Celecoxib: Antiangiogenic and Antitumoral Action / Celecoxib: Acción Antiangiogénica y Antitumoral

SUMMARY: Angiogenesis, a process by which new blood vessels are generated from pre-existing ones, is significantly compromised in tumor development, given that due to the nutritional need of tumor cells, pro-angiogenic signals will be generated to promote this process and thus receive the oxygen and nutrients necessary for its development, in addition to being a key escape route for tumor spread. Although there is currently an increase in the number of studies of various anti-angiogenic therapies that help reduce tumor progression, it is necessary to conduct a review of existing studies of therapeutic alternatives to demonstrate their importance.

La angiogénesis, proceso por el cual se generan nuevos vasos sanguíneos a partir de otros preexistentes, se encuentra comprometida de forma importante en el desarrollo tumoral, dado que por necesidad nutritiva de las células tumorales se generarán señales pro angiogénicas para promover este proceso y así recibir el oxígeno y los nutrientes necesarios para su desarrollo, además de ser una ruta de escape clave para la diseminación tumoral. Si bien, actualmente existe un aumento en la cantidad de estudios de diversas terapias anti angiogénicas que ayudan a reducir el avance tumoral, es necesario realizar una revisión de los estudios existentes de alternativas terapéuticas para demostrar su importancia.

Absenteísmo e suas causas no contexto da saúde dos trabalhadores em oncologia: revisão integrativa / Absenteeism and it's causes in the context of oncology workers health: integrative review / Ausentismo y sus causas en el contexto de la salud de los trabajadores en oncología: revisión integradora

O ritmo elevado de trabalho, somado às demandas físicas e psicológicas, levam ao estresse nos contextos pessoal e laboral, o que faz com que as pessoas se afastem de seus ambientes de trabalho como um dos motivos apontados para a incapacidade para o trabalho. Essa realidade tem sido amplamente observada no ambiente hospitalar, possivelmente associada a problemas relacionados à fadiga da compaixão, geralmente em serviços de oncologia. Dessa forma, a motivação deste estudo foi compreender os motivos do absenteísmo em oncologia, e se esse episódio ocorre devido ao processo de trabalho. Objetivo:Investigar as causas do absenteísmo entre profissionais expostos a riscos ambientais e biopsicossociais em hospitais oncológicos. Metodologia:Trata-se de uma revisaointegrativa sobre o tema do absenteísmo, o que indica novos rumos para futuras investigações. Foi realizada uma revisão da literatura com base em três pilares: 1) O processo de trabalho multidisciplinar em oncologia e o risco de adoecimento; 2) O absentismo dos profissionais de saúde em oncologia; 3) O problema da pandemia de COVID-19 para os trabalhadores da saúde. Posteriormente, foram escolhidos os descritores e a partir deles foram realizadas buscas nas bases de dados eletrônicas PUBMED, LILACS e SCOPUS. Resultados:Obteve-se um resultado de dez estudos. Constatou-se que os principais transtornos, que levam à incapacidade para o trabalho e, por sua vez, ao absenteísmo, foram de origem psíquica (depressão e Síndrome de Burnout) e de origem musculoesquelética. Conclusões:A dupla jornada de trabalho foi citada como fator facilitador para o aparecimento desses transtornos, onde tais cenários não incapacitam o trabalhador para o desenvolvimento de suas atividades, que podem ser temporárias ou permanentes (AU).

The high pace of work, added to the physical and psychological demands, lead to stress in personal and work contexts, which causes people to withdraw from their work environments as one of the reasons mentioned for incapacitation for work. This reality hasbeen widely observed in the hospital setting, possibly associated with problems related to compassion fatigue, usually in oncology services. The motivation of this study was to understand the reasons for absenteeism in oncology, and if this episode occursdue to the work process. Objective:Investigating the causes of absenteeism among professionals exposed to environmental and biopsychosocial risks in cancer hospitals. Methodology:This is a integrative review on the theme of absenteeism, which indicates new directions for future investigations. A literature review was carried out based on three pillars: 1) The multidisciplinary work process in oncology and the risk of illness; 2) The absenteeism of health professionals in oncology; 3) The problem of the COVID-19 pandemic for health workers. Subsequently, the descriptors were chosen and based on them, searches were carried out in the electronic databases PUBMED, LILACS and SCOPUS. Results:A result of ten studies was obtained. It was found that the main disorders, which lead to incapacity for work and, in turn, absenteeism, were of psychic origin (depression and Burnout Syndrome) and of musculoskeletal origin. Conclusions: Texto das conclusões em inglêsThe double work shift was cited as a facilitating factorfor the appearance of these disorders, where such scenarios do not incapacitate the worker to develop their activities, which may be temporary or permanent (AU).

El alto ritmo de trabajo, sumado a las exigencias físicas y psicológicas, genera estrés en el contexto personal y laboral, lo que provoca que las personas se alejen de sus ambientes laborales como una de las razones esgrimidas para la incapacidad detrabajar. Esta realidad ha sido ampliamente observada en el ambiente hospitalario, posiblemente asociada a problemas relacionados con la fatiga por compasión, generalmente en los servicios de oncología. Así, la motivación de este estudio fue comprender las razones del ausentismo en oncología y si este episodio ocurre debido al proceso de trabajo. Objetivo:Investigar las causas del ausentismo entre profesionales expuestos a riesgos ambientales y biopsicosociales en hospitales oncológicos. Metodología:Se trata deuna revisión integradorasobre el tema del ausentismo, que indica nuevos rumbos para futuras investigaciones. Se realizó una revisión de la literatura basada en tres pilares: 1) El proceso de trabajo multidisciplinario en oncología y el riesgo de enfermedad; 2) El ausentismo de los profesionales de la salud en oncología; 3) El problema de la pandemia de COVID-19 para los trabajadores de la salud. Posteriormente se eligieron los descriptores y a partir de ellos se realizaron búsquedas en las bases de datos electrónicas PUBMED, LILACS y SCOPUS. Resultados:Se obtuvo un resultado de diez estudios. Se encontró que los principales trastornos que conducen a la incapacidad para trabajar y, a su vez, al ausentismo, fueron de origen psíquico (depresión y síndrome deBurnout) y de origen músculoesquelético. Conclusiones:La doble jornada laboral fue citada como un factor facilitador para la aparición de estos trastornos, dondedichos escenarios no incapacitan al trabajador para el desarrollo de sus actividades, las cuales pueden ser temporales o permanentes (AU).

Relationship between actinic keratosis and malignant skin lesions on the eyelid / Relação entre ceratose actínica e lesões cutâneas malignas na pálpebra

ABSTRACT Purpose: To evaluate the variables possibly related to actinic keratosis and malignant skin lesions on the eyelid. Methods: A prospective study of patients with suspected eyelid malignancy was conducted. The participants underwent a 2-mm punch biopsy at two opposite sites of the lesion for diagnosis, and the results were compared with those of the histopathological study of the surgical excised specimen. The patients with an actinic keratosis component were divided into two groups (actinic keratosis-associated malignancy and actinic keratosis alone), which were compared for the following variables: age, disease duration, largest diameter, tumor area, Fitzpatrick classification, sex, tumor site and margin involvement. A cluster analysis was also performed. Results: We analyzed 174 lesions, of which 50 had an actinic keratosis component. Actinic keratosis was associated with squamous cell carcinoma in 22% of the cases and to basal cell carcinoma in 38%, which shows that both neoplasms may have contiguous actinic keratosis. Statistical analysis revealed no significant difference among the variables. In a cluster analysis, four groups were identified with malignant lesions in the medial canthus with the largest mean diameter and area. All margin involvements on the lower eyelid were related to malignancy, which means that all cases with margin involvement had an almost 100% risk of malignancy. Conclusions: Larger actinic keratosis lesions in the medial canthus and lesions with margin involvement on the lower eyelid have a greater probability of malignant association.

RESUMO Objetivo: Avaliar as possíveis variáveis relacionadas à ceratose actínica e lesões malignas cutâneas nas pálpebras. Métodos: Estudo prospectivo de pacientes com lesões palpebrais suspeitas de malignidade. Os participantes foram submetidos à biopsia por trépano (punch) de 2-mm em dois pontos opostos da lesão como método diagnóstico e os resultados foram comparados com o estudo histopatológico da peça excisada cirurgicamente. Aqueles que apresentaram ceratose actínica como resultado foram divididos em dois grupos (ceratose actínica associada com malignidade e ceratose actínica isolada) e foram comparados de acordo com as variáveis: idade, tempo de doença, maior diâmetro, área do tumor, classificação de Fitzpatrick, gênero, localização e acometimento da margem palpebral. A análise de cluster também foi realizada. Resultados: Foram analisadas 174 lesões e 50 delas tinham ceratose actínica como componente do tumor. Ceratose actínica esteve associada ao Carcinoma Espinocelular em 22% dos casos e ao Carcinoma Basocelular em 38%, mostrando que ambos podem ter ceratose actínica adjacente. A análise estatística não encontrou diferença entre as variáveis. A análise de cluster identificou quatro grupos e mostrou que lesões malignas no canto medial tinham maiores diâmetro e área. Acometimento da margem na pálpebra inferior relacionou-se em 100% com malignidade, enquanto a ausência de acometimento da margem mostrou menor chance de malignidade. Conclusões: Lesões maiores de ceratose actínica no canto medial e lesões com acometimento da margem palpebral inferior têm maiores chances de associação com malignidade.

Rare tumors: a blue ocean of investigation / 医学前沿

Advances in novel drugs, therapies, and genetic techniques have revolutionized the diagnosis and treatment of cancers, substantially improving cancer patients' prognosis. Although rare tumors account for a non-negligible number, the practice of precision medicine and development of novel therapies are largely hampered by many obstacles. Their low incidence and drastic regional disparities result in the difficulty of informative evidence-based diagnosis and subtyping. Sample exhaustion due to difficulty in diagnosis also leads to a lack of recommended therapeutic strategies in clinical guidelines, insufficient biomarkers for prognosis/efficacy, and inability to identify potential novel therapies in clinical trials. Herein, by reviewing the epidemiological data of Chinese solid tumors and publications defining rare tumors in other areas, we proposed a definition of rare tumor in China, including 515 tumor types with incidences of less than 2.5/100 000 per year. We also summarized the current diagnosis process, treatment recommendations, and global developmental progress of targeted drugs and immunotherapy agents on the status quo. Lastly, we pinpointed the current recommendation chance for patients with rare tumors to be involved in a clinical trial by NCCN. With this informative report, we aimed to raise awareness on the importance of rare tumor investigations and guarantee a bright future for rare tumor patients.

Potencial quimiopreventivo de lipídios estruturados obtidos da Tributirina e Tricaprilina na fase de promoção da hepatocarcinogênese experimental / Chemopreventive potential of structured lipids obtained from Tributyrin and Tricaprylin in the promotion phase of experimental hepatocarcinogenesis

A quimioprevenção do câncer refere-se ao uso de compostos naturais ou sintéticos para prevenir o desenvolvimento das neoplasias antes do estabelecimento da malignidade. O ácido butirico (AB) atua como um potente quimiopreventivo na hepatocarcinogênese, reduzindo o número e o tamanho de lesões pré neoplásicas persistentes (pLPN), induzindo a apoptose e modulando mecanismos epigenéticos. Já o ácido caprílico (AC), além da sua atuação como potencializador de absorção, vem sendo investigado na área da prevenção do câncer. Neste cenário, o objetivo do trabalho visa avaliar a atividade quimiopreventiva de lipídios estruturados (EST) obtidos por interesterificação enzimática da tributirina com a tricaprilina, na fase de promoção da hepatocarcinogênese experimental. Após o processo de interesterificação, o produto final apresentou novos triacilgliceróis com composição de duas moléculas de ácido butírico para uma de ácido caprilíco. Ratos machos isogênicos da linhagem Fischer 344 foram submetidos ao modelo do hepatócito resistente, sendo distribuídos em dois grupos e tratados diariamente por via intragástrica com lipídios estruturados (EST) ou com o seu controle isocalórico, a maltodextrina (MD), durante a fase de promoção. Como esperado, não houve diferença estatística (p>0,05) em relação ao peso inicial e final dos animais dos grupos MD e EST, o que indica ausência de toxicidade dos compostos administrados. Na análise macroscópica do fígado, foi observada uma redução de 33,3% no grupo EST em relação ao número médio de nódulos macroscópicos em comparação ao grupo MD, porém essa redução não atingiu diferença estatística (p>0,05). Para a avaliação das lesões pré neoplásicas (LPN) foi utilizada a marcação imunoistoquímica para glutationa-S-transferase (GST-P). O grupo EST apresentou uma redução no número de lesões em remodelação e total GSTP-P+, quando comparado com o grupo MD (p<0,05). Quando avaliada a % de corpúsculos apoptóticos e índice de proliferação celular, não houve diferença estatística entre os grupos (p>0,05). Animais tratados com lipídios estruturados apresentaram maiores (p<0,05) concentrações de AC e AB por grama de tecido hepático em relação ao tratamento com maltodextrina. Em relação aos danos no DNA, o grupo EST resultou em cometas de comprimentos menores (p<0,05), menores níveis de γ-H2AX (p<0,05) e maiores concentrações de p53 nuclear, quando comparados aos animais que receberam maltodextrina, sugerindo uma proteção contra danos no DNA no grupo tratado com EST. Os resultados mostraram que o tratamento com EST resultou em ações efetivas na fase de promoção da hepatocarcinogênese experimental

Cancer chemoprevention refers to the use of natural or synthetic compounds to prevent the development of neoplasms before the establishment of malignancy. Butyric acid (AB) acts as a potent chemopreventive in hepatocarcinogenesis, reducing the number and size of persistent preneoplastic lesions (pLPN), inducing apoptosis and modulating epigenetic mechanisms. Caprylic acid (CA), in addition to its role as an absorption enhancer, has been investigated in the area of cancer prevention. In this scenario, the objective of this work was to evaluate the chemopreventive activity of structured lipids (EST) obtained by enzymatic interesterification of tributyrin with tricaprylin, in the phase of promotion experimental hepatocarcinogenesis. After the interesterification process, the final product presented new triacylglycerols with a composition of two molecules of butyric acid to one of caprylic acid. Isogenic male Fischer 344 rats were submitted to the resistant hepatocyte model, divided into two groups and treated daily intragastrically with structured lipids (EST) or with its isocaloric control, maltodextrin (MD), during the promotion phase. As expected, there was no statistical difference (p>0.05) in relation to the initial and final weight of the animals in the MD and EST groups, which indicates the absence of toxicity of the administered compounds. In the macroscopic analysis of the liver, a reduction of 33.3% was observed in the EST group in relation to the mean number of macroscopic nodules compared to the MD group, but this reduction did not reach a statistical difference (p>0.05). For the evaluation of pre-neoplastic lesions (PNL) immunohistochemical staining for glutathione-Stransferase (GST-P) was used. The EST group showed a reduction in the number of remodeling lesions and total GSTP-P+, when compared to the MD group (p<0.05). Animals treated with structured lipids had higher (p<0.05) concentrations of AC and AB per gram of liver tissue compared to treatment with maltodextrin. Regarding DNA damage, the EST group resulted in comets of shorter lengths (p<0.05), lower levels of γ-H2AX (p<0.05) and high concentration of nuclear p53, when compared to animals that received maltodextrin, suggesting protection against DNA damage in the EST treated group. The results showed that EST treatment resulted in effective actions in the promotion phase of experimental hepatocarcinogenesis

Focal adhesion kinase inhibition decreases cell viability and induces apoptosis of JAK2 V617F positive cells

Abstract Focal Adhesion Kinase (FAK) protein participates in proliferation, migration, cell survival, and apoptosis process. It has been described as overexpressed in several neoplasms being a promising target for therapy. BCR-ABL negative chronic Myeloproliferative Neoplasms (MPN) are clonal disorders characterized by the excess of proliferation and apoptosis resistance. The identification of the acquired JAK2 V617F mutation in MPN patients allowed a better understanding of pathogenesis. However, there is still no pharmacological treatment that leads all patients to molecular remission, justifying new studies. The present study aimed to evaluate FAK involvement in the viability and apoptosis of HEL and SET-2 cells, both JAK2 V617F positive cell lines. The FAK inhibitor PF 562,271 was used. Cell viability was determined using MTT assay and apoptosis verified by cleaved PARP, cleaved Caspase 3 and Annexin-V/PI staining detection. FAK inhibition significantly reduced HEL and SET-2 cells viability and induced apoptosis. Considering the role of JAK/STAT pathway in MPN, further investigation of FAK participation in the MPN cells proliferation and apoptosis resistance, as well as possible crosstalk between JAK and FAK and downstream pathways may contribute to the knowledge of MPN pathophysiology, the discovery of new molecular targets, and JAK inhibitors resistance mechanisms.

Selective photodynamic effects on cervical adenocarcinoma cells provided by F127 Pluronic®-based micelles modulating hypericin delivery

Abstract Cervical cancer is a leading cause of death among women. The endocervical adenocarcinoma (ECA) represents an aggressive and metastatic type of cancer with no effective treatment options currently available. We evaluated the antitumoral and anti-migratory effects of hypericin (HYP) encapsulated on Pluronic F127 (F127/HYP) photodynamic therapy (PDT) against a human cell line derived from invasive cervical adenocarcinoma (HeLa) compared to a human epithelial cell line (HaCaT). The phototoxicity and cytotoxicity of F127/HYP were evaluated by the following assays: colorimetric assay, MTT, cellular morphological changes by microscopy and long-term cytotoxicity by clonogenic assay. In addition, we performed fluorescence microscopy to analyze cell uptake and subcellular distribution of F127/HYP, cell death pathway and reactive oxygen species (ROS) production. The PDT mechanism was determined with sodium azide and D-mannitol and cell migration by wound-healing assay. The treatment with F127/HYP promoted a phototoxic result in the HeLa cells in a dose-dependent and selective form. Internalization of F127/HYP was observed mainly in the mitochondria, causing cell death by necrosis and ROS production especially by the type II PDT mechanism. Furthermore, F127/HYP reduced the long-term proliferation and migration capacity of HeLa cells. Overall, our results indicate a potentially application of F127/HYP micelles as a novel approach for PDT with HYP delivery to more specifically treat ECA.

¿Cuándo el patólogo debe solicitar inmunomarcación con B-Catenina?: una revisión de la literatura a propósito de dos casos / When should the pathologist request immunostaining with B-catenin?: a review of the literature on two cases

For more than 20 years, immunohistochemistry has represented an auxiliary test of great relevance to support pathological work, however, it should be noted that the pillar of diagnosis continues and will continue to be the classic morphological description based on hematoxylin eosin and the trained eye of the specialist. In neoplastic pathologies, whether benign or malignant, it is becoming increasingly necessary to incorporate new tissue biomarkers that help objectify or confirm the diagnosis of each patient, in order to provide better treatment or a more precise diagnosis about the biological nature of their illness. In this line, there has been intense research in relation to the participation of the Wnt/ß-catenin pathway in the development of various types of tumors, including colon adenocarcinoma, some pancreatic neoplasms and even some tumors of mesenchymal origin, as will be seen. in this work. In this context and based on two clinical cases of special interest, we have prepared a brief review of the literature considering the biological aspects of ß-catenin, tumors where there is currently a true relative consensus that its immunolabeling offers a real contribution to the confirmation of the entity and finally a limited exposition regarding the future of this biomarker in the pathology discipline.

Desde hace más de 20 años la inmunohistoquímica ha representado una prueba auxiliar de gran relevancia para apoyar el trabajo anatomopatológico, no obstante, cabe señalar que, aún el pilar del diagnóstico sigue y seguirá siendo la descripción morfológica clásica basada en hematoxilina eosina y el ojo entrenado del especialista. En las patologías neoplásicas, ya sea benignas, como malignas, se hace cada vez más necesario la incorporación de nuevos biomarcadores tisulares que ayuden a objetivar o confirmar el diagnóstico de cada paciente, con objeto de entregar un mejor tratamiento o un diagnóstico más preciso de la naturaleza biológica de su enfermedad. En esta línea, ha habido intensa investigación en relación con la participación de la vía Wnt/ß-catenina en el desarrollo de varios tipos de cáncer, entre ellos el adenocarcinoma de colon, algunas neoplasias pancreáticas e incluso algunos tumores de origen mesenquimal como se verá en este trabajo. En este contexto y partir de dos casos clínicos de especial interés, hemos preparado una breve revisión de la literatura considerando los aspectos biológicos de la ß-catenina, los tumores donde en la actualidad existe verdadero consenso de que su inmunomarcación ofrece un aporte real a la confirmación de la entidad y finalmente una exposición acotada respecto al futuro de este biomarcador en la disciplina de la anatomía patológica.

The morphological challenge in determining nuclear size and shape in anatomopathological neoplasia analysis / El desafío morfológico en la determinación del tamaño y forma nuclear en el análisis anatomopatológico de neoplasias

SUMMARY: From 1984 stereology was added to unbiased methods and procedures, i.e., counts became more reliable studying morphological images in a random and uniform isotropic way. Therefore, the orientation and sectioning methods adapted to stereological quantification are essential. A critical quantitative subject in practical pathology concerns diagnosing and classifying neoplasias. Pathologists evaluated different types of tumors by determining the nuclear roundness factor (NRF). NRF is calculated by the ratio between the nuclear radius obtained from the area and the perimeter. However, NRF is biased data because it depends on the sectioning orientation, nuclei shape, and section thickness. The stereology proposed an unbiased alternative to assess the nucleus from tumor cells, counteracting NRF quantitatively. Therefore, the volume-weighted mean nuclear volume has been used to prognostic tumors in several organs. In urology, this was used, for example, to study primary carcinoma of the bladder, renal and prostatic carcinomas.

RESUMEN: A partir de 1984 se agregó la estereología a los métodos y procedimientos sin distorción, es decir, los conteos se volvieron más confiables al estudiar imágenes morfológicas de forma aleatoria e isotrópica uniforme. Por tanto, los métodos de orientación y seccionamiento adaptados a la cuantificación estereológica son fundamentales. Un tema cuantitativo crítico en la patología práctica se refiere al diagnóstico y clasificación de las neoplasias. Los patólogos evaluaron diferentes tipos de tumores determinando el factor de redondez nuclear (NRF). NRF se calcula por la relación entre el radio nuclear obtenido del área y el perímetro. Sin embargo, NRF son datos distorsionados debido a que dependen de la orientación de la sección, la forma de los núcleos y el grosor de la sección. La estereología propuso una alternativa imparcial para evaluar el núcleo de las células tumorales, contrarrestando cuantitativamente el NRF. Por lo tanto, el volumen nuclear medio ponderado se ha utilizado para pronosticar tumores en varios órganos. En urología, esto se utilizó, por ejemplo, para estudiar el carcinoma primario de vejiga, carcinomas renales y prostáticos.

Biosensor-based assay of exosome biomarker for early diagnosis of cancer / 医学前沿

Cancer imposes a severe threat to people's health and lives, thus pressing a huge medical and economic burden on individuals and communities. Therefore, early diagnosis of cancer is indispensable in the timely prevention and effective treatment for patients. Exosome has recently become an attractive cancer biomarker in noninvasive early diagnosis because of the unique physiology and pathology functions, which reflects remarkable information regarding the cancer microenvironment, and plays an important role in the occurrence and evolution of cancer. Meanwhile, biosensors have gained great attention for the detection of exosomes due to their superior properties, such as convenient operation, real-time readout, high sensitivity, and remarkable specificity, suggesting promising biomedical applications in the early diagnosis of cancer. In this review, the latest advances of biosensors regarding the assay of exosomes were summarized, and the superiorities of exosomes as markers for the early diagnosis of cancer were evaluated. Moreover, the recent challenges and further opportunities of developing effective biosensors for the early diagnosis of cancer were discussed.

Cancer biology deciphered by single-cell transcriptomic sequencing

Tumors are complex ecosystems in which heterogeneous cancer cells interact with their microenvironment composed of diverse immune, endothelial, and stromal cells. Cancer biology had been studied using bulk genomic and gene expression profiling, which however mask the cellular diversity and average the variability among individual molecular programs. Recent advances in single-cell transcriptomic sequencing have enabled a detailed dissection of tumor ecosystems and promoted our understanding of tumorigenesis at single-cell resolution. In the present review, we discuss the main topics of recent cancer studies that have implemented single-cell RNA sequencing (scRNA-seq). To study cancer cells, scRNA-seq has provided novel insights into the cancer stem-cell model, treatment resistance, and cancer metastasis. To study the tumor microenvironment, scRNA-seq has portrayed the diverse cell types and complex cellular states of both immune and non-immune cells interacting with cancer cells, with the promise to discover novel targets for future immunotherapy.

Role of high-mobility group box 1 in cancer / 中南大学学报(医学版)

High-mobility group box 1 (HMGB1) is a non-histone nuclear protein in most eukaryocytes. Inside the nucleus, HMGB1 plays an important role in several DNA events such as DNA repair, transcription, telomere maintenance, and genome stability. While outside the nucleus, it fulfils more complicated functions, including promoting cell proliferation, inflammation, angiogenesis, immune tolerance and immune escape, which may play a pro-tumoral role.Meanwhile, HMGB1 acts as an anti-tumoral protein by regulating immune cell recruitment and inducing immunogenic cell death (ICD) during the carcinogenesis process. Therefore, abnormal expression of HMGB1 is associated with oncogenesis, development, and metastasis of cancer, which may play a dual role of pro-tumor and anti-tumor.

Avaliação do tratamento quimioterápico paliativo com o esquema LDE- paclitaxel em pacientes portadores de metástases ósseas por neoplasia maligna / Evaluation of palliative chemotherapy treatment with the LDEpaclitaxel regimen in patients with bone metastases from malignant neoplas

Introdução: Pacientes com câncer em estádios avançados e metástases ósseas frequentemente não apresentam condições clínicas para a realização de esquemas quimioterápicos convencionais subsequentes, restringindo as opções de tratamento. Anteriormente, demonstramos que nanopartículas artificiais lipídicas (LDE), semelhantes à lipoproteína de baixa densidade (LDL) rica em colesterol, são captadas por tecidos malignos, e quando associadas aos quimioterápicos, após injeção pela via endovenosa, reduz drasticamente a toxicidade do tratamento. Os objetivos deste presente estudo foram avaliar a resposta clínica ao tratamento quimioterápico com paclitaxel (PTX) associado à LDE; avaliar as toxicidades clínicas e laboratorial, e a capacidade da associação LDE-PTX em reduzir a dor oncológica relacionada às metástases ósseas em pacientes com carcinoma de mama, próstata e pulmão, previamente tratados e não elegíveis para tratamento quimioterápico convencional subsequente. Métodos: Dezoito pacientes (8 com câncer de mama, 5 de próstata e 5 de pulmão) com metástases ósseas foram incluídos. O tratamento consistiu no esquema LDE-PTX na dose convencional do PTX (175 mg/m2 de superfície corpórea de 3/3 semanas) e os pacientes foram avaliados por resposta clínica, redução da dor óssea, uso de medicamentos opióides, e ocorrência de fraturas ósseas patológicas. Resultados: No total, 104 ciclos de quimioterapia foram realizados, e nenhum paciente apresentou toxicidade clínica, laboratorial, assim como não houve fraturas patológicas. Dos 18 pacientes incluídos, 9 tiveram sobrevida livre de progressão de doença 6 meses. Houve em todos os pacientes redução da dor óssea, permitindo substituição da medicação opióide por analgésico não opióide. Conclusão: A melhora significativa na dor óssea sem que tenha ocorrido toxicidade do tratamento, e o tempo de não progressão de doença 6 meses na metade dos pacientes sugere que esses pacientes tenham se beneficiado consistentemente do tratamento com a LDE-PTX. Portanto, a LDE-PTX pode tornar- se uma opção terapêutica interessante em pacientes com carcinomas de próstata, mama ou pulmão em estágios avançados e sem condições clínicas de se submeterem a outros esquemas quimioterápicos convencionais

Introduction: Patients with advanced cancer and bone metastases usually do not have clinical conditions to perform additional conventional chemotherapy regimens, restricting treatment options. Previously, we showed that lipid core nanoparticles (LDE), similar to cholesterol-rich low-density lipoprotein (LDL), are taken up by malignant tissues, and when associated to chemotherapy, after endovenous injection, it drastically decreases the toxicity of the treatment. The objectives of this study were to evaluate the clinical response to chemotherapy treatment with paclitaxel (PTX) associated with LDE; to evaluate the clinical and laboratorial toxicities, and the ability of the LDE-PTX to reduce cancer pain related to bone metastases in patients with breast, prostate or lung carcinoma, previously treated and not eligible for subsequent conventional chemotherapy treatment. Methods: Eighteen patients (8 with breast cancer, 5 with prostate and 5 with lung) with bone metastases were included. Treatment consisted of the LDE-PTX regimen at a conventional dose of PTX (175 mg/m2 body surface area, 3/3 weeks) and patients were evaluated for clinical response, reduction in bone pain, use of opioid medications, and the occurrence of pathological bone fractures. Results: In total, 104 chemotherapy cycles were performed, and none of the patients showed clinical or laboratorial toxicities, as well as there were no pathological fractures. Of the 18 patients evaluated, 9 had progression-fee survival 6 months. Patients had decrease in bone pain allowing replacement of opioid medication by another non-opioid analgesic. Conclusion: Significant improvement in bone pain without treatment toxicity, and time to disease progression of 6 months in half of the patients suggest that these patients have consistently benefited with LDE-PTX treatment. Therefore, LDE-PTX may become an interesting therapeutic option in patients with advanced stage of prostate, breast or lung carcinomas and without clinical conditions to undergo other conventional chemotherapy regimens

Quantitative Characterization of the Chemical Space Governed by Human Carbonic Anhydrases and selenium-containing derivatives of solfonamides

Abstract Due to the fact that different isoforms of carbonic anhydrase play distinct physiological roles, their diseases/disorders involvement are different as well. Involvement in major disorders such as glaucoma, epilepsy, Alzheimer's disease, obesity and cancers, have turned carbonic anhydrase into a popular case study in the field of rational drug design. Since carbonic anhydrases are highly similar with regard to their structures, selective inhibition of different isoforms has been a significant challenge. By applying a proteochemometrics approach, herein the chemical interaction space governed by acyl selenoureido benzensulfonamides and human carbonic anhydrases is explored. To assess the validity, robustness and predictivity power of the proteochemometrics model, a diverse set of validation methods was used. The final model is shown to provide valuable structural information that can be considered for new selective inhibitors design. Using the supplied information and to show the applicability of the constructed model, new compounds were designed. Monitoring of selectivity ratios of new designs shows very promising results with regard to their selectivity for a specific isoform of carbonic anhydrase.

Características de la mortalidad por tumores malignos en la provincia de Matanzas. 1990-2019 / Characteristics of mortality due to malignant tumors in the province of Matanzas. 1990-2019

RESUMEN Introducción: la mortalidad por tumores malignos se caracteriza por un incremento sostenido en el tiempo. En casi la totalidad de la provincia de Matanzas se ha observado esta tendencia en los últimos 30 años, con mayor o menor intensidad. Objetivo : describir algunas características de la mortalidad por cáncer en la provincia de Matanzas. Materiales y métodos: estudio observacional descriptivo retrospectivo de la mortalidad por tumores malignos durante 30 años (1990-2019). Se estimaron tasas crudas y ajustadas de mortalidad, globalmente, por períodos y por sexo. Se obtuvieron porcentajes y se determinó la significación estadística mediante el estadígrafo X2 y el valor de p < 0,05. Resultados: se detectaron diferencias estadísticas significativas entre sexos en cada uno de los períodos. Las tasas crudas y específicas de mortalidad experimentaron una tendencia sostenida al incremento. Cada 0,3 días (aproximadamente cada 8 horas) ocurrió una defunción por cáncer, con diferencias entre las localizaciones. Conclusiones: la tendencia al incremento sostenido de las tasas de mortalidad cruda y ajustada por edad se debe al aumento de las defunciones, pudiendo ser consecuencia, en parte, del envejecimiento poblacional y de un posible incremento de la morbilidad. El sexo masculino apareció como el más expuesto. La frecuencia de la mortalidad por cáncer fue diferente según localizaciones (AU).

ABSCRACT Introduction: Steady increase in time characterized the mortality by malignant tumors in the world as in Cuba. It was observed similar trend in the province of Matanzas in the last 30 years, almost in all body sites, showing higher or less intensity. Objective: To describe some characteristics of mortality by malignant tumors in the province of Matanzas Materials and methods: It is a descriptive observational and retrospective study of the mortality by malignant tumors for 30 years: 1990-2019. Crude and adjusted mortality rates were estimated, globally, by periods and sex. Percentages were estimated and statistical significance was determined through X2 test and p value < 0,05. Results: Statistical significant differences were detected among sexes in all periods. Crude and specific mortality rates showed an increasing steady trend. Every 0.3 days (around 8 hours) one decease took place due to malignant tumors, with differences among sites of the disease. Conclusions: The increasing steady trend of the crude & adjusted mortality rates by age could be, partly, results of the population ageing. Male sex appeared to be the most exposed. Mortality frequency by malignant tumors was different according to sites of the tumor (AU).

Avaliação da morbidade hospitalar e mortalidade por neoplasia: 2015 - 2019 / Evaluation of Hospital Morbity and Neoplasm Mortality: 2015 ­2019 / Evaluación de Morbidad Hospitalaria yMortalidad por Neoplasma: 2015-2019

Introdução:Atualmente, um dos maiores problemas de saúde pública trata-se das doenças crônicas não transmissíveis, que têm gerado elevado número de mortes prematuras. Objetivo:Analisar a morbidade hospitalar e mortalidadepor neoplasiasna população com faixa-etária entre 10 e 59 anos no Brasil, no período de 2015 a 2019.Metodologia:Trata-se de um estudo quantitativo, do tipo observacional, cujo método de investigação caracteriza-se por um estudo epidemiológico ecológico de série temporal em uma série histórica dos últimos cinco anos (2015-2019) disponíveis em meados de Abril de 2021, e extraídos da base nacional de domínio público do Ministério da Saúde intituladadeDepartamento de Informática do Sistema Único de Saúde.Resultados:Observou-seque a distribuição da taxa de mortalidade por neoplasia, por 100.000 habitantes por causa do código relativo à classificação de doençasem população com faixa etária entre 10 e 59 anos, se deu por Neoplasia maligna da mama, como segunda causa de mortes por Neoplasia no quinquênio, seguido por Neoplasia maligna da traqueia, dos brônquios e dos pulmões, Neoplasia maligna do cólon, do reto e do ânus, Neoplasia maligna do estômago e Neoplasia maligna das meninges, do encéfalo e de outras partes do sistema nervoso central.Quanto a taxa de morbidade hospitalar a partir das causas de maior prevalência observa-se que o Leiomioma do útero apresenta maior média no período observado (39.454), mediana de 38.88 e desvio padrão de 2.03, seguido por outras neoplasias in situ e neoplasias benignas e neoplasias de comportamento incerto ou desconhecido com média em 31.724, mediana 30.88 e desvio padrão 0.66.Conclusões:A análise de indicadores da saúde por neoplasias demonstra a tendencia crescente no quinquênio da morbidade hospitalar e mortalidade. De modo que se destacam que sejam alvo de maiores pesquisas e atenções (AU).

Introduction:Currently, one of the biggest public health problems is chronic non-communicable diseases, which have generated a high number of premature deaths.Objective:To analyze hospital morbidity and mortality by neoplasms in the population aged between 10 and 59 years in Brazil, in the period from 2015 to 2019.Methodology:This is a quantitative, observational study, whose research method is characterized by anecological epidemiological study of time series in a historical series of the last five years (2015-2019) available in mid-April 2021, and extracted from the national public domain base of the Ministry of Health entitled Department of Informatics of the Unified Health System.Results:It was observed that the distribution of the mortality rate due to neoplasia, per 100,000 inhabitants due to disease classification code in a population aged between 10 and 59 years, was due to malignant neoplasm of the breast, as the second leading cause of deaths due to neoplasia in the five-year period, followed by malignant neoplasm of the trachea, bronchi and lungs, malignant neoplasm of the colon, rectum and anus, malignant neoplasm of the stomach and malignant neoplasm of the meninges, brain and other parts of the central nervous system. Regarding the hospital morbidity rate from the most prevalent causes, it is observed that the uterus leiomyoma has the highest average in the period observed (39,454), median of38.88 and standard deviation of 2.03, followed by other in situ neoplasms and benign neoplasms and neoplasms of uncertain or unknown behavior with a mean of 31,724, a median of 30.88 and a standard deviation of 0.66.Conclusions:The analysis of health indicators for neoplasms shows the growing trend in the five years of hospital morbidity and mortality. So that they stand out that they are the target of more research and attention (AU).

Introducción: Actualmente, uno de los mayores problemas de salud pública son las enfermedades crónicas no transmisibles, las cuales han generado un elevado número de muertes prematuras.Objetivo: Analizar la morbilidad y mortalidad hospitalaria por neoplasias en la población de 10 a 59 años en Brasil, en el período de 2015 a 2019.Metodología: Se trata de un estudio observacional cuantitativo, cuyo método de investigación se caracteriza por un estudio epidemiológico ecológico de series de tiempo en una serie histórica de los últimos cinco años (2015-2019) disponible a mediados de abril de 2021, y extraída de la base de dominio público nacional. del Ministerio de Salud titulado Departamento de Informática del Sistema Único de Salud.Resultados: Se observó que la distribución de la tasa de mortalidad por neoplasia, por 100.000 habitantes por código de clasificación de enfermedades en una población de entre 10 y 59 años, se debió a neoplasia maligna de mama, como segunda causa de muerte. debido a neoplasia en el período de cinco años, seguida de neoplasia maligna de la tráquea, bronquios y pulmones, neoplasia maligna del colon, recto y ano, neoplasia maligna del estómago y neoplasia maligna de las meninges, cerebro y otras partes del sistema nervioso central. En cuanto a la tasa de morbilidad hospitalaria por las causas más prevalentes, se observa que el leiomioma de útero tiene el promedio más alto en el período observado (39.454), mediana de 38,88 y desviación estándar de 2,03, seguido de otras neoplasias in situ y neoplasias y neoplasias benignas de comportamiento incierto o desconocido con una media de 31.724, una mediana de 30,88 y una desviación estándar de 0,66.Conclusiones: El análisis de los indicadores de salud por neoplasias muestra la tendencia creciente en los cinco años de morbilidad y mortalidad hospitalaria. Para que destaquen que son objeto de más investigación y atención (AU).

O receptor aril de hidrocarbonetos (AhR) em melanomas: associação com mutações BRAF, com a progressão da doença e identificação de ligantes / The aryl hydrocarbon receptor (AhR) in melanomas: association with BRAF mutations, with disease progression and ligand identification

O melanoma é um tipo de câncer de pele geneticamente diverso, que surge diante das transformações em melanócitos. A mutação BRAFV600E está presente em mais de 90% de todas as mutações em BRAF, sendo assim ocorre em cerca de 50% dos casos registrados. As mutações em NRAS, ocupam o segundo lugar entre as mutações mais prevalentes, cerca de 20% dos casos. Informações sobre as assinaturas genéticas, permitiram o desenvolvimento de terapia alvo dirigida. O Vemurafenib, inibidor da quinase BRAFV600E, apresentou inicialmente resultados bastante satisfatórios, contudo existe registro de casos de recidiva e resistência. O receptor aril de hidrocarbonetos é expresso em vários componentes da pele, e assim está relacionado a homeostase e fisiopatologia da pele. Diante disso, a avaliação da expressão do receptor em um painel de linhagens mutadas para NRAS e BRAF, e BRAF resistentes, mostrou-se maior do que a encontrada em melanócitos. Também encontramos maior expressão de mRNA de AhR em linhagens de melanoma derivadas de sítio primário e metastático, mutadas para BRAFV600E, quando comparadas ao melanócito. Agregado a isto, a análise in silico no TCGA (The Cancer Genome Atlas) mostrou que há 18% de alteração genética em AhR, sendo em maior parte a alta regulação de mRNA. Também, a análise do banco público GSE12391, mostrou aumento de mRNA de AhR na fase de crescimento vertical do melanoma. Assim, concluímos que há maior expressão de mRNA e sua importância nas fases de desenvolvimento do melanoma, tanto nos processos iniciais quanto em processos de migração, invasão e metástase. Ainda, encontramos maior mRNA do receptor em linhagens resistentes ao Vemurafenib. Este resultado sustenta a hipótese de que AhR pode ser considerado um marcador de resistência em melanomas. O AhR, inicialmente no citoplasma, quando ativado pode atuar como fator de transcrição regulando vários genes que apresentam sequências definidas, participando de respostas carcinogênicas. Compostos halogenados e moléculas endógenas derivadas das vias de metabolização do triptofano são agonistas do receptor. Anteriormente, nosso grupo mostrou que linhagens de melanoma incubadas com triptamina e DMT exibiram menor clonogenicidade. Diante de uma literatura escassa sobre o papel do DMT no melanoma e com base nestes resultados, nosso objetivo foi avaliar o papel de AhR nesta interface DMT-melanoma. Para isto, nosso objetivo foi construir linhagem editada geneticamente para AhR através da ferramenta CRISPR-Cas9. Vários foram os esforços, sem sucesso, utilizados nas tentativas de comprovar a manutenção de células editadas na cultura. Atrelamos a este resultado a possibilidade de haver duas subpopulações editadas geneticamente pós CRISPR-Cas9, onde uma destas manteve o padrão de crescimento semelhante às células wild type. Devido a este crescimento diferencial, não obtivemos congruências nos ensaios e postulamos a perda do possível nocaute. A partir disso, realizamos ensaios de interactoma para avaliar a interação de DMT-AhR. Nosso resultado sugere a interação de DMT ao receptor sigma 1, e não ao receptor aril de hidrocarbonetos. Desta forma, o interactoma sustenta a hipótese de que DMT não é um ligante de AhR. Para certificar este resultado análises de docking associados a ensaios biológicos, avaliando o papel do receptor, devem ser realizados para averiguar a afinidade e seletividade de DMT como ligante do receptor na linhagem de melanoma

Melanoma is a genetically diverse type of skin cancer, which arises from changes in melanocytes. The BRAFV600E mutation is present in more than 90% of all BRAF mutations, so it occurs in about 50% of registered cases. Mutations in NRAS occupy the second place among the most prevalent mutations, about 20% of cases. Information on genetic signatures allowed the development of targeted therapy. vemurafenib, kinase inhibitor BRAFV600E, initially presented very satisfactory results, however there is a record of cases of relapse and resistance. The aryl hydrocarbon receptor is expressed in several components of the skin and is thus related to homeostasis and skin pathophysiology. Therefore, the evaluation of receptor expression in a panel of strains mutated to NRAS and BRAF, and resistant BRAF, proved to be greater than that found in melanocytes. We also found main expression of AhR mRNA in melanoma strains derived from primary and metastatic site, mutated to BRAFV600E, when compared to melanocyte. Added to this, the in silico analysis in TCGA (The Cancer Genome Atlas) showed that there is 18% of genetic alteration in AhR, being mostly the high regulation of mRNA. Also, an analysis by the public bank GSE12391, showed an increase in AhR mRNA in the vertical growth phase of melanoma. Thus, it is concluded that there is greater expression of mRNA and its importance in the stages of development of melanoma, both in recent processes and in the processes of migration, invasion and metastasis. In addition, we found higher receptor mRNA in strains resistant to vemurafenib. This result supports the hypothesis that AhR can be considered a marker of resistance in melanomas. AhR, initially in the cytoplasm, when activated can act as a transcription factor regulating several genes that have defined sequences, participating in carcinogenic responses. Along with this, we show that along the tumor progression, there is an increase in AhR in the radial growth phase of melanoma. Halogenated compounds and endogenous molecules derived from the tryptophan metabolism pathways are receptor agonists. Previously, our group showed that melanoma strains incubated with tryptamine and DMT exhibited less clonogenicity. In view of a scarce literature on the role of DMT in melanoma and based on these results, our objective was to evaluate the role of AhR in this DMT-melanoma interface. For this, our goal was to build genetically edited strain for AhR using the CRISPR-Cas9 tool. Several efforts were unsuccessful in attempts to prove the maintenance of cells edited in the culture. We linked to this result the possibility of having two subpopulations genetically edited after CRISPR-Cas9, where one of them maintained the growth pattern like wild type cells. Due to this differential growth, we did not obtain congruence in the tests and postulated the loss of the possible knockout. From that, we performed interactome assays to evaluate the DMT-AhR interaction. Our result suggests the interaction of DMT with the sigma 1 receptor, and not the aryl hydrocarbon receptor. Thus, the interactome supports the hypothesis that DMT is not an AhR ligand. To certify this result, docking analyses associated with biological assays, evaluating the role of the receptor, should be performed to ascertain the affinity and selectivity of DMT as a ligand of the receptor in the melanoma lineage

Functional outcomes and oncological fatigue among older cancer patients: a cross-sectional study

Abstract Aim: To characterize functional outcomes and oncological fatigue in older cancer patients, and verify the relation of these outcomes with age, number of hospitalizations, and falls within 12-months. Methods: Cross-sectional study involving 116 older adults with cancer undergoing treatment in a hospital in Santiago de Chile. Participants were assessed for independence on the activity of daily living (Barthel index), functional mobility with "timed up and go" (TUG) test, handgrip strength with a Baseline® Hydraulic Hand Dynamometer, and fatigue with Brief Fatigue Inventory. Information about the number of falls and hospitalizations from the previous 12-months was also collected. Results: 21.6% had experienced at least one fall during the previous 12-months, and 52% had been hospitalized over the same period. Handgrip strength was below the cut-off thresholds for older adults and 78.4% were classified with the risk of falls according to the TUG test. Forty-nine percent of participants experienced moderate fatigue, and 58% were dependent to perform activities of daily living. There was a correlation of TUG results with age (r = 0.204; p = 0.028). Conclusions: Older adults with cancer in our study experienced moderate fatigue, a high dependence to perform activities of daily living, especially those associated with mobility, dressing, and bladder or bowel function. Older adults with cancer are more likely to develop functional decline which leads to increased dependency or death. The data suggests they present functional impairment. Physical activity interventions would benefit this population.

Identificação de alterações bioquímicas em células epiteliais bronquiais humanas normais expostas a fumarato / Identification of biochemical changes in normal human bronchial epitelial cells exposed to fumarate

A reprogramação metabólica de células do câncer é apontada como uma característica essencial para o desenvolvimento da doença (cancer hallmark). Estudos mostram que mutações na enzima fumarato hidratase levam ao aumento da concentração intra e extracelular de fumarato, o que ocorre paralelamente à indução da transformação maligna. Neste trabalho, a fim de entender se o excesso de fumarato extracelular pode propiciar a transformação de células normais, foram quantificados alguns endpoints relacionados aos efeitos do fumarato e à transformação maligna, além de alterações metabólicas em células imortalizadas de epitélio brônquico humano normal (BEAS-2B) expostas ao fumarato. Uma vez que fumarato nas concentrações de 0,1 a 10 mM ao longo de 144 h não foi citotóxico, foram selecionadas as concentrações de 1 mM, 5 mM e 10 mM para as incubações. Fumarato induziu a formação de colônias em soft-agar após o período de sete dias (168 h) de exposição, o que indica a indução de transformação celular. Fumarato é um oncometabólito que inibe enzimas que dependem de α-cetoglutarato como co-substrato, dentre as quais as enzimas ten eleven translocation (TET) que catalisam a formação de 5-hidroximetilcitosina (5-hmC) a partir de 5-metilcitosina (5-mC), o primeiro passo da sequência de reações que levam à desmetilação do DNA. Os níveis totais de 5-hmC estavam diminuídos no DNA das células expostas. Colônias retiradas do soft-agar (controle, 1, 5 e 10 mM de fumarato) foram cultivadas e, após 90 dias em cultura, as células foram submetidas ao ensaio de invasão e migração em câmara de Boyden (transwell), tendo sido observada maior capacidade de migração/invasão das células anteriormente expostas ao fumarato. Foi observada indução de estresse redox nas células expostas ao fumarato. A partir da quantificação de metabólitos intracelulares por HPLC-ESI-MS/MS e HPLC-ESI-Q-TOF, verificamos que as células BEAS-2B absorveram o fumarato adicionado ao meio de cultura, o qual foi convertido intracelularmente a malato, aspartato, argininosuccinato, citrato, succinato e glutamato. O oncometabólito 2-L-hidroxiglutarato foi detectado em níveis aumentados nas células expostas a fumarato, assim como adenosina, enquanto que NAD+ e NADP+ apareceram diminuídos. As alterações metabólicas na presença de fumarato contribuíram para a manutenção do balanço energético das células, ou mesmo para um saldo positivo de energia. A exposição das células a [13C4]fumarato permitiu a análise do fluxo inicial do fumarato absorvido pelas células. A partir dessa análise verificamos que o fumarato absorvido entra no ciclo de Krebs, gerando malato, que é em grande parte desviado para reações externas ao ciclo, como a geração de aspartato e argininosuccinato. Citrato proveniente das reações de [13C4]fumarato no ciclo de Krebs foi detectado em níveis inferiores aos endógenos. O uso de [13C4]fumarato permitiu a visualização da geração de [13C4]succinato, que tem como possível fonte a atividade reversa da succinato desidrogenase. Verificamos também a geração de [13C3]glutamato. Supõe-se que as alterações metabólicas induzidas pelo fumarato absorvido pelas células BEAS-2B contribuam para a modulação da expressão de genes e da atividade de proteínas que favorecem o processo tumorigênico

The metabolic reprogramming of cancer cells is identified as an essential feature for the development of the disease (a cancer hallmark). Studies show that mutations in the enzyme fumarate hydratase lead to increased intra- and extracellular fumarate concentration, which occurs in parallel with the induction of malignant transformation. In this work, in order to understand if excess extracellular fumarate can lead to the transformation of normal cells, some endpoints related to the effects of fumarate and malignant transformation were quantified, as well as metabolic alterations in the immortalized normal human bronchial epithelial cell line BEAS-2B exposed to fumarate. Since fumarate at concentrations from 0.1 to 10 mM over 144 h was not cytotoxic, the concentrations of 1 mM, 5 mM and 10 mM were selected for incubations. Fumarate induced colony formation in soft agar after the seven day (168 h) exposure period, which indicates the induction of cell transformation. Fumarate is an oncometabolite that inhibits α-ketoglutarate-dependent enzymes, among which are ten eleven translocation (TET) enzymes that catalyze the formation of 5-hydroxymethylcytosine (5-hmC) from 5-methylcytosine (5-mC), the first step in the sequence of reactions leading to DNA demethylation. Total 5-hmC levels were decreased in the DNA of exposed cells. Colonies removed from the soft-agar (control, 1, 5 and 10 mM fumarate) were cultured and after 90 days in culture the cells were subjected to the Boyden chamber (transwell) invasion and migration assay, and a greater capacity for migration/invasion of cells previously exposed to fumarate was observed. Redox stress induction was observed in cells exposed to fumarate. From the quantification of intracellular metabolites by HPLC-ESI-MS/MS and HPLC-ESI-Q-TOF, we found that BEAS-2B cells absorbed the fumarate added to the culture medium, which was intracellularly converted to malate, aspartate, argininosuccinate, citrate, succinate and glutamate. The oncometabolite 2-L-hydroxyglutarate was detected at increased levels in cells exposed to fumarate, as well as adenosine, while NAD+ and NADP+ appeared decreased. Metabolic changes in the presence of fumarate contributed to the maintenance of the energy balance of the cells, or even to a positive energy balance. Exposure of cells to [13C4]fumarate allowed the analysis of the initial flow of the fumarate absorbed by the cells. From this analysis we found that the absorbed fumarate entered the Krebs cycle, generating malate, which was largely diverted to reactions outside the cycle, such as the generation of aspartate and argininosuccinate. Citrate from the reactions of [13C4]fumarate in the Krebs cycle was detected at levels lower than endogenous. The use of [13C4]fumarate allowed the detection of [13C4]succinate, which has as its possible source the reverse activity of succinate dehydrogenase. We also observed the generation of [13C3]glutamate. The metabolic changes induced by the absorbed fumarate are supposed to contribute to the modulation of gene expression and protein activity that favor the tumorigenic process