transcript abundance resulted significantly greater in tumor samples rather than in normal skin samples and in patients showing complete response to TNF-based treatment rather than in those showing partial/minimal response. In vitro, melanoma cells' supernatant induced endothelial nitric oxide synthase gene expression by endothelial cells. Nitric oxide synthase inhibition slowed endothelial cells proliferation and, if induced before TNF administration, decreased the cytokine-mediated cytotoxicity on endothelial cells. Conclusions: Taken together, these findings support the hypothesis that high expression of endothelial nitric oxide synthase in the tumor microenvironment might increase or be a marker for endothelial cells sensitivity to TNF. These observations may have important prognostic and/or therapeutic implications in the clinical setting

Circulating Cell-Free DNA in Dogs with Mammary Tumors: Short and Long Fragments and Integrity Index

Circulating cell-free DNA (cfDNA) has been considered an interesting diagnostic/prognostic plasma biomarker in tumor-bearing subjects. In cancer patients, cfDNA can hypothetically derive from tumor necrosis/apoptosis, lysed circulating cells, and some yet unrevealed mechanisms of active release. This study aimed to preliminarily analyze cfDNA in dogs with canine mammary tumors (CMTs). Forty-four neoplastic, 17 non-neoplastic disease-bearing, and 15 healthy dogs were recruited. Necrosis and apoptosis were also assessed as potential source of cfDNA on 78 CMTs diagnosed from the 44 dogs. The cfDNA fragments and integrity index significantly differentiated neoplastic versus non-neoplastic dogs (P<0.05), and allowed the distinction between benign and malignant lesions (P<0.05). Even if without statistical significance, the amount of cfDNA was also affected by tumor necrosis and correlated with tumor size and apoptotic markers expression. A significant (P<0.01) increase of Bcl-2 in malignant tumors was observed, and in metastatic CMTs the evasion of apoptosis was also suggested. This study, therefore, provides evidence that cfDNA could be a diagnostic marker in dogs carrying mammary nodules suggesting that its potential application in early diagnostic procedures should be further investigated

Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations

The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC. \uc2\ua9 2012 Springer Science+Business Media Dordrecht