A web search market model

In this work we analyze a web search market where there is real competition between search engines (which also are advertising agencies). We will show that in this kind of market the revenue of the search engines depends on the precision of the predictions of users' preferences and that advertisers and search engines' users can gain from the competition between search engines.ope

Theory grounded design of genetic programming and parallel evolutionary algorithms

Evolutionary algorithms (EAs) have been successfully applied to many problems and applications. Their success comes from being general purpose, which means that the same EA can be used to solve different problems. Despite that, many factors can affect the behaviour and the performance of an EA and it has been proven that there isn't a particular EA which can solve efficiently any problem. This opens to the issue of understanding how different design choices can affect the performance of an EA and how to efficiently design and tune one. This thesis has two main objectives. On the one hand we will advance the theoretical understanding of evolutionary algorithms, particularly focusing on Genetic Programming and Parallel Evolutionary algorithms. We will do that trying to understand how different design choices affect the performance of the algorithms and providing rigorously proven bounds of the running time for different designs. This novel knowledge, built upon previous work on the theoretical foundation of EAs, will then help for the second objective of the thesis, which is to provide theory grounded design for Parallel Evolutionary Algorithms and Genetic Programming. This will consist in being inspired by the analysis of the algorithms to produce provably good algorithm designs

Pivotal role of micro-CT technology in setting up an optimized lung fibrosis mouse model for drug screening

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with no curative pharmacological treatment. The most used animal model of IPF for anti-fibrotic drug screening is bleomycin (BLM)-induced lung fibrosis. However, several issues have been reported: the balance among disease resolution, an appropriate time window for therapeutic intervention and animal welfare remain critical aspects yet to be fully elucidated. In this study, C57Bl/6 male mice were treated with BLM via oropharyngeal aspiration (OA) following either double or triple administration. The fibrosis progression was longitudinally assessed by micro-CT every 7 days for 4 weeks after BLM administration. Quantitative micro-CT measurements highlighted that triple BLM administration was the ideal dose regimen to provoke sustained lung fibrosis up to 28 days. These results were corroborated with lung histology and Bronchoalveolar Lavage Fluid cells. We have developed a mouse model with prolonged lung fibrosis enabling three weeks of a curative therapeutic window for the screening of putative anti-fibrotic drugs. Moreover, we have demonstrated the pivotal role of longitudinal micro-CT imaging in reducing the number of animals required per experiment in which each animal can be its own control. This approach permits a valuable decrease in costs and time to develop disease animal models

Prognostic factors in gemcitabine-cisplatin polychemotherapy regimens in pancreatic cancer: XPD-Lys751Gln polymorphism strikes back

: The use of platinated agents in combination chemotherapy regimens for advanced pancreatic cancer is controversial owing to the lack of an outstanding impact on the outcome and a substantial increase in hematologic and extra-hematologic toxicities. Pharmacogenetic studies to identify patients who could benefit most from such therapies are urgently needed. The Xeroderma-Pigmentosum group-D polymorphism at codon-751 (XPD-Lys751Gln) emerged as the most significant independent predictor for death- and progression-risk in our previous study on functional polymorphisms in 122 advanced pancreatic cancer patients treated with cisplatin-docetaxel-capecitabine-gemcitabine and cisplatin-epirubicin-capecitabine-gemcitabine (or EC-GemCap). To confirm the prognostic role of this variable, we further evaluated the correlation of XPD-Lys751Gln with outcome in another 125 patients treated with the same regimens, and 90 treated with gemcitabine monotherapy. Genotyping was successfully carried out in the vast majority of DNA samples. Genotype frequencies followed Hardy-Weinberg equilibrium, and XPD-Lys751Gln was associated with differential progression-free and overall-survival. Multivariate analysis confirmed its prognostic significance in platinum-based regimens. In particular, XPD-Gln751Gln was significantly associated with risk of death (hazard ratio, HR = 1.7, 95% confidence interval [CI], 1.1-2.6, p = 0.011) and risk of progression (HR = 1.7, 95% CI, 1.1-2.5, p = 0.013). No correlation was observed in gemcitabine monotherapy-treated patients. The analysis of DNA damage using extra-long-PCR in lymphocytes supported the association of XPD-Gln751Gln with greater resistance to cisplatin-induced damage. The increasing evidence of XPD-Lys751Gln impact on the outcome of gemcitabine-cisplatin-based polychemotherapy leads to plan prospective studies to validate the role of this polymorphism as a new tool for optimization of the currently available treatments in pancreatic cancer

Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: a phase II randomised trial

Background: New strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting. Methods: Patients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; β .10, the target accrual was 26 patients per arm. Results: 28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7-186). Main grade 3-4 toxicity was thrombocytopenia, neutropenia and hand-foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0-10.6%) and 22.2% (95% CI: 6.2-38.2%; P<0.01); 2 y overall survival was 7.1% (95% CI: 0-16.8%) and 22.9% (95% CI: 5.8-40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02). Conclusion: This is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2 y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population

A polymorphism in the promoter is associated with EZH2 expression but not with outcome in advanced pancreatic cancer patients

Aim: EZH2 expression is a prognostic marker in radically resected pancreatic ductal adenocarcinoma (PDAC) patients. Here we investigated its role in locally advanced/metastatic patients, as well as candidate polymorphisms. Materials & methods: EZH2 expression and polymorphisms were evaluated by quantitative reverse transcription PCR in 32 laser microdissected tumors, while polymorphisms were also studied in blood samples from two additional cohorts treated with gemcitabine monotherapy (n = 93) or polychemotherapeutic regimens (n = 247). Results: EZH2 expression correlated with survival and with the rs6958683 polymorphism in the first cohort of patients, but this polymorphism was not associated with survival in our larger cohorts. Conclusion: EZH2 is a prognostic factor for locally advanced/metastatic PDACs, while candidate polymorphisms cannot predict clinical outcome. Other factors involved in EZH2 regulation, such as miR-101, should be investigated in accessible samples in order to improve the clinical management of advanced PDAC

Clinical and Translational Results of a Phase II Randomized Trial of Maintenance Sunitinib or Observation in Metastatic Pancreatic Adenocarcinoma

Context To prolong chemotherapy over 6 months in metastatic pancreatic adenocarcinoma (MPA) has unproven benefit and is hampered by cumulative toxicity. Objective This phase II trial explored the role of maintenance sunitinib (MS), using an observation (O) group as calibration arm. The predictive role of circulating endothelial cells (CEC) and of functional polymorphisms (SNPs) of genes involved in sunitinib activity, metabolism and transport (VEGFA, VEGFR-2, CYP3A5, CYP1A1, ABCB1, ABCG2) was explored. Methods Patients with pathologic diagnosis of MPA, PS >50%, no PD after 6 months of chemotherapy were randomized to O (arm A) or MS (37.5 mg daily) for 6 months (arm B). Primary endpoint was PFS-6. The target enrolment was 26 patients among whom >5 PFS-6 were necessary to declare MS of interest. CEC and SNPs were evaluated on baseline blood samples. Results Twenty-eight patients were assigned arm A and 28 arm B, one of whom was ineligible (kidney cancer). Baseline characteristics were balanced; previous chemotherapy was (A/B): gemcitabine 2/3; combination chemotherapy 25/25. Median duration of MS was 2.8 months. Grade 3-4 toxicity (arm B) was 15% neutropenia; 12% thrombocytopenia and hand-foot syndrome, 8% diarrhea. PFS-6 was 4% and 22%; median PFS was 2.0 and 3.2 months (P=0.01); 2-year OS was 5% and 22% (P=0.12). CEC analysis (n=46; 84%) showed a longer median PFS in untreated patients with CEC <30 when compared to >30 (2.9 versus 1.9 months; P=0.08); a significantly increased PFS in patients with CEC >30 treated by MS versus O (3.4 months; P=0.02); no PFS difference between arms in patients with CEC <30. Genotyping analysis (n=43; 78%) showed a longer median OS among arm B patients with ABCB1 3435TT genotype as compared to 3435CC/CT genotype (26 versus 7 months; P=0.11); and with VEGFA -634GC-CC genotype as compared to -634GG genotype (11 versus 6 months; P=0.013). Conclusions MS fulfilled the primary endpoint of the trial and yielded remarkable OS figures. CEC and SNPs may be useful to predict benefit from MS

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted