La UNED en TVE-2 Desde el ano 2007 se viene conmemorando el dia 18 de Octubre como Dia Europeo co... more La UNED en TVE-2 Desde el ano 2007 se viene conmemorando el dia 18 de Octubre como Dia Europeo contra la Trata de Seres Humanos con el objetivo de recordar a todas aquellas personas que son utilizadas como mercancias, privadas de sus derechos fundamentales. La trata sigue siendo una realidad invisible presente en la mayor parte de los paises del mundo y Espana no es una excepcion.
Background: Cancer initiation and progression are driven by genetic and epigenetic changes. Altho... more Background: Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/ exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation. Results: Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer. Conclusions: We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.
Introduction: Vultures are often exposed to spent lead ammunition from carcasses of game. Exposur... more Introduction: Vultures are often exposed to spent lead ammunition from carcasses of game. Exposure may have increased after the ban on abandoning carcasses of domestic ruminants in the field, because vultures consume hunting residues more frequently and because malnutrition may induce mobilization of lead stores. Materials and Methods: An adult female griffon vulture (Gyps fulvus) found in Freixo-de-Espada-a-Cinta, Portugal, showing extreme weakness, anorexia, depression and green-stained faeces, died 24 h after admission. A blood sample was taken and, during necropsy examination, liver and kidney were also collected for histopathological analysis and lead detection by inductively coupled plasma mass spectrometry. Results: Necropsy examination revealed crop impaction, gall bladder and stomach distension and right lung aspiration pneumonia. Nine lead bullets were found in the stomach. Histopathology revealed hepatocellular cytoplasmic haemosiderin accumulation. Blood, liver and kidney had lead concentrations of 1384.4 mg/dl ww, 308.6 mg/g dw and 34.6 mg/g dw, respectively. Conclusions: The low gastric pH of raptors promotes the rapid dissolution and subsequent absorption of lead. Acute lead poisoning is one of the most important causes of mortality in raptors and, since the conservation status of this species in Portugal is near threatened, effective measures are needed to prevent it.
Figure S5. FACS gating strategy to analyze white blood cell population in WT and Fanca-deficient ... more Figure S5. FACS gating strategy to analyze white blood cell population in WT and Fanca-deficient mice.
Figure S2. Additional data on gefitinib and afatinib in vivo mouse xenograft experiments. Weight ... more Figure S2. Additional data on gefitinib and afatinib in vivo mouse xenograft experiments. Weight control.
Figure S6. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient ... more Figure S6. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient mice.
Purpose:Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposi... more Purpose:Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia.Experimental Design:We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety.Results:Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefi...
Figure S7. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient ... more Figure S7. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient mice.
Figure S8. Additional data on genotoxicity in blood samples from WT or Fanca-deficient mice, by g... more Figure S8. Additional data on genotoxicity in blood samples from WT or Fanca-deficient mice, by gefitinib and afatinib treatment.
La UNED en TVE-2 Desde el ano 2007 se viene conmemorando el dia 18 de Octubre como Dia Europeo co... more La UNED en TVE-2 Desde el ano 2007 se viene conmemorando el dia 18 de Octubre como Dia Europeo contra la Trata de Seres Humanos con el objetivo de recordar a todas aquellas personas que son utilizadas como mercancias, privadas de sus derechos fundamentales. La trata sigue siendo una realidad invisible presente en la mayor parte de los paises del mundo y Espana no es una excepcion.
Background: Cancer initiation and progression are driven by genetic and epigenetic changes. Altho... more Background: Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/ exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation. Results: Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer. Conclusions: We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.
Introduction: Vultures are often exposed to spent lead ammunition from carcasses of game. Exposur... more Introduction: Vultures are often exposed to spent lead ammunition from carcasses of game. Exposure may have increased after the ban on abandoning carcasses of domestic ruminants in the field, because vultures consume hunting residues more frequently and because malnutrition may induce mobilization of lead stores. Materials and Methods: An adult female griffon vulture (Gyps fulvus) found in Freixo-de-Espada-a-Cinta, Portugal, showing extreme weakness, anorexia, depression and green-stained faeces, died 24 h after admission. A blood sample was taken and, during necropsy examination, liver and kidney were also collected for histopathological analysis and lead detection by inductively coupled plasma mass spectrometry. Results: Necropsy examination revealed crop impaction, gall bladder and stomach distension and right lung aspiration pneumonia. Nine lead bullets were found in the stomach. Histopathology revealed hepatocellular cytoplasmic haemosiderin accumulation. Blood, liver and kidney had lead concentrations of 1384.4 mg/dl ww, 308.6 mg/g dw and 34.6 mg/g dw, respectively. Conclusions: The low gastric pH of raptors promotes the rapid dissolution and subsequent absorption of lead. Acute lead poisoning is one of the most important causes of mortality in raptors and, since the conservation status of this species in Portugal is near threatened, effective measures are needed to prevent it.
Figure S5. FACS gating strategy to analyze white blood cell population in WT and Fanca-deficient ... more Figure S5. FACS gating strategy to analyze white blood cell population in WT and Fanca-deficient mice.
Figure S2. Additional data on gefitinib and afatinib in vivo mouse xenograft experiments. Weight ... more Figure S2. Additional data on gefitinib and afatinib in vivo mouse xenograft experiments. Weight control.
Figure S6. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient ... more Figure S6. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient mice.
Purpose:Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposi... more Purpose:Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia.Experimental Design:We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety.Results:Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefi...
Figure S7. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient ... more Figure S7. Additional data on gefitinib and afatinib toxicity analysis in WT and Fanca-deficient mice.
Figure S8. Additional data on genotoxicity in blood samples from WT or Fanca-deficient mice, by g... more Figure S8. Additional data on genotoxicity in blood samples from WT or Fanca-deficient mice, by gefitinib and afatinib treatment.
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