Estudi d’alteracions genètiques predictores de resposta al tractament amb cetuximab en càncer colorectal

Projecte de recerca elaborat a partir d’una estada al Cancer Center, Massachusetts General Hospital- Harvard School of Medicine, Boston, Estats Units entre gener i juny 2007. El desenvolupament de nous fàrmacs dirigits a dianes moleculars específiques ha suposat un gran avanç en el tractament del càncer. El millor coneixement dels mecanismes que determinen la sensibilitat a aquests tractaments biològics és crucial per poder oferir tractaments selectius, optimitzar l'índex terapèutic i controlar l'elevat cost d'aquests fàrmacs. Tal com ha demostrat el grup liderat pel Dr. Settleman i altres, la sensibilitat del tumor a nous fàrmacs dirigits a diana molecular ve determinada en part per alteracions genètiques de les cèl.lules tumorals. El paradigma és la resposta clínica a fàrmacs inhibidors tirosin-cinasa d’ EGFR dels pacients amb càncer de pulmó amb mutacions d'EGFR. Donada la importància de trobar marcadors predictors de sensibilitat a les noves teràpies biològiques, la detecció a gran escala d' alteraciones genètiques i las seva correlació amb la sensibilitat al tractament amb aquests fàrmacs en models preclínics és un primer pas essencial per a un posterior desenvolupament a nivell clínic. En aquest estudi vam establir una plataforma de cribatge d’alta densitat (high throughput screening) de línies cel.lulars que ens permet detectar alteracions genètiques predictores de resposta a fàrmacs dirigits a diana molecular específica. Presentem el desenvolupament d'aquesta plataforma i el resultat de dues aplicacions específiques(... )

I. Identification and characterisation of epigenetically altered tumor supressor genes by proteomic and genomic approches / II. Studies of genes regualted by MeCP2 union to its promoter regions by proteomic and genmomic approches

DNA methylation has an important impact on normal cell physiology, thus any defects in this mechanism may be related to the development of various diseases In this project we are interested in identifying epigeneticaliy modified genes, in general controlled by processes related to the DNA methylation, by means of a new strategy combining protomic and genomic analyses. First, the two Dimensional-Difference Gel Electrophoresis (2-DIGE) protein analyses of extracts obtained from HCT-116 wt and double knockout for DNMT1 and DNMT3b (DKO) cells revealed 34 proteins overexpressed in the condition of DNMTs depletion. From five genes with higher transcript lavels in DKO cells, comparing with HCT-116 wt. oniy AKR1B1, UCHLl and VIM are melhylated in HCT-116. As expected. the DNA methvlation 1s lost in DKO cells. The rneth,vl ation of VIM and UCHLl promoters in some cancer samples has already been repaired, thus further studies has been focused on AKRlBI. AKR1B1 expression due lo DNA methyiaton of promoter region seems to occur specilfically in the colon cancer cell Iines. which was confirmed in the DNA rnethylation status and expression analyses. performed on 32 different cancer cell lines (including colon, breast, lymphoma, leukemia, neuroblastoma, glioma and lung cancer cell Iines) as well as normal colon and normal lymphocytes samples. AKRIBI expression after treatments with DNA demethvlating agent (AZA) was rescued in 5 coloncancer cell lines (including genetic regulation of the candidate gene. The methylation status of the rest of the genes identified in proteomic analysis was checked by methylation specific PCR (MSP) experiment and all appeared to be unmethylated. The similar research has been done also bv means of Mecp2-null mouse model For 14 selected candidate genes the analyses of expression leveis, methylation Status and MeCP2 interaction with promoters are currently being performed.

Implementing a Cancer Fast-track programme between primary and specialised care in Catalonia(Spain): amixed methods study

BACKGROUND: The Cancer Fast-track Programme's aim was to reduce the time that elapsed between well-founded suspicion of breast, colorectal and lung cancer and the start of initial treatment in Catalonia (Spain). We sought to analyse its implementation and overall effectiveness. METHODS: A quantitative analysis of the programme was performed using data generated by the hospitals on the basis of seven fast-track monitoring indicators for the period 2006-2009. In addition, we conducted a qualitative study, based on 83 semistructured interviews with primary and specialised health professionals and health administrators, to obtain their perception of the programme's implementation. RESULTS: About half of all new patients with breast, lung or colorectal cancer were diagnosed via the fast track, though the cancer detection rate declined across the period. Mean time from detection of suspected cancer in primary care to start of initial treatment was 32 days for breast, 30 for colorectal and 37 for lung cancer (2009). Professionals associated with the implementation of the programme showed that general practitioners faced with suspicion of cancer had changed their conduct with the aim of preventing lags. Furthermore, hospitals were found to have pursued three specific implementation strategies (top-down, consensus-based and participatory), which made for the cohesion and sustainability of the circuits. CONCLUSION: The programme has contributed to speeding up diagnostic assessment and treatment of patients with suspicion of cancer, and to clarifying the patient pathway between primary and specialised care.

REGSTATTOOLS: freeware statistical tools for the analysis of disease population databases used in health and social studies

Background: The repertoire of statistical methods dealing with the descriptive analysis of the burden of a disease has been expanded and implemented in statistical software packages during the last years. The purpose of this paper is to present a web-based tool, REGSTATTOOLS http://regstattools.net intended to provide analysis for the burden of cancer, or other group of disease registry data. Three software applications are included in REGSTATTOOLS: SART (analysis of disease"s rates and its time trends), RiskDiff (analysis of percent changes in the rates due to demographic factors and risk of developing or dying from a disease) and WAERS (relative survival analysis). Results: We show a real-data application through the assessment of the burden of tobacco-related cancer incidence in two Spanish regions in the period 1995-2004. Making use of SART we show that lung cancer is the most common cancer among those cancers, with rising trends in incidence among women. We compared 2000-2004 data with that of 1995-1999 to assess percent changes in the number of cases as well as relative survival using RiskDiff and WAERS, respectively. We show that the net change increase in lung cancer cases among women was mainly attributable to an increased risk of developing lung cancer, whereas in men it is attributable to the increase in population size. Among men, lung cancer relative survival was higher in 2000-2004 than in 1995-1999, whereas it was similar among women when these time periods were compared. Conclusions: Unlike other similar applications, REGSTATTOOLS does not require local software installation and it is simple to use, fast and easy to interpret. It is a set of web-based statistical tools intended for automated calculation of population indicators that any professional in health or social sciences may require.

Les xifres del tabac

Les persones tendim a quantificar les coses, malgrat que costa capir plenament les implicacions dels valors que obtenim si no disposem del context adequat on situar-los. Per exemple, sabem que al món hi ha més de mil milions de fumadors; que aquests tenen 20 vegades més probabilitats de desenvolupar un càncer de pulmó; que cada any es diagnostiquen un milió de casos nous [...].