RP5-1120P11.3 promotes hepatocellular carcinoma development via the miR-196b-5p-WIPF2 axis.

Hepatocellular carcinoma (HCC) remains a huge threat to human health even though the diagnosis and treatment strategies have improved rapidly in the past few decades. Increasing evidence has illustrated the critical role noncoding RNA and their regulatory network play in the pathology of HCC. Here, we identified a novel long noncoding RNA, RP5-1120P11.3, that is ectopically expressed in HCC. Further characterization of RP5-1120P11.3 revealed that it promoted proliferation and invasion of HCC cells while inhibiting apoptosis. Importantly, our data revealed that miR-196b-5p interacted with and was regulated by RP5-1120P11.3 via a sponging mechanism. Inhibition of miR-196b-5p attenuated the phenotypes resulting from RP5-1120P11.3 inhibition. Moreover, our data showed that miR-196b-5p inhibited the expression of WIPF2 in HCC, illustrating a regulatory axis of RP5-1120P11.3-miR-196b-5p-WIPF2 that facilitated the progression of HCC. In addition, our data showed that RP5-1120P11.3 contributed to xenograft generation in vivo by regulating miR-196b-5p and WIPF2. These findings suggested that the RP5-1120P11.3-miR-196b-5p-WIPF2 axis is a potential target for treatment of HCC.

Liver antioxidant and aerobic status improves after metformin and melatonin administration in a rat model of high-fat diet and mammary carcinogenesis.

Oxidative stress is involved in the development of various cancers. In the present study, the effect of long-term administration of peroral antidiabetic metformin and pineal hormone melatonin on liver antioxidant and aerobic status in female Sprague-Dawley rats carrying mammary tumors induced by N-methyl-N-nitrosourea was evaluated. Both substances were administered in a preventive and curative manner (12 days before and 16 weeks after the carcinogen application). Carcinogen administration induced oxidative stress: the level of thiobarbituric acid reactive substances (TBARS) considered as a marker of reactive oxygen species (ROS) generation in liver increased as well as the level of oxidatively modified protein content (OMP; aldehyde and ketone derivates). Metformin administration restored succinate dehydrogenase and lactate dehydrogenase activity and associated ROS production and OMP content to the level of intact rats, with predominant activation of superoxide dismutase (SOD) and glutathione reductase (GR). Melatonin alone and in combination with metformin also decreased TBARS content. OMP content decreased in all groups receiving chemoprevention. The rise in total antioxidant capacity after melatonin and particularly metformin and melatonin combination might result from the initiation of anaerobic metabolism and increasing SOD, GR, and glutathione peroxidase activity. Long-term administration of metformin and melatonin exerts antioxidant properties in liver, especially in combination.

The oral cavity microbiota: between health, oral disease, and cancers of the aerodigestive tract.

Many studies show that the human microbiome plays a critical role in the chronic pathologies of obesity, inflammatory bowel diseases, and diabetes. More recently, the interaction between cancer and the microbiome has been highlighted. Most studies have focused on the gut microbiota because it represents the most extensive bacterial community, and the body of evidence correlating it with gut syndromes is increasing. However, in the strict sense, the gastrointestinal (GI) tract begins in the oral cavity, and special attention should be paid to the specific flora of this cavity. This study reviewed the current knowledge about the various microbial ecosystems of the upper part of the GI tract and discussed their potential link to carcinogenesis. The overall composition of the microbial communities, as well as the presence or absence of "key species", in relation to carcinogenesis is addressed. Alterations in the oral microbiota can potentially be used to predict the risk of cancer. Molecular advances and the further monitoring of the microbiota will increase our understanding of the role of the microbiota in carcinogenesis and open new perspectives for future therapeutic and prophylactic modalities.

[Update on molecular classifications and new histological classification of bladder cancer]. / Mise au point sur les classifications moléculaires et la nouvelle classification histologique du cancer de la vessie.

OBJECTIVE: Comment the new WHO histological classification of tumors of the urinary system and male genital organs 2016 and expose the state of art about urothelial carcinogenesis and molecular modifications of bladder cancer, with the consequences on the treatments. MATERIAL AND METHOD: A systematic review of the literature search was performed from the data base PubMed, focused on the following keywords: "bladder cancer", "molecular", "subtypes". RESULTS: The new WHO histological classification of tumors of the urinary system 2016 confirm the importance of pathology in determining the care of patients, especially the grade, the histological type and the infiltration, while taking into account the difficulties. In 2014, the Cancer Genome Atlas reported genetic modifications of bladder cancer. Recently, several studies explored molecular anomalies of bladder cancer and elaborated molecular classifications, analyzing their predictive value. According to the groups, different molecular subtype had been defined: Urobasal A, Urobasal B, genomically unstable, infiltrated, squamous cell carcinoma-like and p53-like luminal bladder cancers. This latter subgroup seems to be chemoresistant. CONCLUSIONS: The molecular biology and classifications allow a better understanding of bladder cancer and could complete in near future histological data to improve patient management.

[Carcinogenic pathways and natural history of upper tract urothelial carcinomas: state-of-the-art review for the yearly scientific report of the French National Association of Urology]. / Voies de carcinogenèse et histoire naturelle des tumeurs de la voie excrétrice supérieure: état de l'art pour le rapport annuel de l'Association française d'urologie.

OBJECTIVE: To describe natural history and carcinogenesis of upper tract urothelial carcinoma (UTUC). METHODS: A systematic review of the scientific literature was performed in the Medline database (Pubmed) using different associations of the following keywords: upper tract urothelial carcinoma; clonality; carcinogenesis; mutation; chromosomal instability; Lynch syndrome; genetic polymorphism. RESULTS: Local development of UTUC is characterized by a highly prevalent multifocality that might be explained by the overlap of "field change" and "intraluminal seeding and implantation" theories. UTUC and bladder tumors share common carcinogenesis mechanisms such as mutations of FGFR3 and TP53 defining two distinct pathways of pathogenesis. Epigenetic alterations corresponding to the hypermethylation of different promoters regulating genes expression and chromosomal instability such as chromosome 9 deletions are also involved in UTUC carcinogenesis. Furthermore, specific genetic risk factors fro UTUC including Lynch syndrome and different polymorphisms might explain an individual susceptibility for developing these tumors. CONCLUSIONS: Significant advances have been done in the field of basic research in UTUCs in recent years and have been of particular interest to provide better descriptions of their natural history. Despite these important findings however, some carcinogenic mechanisms remains not elucidated and unknown in the field of UTUC so far.

[Cellular and molecular mechanisms of carcinogenic side effects and resistance to BRAF inhibitors in metastatic melanoma with BRAFV600 mutation: state of the knowledge]. / Effets secondaires carcinogènes et résistances aux thérapies ciblées anti-BRAF.

Cutaneous melanoma is a malignant tumor with a high metastatic potential. If an early treatment is associated with a favorable outcome, the prognosis of metastatic melanoma remains poor. Advances in molecular characterization of cancers, notably the discovery of BRAF gene mutations in metastatic melanoma, allowed to the recent development of targeted therapies against mutated BRAF protein. Despite high tumor response rates observed in clinical trials, these new drugs are associated with frequent secondary tumor resistance occurrence and paradoxical carcinogenic side effects. The cellular and molecular mechanisms of these carcinogenic side effects and secondary resistance are not yet fully elucidated and are actually intensely studied. This review of the literature focus on the mechanisms of these carcinogenic side effects and on the tumor resistance associated with anti-BRAF targeted therapies.

[Bronchial carcinoma and tobacco: An update]. / Cancer bronchique et tabac : mise à jour.

Lung cancer remains the most lethal cancer. The most common cause is smoking, which is also preventable, unlike the causes of other types of cancer. A genetic characteristic has emerged over several years, which explains particular profiles of smokers, or highly dependent smokers. The emergence of new therapies for the treatment of lung cancer, and the impact of tobacco on reducing the effectiveness of these therapies must challenge practitioners to obtain a complete cessation of smoking regardless of the stage of the disease.

Doença hepática gordurosa não-alcoólica e neoplasias extra-hepáticas: uma revisão narrativa / Non-alcoholic fatty liver disease and extra-hepatic cancer: a narrative review

ABSTRACT Background: Recently, significant associations between non-alcoholic fatty liver disease (NAFLD) and extra-hepatic cancer have been reported. Objective: To carry out a comprehensive review of the current evidence in the literature on the association between NAFLD and extra-hepatic cancer. Methods: A narrative literature review was performed through an online search for the MeSH terms "fatty liver" and "cancer" in MEDLINE (via PubMed) and LILACS (via BVS). Original studies that described the impact of NAFLD on different types of extra-hepatic malignancies were included. Results: After careful analysis, nine prospective cohort studies, one retrospective cohort study, three case-control studies, and three cross-sectional studies were selected. Conclusion: There is consistent evidence on the association between NAFLD and extra-hepatic carcinogenesis, especially in relation to colorectal, gastric, pancreatic, breast, prostate, and bladder cancers.

RESUMO Contexto: Recentemente, associações significativas entre a doença hepática gordurosna não-alcoólica (DHGNA) e neoplasias extra-hepáticas têm sido descritas. Objetivo: Realizar uma revisão abrangente acerca das evidências atuais na literatura sobre a associação entre DHGNA e neoplasias extra-hepáticas. Métodos: Uma revisão narrativa de literatura foi realizada através da busca on-line pelos descritores "fígado gorduroso" e "câncer" em MEDLINE (através do PubMed) e LILACS (através da BVS). Estudos originais que descreveram o impacto da DHGNA em diferentes tipos de neoplasias malignas extra-hepáticas foram incluídos. Resultados: Após análise criteriosa, nove estudos prospectivos de coorte, um coorte histórica, três estudos de caso-controle, e três estudos transversais foram selecionados. Conclusão: Existem evidências consistentes a respeito da associação entre DHGNA e a carcinogênese extra-hepática, especialmente em relação aos cânceres de cólon e reto, estômago, pâncreas, mama, próstata e bexiga.

[Gut microbiota: What impact on colorectal carcinogenesis and treatment?] / Le microbiote intestinal : quels impacts sur la carcinogenèse et le traitement du cancer colorectal ?

The gut microbiota, composed of 1014 microorganisms, is now considered as a "hidden organ", regarding to its digestive, metabolic and immune functions, which are helpful to its host. For the last 15 years, advances in molecular biology have highlighted the association of gut microbiota dysbiosis with several diseases, including colorectal cancer. An increased abundance of some bacteria (including Fusobacterium nucleatum, Bacteroides fragilis, Escherichia coli) is associated with cancer, whereas others seem to be protective (Faecalibacterium prausnitzii). Several mechanisms, which are species-specific, are involved in colorectal carcinogenesis. Most of the time, bacterial toxins are involved in pro-inflammatory processes and in activation of angiogenesis and cellular proliferation pathways. The identification of these bacteria leads to envisage the gut microbiota as potential screening tool for colorectal cancer. Recent studies showed a relation between the gut microbiota and the efficacy and toxicity of chemotherapies (oxaliplatin, irinotecan) and immunotherapies (including ipilimumab). Therapeutic approaches targeting the gut microbiota are now available (probiotics, fecal microbiota transplantation…). New therapeutic strategy combining both chemotherapy and/or immunotherapy with an adjuvant treatment targeting the gut microbiota can now be developed in order to improve treatment response and tolerance.

Modelos pré-clínicos de câncer hepático / Preclinical models of liver câncer

ABSTRACT Background: This manuscript provides an overview of liver carcinogenesis in murine models of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Objective: A review through MEDLINE and EMBASE was performed to assess articles until August 2022. Methods: Search was conducted of the entire electronic databases and the keywords used was HCC, CCA, carcinogenesis, animal models and liver. Articles exclusion was based on the lack of close relation to the subject. Carcinogenesis models of HCC include HCC induced by senescence in transgenic animals, HCC diet-induced, HCC induced by chemotoxicagents, xenograft, oncogenes, and HCC in transgenic animals inoculated with B and C virus. The models of CCA include the use of dimethylnitrosamine (DMN), diethylnitrosamine (DEN), thioacetamide (TAA), and carbon tetrachloride (CCl4). CCA murine models may also be induced by: CCA cells, genetic manipulation, Smad4, PTEN and p53 knockout, xenograft, and DEN-left median bile duct ligation. Results: In this review, we described different murine models of carcinogenesis that reproduce the key points for HCC and CCA genesis allowing a better understanding of its genetic, physiopathological, and environmental abnormalities. Conclusion: Each model has its advantages, disadvantages, similarities, and differences with the corresponding human disease and should be chosen according to the specificity of the study. Ultimately, those models can also be used for testing new anticancer therapeutic approaches.

RESUMO Contexto: Este manuscrito fornece uma visão geral da carcinogênese hepática em modelos murinos de carcinoma hepatocelular (CHC) e colangiocarcinoma (CCA). Objetivo: Realizar uma revisão de artigos científicos até agosto de 2022 utilizando as bases de dados MEDLINE e EMBASE. Métodos: A busca foi realizada em todas as bases de dados eletrônicas e as palavras-chave usadas foram CHC, CCA, carcinogenesis, modelos animais e fígado. A exclusão dos artigos baseou-se na falta de estreita relação com o assunto. Os modelos de carcinogênese do CHC incluíram: CHC induzido por senescência em animais transgênicos, CHC induzido por dieta, CHC induzido por agentes quimiotóxicos, xenoenxerto, oncogenes e CHC em animais transgênicos inoculados com vírus B e C. Os modelos de CCA incluíram: o uso de dimetilnitrosamina (DMN), dietilnitrosamina (DEN), tioacetamida (TAA) e tetracloreto de carbono (CCl4). Os modelos murinos de CCA induzidos por incluir: células de CCA, manipulação genética, animais nocaute para Smad4, PTEN e p53, xenoenxerto e ligadura do ducto biliar mediano esquerdo. Resultados: Nesta revisão, descrevemos diferentes modelos murinos de carcinogênese que reproduzem os pontos-chave para a gênese do CHC e do CCA, permitindo uma melhor compreensão de suas anormalidades genéticas, fisiopatológicas e ambientais. Conclusão: Cada modelo tem suas vantagens, desvantagens, semelhanças e diferenças com a doença humana correspondente e deve ser escolhido de acordo com a especificidade do estudo. Em última análise, esses modelos também podem ser utilizados para testar novas abordagens terapêuticas anticancerígenas.

Associação entre lesões de hpv e os carcinomas genitais e da cavidade oral: uma revisão narrativa / Association between hpv lesions and genital and oral cavity carcinomas: a narrative review / Asociación entre lesiones por vph y carcinomas genitales y de cavidad oral: una revisión narrativa

Os Papilomavírus Humano (HPVs) são membros da família Papilomaviridae. O vírus destaca-se pelo seu tropismo por células epiteliais, infectando exclusivamente mucosa epitelial e cutânea. O HPV-16 e HPV-18 são subtipos classificados como de alto risco, conhecidos por sua oncogenicidade, fortemente associados aos cânceres anais, genitais e de orofaringe. Lesões por HPV representam um grande grupo de doenças sexualmente transmissíveis. O objetivo do presente estudo consistiu em realizar uma revisão narrativa sobre a associação entre lesões por HPV e carcinomas genitais e da cavidade oral. Realizamos uma busca na base de dados eletrônicos PubMed, Lilacs, Scielo, Medline e Google Scholar, sendo utilizados artigos publicados entre os anos de 2017-2021, ao fim, foram selecionados 36 artigos. Grande parte das infecções por HPV são subclínicas, ou seja, não apresentam sintomatologia importante e tendem a desaparecer espontaneamente. Desta forma, faz-se necessário ter conhecimento a respeito dos aspectos clínicos e comportamentais dessas lesões, possibilitando o diagnóstico precoce, evitando a evolução para estágios mais invasivos, favorecendo um tratamento efetivo e melhor prognóstico.

Human Papillomaviruses (HPVs) are members of the Papilomaviridae family. The virus stands out for its tropism for epithelial cells, exclusively infecting epithelial and cutaneous mucosa. O HPV-16 and HPV-18 are subtypes classified as high risk, known for their oncogenicity, strongly associated with anal, genital and oropharyngeal cancers. HPV lesions represent a large group of sexually transmitted diseases. The objective of this study was to carry out a narrative review on the association between HPV lesions and genital and oral cavity carcinomas. We carried out a search in the electronic databases PubMed, Lilacs, Scielo, Medline and Google Scholar, using articles published between the years of 2017-2021, at the end, foram selected 36 articles. A large part of HPV infections are subclinical, or seem to, do not present significant symptoms and tend to disappear spontaneously. In this way, it is necessary to be aware of the two clinical and behavioral aspects of these injuries, enabling early diagnosis, avoiding evolution to more invasive stages, favoring effective treatment and better prognosis.

Los virus del papiloma humano (VPH) son miembros de la familia Papillomaviridae. El virus destaca por su tropismo por las células epiteliales, infectando exclusivamente mucosas epiteliales y cutáneas. El VPH-16 y el VPH-18 son subtipos clasificados como de alto riesgo, conocidos por su oncogenicidad, fuertemente asociados con cánceres anales, genitales y orofaríngeos. Las lesiones por VPH representan un gran grupo de enfermedades de transmisión sexual. El objetivo del presente estudio fue realizar una revisión narrativa sobre la asociación entre las lesiones por VPH y los carcinomas genitales y de cavidad oral. Realizamos una búsqueda en la base de datos electrónica PubMed, Lilacs, Scielo, Medline y Google Scholar, utilizando artículos publicados entre los años 2017-2021, al final se seleccionaron 36 artículos. La mayoría de las infecciones por VPH son subclínicas, es decir, no presentan síntomas importantes y tienden a desaparecer espontáneamente. Por lo tanto, es necesario tener conocimiento sobre los aspectos clínicos y conductuales de estas lesiones, que permitan un diagnóstico precoz, evitando la progresión a estadios más invasivos, favoreciendo un tratamiento eficaz y un mejor pronóstico.

Avaliação do efeito carcinogênico do bromazepam em Drosophila melanogaster / Evaluation of carcinogen bromazepam effect in Drosophila melanogaster

Introdução: embora o câncer seja um dos maiores problemas de saúde pública enfrentados mundialmente, diversas substâncias presentes no meio, como os fármacos, não estão muito bem elucidadas sobre seu possível potencial carcinogênico. Entre eles, estão os benzodiazepínicos, fármacos que possuem crescente aumento do consumo desde o século XX e, principalmente, na segunda década do século XXI, por suas ações ansiolíticas, sedativas e anticonvulsivantes. Objetivo: avaliar o efeito carcinogênico do bromazepam por meio do teste para detecção de tumores epiteliais (ETT) em Drosophila melanogaster. Metodologia: para realização do ETT foram utilizadas duas linhagens mutantes de D. melanogaster: wts (fêmeas) e mwh (machos). As larvas descendentes desse cruzamento foram tratadas isoladamente com cinco concentrações de bromazepam, sendo elas: 0,0375; 0,075; 0,15; 0,30 e 0,60 mM. A Doxorrubicina foi utilizada como controle positivo e a água ultrapura como controle negativo. Após tratamento, coleta e armazenamento, as moscas foram analisadas, identificando-se as frequências tumorais, por região corporal, em cada concentração testada. Resultados: o bromazepam não apresentou efeito carcinogênico em nenhuma das concentrações experimentadas neste estudo, não havendo diferença estatisticamente significativa nas frequências tumorais observadas nos indivíduos tratados com bromazepam quando comparadas à frequência obtida nos indivíduos tratados com o controle negativo. Conclusão: Nas presentes condições experimentais, o bromazepam não apresentou atividade carcinogênica, no entanto, há a necessidade de novos estudos, com diferentes metodologias e diferentes organismos testes, para a maior compreensão da ação do bromazepam no organismo.

Introduction: although cancer is one of the biggest public health problems faced worldwide, several substances present in the environment, such as drugs are not very well understood about its possible carcinogenic potential. Among them are benzodiazepines, drugs that have increased their consumption since the 20th century and, mainly, in the second decade of the 21st century, due to their anxiolytic, sedative and anticonvulsant actions. Objective: Evaluate the carcinogenic effect of bromazepam through the test to detect epithelial tumor clones (ETT) in Drosophila melanogaster. Methodology: to perform the ETT, two mutant strains of D. melanogaster were used: wts (female) and mwh (male). The descending larves of this cross were treated separately with five concentrations of bromazepam, namely: 0.0375; 0.075; 0.15; 0.30 and 0.60 mM. Doxorubicin was used as a positive control and ultrapure water as a negative control. After treatment, collection and storage, the flies were analyzed, identifying the tumor frequencies, by body region, at each concentration tested. Results: bromazepam did not have a carcinogenic effect at any of the concentrations experienced in this study, with no statistically significant difference in tumor frequencies observed in individuals treated with bromazepam when compared to the frequency obtained in individuals treated with the negative control. Conclusion: In the present experimental conditions, bromazepam did not show carcinogenic activity, however, there is a need for further studies with different methodologies and different test organisms to better understand the action of bromazepam in the body.

Endocrine disruptors (EDs) and hormone-dependent cancers: Correlation or causal relationship?

The selective increase in the incidence of hormone-dependent cancers (breast, prostate, testicular) in industrialized countries is associated with the increasing number of endocrine disruptors (EDs) in the environment and raises questions about the role of EDs in mammary carcinogenesis. Answering these questions is difficult because the number of EDs is large and varies with time. Moreover hormonal carcinogenesis is multifactorial and progresses slowly and in stages. This discussion will be limited to breast cancer and three EDs: distilbene, bisphenol A (BPA), and dichlorodiphenyltrichloroethane (DDT). All these three EDs bind estrogen receptors, albeit with widely different affinities. Several complementary approaches have been used: French cancer records, epidemiological studies on cohorts followed over several decades, numerous in vitro experimental studies using cell cultures and in vivo animal studies. These approaches all converge to the same result, strongly suggesting a causal relationship between EDs and precancerous lesions. Except for distilbene, the mechanisms and molecular targets involved are still unclear, which makes it difficult to look for substitute products that are just as efficient, but less toxic.

Exposição a agrotóxicos e desenvolvimento de câncer no contexto da saúde coletiva: o papel da agroecologia como suporte às políticas públicas de prevenção do câncer / Exposure to pesticides and cancer development in the context of public health: the role of agroecology as a support for public cancer prevention policies

RESUMO Atualmente, a agricultura brasileira é caracterizada pelo crescente consumo de agrotóxicos e fertilizantes químicos, inserindo-se no modelo de produção baseado nos fundamentos do agronegócio. As novas técnicas de cultivo baseadas no agronegócio resultaram na expansão das monoculturas sobre os ecossistemas naturais, com o consequente desmatamento, desequilíbrio e perda da biodiversidade; e o aumento da contaminação do solo, da água e do ar pelos agrotóxicos. No que tange à saúde humana, a literatura científica tem demonstrado que a contaminação química decorrente do uso de agrotóxicos na agricultura implica adoecimento dos trabalhadores rurais expostos ocupacionalmente aos agrotóxicos, dos moradores da área rural, além de consumidores de alimentos contendo resíduos de agrotóxicos. Entre os efeitos sobre a saúde humana associados à exposição a agrotóxicos, os mais preocupantes são as intoxicações crônicas, caracterizadas por infertilidade, abortos, malformações congênitas, neurotoxicidade, desregulação hormonal, imunotoxicidade, genotoxicidade e câncer. Sendo assim, neste ensaio, apresenta-se uma revisão narrativa com dados presentes na literatura científica nacional e internacional referentes à associação entre a exposição a agrotóxicos e o desenvolvimento de câncer no contexto da saúde coletiva e o papel da alimentação saudável e da agroecologia como suporte às políticas públicas de prevenção do câncer.

ABSTRACT Currently, Brazilian agriculture is characterized by the growing consumption of pesticides and chemical fertilizers, forming part of the production model based on the fundamentals of agribusiness. The new farming techniques based on agribusiness resulted in the expansion of monocultures over natural ecosystems, with the consequent deforestation, imbalance, and loss of biodiversity; and the increased contamination of soil, water, and air by pesticides. With regard to human health, the scientific literature has shown that chemical contamination resulting from the use of pesticides in agriculture implies the illness of rural workers occupationally exposed to pesticides, of rural residents, in addition to consumers of food containing pesticide residues. Among the effects on human health associated with exposure to pesticides, the most worrying are chronic intoxications, characterized by infertility, abortions, congenital malformations, neurotoxicity, hormonal dysregulation, immunotoxicity, genotoxicity, and cancer. Therefore, in this essay, we will present a narrative review with data from national and international scientific literature regarding the association between exposure to pesticides and the development of cancer in the context of public health and the role of healthy eating and agroecology as a support for public cancer prevention policies.

Chemopreventive agents on a mouse skin carcinogenesis model: an integrative review / Agentes quimiopreventivos em um modelo de carcinogênese de pele em camundongos: uma revisão integrativa / Agentes quimiopreventivos en un modelo de carcinogénesis cutánea en ratón: una revisión integradora

Squamous cell carcinoma (SCC) is a non-melanoma skin cancer, with chronic sun exposure as the main risk factor. Excisional surgery is the most indicated treatment; however, patients can suffer functional, aesthetic, and psychological damage depending on the lesion site. Topical administration of 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-Tetradecanoylphorbol-13- acetate (TPA) induce to the appearance of benign skin tumors in mice, some of which develop into SCC. This protocol has been used to analyze the effects of many chemopreventive agents that may block or inhibit the mechanisms of action of chemical carcinogenesis. We compared the effects of chemopreventive agents in an induced skin carcinogenesis animal model. In the Scopus, PubMed, and EMBASE databases, we searched for manuscripts published between June 16, 2011, and June 16, 2021. We excluded studies conducted in vitro or on transgenic mice; in addition, studies without drug dosage, route of administration, or tumor incidence were excluded. We selected 26 studies and analyzed their main characteristics and the outcomes of tumorigenesis analysis. Most chemopreventive agents have shown excellent potential to inhibit the development of skin tumors. This review also discusses the standardization of studies in animal models to ensure better responses and future randomized clinical trials for cancer treatment and prevention.

O carcinoma espinocelular cutâneo (CEC) é um câncer de pele não melanoma, com a exposição solar crônica como o principal fator de risco. A cirurgia excisional é o tratamento mais indicado; entretanto, os pacientes podem sofrer danos funcionais, estéticos e psicológicos dependendo do local da lesão. A administração tópica de 7,12-dimetilbenz[a]antraceno (DMBA) e 12-O- Tetradecanoilforbol-13-acetato (TPA) induz ao aparecimento de tumores cutâneos benignos em camundongos, alguns dos quais evoluíram para CEC. Este protocolo tem sido utilizado para analisar os efeitos de muitos agentes quimiopreventivos que podem bloquear ou inibir os mecanismos de ação da carcinogênese química. Comparamos os efeitos de agentes quimiopreventivos em um modelo animal que foi induzido à carcinogênese de pele. Nas bases de dados Scopus, PubMed e EMBASE, buscamos manuscritos publicados entre 16 de junho de 2011 e 16 de junho de 2021. Excluímos estudos realizados in vitro ou em camundongos transgênicos; além disso, estudos sem dosagem de drogas, via de administração ou incidência de tumores foram excluídos. Selecionamos 26 estudos e analisamos suas principais características e os resultados da análise da tumorigênese. A maioria dos agentes quimiopreventivos tem demonstrado excelente potencial para inibir o desenvolvimento de tumores cutâneos. Esta revisão também discute a padronização de estudos em modelos animais para garantir melhores respostas e futuros ensaios clínicos randomizados para tratamento e prevenção do câncer.

El carcinoma de células escamosas (CCE) es un cáncer de piel no melanoma, cuyo principal factor de riesgo es la exposición crónica al sol. La cirugía de escisión es el tratamiento más indicado; sin embargo, los pacientes pueden sufrir daños funcionales, estéticos y psicológicos dependiendo de la localización de la lesión. La administración tópica de 7,12-dimetilbenz[a]antraceno (DMBA) y 12-O-Tetradecanoilforbol-13-acetato (TPA) inducen a la aparición de tumores cutáneos benignos en ratones, algunos de los cuales se convierten en CCE. Este protocolo se ha utilizado para analizar los efectos de muchos agentes quimiopreventivos que pueden bloquear o inhibir los mecanismos de acción de la carcinogénesis química. Comparamos los efectos de los agentes quimiopreventivos en un modelo animal de carcinogénesis cutánea inducida. En las bases de datos Scopus, PubMed y EMBASE, se buscaron los manuscritos publicados entre el 16 de junio de 2011 y el 16 de junio de 2021. Se excluyeron los estudios realizados in vitro o en ratones transgénicos; además, se excluyeron los estudios sin dosis de fármacos, vía de administración o incidencia tumoral. Se seleccionaron 26 estudios y se analizaron sus características principales y los resultados del análisis de la tumorigénesis. La mayoría de los agentes quimiopreventivos han mostrado un excelente potencial para inhibir el desarrollo de tumores cutáneos. Esta revisión también analiza la estandarización de los estudios en modelos animales para garantizar mejores respuestas y futuros ensayos clínicos aleatorios para el tratamiento y la prevención del cáncer.

Doença Periodontal e Câncer: Qual a Relação? / Periodontal Disease and Cancer: What is the Relationship?

A Doença Periodontal (DP), caracterizada por uma inflamação crônica associada a um quadro de disbiose, foi relacionada a diversas patologias no organismo humano. Estudos recentes revelam uma forte associação entre a DP e o câncer. O objetivo deste artigo foi realizar uma revisão narrativa de literatura sobre a relação entre ambas as doenças. Uma pesquisa foi executada nos bancos de dados Biblioteca Virtual em Saúde (BVS), PubMed e Wiley Online Library, com os descritores em saúde (DECs): "Doença Periodontal" e "Carcinogêne- se" e "Neoplasma", e seus correspondentes em inglês, "Periodontal Disease" and "Carcinogenesis" and "Neoplasm". Os critérios de in- clusão foram artigos completos publicados em inglês, português e/ ou espanhol de 2010 a 2020, resultando em 22 artigos. Verificou-se que, embora o processo inflamatório decorrente da DP ocorra de forma local na cavidade oral, as células inflamatórias e seus produtos, os periodontopatógenos - responsáveis por essa inflamação em conjunto com a resposta imune do hospedeiro - e os componentes bacterianos podem agir no organismo em geral. As consequências são possíveis alterações no ciclo celular, na proliferação celular, na apoptose, nas respostas imunes e inflamatórias. Ademais, os patógenos periodontais são capazes de interagir diretamente com células do organismo e assim, estimular a carcinogênese, progressão tumoral e/ou metástases. Esses fatos estudados em conjunto com a epigenética têm relevado uma associação positiva entre diversos cânceres e a DP. Concluiu-se que, apesar de alguns mecanismos envolvidos na associação permanecerem incertos, os estudos epidemiológicos têm acrescentado um novo panorama para a correlação.

Periodontal disease (PD), characterized by chronic inflammation associated with dysbiosis, has been linked to several pathologies in the human body. Recent studies reveal a strong association between PD and cancer. The objective of this article was to carry out a narrative review of the literature on the relationship between both diseases. A search was performed in the Virtual Health Library (BVS), PubMed and Wiley Online Library databases, with the health descriptors (DECs) in Portuguese: "Doença Periodontal" and "Carcinogênese" and "Neoplasma", and their correspondents in English, "Periodontal Disease" and "Carcinogenesis" and "Neoplasm". The inclusion criteria were complete articles published in English, Portuguese and/ or Spanish from 2010 to 2020, resulting in 22 articles. It was found that, although the inflammatory process resulting from PD occurs locally in the oral cavity, the inflammatory cells and their products, the periodontopathogens -- responsible for this inflammation together with the host's immune response -- and the bacterial components can act on the organism in general. Consequences are possible changes in the cell cycle, cell proliferation, apoptosis, immune and inflammatory responses. In addition, periodontal pathogens are able to interact directly with cells in the body and thus stimulate carcinogenesis, tumor progression and/or metastasis. These facts studied in conjunction with epigenetics have revealed a positive association between several cancers and PD. It was concluded that, although some mechanisms involved in the association remain uncertain, epidemiological studies have added a new panorama for the correlation

Food nitrates and nitrites as possible causes of cancer: A review / Nitratos y nitratos alimentarios como posibles causas de cáncer: una revisión / Nitratos e nitratos dietéticos como possíveis causas de câncer: uma revisão

SUMMARY Introduction: Nitrates and nitrites can be found in meat and dairy products, vegetables, and fruits. The consumption of these preservatives has been associated with the emergence of gastric, colorectal cancer and non-Hodgkin's lymphoma, although studies are still inconclusive. Methodology: It is a review of literature of the narrative type, in which there was a recovery of articles published in English and Portuguese, in the databases SciELO, Lilacs, Science Direct and Capes journals. Articles related to nitrates and nitrites in foods were included, as well as articles that correlated the consumption of these preservatives with the appearance of cancers, regardless of the year of publication, although articles published between the years 2009 to 2019 were prioritized. Results: Nitrates and nitrites are generally associated with industrialized food products; therefore, it is possible to observe the presence of these salts in a wide variety of foods. The excessive consumption of nitrates and nitrites, whether through water or food, has been associated with a great diversity of diseases, stimulating the development of several studies investigating, including, the correlation between the consumption of these preservatives and the appearance of cancers. Conclusion: It is observed that nitrates and nitrites form compounds with a carcinogenic potential, making them interesting to avoid excessive consumption of these preservatives.

RESUMEN Introducción: Los nitratos y nitritos pueden ser encontrados en carnes y productos lácteos, verduras y frutas. El consumo de estos conservantes ha sido asociado con la aparición de cáncer gástrico, colorrectal y linfoma no Hodgkin, aunque los estudios aún no son concluyentes. Metodología: Se hizo una revisión de tipo narrativo de la literatura, en la que se recuperaron artículos publicados en inglés y portugués, en las bases de datos SciELO, Lilacs, Science Direct y revistas Capes. Se incluyeron artículos relacionados con nitratos y nitritos en alimentos, así como artículos que correlacionaban el consumo de estos conservantes con la aparición de cánceres, independientemente del año de publicación, aunque se priorizaron artículos publicados entre los años 2009 a 2019. Resultados: Los nitratos y nitritos se asocian generalmente con productos alimenticios industrializados; por tanto, es posible observar la presencia de estas sales en una amplia variedad de alimentos. El consumo excesivo de nitratos y nitritos, ya sea a través del agua o de los alimentos, se ha asociado a una gran diversidad de enfermedades, estimulando el desarrollo de varios estudios que investigan, entre ellos, la correlación entre el consumo de estos conservantes y la aparición de cánceres. Conclusión: Así, se observa que los nitratos y nitritos, forman compuestos con potencial carcinogénico, por lo que resulta interesante evitar el consumo excesivo de estos conservantes.

RESUMO Introdução: Nitratos e nitritos podem ser encontrados em carnes e laticínios, vegetais e frutas. O consumo desses conservantes tem sido associado ao desenvolvimento de câncer gástrico e colorretal e linfoma não Hodgkin, embora os estudos ainda não sejam conclusivos. Metodologia: Trata-se de uma revisão de literatura do tipo narrativa, na qual houve a recuperação de artigos publicados em inglês e português, nas bases de dados SciELO, Lilacs, Science Direct e Periódicos Capes. Foram incluídos artigos relacionados a nitratos e nitritos em alimentos, bem como artigos que correlacionassem o consumo desses conservantes com o aparecimento de cânceres, independentemente do ano de publicação, embora tenham sido priorizados os artigos publicados entre os anos de 2009 a 2019. Resultados: Nitratos e nitritos são geralmente associados a produtos alimentícios industrializados; portanto, é possível observar a presença desses sais em uma grande variedade de alimentos. O consumo excessivo de nitratos e nitritos, seja pela água ou pelos alimentos, tem sido associado a uma grande diversidade de doenças, estimulando o desenvolvimento de diversos estudos que investiguem, inclusive, a correlação entre o consumo desses conservantes e o aparecimento de cânceres. Conclusão: Assim, observa-se que nitratos e nitritos formam compostos com potencial carcinogê-nico, por isso é interessante evitar o consumo excessivo desses conservantes.

Is there a link between non-alcoholic fatty liver disease aspects and pancreatic cancer? Results of a case-matched study / Existe ligação entre a doença hepática gordurosa não alcoólica e o câncer de pâncreas? Resultados de estudo caso-controle

ABSTRACT Background and Aims: An association between non-alcoholic fatty liver disease (NAFLD) and pancreatic ductal adenocarcinoma (PDAC) has been previously suggested. This study aims at investigating this association and at identifying potential links between variables of the NAFLD spectrum and PDAC. Methods: A cross-sectional case-matched analytical and comparative study was carried out to analyze patients undergoing surgical resection of PDAC and compare them to a control group of individuals undergoing cholecystectomy at a public tertiary teaching hospital, matched by sex, age and BMI. Hepatic histopathological examinations were compared between cases and controls. Results: Of 56 individuals, 36 were male (64.3%) and the median age was 61.5 years old (interquartile range: 57.5 - 70). The participants' median BMI was 24.3 kg/m2 (interquartile range: 22.1-26.2 kg/m2). Microvesicular steatosis (p=0.04), hepatocellular ballooning (p=0.02), fibrosis (p=0.0003) and steatohepatitis (p=0.03) were significantly more frequent in the group of cases. Odds ratios for hepatocellular ballooning (6.2; 95%CI: 1.2-31.8; p=0.03), fibrosis (9.3; 95%CI: 2.5-34.1; p=0.0008) and steatohepatitis (3.9; 95%CI: 1.1-14.3; p=0.04) were statistically significant in relation to the PDAC prevalence. Conclusions: Significant associations were identified between histopathological aspects of NAFLD (microvesicular steatosis, hepatocellular ballooning, fibrosis, and steatohepatitis) and PDAC.

RESUMO Histórico e objetivos: a associação entre a doença hepática gordurosa não alcoólica (DHGNA) e o adenocarcinoma ductal pancreático (ACDP) foi sugerida anteriormente. Este estudo visa investigar esta associação e identificar possíveis ligações entre as variáveis do espectro da DHGNA e o ACDP. Métodos: foi realizado estudo transversal caso-controle analítico e comparativo para analisar pacientes submetidos a ressecção cirúrgica de ACDP e compará-los a grupo controle de indivíduos submetidos a colecistectomia em hospital público terciário de ensino, pareados por sexo, idade e IMC. Os exames histopatológicos hepáticos foram comparados entre casos e controles. Resultados: dos 56 indivíduos, 36 eram do sexo masculino (64,3%) e a idade mediana era de 61,5 anos de idade (intervalo interquartil 57,5-70). A mediana do IMC dos participantes foi de 24,3 kg/m2 (intervalo interquartil 22,1 26,2). Esteatose microvesicular (p = 0,04), balonização hepatocelular (p = 0,02), fibrose (p = 0,0003) e esteato-hepatite (p = 0,03) foram significativamente mais frequentes no grupo de casos. As razões de chances para balonização hepatocelular (6,2; IC 95%: 1,2 - 31,8; p = 0,03), fibrose (9,3; IC 95%: 2,5 - 34,1; p = 0,0008) e esteato-hepatite (3,9; IC 95%: 1,1 - 14,3; p = 0,04) foram estatisticamente significativas em relação à prevalência de ACDP. Conclusões: houve associações significativas entre aspectos histopatológicos de DHGNA (esteatose microvesicular, balonização hepatocelular, fibrose e esteato-hepatite) e a ocorrência de ACDP.

Imagiological Diagnosis of Gastrointestinal Diseases - Diagnostic Criteria of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the leading causes of neoplastic morbidity and mortality worldwide, and despite recent treatment advances, the prognosis remains dismal, with a 5-year mortality rate of 85%. The surveillance and timely diagnosis is therefore of crucial importance in order to improve survival rates and alleviate the health burden imposed by the HCC. Previously, HCC diagnosis warranted liver biopsy, an invasive process with limited diagnostic accuracy. In the past 15 years, HCC diagnosis based solely on imaging criteria was accepted by all the major national and international guidelines, and is now widely employed across the globe. Current European guidelines for the HCC diagnosis support the use of both dynamic contrasted computer tomography as well as magnetic resonance imaging for the non-invasive diagnosis of HCC for nodules >1 cm in a cirrhotic liver. The non-invasive diagnosis of HCC depends on radiological hallmarks, such as homogeneous contrast uptake during the arterial phase and wash-out during the venous and late phases, but while such tumoral behaviour is frequent in nodules >2 cm, high-end equipment and superior expertise is often needed for the correct diagnosis of early HCC. Nevertheless, the accuracy of imaging techniques for the diagnosis of HCC is permanently improving, and supports the progressively reduced need for liver biopsy during liver nodule workout in a cirrhotic liver.

O carcinoma hepatocelular (CHC) é uma das principais causas de morbi-mortalidade a nível mundial, e apesar de avanços no tratamento, o prognóstico é sombrio, com uma mortalidade aos 5 anos de 85%.Assim, reveste-se de particular importância a vigilância e diagnóstico precoce do CHC, de forma a alterar substancialmente as taxas de sobrevida desta neoplasia.Previamente, o diagnóstico do CHC exigia a realização de uma biópsia hepática, uma técnica invasiva com acuidade diagnóstica limitada. Nos últimos 15 anos, o diagnóstico baseado em técnicas de imagem foi sendo progressivamente aceite pelas principais recomendações nacionais e internacionais, e é agora extensamente aplicado em todo o mundo.As recomendações europeias mais recentes para o diagnóstico do CHC aceitam a utilização de tomografia computorizada contrastada e ressonância magnética contrastada para o diagnóstico não invasivo de CHC em nódulos >1 cm no fígado cirrótico. Este diagnóstico depende da presença de alterações imagiológicas típicas, como a hipercaptação homogénea de contraste na fase arterial e o wash-out nas fases portal e tardia, características frequentes em nódulos >2 cm, mas de difícil identificação em CHC de dimensões reduzidas.Em conclusão, as técnicas imagiológicas para o diagnóstico do CHC apresentam uma acuidade diagnóstica progressivamente mais elevada, e permitirão reduzir significativamente a necessidade de biópsia hepática durante a abordagem de nódulos hepáticos num fígado cirrótico.

[Recent advances in bladder urothelial carcinogenesis]. / Altérations moléculaires au cours de la carcinogenèse urothéliale vésicale.

Bladder cancer is the sixth cause of cancer mortality in France and prognosis of muscle-invasive tumors remains poor due to lack of effective treatments. Recent advances in molecular biology applied to tumors and results of recent genome-wide studies have brought a important impact on the understanding of bladder carcinogenesis. Main molecular alterations concern FGFR3, TP53 and HER2, and it is now possible to distinguish three subgroups of tumors according to molecular profile. This paper proposes a review of different genetic and epigenetic alterations in bladder cancer, their potential role as theranostic markers in clinical oncology and new targeted therapies according to the concept of personalized medicine.