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1.
Theranostics ; 11(16): 7671-7684, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335957

RESUMO

Snail1 is a transcriptional factor required for epithelial to mesenchymal transition and activation of cancer-associated fibroblasts (CAF). Apart from that, tumor endothelial cells also express Snail1. Here, we have unraveled the role of Snail1 in this tissue in a tumorigenic context. Methods: We generated transgenic mice with an endothelial-specific and inducible Snail1 depletion. This murine line was crossed with MMTV-PyMT mice that develop mammary gland tumors and the consequence of Snail1 depletion in the endothelium were investigated. We also interfere Snail1 expression in cultured endothelial cells. Results: Specific Snail1 depletion in the endothelium of adult mice does not promote an overt phenotype; however, it delays the formation of mammary gland tumors in MMTV-PyMT mice. These effects are associated to the inability of Snail1-deficient endothelial cells to undergo angiogenesis and to enhance CAF activation in a paracrine manner. Moreover, tumors generated in mice with endothelium-specific Snail1 depletion are less advanced and show a papillary phenotype. Similar changes on onset and tumor morphology are observed by pretreatment of MMTV-PyMT mice with the angiogenic inhibitor Bevacizumab. Human breast papillary carcinomas exhibit a lower angiogenesis and present lower staining of Snail1, both in endothelial and stromal cells, compared with other breast neoplasms. Furthermore, human breast tumors datasets show a strong correlation between Snail1 expression and high angiogenesis. Conclusion: These findings show a novel role for Snail1 in endothelial cell activation and demonstrate that these cells impact not only on angiogenesis, but also on tumor onset and phenotype.


Assuntos
Neoplasias da Mama/genética , Fatores de Transcrição da Família Snail/metabolismo , Animais , Neoplasias da Mama/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Feminino , Fibroblastos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica/patologia , Fatores de Transcrição da Família Snail/genética , Fatores de Transcrição/metabolismo
2.
Oncogene ; 40(31): 5042-5048, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34140639

RESUMO

Invasive malignant melanoma (MM) is an aggressive tumor with no curative therapy in advanced stages. Chemotherapy has not demonstrated its efficacy in MM and current treatment for tumors carrying the most frequent BRAFV600E mutation consists of BRAF inhibitors alone or in combination with MAPK pathway inhibitors. We previously found that BRAF inhibition prevents activation of the DNA-damage repair (DDR) pathway in colorectal cancer thus potentiating the effect of chemotherapy. We now show that different chemotherapy agents inflict DNA damage in MM cells, which is efficiently repaired, associated with activation of the ATM-dependent DDR machinery. Pharmacologic inhibition of BRAF impairs ATM and DDR activation in these cells, leading to sustained DNA damage. Combination treatments involving DNA-damaging agents and BRAF inhibitors increase tumor cell death in vitro and in vivo, and impede MM regrowth after treatment cessation. We propose to reconsider the use of chemotherapy in combination with BRAF inhibitors for MM treatment.

3.
Dis Esophagus ; 34(7)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-33558874

RESUMO

BACKGROUND: Cardiac-type epithelium has been proposed as the precursor of intestinal metaplasia in the development of Barrett's esophagus. Dysregulation of microRNAs (miRNAs) and their effects on CDX2 expression may contribute to intestinalization of cardiac-type epithelium. The aim of this study was to examine the possible effect of specific miRNAs on the regulation of CDX2 in a human model of Barrett's esophagus. METHODS: Microdissection of cardiac-type glands was performed in biopsy samples from patients who underwent esophagectomy and developed cardiac-type epithelium in the remnant esophagus. OpenArray™ analysis was used to compare the miRNAs profiling of cardiac-type glands with negative or fully positive CDX2 expression. CDX2 was validated as a miR-24 messenger RNA target by the study of CDX2 expression upon transfection of miRNA mimics and inhibitors in esophageal adenocarcinoma cell lines. The CDX2/miR-24 regulation was finally validated by in situ miRNA/CDX2/MUC2 co-expression analysis in cardiac-type mucosa samples of Barrett's esophagus. RESULTS: CDX2 positive glands were characterized by a unique miRNA profile with a significant downregulation of miR-24-3p, miR-30a-5p, miR-133a-3p, miR-520e-3p, miR-548a-1, miR-597-5p, miR-625-3p, miR-638, miR-1255b-1, and miR-1260a, as well as upregulation of miR-590-5p. miRNA-24-3p was identified as potential regulator of CDX2 gene expression in three databases and confirmed in esophageal adenocarcinoma cell lines. Furthermore, miR-24-3p expression showed a negative correlation with the expression of CDX2 in cardiac-type mucosa samples with different stages of mucosal intestinalization. CONCLUSION: These results showed that miRNA-24-3p regulates CDX2 expression, and the downregulation of miRNA-24-3p was associated with the acquisition of the intestinal phenotype in esophageal cardiac-type epithelium.


Assuntos
Adenocarcinoma , Esôfago de Barrett , Neoplasias Esofágicas , MicroRNAs , Adenocarcinoma/genética , Esôfago de Barrett/genética , Fator de Transcrição CDX2/genética , Epitélio , Neoplasias Esofágicas/genética , Humanos , MicroRNAs/genética
4.
Genome Med ; 13(1): 15, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33517887

RESUMO

BACKGROUND: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. METHODS: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. RESULTS: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support. CONCLUSIONS: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

5.
Gut ; 70(2): 319-329, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32409590

RESUMO

OBJECTIVES: To characterise the association between type 2 diabetes mellitus (T2DM) subtypes (new-onset T2DM (NODM) or long-standing T2DM (LSDM)) and pancreatic cancer (PC) risk, to explore the direction of causation through Mendelian randomisation (MR) analysis and to assess the mediation role of body mass index (BMI). DESIGN: Information about T2DM and related factors was collected from 2018 PC cases and 1540 controls from the PanGenEU (European Study into Digestive Illnesses and Genetics) study. A subset of PC cases and controls had glycated haemoglobin, C-peptide and genotype data. Multivariate logistic regression models were applied to derive ORs and 95% CIs. T2DM and PC-related single nucleotide polymorphism (SNP) were used as instrumental variables (IVs) in bidirectional MR analysis to test for two-way causal associations between PC, NODM and LSDM. Indirect and direct effects of the BMI-T2DM-PC association were further explored using mediation analysis. RESULTS: T2DM was associated with an increased PC risk when compared with non-T2DM (OR=2.50; 95% CI: 2.05 to 3.05), the risk being greater for NODM (OR=6.39; 95% CI: 4.18 to 9.78) and insulin users (OR=3.69; 95% CI: 2.80 to 4.86). The causal association between T2DM (57-SNP IV) and PC was not statistically significant (ORLSDM=1.08, 95% CI: 0.86 to 1.29, ORNODM=1.06, 95% CI: 0.95 to 1.17). In contrast, there was a causal association between PC (40-SNP IV) and NODM (OR=2.85; 95% CI: 2.04 to 3.98), although genetic pleiotropy was present (MR-Egger: p value=0.03). Potential mediating effects of BMI (125-SNPs as IV), particularly in terms of weight loss, were evidenced on the NODM-PC association (indirect effect for BMI in previous years=0.55). CONCLUSION: Findings of this study do not support a causal effect of LSDM on PC, but suggest that PC causes NODM. The interplay between obesity, PC and T2DM is complex.

6.
J Pathol ; 253(2): 174-185, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33079429

RESUMO

Cystic neoplasms of the pancreas are an increasingly important public health problem. The majority of these lesions are benign but some progress to invasive pancreatic ductal adenocarcinoma (PDAC). There is a dearth of mouse models of these conditions. The orphan nuclear receptor NR5A2 regulates development, differentiation, and inflammation. Germline Nr5a2 heterozygosity sensitizes mice to the oncogenic effects of mutant Kras in the pancreas. Here, we show that - unlike constitutive Nr5a2+/- mice - conditional Nr5a2 heterozygosity in pancreatic epithelial cells, combined with mutant Kras (KPN+/- ), leads to a dramatic replacement of the pancreatic parenchyma with cystic structures and an accelerated development of high-grade PanINs and PDAC. Timed histopathological analyses indicated that in KPN+/- mice PanINs precede the formation of cystic lesions and the latter precede PDAC. A single episode of acute caerulein pancreatitis is sufficient to accelerate the development of cystic lesions in KPN+/- mice. Epithelial cells of cystic lesions of KPN+/- mice express MUC1, MUC5AC, and MUC6, but lack expression of MUC2, CDX2, and acinar markers, indicative of a pancreato-biliary/gastric phenotype. In accordance with this, in human samples we found a non-significantly decreased expression of NR5A2 in mucinous tumours, compared with conventional PDAC. These results highlight that the effects of loss of one Nr5a2 allele are time- and cell context-dependent. KPN+/- mice represent a new model to study the formation of cystic pancreatic lesions and their relationship with PanINs and classical PDAC. Our findings suggest that pancreatitis could also contribute to acceleration of cystic tumour progression in patients. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Carcinoma Ductal Pancreático/genética , Progressão da Doença , Células Epiteliais/patologia , Feminino , Heterozigoto , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Cisto Pancreático/patologia , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores Citoplasmáticos e Nucleares/genética
7.
Sci Rep ; 10(1): 18344, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110094

RESUMO

Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1-3 and Atypical Flat Lesions-AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.


Assuntos
Adenocarcinoma/cirurgia , Ductos Pancreáticos/cirurgia , Neoplasias Pancreáticas/cirurgia , Lesões Pré-Cancerosas/prevenção & controle , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Adenocarcinoma/patologia , Idoso de 80 Anos ou mais , Animais , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Ligadura/métodos , Camundongos , Pâncreas/patologia , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/patologia , Análise Serial de Tecidos
8.
Environ Res ; 190: 109781, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32791343

RESUMO

INTRODUCTION: Reasons why pancreatic ductal adenocarcinoma (PDAC) continues to have poor survival are only partly known. No previous studies have analyzed the combined influence of KRAS mutations, persistent organic pollutants (POPs), and trace elements upon survival in PDAC or in any other human cancer. OBJECTIVE: To analyze the individual and combined influence of KRAS mutations, POPs, and trace elements upon survival from PDAC. METHODS: Incident cases of PDAC (n = 185) were prospectively identified in five hospitals in Eastern Spain in 1992-1995 and interviewed face-to-face during hospital admission. KRAS mutational status was determined from tumour tissue through polymerase chain reaction and artificial restriction fragment length polymorphism. Blood and toenail samples were obtained before treatment. Serum concentrations of POPs were analyzed by high-resolution gas chromatography with electron-capture detection. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Multivariable Cox proportional hazards regression was used to assess prognostic associations. RESULTS: Patients with a KRAS mutated tumor had a 70% higher risk of early death than patients with a KRAS wild-type PDAC (hazard ratio [HR] = 1.7, p = 0.026), adjusting for age, sex, and tumor stage. KRAS mutational status was only modestly and not statistically significantly associated with survival when further adjusting by treatment or by treatment intention. The beneficial effects of treatment remained unaltered when KRAS mutational status was taken into account, and treatment did not appear to be less effective in the subgroup of patients with a KRAS mutated tumor. POPs did not materially influence survival: the adjusted HR of the highest POP tertiles was near unity for all POPs. When considering the joint effect on survival of POPs and KRAS, patients with KRAS mutated tumors had modest and nonsignificant HRs (most HRs around 1.3 to 1.4). Higher concentrations of lead, cadmium, arsenic, vanadium, and aluminium were associated with better survival. When KRAS status, POPs, and trace elements were simultaneously considered along with treatment, only the latter was statistically significantly related to survival. CONCLUSIONS: In this study based on molecular, clinical, and environmental epidemiology, KRAS mutational status, POPs, and trace elements were not adversely related to PDAC survival when treatment was simultaneously considered; only treatment was independently related to survival. The lack of adverse prognostic effects of POPs and metals measured at the time of diagnosis provide scientific and clinical reassurance on the effects of such exposures upon survival of patients with PDAC. The weak association with KRAS mutations contributes to the scant knowledge on the clinical implications of a genetic alteration highly frequent in PDAC.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Oligoelementos , Adenocarcinoma/genética , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Mutação , Neoplasias Pancreáticas/genética , Poluentes Orgânicos Persistentes , Proteínas Proto-Oncogênicas p21(ras)/genética , Espanha
9.
EMBO Rep ; 21(6): e49708, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32270911

RESUMO

The intestinal epithelium is a paradigm of adult tissue in constant regeneration that is supported by intestinal stem cells (ISCs). The mechanisms regulating ISC homeostasis after injury are poorly understood. We previously demonstrated that IκBα, the main regulator of NF-κB, exerts alternative nuclear functions as cytokine sensor in a subset of PRC2-regulated genes. Here, we show that nuclear IκBα is present in the ISC compartment. Mice deficient for IκBα show altered intestinal cell differentiation with persistence of a fetal-like ISC phenotype, associated with aberrant PRC2 activity at specific loci. Moreover, IκBα-deficient intestinal cells produce morphologically aberrant organoids carrying a PRC2-dependent fetal-like transcriptional signature. DSS treatment, which induces acute damage in the colonic epithelium of mice, results in a temporary loss of nuclear P-IκBα and its subsequent accumulation in early CD44-positive regenerating areas. Importantly, IκBα-deficient mice show higher resistance to damage, likely due to the persistent fetal-like ISC phenotype. These results highlight intestinal IκBα as a chromatin sensor of inflammation in the ISC compartment.


Assuntos
Intestinos , Células-Tronco , Animais , Mucosa Intestinal , Camundongos , Inibidor de NF-kappaB alfa/genética , Fenótipo
10.
J Surg Oncol ; 121(7): 1084-1089, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32153051

RESUMO

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate whether the amount of signet ring cells (SRCs) affects clinicopathological characteristics and prognosis of poorly cohesive (PC) gastric tumours. STUDY DESIGN: One hundred seventy-three patients with PC tumours treated at three European centres from 2004 to 2014 were reclassified in three categories: (a) pure SRC cancers (SRC1) (≥90% SRCs); (b) PC carcinoma with SRC component (SRC2) (>10%, <90% SRCs); (c) PC carcinoma not otherwise specified (SRC3) (≤10% SRCs). RESULTS: The percentage of SRCs was inversely related to the pT stage (Spearman's ρ = -0.174, P < .001) and the number of positive nodes coded as a continuous variable (P = .009). Five year cancer-related survival was significantly higher (58%, 95% confidence interval [CI]: 36%-75%) in SRC1 compared with SRC2 (39%, 95% CI: 28%-50%) and SRC3 (38%, 95% CI: 22%-53%), (P = .048). In multivariable analysis, the impact of PC categories on cancer-related survival was significant when controlling for sex, age, pT, pN, and curativity (hazard ratio [HR] of sSRC2 vs SRC1 = 2.08, 95% CI: 1.01-4.29, P = .046; HR of SRC3 vs SRC1 = 2.38, 95% CI: 1.05-5.41, P = .039). CONCLUSION: The percentage of SRCs was inversely related to tumour aggressiveness, with long-term survival significantly higher in SRC1 compared with SRC2 and SRC3 tumours.


Assuntos
Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células em Anel de Sinete/mortalidade , Adesão Celular/fisiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade
11.
Rev. esp. patol ; 53(1): 3-9, ene.-mar. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-195570

RESUMO

Existe una evidente preocupación a nivel mundial por la falta de popularidad de la especialidad de Anatomía Patológica entre los estudiantes de medicina y por las altas tasas de abandono durante la residencia. En España la situación es similar, con una tasa de deserción estimada superior al 20% cada año. En el presente estudio, se propone analizar transversalmente los factores relacionados con la motivación, formación docente y satisfacción respecto al periodo de formación, mediante una encuesta dirigida a residentes de 3.er y 4.o año de formación y adjuntos en sus 3 primeros años como especialistas. Obtuvimos un total de 155 participantes de diferentes comunidades autónomas. Según nuestros resultados, la Anatomía Patológica en España es una especialidad con altos niveles de satisfacción entre quienes la eligen. La sensación de satisfacción con la especialidad se correlacionó significativamente con dos factores: el conocimiento previo que se tenía sobre ella en el momento de elegirla y la calidad de la formación docente recibida. Detectamos cierta heterogeneidad en los centros de formación, y los puntos más débiles que necesitan ser mejorados son la formación en la realización de técnicas moleculares, en la metodología para la investigación y en la punción-aspiración con aguja fina. Mejorar la calidad de la formación recibida es factible y atañe a todos aquellos especialistas que desempeñan funciones docentes en hospitales acreditados para la formación de residentes


The unpopularity of Pathology among medical students is of concern worldwide, as is the high drop-out rate during the speciality training programme. Spain is no exception, with an estimated annual drop-out rate greater than 20%. In the present study, we aimed to analyse factors related to motivation, teaching and satisfaction with post-graduate training. Postgraduates in their 3rd and 4th year of speciality training programmes and pathologists during their first three years as specialists were asked to fill in a questionnaire; 155 participants from different parts of Spain took part in the study. Our results revealed a high level of satisfaction among those who had chosen pathology as their specialty and that their satisfaction correlated significantly with two factors: a previous knowledge of the speciality when choosing it and the quality of the training received. We detected certain differences amongst different training centres. The weakest points and thus those that need to be improved were training in molecular techniques, research methods and fine needle aspiration. Improving speciality training is certainly possible and should be the concern of all those who are responsible for postgraduate education in teaching hospitals


Assuntos
Humanos , Patologia/educação , Internato e Residência , Inquéritos e Questionários , Espanha
12.
Cancer Epidemiol Biomarkers Prev ; 29(5): 1009-1018, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32051190

RESUMO

BACKGROUND: Despite smoking being a well-established risk factor for pancreatic cancer, there is a need to further characterize pancreatic cancer risk according to lifespan smoking patterns and other smoking features, such as tobacco type. Our aim was to deeply investigate them within a large European case-control study. METHODS: Tobacco smoking habits and other relevant information were obtained from 2,009 cases and 1,532 controls recruited in the PanGenEU study using standardized tools. Multivariate logistic regression analysis was performed to evaluate pancreatic cancer risk by smoking characteristics and interactions with other pancreatic cancer risk factors. Fractional polynomials and restricted cubic splines were used to test for nonlinearity of the dose-response relationships and to analyze their shape. RESULTS: Relative to never-smokers, current smokers [OR = 1.72; 95% confidence interval (95% CI), 1.39-2.12], those inhaling into the throat (OR = 1.48; 95% CI, 1.11-1.99) or chest (OR = 1.33; 95% CI, 1.12-1.58), and those using nonfiltered cigarettes (OR = 1.69; 95% CI, 1.10-2.61), were all at an increased pancreatic cancer risk. Pancreatic cancer risk was highest in current black tobacco smokers (OR = 2.09; 95% CI, 1.31-3.41), followed by blond tobacco smokers (OR = 1.43; 95% CI, 1.01-2.04). Childhood exposure to tobacco smoke relative to parental smoking was also associated with increased pancreatic cancer risk (OR = 1.24; 95% CI, 1.03-1.49). Dose-response relationships for smoking duration, intensity, cumulative dose, and smoking cessation were nonlinear and showed different shapes by tobacco type. Effect modification by family history of pancreatic cancer and diabetes was likely. CONCLUSIONS: This study reveals differences in pancreatic cancer risk by tobacco type and other habit characteristics, as well as nonlinear risk associations. IMPACT: This characterization of smoking-related pancreatic cancer risk profiles may help in defining pancreatic cancer high-risk populations.

13.
Rev Esp Patol ; 53(1): 3-9, 2020.
Artigo em Espanhol | MEDLINE | ID: mdl-31932007

RESUMO

The unpopularity of Pathology among medical students is of concern worldwide, as is the high drop-out rate during the speciality training programme. Spain is no exception, with an estimated annual drop-out rate greater than 20%. In the present study, we aimed to analyse factors related to motivation, teaching and satisfaction with post-graduate training. Postgraduates in their 3rd and 4th year of speciality training programmes and pathologists during their first three years as specialists were asked to fill in a questionnaire; 155 participants from different parts of Spain took part in the study. Our results revealed a high level of satisfaction among those who had chosen pathology as their specialty and that their satisfaction correlated significantly with two factors: a previous knowledge of the speciality when choosing it and the quality of the training received. We detected certain differences amongst different training centres. The weakest points and thus those that need to be improved were training in molecular techniques, research methods and fine needle aspiration. Improving speciality training is certainly possible and should be the concern of all those who are responsible for postgraduate education in teaching hospitals.


Assuntos
Escolha da Profissão , Internato e Residência , Motivação , Patologistas/psicologia , Patologia/educação , Adulto , Autopsia/estatística & dados numéricos , Biópsia/estatística & dados numéricos , Estudos Transversais , Feminino , Humanos , Internato e Residência/estatística & dados numéricos , Masculino , Biologia Molecular/métodos , Biologia Molecular/estatística & dados numéricos , Patologistas/estatística & dados numéricos , Patologia Molecular/educação , Satisfação Pessoal , Pesquisa/educação , Faculdades de Medicina/estatística & dados numéricos , Espanha , Estudantes de Medicina/psicologia , Estudantes de Medicina/estatística & dados numéricos , Inquéritos e Questionários/estatística & dados numéricos
14.
Mol Cancer Ther ; 18(11): 2135-2145, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31484705

RESUMO

Despite the clinical benefit of trastuzumab, eventually all HER2-amplified gastric cancer tumors develop drug resistance. We aimed to identify molecular mechanisms of acquired resistance to trastuzumab in gastric cancer by using well-established cell line-based preclinical models, as well as samples from patients with HER2-positive gastric cancer treated with trastuzumab. We studied trastuzumab resistance in NCI-N87 and OE19, two gastric cancer cell lines that overexpress HER2 receptor and are trastuzumab sensitive. Differences at protein, DNA, and RNA levels between the parental and resistant cells were characterized and functional studies were performed. Paired pre- and post-trastuzumab blood and tissue samples from patients with gastric cancer treated with trastuzumab were analyzed. We found that resistant cells were associated with increased activation of MAPK/ERK and PI3K/mTOR pathways driven by SRC activation. Upstream, resistant cells showed increased coexpression of multiple HER-family ligands that allowed for compensatory activation of alternative HER receptors upon HER2 blockade. Simultaneous inhibition of EGFR, HER2, and HER3 by the novel antibody mixture, Pan-HER, effectively reverted trastuzumab resistance in vitro and in vivo Similarly, an increase in HER-family ligands was observed in serum and tumor from patients with gastric cancer after trastuzumab therapy. We propose that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastuzumab therapy. Resistance is reverted by simultaneous inhibition of EGFR, HER2, and HER3, thereby revealing a potential therapeutic strategy to overcome trastuzumab resistance in patients with gastric cancer.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Receptores ErbB/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para Cima , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Serina-Treonina Quinases TOR/metabolismo , Trastuzumab
15.
Mol Cell ; 75(4): 669-682.e5, 2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31302002

RESUMO

Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKα activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKα or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKα kinases in the DDR and reveal a combination strategy for cancer treatment.


Assuntos
Dano ao DNA , Resistencia a Medicamentos Antineoplásicos , Fluoruracila/farmacologia , Quinase I-kappa B/metabolismo , Irinotecano/farmacologia , Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias , Neoplasias , Animais , Reparo do DNA/efeitos dos fármacos , Reparo do DNA/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Células HCT116 , Humanos , Quinase I-kappa B/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Camundongos , Camundongos Nus , Metástase Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Telômero/genética , Telômero/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Cancer ; 144(7): 1540-1549, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30229903

RESUMO

Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.


Assuntos
Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Estudos de Casos e Controles , Biologia Computacional/métodos , Europa (Continente)/epidemiologia , Feminino , Ontologia Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Masculino , Razão de Chances , Fatores de Risco
17.
Environ Res ; 169: 417-433, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30529143

RESUMO

BACKGROUND: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases. OBJECTIVES: First, to summarize the main design features of a prospective case-control study -nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort- on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles. METHODS: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models. RESULTS: There were differences among countries in subjects' characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p'-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB. CONCLUSIONS: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects' characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.


Assuntos
Exposição Ambiental/estatística & dados numéricos , Poluentes Ambientais , Neoplasias Pancreáticas/epidemiologia , Estudos de Casos e Controles , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Plasma , Bifenilos Policlorados , Estudos Prospectivos , Espectrometria de Massas em Tandem
18.
Oncotarget ; 9(68): 32984-32996, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-30250644

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is the most frequent type of pancreatic cancer and one of the deadliest diseases overall. New biomarkers are urgently needed to allow early diagnosis, one of the only factors that currently improves prognosis. Here we analyzed whether the detection of circulating galectin-1 (Gal-1), a soluble carbohydrate-binding protein overexpressed in PDA tissue samples, can be used as a biomarker for PDA. Gal-1 levels were determined by ELISA in plasma from healthy controls and patients diagnosed with PDA, using three independent cohorts. Patients with chronic pancreatitis (CP) were also included in the study to analyze the potential of Gal-1 to discriminate between cancer and inflammatory process. Plasma Gal-1 levels were significantly increased in patients with PDA as compared to controls in all three cohorts. Gal-1 sensitivity and specificity values were similar to that of the CA19-9 biomarker (the only FDA-approved blood test biomarker for PDA), and the combination of Gal-1 and CA19-9 significantly improved their individual discriminatory powers. Moreover, high levels of Gal-1 were associated with lower survival in patients with non-resected tumors. Collectively, our data indicate a strong potential of using circulating Gal-1 levels as a biomarker for detection and prognostics of patients with PDA.

19.
Oncoimmunology ; 7(9): e1477460, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30228947

RESUMO

Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.

20.
Ann Surg ; 268(5): 731-739, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30138162

RESUMO

OBJECTIVE: To compare perioperative outcomes of pancreatoduodenectomy (PD) performed through the laparoscopic route or by open surgery. SUMMARY BACKGROUND DATA: Laparoscopic PD is being progressively performed in selected patients. METHODS: An open-label single-center RCT was conducted between February 2013 and September 2017. The primary endpoint was the length of hospital stay (LOS). Secondary endpoints were operative time, transfusion requirements, specific pancreatic complications (pancreatic or biliary fistula, pancreatic hemorrhage, and delayed gastric emptying), Clavien-Dindo grade ≥ 3 complications, comprehensive complication index (CCI) score, poor quality outcome (PQO), and the quality of pathologic resection. Analyses were performed on an intention to treat basis. RESULTS: Of 86 patients assessed for PD, 66 were randomized (34 laparoscopic approach, 32 open surgery). Conversion to an open procedure was needed in 8 (23.5%) patients. Laparoscopic versus open PD was associated with a significantly shorter LOS (median 13.5 vs. 17 d; P = 0.024) and longer median operative time (486 vs. 365 min; P = 0.0001). The laparoscopic approach was associated with significantly better outcomes regarding Clavien-Dindo grade ≥ 3 complications (5 vs. 11 patients; P = 0.04), CCI score (20.6 vs. 29.6; P = 0.038), and PQO (10 vs. 14 patients; P = 0.041). No significant differences in transfusion requirements, pancreas-specific complications, the number of lymph nodes retrieved, and resection margins between the two approaches were found. CONCLUSIONS: Laparoscopic PD versus open surgery is associated with a shorter LOS and a more favorable postoperative course while maintaining oncological standards of a curative-intent surgical resection. TRIAL REGISTRY: ISRCTN93168938.


Assuntos
Laparoscopia/métodos , Pancreaticoduodenectomia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Feminino , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia , Complicações Pós-Operatórias/classificação , Estudos Prospectivos , Qualidade de Vida , Espanha , Resultado do Tratamento
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