Resumen (Objetivo) Tryapanosoma cruzi, un agente causal de la enfermedad de Chagas, es un parásito que presenta una alternancia en su ciclo de vida entre un hospedador invertebrado (triatomino) y uno vertebrado (mamífero). Varios estudios han demostrado que en T. cruzi, HSP83 (homólogo de HSP90) es esencial para la división celular y el control de la respuesta al estrés térmico. Esta investigación se concentró en el estudio de la clonación, la caracterización bioinformática y la expresión del gen de la proteína de choque térmico HSP83 de T. cruzi para estudios posteriores sobre señalización. (Metodología) El ARN fue extraído de epimagostigotes T. cruci (clon EPm6/MOHM/VE/2007/ 6c), utilizando un kit comercial. El ADNc que codifica HSP83 se obtuvo utilizando RT-PCR, a partir del ARNm extraído, para lo cual se diseñaron los cebadores con base en la secuencia HSP83 de la cepa T. cruzi CL Brener. La clonación se realizó usando pGEM®T-Easy y se subclonó en el vector de expresión pQE30. Se efectuó la caracterización bioinformática y de secuencias. El gen se expresó y la proteína recombinante se purificó por cromatografía de afinidad, igual que se identificó por inmunotransferencia. (Resultados) El análisis de secuencia mostró similitud con el gen HSP83 de Trypanosoma cruzi y se observaron dominios HSP, así como epítopos B en la secuencia. Después de 3 horas de inducción con IPTG, se obtuvo una proteína recombinante con un peso aproximado de 83 kDa. La reacción de inmunotransferencia con suero hiperinmune anti-epimastigote de T. cruzi permitió la detección de una sola banda con un peso molecular de aproximadamente 83 kDa. (Conclusiones) Todos los resultados indican que se logró la clonación y caracterización de HSP83 de Trypanosoma cruzi.

Resumo (Objetivo) O Tryapanosoma cruzi, agente causador da doença de Chagas, é um parasita que apresenta uma alternância em seu ciclo de vida entre um hospedeiro invertebrado triatomíneo) e um vertebrado(mamífero). Vários estudos demonstraram que, no T. cruzi, a HSP83 (homóloga da HSP90) é essencial para a divisão celular e o controle da resposta ao estresse térmico. Esta pesquisa concentrou-se no estudo da clonagem, caracterização bioinformática e expressão do gene da proteína de choque térmico HSP83 do T. cruzi para estudos adicionais de sinalização. (Metodologia) O RNA foi extraído de epimastigotas de T. cruzi (clone EPm6/MOHM/VE/2007/ 6c) usando um kit comercial. O cDNA que codifica a HSP83 foi obtido por meio de RT-PCR a partir do mRNA extraído, para o qual os primers foram projetados com base na sequência da HSP83 da cepa T. cruzi CL Brener. A clonagem foi realizada com o pGEM®T-Easy e subclonada no vetor de expressão pQE30. Foi realizada a caracterização bioinformática e de sequência. O gene foi expresso e a proteína recombinante foi purificada por cromatografia de afinidade e identificada por imunotransferência. (Resultados) A análise da sequência mostrou similaridade com o gene HSP83 do Trypanosoma cruzi e os domínios HSP, bem como os epítopos B, foram observados na sequência. Após 3 horas de indução com IPTG, foi obtida uma proteína recombinante com peso aproximado de 83 kDa. A imunotransferência com soro hiperimune antiepimastigota de T. cruzi permitiu a detecção de uma única banda com peso molecular de aproximadamente 83 kDa. (Conclusões) Todos os resultados indicam que a clonagem e a caracterização da HSP83 do Trypanosoma cruzi foram alcançadas.

Abstract (Objective) Trypanosoma cruzi, a causal agent of Chagas’ disease, is a parasite whose life cycle alternates between an invertebrate (triatomine) and a vertebrate (mammal) host. Various studies have shown that in T. cruzi, HSP83 (a homolog of HSP90) is essential for cell division and control of the response to thermal stress. This investigation focused on studying the cloning, bioinformatic characterization, and expression of the heat shock protein HSP83 T. cruzi gene for further cell signaling studies. (Methodology) RNA was extracted from T. cruzi epimastigotes (EPm6 clone, MHOM/VE/2007/ 6c) using a commercial kit. The cDNA encoding HSP83 was determined using RT-PCR on extracted mRNA, for which the primers were designed based on the HSP83 sequence of T. cruzi strain CL Brener. Cloning was performed using pGEM®T-Easy and subcloned into the expression vector pQE30. Sequence and bioinformatic characterization were performed. The gene was expressed, and the recombinant protein was purified using affinity chromatography and identified through immunoblotting. (Results) Sequence analysis showed similarity to the gene encoding HSP83 from Trypanosoma cruzi, and HSP domains and B epitopes in the sequence were also observed. After 3 hours of induction with IPTG, a recombinant protein with an approximate weight of 83 kDa was obtained. The immunoblotting reaction with hyperimmune anti-T. cruzi epimastigote serum helped detect a single band with a molecular weight of nearly 83 kDa. (Conclusions) All results indicate that the cloning and characterization of HSP83 from Trypanosoma cruzi was achieved.

SUMMARY OBJECTIVE: Vascular endothelial growth factor is a signaling protein created by cells performing important bodily functions. Vascular endothelial growth factor is abundant in the lung, and plasma levels are elevated in patients with severe pulmonary arterial hypertension. An association between soluble urokinase plasminogen activator receptor, an inflammatory biomarker, and soluble urokinase plasminogen activator receptor levels and interstitial pulmonary and vascular involvement (e.g., development of pulmonary hypertension) has been shown in SSc patients. The tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio, which has been recommended as a useful diagnostic tool in the last guideline, is one of the additional echocardiographic signs suggestive of pulmonary hypertension. We aimed to examine whether these biomarkers contribute to the diagnosis and management of pulmonary hypertension. METHODS: Patients with group E chronic obstructive lung disease were included in this prospective study. Demographic data, echocardiographic signs about the right ventricle (right atrium area, tricuspid annular plane systolic excursion/systolic pulmonary artery pressure, fractional area change, and right ventricular outflow tract), and peripheral blood analysis were examined and recorded. RESULTS: A total of 70 patients, 12 of whom were female, were analyzed in the study. The mean age was 66.6±8.7 years. The mean vascular endothelial growth factor-A and soluble urokinase plasminogen activator receptor were 91.05±70.7 and 955.8±571.1, and their Pearson correlation coefficients between vascular endothelial growth factor-A and tricuspid annular plane systolic excursion/systolic pulmonary artery pressure, and soluble urokinase plasminogen activator receptor and tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio were 0.341 (p=0.004) and −0.045 (p=0.70), respectively. The linear regression model included four variables with significant correlation (vascular endothelial growth factor-A, right atrium area, fractional area change, and right ventricular outflow tract). Three steps were performed, and adjusted r2 was 0.22, 0.22, 0.20, and p<0.001 for each step. Vascular endothelial growth factor-A and right ventricular outflow tract remained in the last step. It was detected a standardized coefficient beta of 0.322 (p=0.004) and a 95%CI 0.000–0.001 for vascular endothelial growth factor-A. CONCLUSION: Vascular endothelial growth factor-A is correlated with the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio and not with soluble urokinase plasminogen activator receptor. OBJECTIVE functions hypertension biomarker e.g., eg e g (e.g. excursionsystolic excursion guideline METHODS study data change tract, , tract) recorded RESULTS 7 1 female 66687 66 6 8 66.6±8. years factorA 9105707 91 05 91.05±70. 95585711 955 571 955.8±571.1 0341 0 341 0.34 p=0.004 p0004 p 004 (p=0.004 0045 045 −0.04 p=0.70, p070 p=0.70 (p=0.70) respectively factorA, A, tract. . performed r 022 22 0.22 020 20 0.20 p0001 001 p<0.00 step 0322 322 0.32 95CI CI 95 00000001 000 0.000–0.00 factorA. A. CONCLUSION e.g. (e.g 6668 66.6±8 910570 9 91.05±70 9558571 57 955.8±571. 034 34 0.3 p=0.00 p000 00 (p=0.00 04 −0.0 p07 p=0.7 (p=0.70 02 2 0.2 p<0.0 032 32 0000000 0.000–0.0 e.g 666 66.6± 91057 91.05±7 955857 5 955.8±571 03 3 0. p=0.0 p00 (p=0.0 −0. p0 p=0. (p=0.7 p<0. 000000 0.000–0. 66.6 9105 91.05± 95585 955.8±57 (p=0. −0 p=0 p<0 00000 0.000–0 66. 910 91.05 9558 955.8±5 (p=0 − p= p< 0000 0.000– 91.0 955.8± (p= 0.000 91. 955.8 (p 0.00 955. 0.0

RESUMEN: Resveratrol (RES) y quercetina (QRC), es un agente prometedor y relevante tanto para la quimioprevención como para el tratamiento del cáncer a través de varias vías de señalización, involucrado en su actividad anticancerígena relacionada con su potencial quimioterapéutico, asociado con la inducción de la generación de especies reactivas del oxígeno (ROS) en células cancerosas, lo que lleva a apoptosis. En nuestro estudio, hemos resumido los mecanismos de acción de RES y QRC, y sus implicaciones farmacológicas y posibles aplicaciones terapéuticas en la terapia del cáncer. Después del tratamiento de las células Hep 2 con QRC o RES, las vías de muerte, tal como la liberación de citocromo c, las vías ERK1/2 e IRS-1, se regulaban positivamente, mientras que la vía de supervivencia celular, incluida PI3K/AKT, se regulaba negativamente. El RES y el QRC provocaron oncosis, hipertrofia celular, hipercondensación de la cromatina, rotura de la membrana plasmática y nuclear y formación de cuerpos apoptóticos. Las mediciones morfométricas de algunos parámetros celulares y nucleares mostraron que RES y QRC indujeron un aumento en las células y el tamaño nuclear, la proporción nucleocitoplasmática se mantuvo por debajo de 1 (N- Cyt R <1), signo de baja actividad nuclear. RES y QRC indujeron la apoptosis de las células Hep2 aumentando los marcadores de estrés oxidativo, MDA, y modulando las enzimas desintoxicantes, CAT y SOD. Los resultados de nuestro estudio demuestran las propiedades antiproliferativas y proapoptóticas de la quercetina y el resveratrol con respecto al cáncer de laringe.

SUMMARY: Resveratrol (RES) and quercetine (QRC), is a promising agent relevant for both cancer chemoprevention and treatment via several signaling pathways, involved in their anticancer activity related to its chemotherapeutic potential, associated with the induction of ROS generation in cancer cells, leading to apoptosis. In our study, we have summarized the mechanisms of action of RES and QRC, and their pharmacological implications and potential therapeutic applications in cancer therapy. After treatment of Hep 2 cells with QRC or RES, the death pathways such as the cytochrome c release, ERK1/2 and IRS-1 pathways were upregulated, while cell survival pathway, including PI3K/AKT were downregulated. The RES and QRC caused oncosis, cells hypertrophy, hypercondensatin of chromatin, rupture of the plasma membrane and nuclear membrane, and formation of apoptotic bodies. Morphometric measurements of some cellular and nuclear parameters showed that RES and QRC induced an increase in cells and nuclear size, the nucleocytoplasmic ratio remained below 1 (N-Cyt R < 1), sign of low nuclear activity. The RES and QRC induced apoptosis of Hep2 cells by increasing of oxidative stress markers, MDA, and by modulating detoxifying enzymes, CAT and SOD. Our study results prove antiproliferative and proapoptotic properties of quercetin and resveratrol with regard to larynx cancer.

Abstract Background Molecularly targeted therapies, such as monoclonal antibodies (mAbs) and Janus Kinase inhibitors (JAKis), have emerged as essential tools in the treatment of dermatological diseases. These therapies modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. This review aims to provide an updated summary of targeted immune therapies for inflammatory skin diseases, considering their pathophysiology, efficacy, dosage, and safety profiles. Methods The review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A systematic search was conducted on PubMed over the past 10 years, focusing on randomized clinical trials, case reports, and case series related to targeted immune therapies in dermatology. Eligibility criteria were applied, and data were extracted from each study, including citation data, study design, and results. Results We identified 1360 non-duplicate articles with the initial search strategy. Title and abstract review excluded 1150, while a full-text review excluded an additional 50 articles. The review included 143 studies published between 2012 and 2022, highlighting 39 drugs currently under investigation or in use for managing inflammatory skin diseases. Study limitations The heterogeneity of summarized information limits this review. Some recommendations originated from data from clinical trials, while others relied on retrospective analyses and small case series. Recommendations will likely be updated as new results emerge. Conclusion Targeted therapies have revolutionized the treatment of chronic skin diseases, offering new options for patients unresponsive to standard treatments. Paradoxical reactions are rarely observed. Further studies are needed to fully understand the mechanisms and nature of these therapies. Overall, targeted immune therapies in dermatology represent a promising development, significantly improving the quality of life for patients with chronic inflammatory skin diseases. mAbs (mAbs JAKis, JAKis , (JAKis) diseases pathways agents pathophysiology efficacy dosage profiles Metaanalyses Meta PRISMA (PRISMA guidelines 1 years trials reports applied design 136 nonduplicate non duplicate strategy 1150 fulltext full text 5 14 201 2022 3 emerge treatments observed Overall development (JAKis 13 115 20 202 11 2

ABSTRACT Introduction: Although most individuals recover after acute infection by SARS-CoV-2, others may suffer from persistent symptoms with potential medium and long-term consequences on the performance of activities and participation, with possible implications for their fitness for work. Objective: To analyze the persistence of symptoms twelve months after SARS-CoV-2 infection, and the perception of the performance level in activities and participation in life situations, of workers in a company of the industrial sector in the Aveiro Region. Methodology: An observational study, developed in an Occupational Health Service of an industrial company in the region of Aveiro, including workers with positive SARS-COV-2 RT-PCR/TRAg test, between October/2020-January/2022. After signaling the infection, the Occupational Health Team applied a questionnaire collecting sociodemographic variables, a list of common symptoms during the acute phase of infection by SARS-COV-2, and the perceived functionality assessed by the Portuguese version of WHODAS 2.0-PT12 (where '12 points' means the most functionality). At twelve months, they filled out another list of persistent symptoms after SARS-CoV-2 infection and again WHODAS 2.0-PT12. Data analysis included descriptive statistics and univariate and multivariate linear regression. The analysis was conducted with the software JASP 0.16.3. Results: Eighty-five workers were infected with SARS-CoV-2, with a mean age of 36.1± 9.8years, 77.7% were male, 36.7% had higher education and 17.7% reported at least one chronic condition. At twelve months, thirty workers (35.3%) reported persistent symptoms, with fatigue (27.7%) and arthralgia (14.4%) being the most mentioned. The mean WHODAS 2.0 in the two evaluation moments was 19.2±8.0 vs 15.7±5.0. Significant associations between WHODAS 2.0 items and persistent symptoms of fatigue, headache, cough, myalgia, arthralgia, and previous chronic disease were found. Conclusions: Persistent symptoms twelve months after acute SARS-CoV-2 infection have repercussions on workers' self-perception of performance in some activities and participation in life situations. The occupational health team can implement continuous surveillance of the infected worker's health, assess the presence of persistent symptoms of this infection, and implement an individualized rehabilitation program, which minimizes the impact of the persistence of symptoms on their work performance, and in activities and participation in life situations.

RESUMO Introdução: Embora a maioria dos indivíduos recupere após a infeção aguda por SARS-CoV-2, outros podem apresentar sintomas persistentes com potenciais consequências a médio e longo prazo no desempenho de atividades e participação, com eventuais implicações na sua aptidão para o trabalho. Objetivo: Analisar a persistência de sintomas aos doze meses após infeção por SARS-CoV-2 e perceção do nível de desempenho em atividades e participação em situações de vida de trabalhadores do setor industrial numa empresa da Região de Aveiro. Metodologia: Estudo observacional, desenvolvido num Serviço de Saúde Ocupacional de uma empresa industrial da região de Aveiro, incluindo trabalhadores com teste SARS-COV-2 RT-PCR/TRAg positivo, entre outubro/2020-janeiro/2022. Após sinalização da infeção, a Equipa de Saúde Ocupacional aplicou um questionário recolhendo as variáveis sociodemográficas, uma lista de sintomas comuns durante a fase aguda da infeção por SARS-COV-2 e a funcionalidade percebida avaliada pela versão portuguesa da WHODAS 2.0-PT12 (onde '12 pontos' significa a maior funcionalidade). Aos doze meses, preencheram outra lista de sintomas persistentes após a infeção por SARS-CoV-2 e novamente a WHODAS 2.0-PT12. A análise dos dados incluiu estatística descritiva e regressão logística univariada e multivariada. A condução da análise foi realizada com o software JASP 0,16.3. Resultados: Oitenta e cinco trabalhadores encontravam-se infetados com SARS-CoV-2, com idade média de 36,1±9,8anos, 77,7% eram do sexo masculino, 36,7% possuíam escolaridade superior e 17,7% relataram pelo menos uma condição crónica. Aos doze meses, trinta trabalhadores (35,3%) relataram sintomas persistentes, sendo a fadiga (27,7%) e artralgia (14,4%) os mais mencionados. A média da WHODAS 2.0 nos dois momentos de avaliação foi 19,2±8,0 vs 15,7±5,0. Foram encontradas associações significativas entre os itens da WHODAS 2.0 e os sintomas persistentes fadiga, cefaleia, tosse, mialgia, artralgia e doença crónica prévia. Conclusões: Os sintomas persistentes doze meses após a infeção aguda por SARS-CoV-2 têm repercussão na autoperceção do desempenho em algumas atividades e participação em situações de vida dos trabalhadores. A equipa de saúde ocupacional deve realizar a vigilância contínua da saúde do trabalhador infetado, avaliando a presença de sintomas persistentes desta infeção e poderá implementar um programa de intervenção individualizado, que minimize o impacto da persistência dos sintomas no seu desempenho laboral, assim como, em atividades e participação em situações de vida.

ABSTRACT SARS-CoV-2 and its consequences constitute a challenge for global public health. The impact on the structure-function relationship at the lung level is an area of active research, where post-COVID-19 pulmonary fibrosis stands out worryingly. CIMAvax-EGF® is a vaccine that induces a powerful anti-EGF immune response and is used in the treatment of oncological diseases such as lung neoplasms. Clinical trials have demonstrated a strong safety profile, despite this being a vulnerable population. Among the key molecular pathways in fibrosis, transforming growth factor beta stands out for its role, based on its critical activity in myofibroblastic transformation and epithelial-mesenchymal transition; at the molecular level, signaling mediated by the epidermal growth factor receptor is a point of confluence between fibrosis and neoplasms of epithelial origin. In this context, the results of the introduction of CIMAvax-EGF® in the treatment of patients with advanced non-small cell lung neoplasia suggest a clinically significant containment effect. In this manuscript, we address, based on experimental and clinical evidence, the assumptions that rationally justify a measurable therapeutic benefit in patients with post-COVID-19 respiratory disorders, with the use of CIMAvax-EGF®.

RESUMEN El SARS-CoV-2 y sus secuelas se constituyen reto para la salud pública global. La repercusión sobre la relación estructura-función a nivel pulmonar, es un área de investigación activa, donde la fibrosis pulmonar pos-COVID-19 destaca preocupantemente. CIMAvax-EGF® es un vacunal inductor de una potente respuesta inmune anti-EGF y es empleada en el tratamiento de enfermedades oncológicas como las neoplasias de pulmón. Los ensayos clínicos han demostrado un sólido perfil de seguridad, a pesar de ser esta una población vulnerable. Entre las rutas moleculares calves en la fibrosis, destaca por su rol el factor de crecimiento transformante beta, en base a su actividad crítica en la trasformación miofibroblástica y la transición epitelio-mesénquima; a nivel molecular la señalización mediada por el receptor de factor de crecimiento epidérmico es un punto de confluencia entre la fibrosis y las neoplasias de origen epitelial. En este contexto los resultados de la introducción de CIMAvax-EGF® en el tratamiento de pacientes con neoplasia de pulmón de células no pequeñas avanzada, sugieren un efecto de contención clínicamente significativo. En este manuscrito abordamos, en base a evidencias experimentales y clínicas, los supuestos que justifican racionalmente un beneficio terapéutico medible en pacientes con trastornos respiratorios post-COVID-19, con el uso de CIMAvax-EGF®.

Abstract: Atopic dermatitis (AD) is a chronic, non-infectious inflammatory dermatosis, with increasing prevalence in recent decades. Due to its chronic and recurrent nature, it diminishes the quality of life of patients and their families. In recent years, advances in the understanding of AD’s pathophysiology have driven the development of targeted therapies such as monoclonal antibodies (mAbs) and Janus kinase inhibitors (JAKis) which modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. Four targeted therapies have been approved in the USA for the treatment of severe/refractory cases: dupilumab, tralokinumab, abrocitinib, and upadacitinib. This manuscript aims to present an update on the pathophysiology of AD, describe the new treatments available, and provide an analysis of the initial results of the use of these treatments in the pediatric population. We concluded that the high cost of these treatments often limits their prescription to situations where cases of atopic dermatitis are resistant to other conventional therapeutic options or when the disease reaches a severe degree. This underscores the importance of careful and accurate decision-making in the medical management of AD to ensure the efficient use of these therapeutic resources.

Resumen: La dermatitis atópica (DA) es una dermatosis crónica e inflamatoria no infecciosa, con prevalencia creciente en las últimas décadas. De curso crónico y recurrente, deteriora la calidad de vida de los pacientes y su familia. Los avances en la comprensión de la fisiopatología de la DA han impulsado el desarrollo de terapias dirigidas, como los anticuerpos monoclonales (mAb) y los inhibidores de la quinasa Janus (JAKis), las cuales modulan el sistema inmunológico a través de vías de señalización específicas, ofreciendo alternativas efectivas a los agentes inmunosupresores sistémicos tradicionales. En EE.UU. se han aprobado cuatro terapias dirigidas para el tratamiento de los casos severos/refractarios: dupilumab, tralokinumab, abrocitinib y upadacitinib. El objetivo de este manuscrito es presentar una actualización sobre la fisiopatología de la DA, describir los nuevos tratamientos disponibles y realizar un análisis de los resultados iniciales de la utilización de dichos tratamientos en pediatria. Se concluye que el alto costo de estos tratamientos suele limitar su prescripción a situaciones en las que los casos de DA son resistentes a otras opciones terapéuticas convencionales o cuando su curso es severo. Se resalta la importancia de toma de decisiones cuidadosa y precisa en la atención médica de la DA, con el fin de garantizar el uso eficiente de estos recursos terapéuticos.

Abstract Parkinson's disease is caused by the death process of dopaminergic neurons in the substantia nigra, pars compacta of the brain. Although its etiology is unknown, the finding of Lewy bodies, formed by alpha-synuclein, in the intestine suggests a source of microbial production that travels to the central nervous system, mainly through the pneumogastric nerve. To understand how the microbiota-gut-brain axis works and influences a healthy person or person with Parkinson's disease, a systematic review of scientific articles from the last five years was carried out in the Scopus database. It has been shown that the signaling network that regulates the microbiota-gut-brain axis in a bidirectional communication network is present during the neurodevelopment of the individual and at the onset of Parkinson's disease, therefore, the microbiota represents the entry point of internal factors that disrupt communication and neurological dysfunction. As the diversity of the microbiota changes at various stages of the individual's development for multiple reasons, such as diet, hygiene patterns, interaction with animals and parasites, and medication, among other factors; it is necessary to know the state of the current microbiota, understand its function in the enteric nervous system and its influence on the central nervous system, especially if it is the etiopathogenesis of neurodegenerative diseases. The discovery of diagnostic biomarkers and neuroprotective therapies holds the promise of significantly improving the quality of life for individuals with Parkinson's disease.

Resumen La enfermedad de Parkinson es producida por un proceso de muerte de neuronas dopaminérgicas en la sustancia negra, pars compacta del cerebro. Aunque su etiología es desconocida, el hallazgo de cuerpos de Lewy, constituidos por alfa sinucleína, en el intestino sugiere una fuente de producción microbiana que viaja hasta el sistema nervioso central, principalmente a través del nervio vago. Para comprender cómo funciona el eje microbiota-intestino-cerebro e influye en una persona sana o con enfermedad de Parkinson, se realizó una revisión sistemática de artículos científicos de los últimos cinco años en la base de datos Scopus. Se ha demostrado que la red de señalización que regula el eje microbiota-intestino-cerebro en una comunicación bidireccional está presente durante el neurodesarrollo del individuo y en el inicio de la enfermedad de Parkinson, por lo tanto, la microbiota representa la vía de entrada de factores internos que generan la desregulación de la comunicación y una disfunción neurológica. Como la diversidad de la microbiota cambia en diversas etapas del desarrollo del individuo por múltiples razones, como hábitos alimentarios, patrones de higiene, interacción con animales y parásitos, medicación, entre otros; es necesario conocer el estado de la microbiota actual, comprender cuál es su función en el sistema nervioso entérico e influencia en el sistema nervioso central, sobre todo si se trata de la etiopatogenia de enfermedades neurodegenerativas. El descubrimiento de biomarcadores de diagnóstico y una terapia neuroprotectora ayudará a mejorar la calidad de vida de personas con enfermedad de Parkinson.

Abstract Objectives: This paper aims to review data on the association of obesity and iron deficiency in children and adolescents, exposing the possible involvement of hepcidin and interleukin-6 (IL-6), obesity’s inflammation biomarkers. Data source: Articles from PUBMED and WEB OF SCIENCE database with no chronological limit were reviewed to write this systematic review. Keywords such as children, obesity, iron deficiency, and hepcidin were used. After deleting duplicated and review articles, 91 were screened, and 39 were selected as eligible. Sixteen articles were included because they involved serum hepcidin levels in obese children and adolescents as outcomes. Summary of findings: Finally, those 16 articles were organized in two tables: one includes therapeutic interventions, and the other does not. As hepcidin was discovered in 2000, the first articles that presented serum hepcidin’s quantification in obese children and adolescents, homeostasis iron markers, and their possible association with obesity’s inflammatory environment began to be published in 2008. Conclusions: Obesity’s chronic inflammation state leads to the production of IL-6, which acts as a signaling molecule for hepcidin synthesis, resulting in iron deficiency, which is common in obese children and adolescents who respond inadequately to iron supplementation. On the other hand, that population responds adequately to therapeutic intervention programs that lead to weight loss, guaranteeing iron homeostasis improvement. Therefore, perhaps it is time to discuss serum hepcidin level quantification as part of evaluating children and adolescents with iron deficiency, which could guide clinical choices that might lead to better therapeutic outcomes. Objectives interleukin6 interleukin 6 interleukin- IL6, IL6 IL , (IL-6) obesitys s biomarkers source used 9 screened 3 eligible outcomes findings Finally 1 tables interventions not 2000 hepcidins markers 2008 Conclusions Obesitys Obesity 6, IL-6 synthesis supplementation hand loss improvement Therefore (IL-6 200 IL- (IL- 20 (IL 2

ABSTRACT Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks receptors for targeted therapy. Deeper insight into the molecular mechanisms regulating TNBC metastasis is urgently needed. The epithelial-mesenchymal transition process facilitates the metastasis of neighboring epithelial tumor cells. Protein kinase, membrane-associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, is upregulated in BC, and its high expression predicts poor prognosis in BC patients. Notch signaling activation is a pathognomonic feature of TNBC. PKMYT1 has been found to induce EMT in non-small cell lung cancer by activating Notch signaling. However, whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling remains unknown. Objectives: The objective of this study was to investigate whether PKMYT1 exerts effects on TNBC progression by regulating Notch signaling. Methods: Fifty cases of surgically resected BC samples (tumor and adjacent non-tumor tissue samples) were collected from patients diagnosed with BC. We measured the expression of PKMYT1 in clinical samples with real-time quantitative polymerase chain reaction (RT-qPCR). For in vitro analysis, RT-qPCR and Western blotting were conducted to evaluate PKMYT1 expression in TNBC cells. Then, the viability, migration, and invasion of TNBC cells were detected by cell counting kit-8 assays, wound healing assays, and Transwell assays. The EMT event was examined by evaluating the levels of EMT-associated proteins. For in vivo analysis, xenograft models in nude mice were established to explore PKMYT1 roles. E-cadherin and Ki67 expression in xenograft models were estimated by immunohistochemistry staining. Hematoxylin and eosin staining was performed to assess tumor metastasis. The underlying mechanisms by which PKMYT1 affected the malignant phenotypes of TNBC cells were explored by Western blotting measuring the pathway-associated proteins. Results: PKMYT1 was upregulated in BC tissues and cells, and its knockdown prevented cell proliferation, migration, invasion, and EMT event in TNBC. Mechanistically, Notch signaling was inactivated by PKMYT1 depletion, and Notch activation abolished the PKMYT1 silencing-induced inhibition in the malignant phenotypes of TNBC cells. For in vivo analysis, PKMYT1 knockdown inhibited tumorigenesis and metastasis of TNBC. Conclusion: PKMYT1 promotes EMT, proliferation, migration, and invasion of TNBC cells and facilitates tumor growth and metastasis by activating Notch signaling.

ABSTRACT Background: Adriamycin (ADM) resistance remains an obstacle to gastric cancer chemotherapy treatment. Objective: The objective of this study was to study the role and mechanism of transcription factor E2F7 in sensitivity to ADM chemotherapeutic agents in gastric cancer. Methods: Cell viability and cell sensitivity were assessed by CCK-8 and IC50 values of ADM were calculated. The impact of ADM on cellular proliferative capacity was assessed through colony formation assay. The binding relationship between E2F7 and PKMYT1 was then verified by dual luciferase assay and chromatin immunoprecipitation assay. ERK1/ERK2 and p-ERK1/p-ERK2 protein expression levels were detected by western blot. Results: In both gastric cancer tissue and ADM-resistant cells, a conspicuous upregulation of E2F7 and PKMYT1 was observed. Upregulated PKMYT1 was notably enriched in the MAPK signaling pathway. Enhanced levels of E2F7 were shown to not only drive gastric cancer cell proliferation but also engender a reduction in the sensitivity of these cells to ADM. Furthermore, PKMYT1 emerged as a downstream target of E2F7. Activation of E2F7 culminated in the transcriptional upregulation of PKMYT1, and silencing E2F7 reversed the inhibitory impact of PKMYT1 overexpression on ADM sensitivity in gastric cancer cells. Conclusion: E2F7/PKMYT1 axis might promote the proliferation and partially inhibit ADM sensitivity of gastric cancer cells by activating the MAPK pathway.

Abstract Neuregulins (NRGs) are a family of signaling proteins that bind to receptor tyrosine kinases of the ErbB family (ErbB2 to ErbB4), which can homo- or heterodimerize depending on their structural features and cell type. Many studies have proposed that decreased NRG levels are a common characteristic of obesity. In liver and adipose tissue, the increase in NRG expression has protective effects against obesity. However, it is still unknown whether ErbBs expression is altered in this pathology. We hypothesized that high fat diet-induced obesity downregulates ErbB receptors expression in obese mice compared to normal weight mice. Males C57BL/6 mice (n=6-7 for each group) were fed for 12 weeks and divided into: (i) control diet (CD; 10%-kcal fat, 20%-kcal protein, 70%-kcal carbohydrates), and (ii) high fat diet (HFD; 60%-kcal fat, 20%-kcal protein, 20%-kcal carbohydrates). General parameters and ErbBs expression (qPCR, immunohistochemistry and Western blot) were evaluated. We observed a significant increase in final body weight (47%), adipose tissue to body weight ratio (244%) and HOMA-IR (69%), among other parameters, in obese mice. In HFD group significantly decreased ErbB2 (48%) and ErbB3 (66%) mRNA levels in liver (no change in ErbB4), and ErbB2 (43%), ErbB3 (76%) and ErbB4 (35%) in adipose tissue, compared to CD. Furthermore, ErbB2 and ErbB3 protein levels decreased significantly in HFD group compared to the CD in liver. Therefore, our results suggest that HFD-induced obesity significantly decreases ErbBs expression in liver and adipose tissue in this murine model, that may be associated with alterations in the NRG pathway in obese mice.

Resumen Las neuregulinas (NRGs) son una familia de proteínas de señalización que se unen a receptores tirosina quinasas de la familia ErbB (ErbB2 a ErbB4), que pueden homo- o heterodimerizar dependiendo de sus características estructurales y del tipo celular. Estudios han propuesto que la disminución de los niveles de NRG es una característica común de la obesidad. En el hígado y el tejido adiposo (TA), el aumento de la expresión de NRG tiene efectos protectores contra la obesidad. Sin embargo, aún se desconoce si la expresión de ErbBs está alterada en esta patología. Nuestra hipótesis es que la obesidad inducida por una dieta alta en grasas (DAG) disminuye la expresión de los ErbB en ratones obesos. Ratones machos C57BL/6 (n=6-7 para c/grupo) fueron alimentados durante 12 semanas y divididos en: (i) dieta control (DC; 10%-kcal grasa, 20%-kcal proteína, 70%-kcal carbohidratos), y (ii) DAG (60%-kcal grasa, 20%-kcal proteína, 20%-kcal carbohidratos). Se evaluaron los parámetros generales y la expresión de ErbBs (qPCR, inmunohistoquímica y Western blot). Observamos un aumento significativo del peso corporal final (47%), de la relación tejido adiposo/peso corporal (244%) y del HOMA-IR (69%), entre otros parámetros, en ratones obesos. En este grupo disminuyó significativamente los niveles de ARNm de ErbB2 (48%) y ErbB3 (66%) en el hígado (sin cambios en ErbB4), y de ErbB2 (43%), ErbB3 (76%) y ErbB4 (35%) en el TA. Además, los niveles de proteína ErbB2 y ErbB3 disminuyeron significativamente, en comparación con el grupo DC en el hígado. Nuestros resultados sugieren que la obesidad inducida por DAG disminuye significativamente la expresión de ErbBs en el hígado y el TA, que puede estar asociado con alteraciones en la vía NRG en ratones obesos.

RESUMEN El craneofaringioma es un tumor de histología benigna que, sin embargo, puede provocar graves secuelas por su ubicación y crecimiento en la región selar y supraselar. Se caracteriza por ser localmente agresivo dado su capacidad de invadir localmente, y por presentar una alta tasa de recurrencia. Histológicamente se describen dos tumores distintos, previamente considerados subtipos. El craneofaringioma adamantinomatoso es el más frecuente en niños y es causado por una mutación activante del gen CTNNB1, que codifica para una forma mutante de β-catenina. Por otro lado, el craneofaringioma papilar se presenta casi exclusivamente en adultos, y se asocia a mutaciones en el oncogen BRAF y activación de la vía de señalización MAPK. Los síntomas de ambos tipos tumorales son secundarios al déficit hormonal, a hidrocefalia o alteración visual. El tratamiento debe realizarse en centros con alta experiencia e involucra la participación de un equipo multidisciplinario, buscando un balance entre una resección amplia y la protección de la funcionalidad del hipotálamo. La radioterapia ha demostrado disminuir la recidiva tumoral. Actualmente existen nuevos tratamientos médicos basados en terapias targets moleculares.

ABSTRACT Craniopharyngioma is a tumor of benign histology, although it can cause serious sequelae due to its location and growth in the sellar and suprasellar region. It is characterized by being aggressive due to its ability to invade locally, and by its high recurrence rate. Histologically, two distinct tumors have been acknowledged, which were previously considered subtypes. The adamantinomatous craniopharyngioma is the most frequent in children and is caused by an activating mutation of the CTNNB1 gene, which codes for a mutant form of β-catenin. Whereas, papillary craniopharyngioma develops almost exclusively in adults, and it is associated with mutations in the BRAF oncogene and activation of the MAPK signaling pathway. The symptoms of both of these tumor types are secondary to hormonal deficits, hydrocephalus or visual disturbances. Treatment should be performed in centers with experience in them, achieving a balance between a wide resection and protection of hypothalamic function. Radiotherapy has proven to reduce tumor recurrence, with a current focus on the development of medical treatments based on molecular targets.

Abstract: Atopic dermatitis (AD) is a chronic, non-infectious inflammatory dermatosis, with increasing prevalence in recent decades. Due to its chronic and recurrent nature, it diminishes the quality of life of patients and their families. In recent years, advances in the understanding of AD’s pathophysiology have driven the development of targeted therapies such as monoclonal antibodies (mAbs) and Janus kinase inhibitors (JAKis) which modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. Four targeted therapies have been approved in the USA for the treatment of severe/refractory cases: dupilumab, tralokinumab, abrocitinib, and upadacitinib. This manuscript aims to present an update on the pathophysiology of AD, describe the new treatments available, and provide an analysis of the initial results of the use of these treatments in the pediatric population. We concluded that the high cost of these treatments often limits their prescription to situations where cases of atopic dermatitis are resistant to other conventional therapeutic options or when the disease reaches a severe degree. This underscores the importance of careful and accurate decision-making in the medical management of AD to ensure the efficient use of these therapeutic resources.

Resumen: La dermatitis atópica (DA) es una dermatosis crónica e inflamatoria no infecciosa, con prevalencia creciente en las últimas décadas. De curso crónico y recurrente, deteriora la calidad de vida de los pacientes y su familia. Los avances en la comprensión de la fisiopatología de la DA han impulsado el desarrollo de terapias dirigidas, como los anticuerpos monoclonales (mAb) y los inhibidores de la quinasa Janus (JAKis), las cuales modulan el sistema inmunológico a través de vías de señalización específicas, ofreciendo alternativas efectivas a los agentes inmunosupresores sistémicos tradicionales. En EE.UU. se han aprobado cuatro terapias dirigidas para el tratamiento de los casos severos/refractarios: dupilumab, tralokinumab, abrocitinib y upadacitinib. El objetivo de este manuscrito es presentar una actualización sobre la fisiopatología de la DA, describir los nuevos tratamientos disponibles y realizar un análisis de los resultados iniciales de la utilización de dichos tratamientos en pediatria. Se concluye que el alto costo de estos tratamientos suele limitar su prescripción a situaciones en las que los casos de DA son resistentes a otras opciones terapéuticas convencionales o cuando su curso es severo. Se resalta la importancia de toma de decisiones cuidadosa y precisa en la atención médica de la DA, con el fin de garantizar el uso eficiente de estos recursos terapéuticos.