Low frequency of defective mismatch repair in a population-based series of upper urothelial carcinoma

BACKGROUND: Upper urothelial cancer (UUC), i.e. transitional cell carcinomas of the renal pelvis and the ureter, occur at an increased frequency in patients with hereditary nonpolyposis colorectal cancer (HNPCC). Defective mismatch repair (MMR) specifically characterizes HNPCC-associated tumors, but also occurs in subsets of some sporadic tumors, e.g. in gastrointestinal cancer and endometrial cancer. METHODS: We assessed the contribution of defective MMR to the development of UUC in a population-based series from the southern Swedish Cancer Registry, through microsatellite instability (MSI) analysis and immunohistochemical evaluation of expression of the MMR proteins MLH1, PMS2, MSH2, and MSH6. RESULTS: A MSI-high phenotype was identified in 9/216 (4%) successfully analyzed patients and a MSI-low phenotype in 5/216 (2%). Loss of MMR protein immunostaining was found in 11/216 (5%) tumors, and affected most commonly MSH2 and MSH6. CONCLUSION: This population-based series indicates that somatic MMR inactivation is a minor pathway in the development of UUC, but tumors that display defective MMR are, based on the immunohistochemical expression pattern, likely to be associated with HNPCC

Geography of non-melanoma skin cancer and ecological associations with environmental risk factors in England.

This is the author's peer reviewed version of the article. Please cite the published, final version which is available via the DOI link in this record.This study investigates the geography of non-melanoma skin cancer (NMSC) in England, and ecological associations with three widespread environmental hazards: radon, arsenic and ultraviolet radiation from the sun.European Regional Development FundEuropean Social Fund Convergence Programme for Cornwall and the Isles of Scill

Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium

<p>Abstract</p> <p>Background</p> <p>Exposure to the toxic metals arsenic and cadmium is associated with detrimental health effects including cancers of various organs. While arsenic and cadmium are well known to cause adverse health effects at high doses, the molecular impact resulting from exposure to environmentally relevant doses of these metals remains largely unexplored.</p> <p>Results</p> <p>In this study, we examined the effects of <it>in vitro </it>exposure to either arsenic or cadmium in human TK6 lymphoblastoid cells using genomics and systems level pathway mapping approaches. A total of 167 genes with differential expression were identified following exposure to either metal with surprisingly no overlap between the two. Real-time PCR was used to confirm target gene expression changes. The gene sets were overlaid onto protein-protein interaction maps to identify metal-induced transcriptional networks. Interestingly, both metal-induced networks were significantly enriched for proteins involved in common biological processes such as tumorigenesis, inflammation, and cell signaling. These findings were further supported by gene set enrichment analysis.</p> <p>Conclusions</p> <p>This study is the first to compare the transcriptional responses induced by low dose exposure to cadmium and arsenic in human lymphoblastoid cells. These results highlight that even at low levels of exposure both metals can dramatically influence the expression of important cellular pathways.</p

PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts

Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1+/− genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients

Hodnocení schopnosti modelů ANFIS a SVMR předpovídat inhibici koroze cerových konverzních povlaků

Tato práce se zabývá inhibičním účinkem konverzního povlaku ceru na různé hliníkové slitiny. K předpovědi inhibičního účinku povlakovaných slitin Al byly vyvinuty dvě různé výpočetní metody, ANFIS (fuzzy inferenční systém založený na adaptivní síti) a SVMR (regrese s podpůrnými vektory). Korozní chování povlakovaných vzorků bylo rovněž zkoumáno pomocí potenciodynamické polarizační zkoušky. Výsledky ukázaly, že vrstva oxidu ceru snižuje korozní rychlost Al-slitin, ale účinnost ochranné vrstvy závisí na složení slitiny. Na základě experimentálních výsledků byly legující prvky hliníku použity jako vstupní parametry pro trénování modelů. Optimální model ANFIS byl vyvinut ruční změnou parametrů shlukování. Optimální struktury bylo dosaženo, když byly faktor squash, rozsah vlivu a poměr odmítnutí a poměr akceptace zvoleny jako 15, 0,3 a 0,5 v uvedeném pořadí. Střední kvadratická chyba (RMSE) optimalizovaného fuzzy modelu byla 3,67 × 10-5. Různá statistická kritéria ukázala, že model ANFIS (R2 = 0,99) dokázal předpovědět inhibiční sílu přesněji než SVMR s R2 = 0,86. Byl tak vytvořen predikční model pro klasifikaci a predikci povlakovaných Al slitin AA1xxx až AA8xxx, který by mohl vyřešit nedostatek datových souborů. Kromě toho zkoumání vlivu vstupů a analýza citlivosti modelu ANFIS ukázaly pozoruhodný vliv legujících prvků Mg, Mn a Zn na inhibiční sílu povlakovaných Al-slitin. Výsledky rovněž ukázaly, že vyšší inhibiční účinnosti bylo dosaženo u povlakovaných hliníkových slitin řad 5xxx a 6xxx.This work investigates the inhibition effect of cerium conversion coating on various aluminium alloys. Two different computational methods, ANFIS (adaptive-network-based fuzzy inference system) and SVMR (support vector machine regression) were developed to predict the inhibitory power of coated Al-alloys. The corrosion behaviour of the coated samples was also examined using potentiodynamic polarization testing. Results showed that the cerium oxide layer decreased the corrosion rate of Al-alloys, but the efficiency of the protective layer depended on the alloying composition. From the experimental results, the alloying elements of aluminium were used as input parameters to train the models. The optimum ANFIS model was developed by varying the clustering parameters manually. The optimum structure is achieved when the squash factor, the range of influence, and the reject ratio and accept ratio are taken as 15, 0.3, and 0.5 respectively. The root-mean-square error (RMSE) of the optimized fuzzy model was 3.67 × 10–5. Various statistical criteria showed that the ANFIS model (R2 = 0.99) could predict inhibitory power more accurately than SVMR with R2 = 0.86. A predictive model was thus created to classify and predict coated Al-alloys AA1xxx to AA8xxx, which could solve the shortage of data sets. Furthermore, investigation of the effect of the inputs and a sensitivity analysis for the ANFIS model showed the remarkable impact of Mg, Mn, and Zn alloying elements on the inhibitory power of coated Al-alloys. The results also indicated that higher inhibition efficiencies were obtained for coated 5xxx and 6xxx aluminium series