Analysis of High-Risk Neuroblastoma Transcriptome Reveals Gene Co-Expression Signatures and Functional Features.

Neuroblastoma represents a neoplastic expansion of neural crest cells in the developing sympathetic nervous system and is childhood's most common extracranial solid tumor. The heterogeneity of gene expression in different types of cancer is well-documented, and genetic features of neuroblastoma have been described by classification, development stage, malignancy, and progression of tumors. Here, we aim to analyze RNA sequencing datasets, publicly available in the GDC data portal, of neuroblastoma tumor samples from various patients and compare them with normal adrenal gland tissue from the GTEx data portal to elucidate the gene expression profile and regulation networks they share. Our results from the differential expression, weighted correlation network, and functional enrichment analyses that we performed with the count data from neuroblastoma and standard normal gland samples indicate that the analysis of transcriptome data from 58 patients diagnosed with high-risk neuroblastoma shares the expression pattern of 104 genes. More importantly, our analyses identify the co-expression relationship and the role of these genes in multiple biological processes and signaling pathways strongly associated with this disease phenotype. Our approach proposes a group of genes and their biological functions to be further investigated as essential molecules and possible therapeutic targets of neuroblastoma regardless of the etiology of individual tumors.

Comparison of Phytochemical Composition and Untargeted Metabolomic Analysis of an Extract from Cnidoscolus aconitifolius (Mill.) I. I. Johnst and Porophyllum ruderale (Jacq.) Cass. and Biological Cytotoxic and Antiproliferative Activity In Vitro.

Cnidoscolus aconitifolius (CA) and Porophyllum ruderale (PR) are representative edible plants that are a traditional food source in Mexico. This research aimed to analyze the phytochemical composition and untargeted metabolomics analysis of CA and PR and evaluate their antiproliferative effect in vitro. The phytochemical composition (UPLC-DAD-QToF/MS-ESI) identified up to 38 polyphenols and selected organic acids that were clustered by the untargeted metabolomics in functional activities linked to indolizidines, pyridines, and organic acids. Compared with PR, CA displayed a higher reduction in the metabolic activity of human SW480 colon adenocarcinoma cells (LC50: 10.65 mg/mL), and both extracts increased the total apoptotic cells and arrested cell cycle at G0/G1 phase. PR increased mRNA Apc gene expression, whereas both extracts reduced mRNA Kras expression. Rutin/epigallocatechin gallate displayed the highest affinity to APC and K-RAS proteins in silico. Further research is needed to experiment on other cell lines. Results suggested that CA and PR are polyphenol-rich plant sources exhibiting antiproliferative effects in vitro.

Vibrio eleionomae sp. nov., isolated from shrimp (Penaeus vannamei) pond water.

A novel Vibrio strain (CAIM 722T=SW9T=DSM 24596T) was isolated in 2003 from water of a shrimp (Penaeus vannamei) culture pond located in Los Mochis, Sinaloa, Mexico, and taxonomically characterized using a polyphasic approach. The 16S rRNA gene sequence clustered within those of the genus Vibrio, showing high similarity to the type strains of the Porteresiae clade. Multilocus sequence analysis using eight housekeeping genes (ftsZ, gapA, gyrB, mreB, pyrH, recA, rpoA, topA and 16S rRNA) and phylogenetic analysis with 139 single-copy genes showed that the strain forms an independent branch. Whole genome sequencing and genomic analyses (average nucleotide identity, OrthoANI, average amino acid identity and in silico DNA-DNA hybridization) produced values well below the thresholds for species delineation with all methods tested. In addition, a phenotypic characterization was performed to support the description and differentiation of the novel strain from related taxa. The results obtained demonstrate that the strain represent a novel species, for which the name Vibrio eleionomae sp. nov. is proposed.

Asociación entre el riesgo nutricional, estancia hospitalaria y diagnóstico médico en pacientes de un hospital del seguro social peruano

Objetivo: Determinar la asociación que existe entre el riesgo nutricional, la estancia hospitalaria y el diagnóstico médico en pacientes hospitalizados en el Centro Especializado de Rehabilitación Profesional (CERP) del Hospital Nacional Guillermo Almenara Irigoyen. Materiales y métodos: Se realizó un estudio observacional de cohorte longitudinal, retrospectivo, que incluyó a las personas hospitalizadas durante el periodo comprendido entre el 1 de julio del 2021 y el 27 de febrero del 2022. Hubo un seguimiento de los pacientes hasta su alta del centro hospitalario (egreso). Se excluyeron los individuos menores de 18 años, gestantes o puérperas, y cuya permanencia fue menor a 24 horas. Los datos de interés fueron recogidos a partir de la revisión de las historias clínicas y kárdex de nutrición. La variable principal fue el riesgo nutricional, el cual fue detectado mediante el Nutritional Risk Screening (NRS) 2002; las variables secundarias fueron los grupos etarios, el sexo, la estancia hospitalaria, el diagnóstico médico principal, la condición de egreso y el estado nutricional. En el análisis de los datos, para la comparación de variables cualitativas o categóricas se utilizó la prueba chi-cuadrado y para variables cuantitativas, la prueba t de Student y ANOVA. Se consideró significancia estadística al valor de p < 0,05. Resultados: Se incluyó un total de 1 929 pacientes. La prevalencia del riesgo nutricional fue 33,13 %. Los pacientes con esta condición presentaron tasas de mortalidad más altas (57,51 %). Se observó que la prevalencia del riesgo nutricional está relacionada con una mayor estancia hospitalaria (4,6 días más) (p < 0,001), con el diagnóstico nutricional de delgadez (48,67 %) (p < 0,001) y con el diagnóstico médico, donde la enfermedad oncológica es la más asociada (50,93 %). Conclusiones: El riesgo nutricional se asocia a una evolución negativa de la enfermedad, lo que origina un aumento de la estancia hospitalaria, la tasa de mortalidad y, por ende, los costos intrahospitalarios. Es importante realizar su detección temprana para poder brindar intervenciones nutricionales adecuadas.

Objective: To determine the association between nutritional risk, hospital stay and medical diagnosis among patients admitted at Centro Especializado de Rehabilitación Profesional (CERP) of Hospital Nacional Guillermo Almenara Irigoyen. Materials and methods: An observational retrospective longitudinal cohort study was conducted with inpatients between July 1, 2021 and February 27, 2022. The patients were followed up until they left the hospital (discharge). Individuals under 18 years of age, pregnant or puerperal women, and those whose stay was less than 24 hours were excluded. The data of interest was collected from the patients' medical records and diet cards. The main variable was the nutritional risk, which was detected using the Nutritional Risk Screening (NRS) 2002. The secondary variables were age group, sex, hospital stay, main medical diagnosis, discharge condition and nutritional status. Data analysis was performed using the chi-square test to compare the qualitative or categorical variables, and the Student's t-test and ANOVA for the quantitative variables. A value of p < 0.05 was considered as statistically significant. Results: A total of 1,929 patients were included in the study. Nutritional risk prevalence accounted for 33.13 %. Patients with this condition showed the highest mortality rates (57.51 %). It was found that nutritional risk prevalence was related to a longer hospital stay (4.6 more days) (p < 0.001), a diagnosis of constitutional thinness (48.67 %) (p < 0.001) and the medical diagnosis, being oncology disorders the most associated ones (50.93 %). Conclusions: Nutritional risk is associated with disease progression, resulting in an increased hospital stay, mortality rate and therefore hospital costs. Early detection is important to provide adequate dietary interventions.

Metallodrugs: an approach against invasion and metastasis in cancer treatment.

Cancer is a heterogeneous and multifactorial disease that causes high mortality throughout the world; therefore, finding the most effective therapies is a major research challenge. Currently, most anticancer drugs present a limited number of well-established targets, such as cell proliferation or death; however, it is important to consider that the worse progression of cancer toward pathological stages implies invasion and metastasis processes. Medicinal Inorganic Chemistry (MIC) is a young area that deals with the design, synthesis, characterization, preclinical evaluation, and mechanism of action of new inorganic compounds, called metallodrugs. The properties of metallic ions allow enriching of strategies for the design of new drugs, enabling the adjustment of physicochemical and stereochemical properties. Metallodrugs can adopt geometries, such as tetrahedral, octahedral, square planar, and square planar pyramid, which adjusts their arrangement and facilitates binding with a wide variety of targets. The redox properties of some metal ions can be modulated by the presence of the bound ligands to adjust their interaction, thereby opening a range of mechanisms of action. In this regard, the mechanisms of action that trigger the biological activity of metallodrugs have been generally identified by: (a) coordination of the metal to biomolecules (for instance, cisplatin binds to the N7 in DNA guanine, as Pt-N via coordination of the inhibition of enzymes); (b) redox-active; and (c) ROS production. For this reason, a series of metallodrugs can interact with several specific targets in the anti-invasive processes of cancer and can prevent metastasis. The structural base of several metal compounds shows great anticancer potential by inhibiting the signaling pathways related to cancer progression. In this minireview, we present the advances in the field of antimetastatic effects of metallodrugs.

BAX But Not BCL2 Is Necessary for Apoptosis in Neuroblastoma Cells Treated With Casiopeína® IIIia.

BACKGROUND/AIM: The emerging antineoplastics Casiopeínas® induce uncoupling of the respiratory chain, production of reactive oxygen species (ROS), entry of Bax into mitochondria, and exit of Ca2+ and Bcl-2 from them, leading to apoptosis. This study aimed to elucidate whether BAX and BCL2 are necessary for apoptosis. MATERIALS AND METHODS: We silenced BAX and BCL2 by CRISPR-Cas9, assessed ROS and calcium retention capacity (CRC) by spectrofluorometry, and caspase-3 with inmunoblotting in neuroblastoma (NB) cells and 3T3-L1 fibroblasts treated with cisplatin and Casiopeína IIIia (CasIIIia). RESULTS: We observed an increase in O2•- production only in BCL2KO NB cells treated with cisplatin (three-fold) and CasIIIia (five-fold), whereas the production of H2O2 in BCL2KO NB cells treated with cisplatin and CasIIIia increased five-fold and three-fold, respectively. The baseline calcium-retention capacity (CRC) was 1.7 relative fluorescence units (RFU) in both cell types. In BAXKO, cisplatin and CasIIIia increased CRC to ~2.3 RFU, and in BCL2KO, they decreased CRC to ~1.1 RFU. We did not detect caspase-3 in BAXKO NB cells. CONCLUSION: Only BAX is essential for CasIIIia-induced apoptosis.

Interpretation systems, therapeutic itineraries and repertoires of leprosy patients in a low prevalence country. / Sistemas de interpretación, itinerarios y repertorios terapéuticos de pacientes con lepra en un país con baja prevalencia.

OBJECTIVES: In Peru, despite the small number of cases, there is evidence of late diagnosis and hidden prevalence of leprosy. In this context the objective of the study was to know the interpretation systems on leprosy, itineraries and therapeutic repertoires of patients diagnosed with leprosy who are in treatment or who have finished treatment. MATERIALS AND METHODS: A qualitative study was carried out, applying se mi-structured interviews to patients diagnosed with leprosy from the Loreto and Ucayali regions. RESULTS: 30 patients were interviewed. Most did not know the mechanism of leprosy transmission. In relation to therapeutic itineraries, patients generally went to health facilities on the recommendation of third parties who knew the disease. In some cases, health personnel made a bad diagnosis. The importance of the treatment indicated by the "Ministerio de Salud" (Ministry of Health) is recognized; however, economic factors and the distance to health facilities negatively affect adherence to treatment. In addition, it was evidenced that stigma persists towards the disease. CONCLUSIONS: Patients recognize the importance of treatment; however, they express misconceptions about the pathogenesis of leprosy, and weaknesses in the health system are also identified. These problems would lead to delay in diagnosis and treatment. It is recommended to strengthen control strategies and decentralize the care of leprosy with the participa tion of the community, patients, health personnel and healers, considering the identified barriers and a probable underdiagnosis in women.

OBJETIVOS: En Perú, a pesar del escaso número de casos, existe evidencia de un diagnóstico tardío y prevalencia oculta de la lepra. En este contexto el objetivo del estudio fue conocer los sistemas de inter pretación sobre la lepra, itinerarios y repertorios terapéuticos de pacientes con diagnóstico de lepra que se encuentren en tratamiento o con tratamiento culminado. MATERIALES Y MÉTODOS: Se realizó un estudio cualitativo, aplicando entrevistas semiestructuradas a pacientes con diagnóstico de lepra de las regiones de Loreto y Ucayali. RESULTADOS: Se entrevistaron a 30 pacientes. La mayoría no conocía el mecanismo de transmisión de la lepra. En relación con los itinerarios terapéuticos, los pacientes generalmente acudie ron a los establecimientos de salud por recomendación de terceros que conocían la enfermedad. En al gunos casos, el personal de salud realizó un mal diagnóstico. Se reconoce la importancia del tratamiento indicado por el Ministerio de Salud; sin embargo, factores económicos y la distancia a los establecimien tos de salud afectan de forma negativa la adherencia al tratamiento. Además, se evidenció que persiste el estigma de la enfermedad. CONCLUSIONES: Los pacientes reconocen la importancia del tratamiento, sin embargo, manifiestan ideas equivocadas sobre la patogenia de la lepra, además se identifican debilidades en el sistema de salud. Estos problemas conllevarían al retraso en el diagnóstico y tratamiento. Se reco mienda fortalecer las estrategias de control y descentralizar la atención de la lepra con la participación de la comunidad, pacientes, personal de salud y curanderos, considerando las barreras identificadas y un probable infradiagnóstico en la mujer.

Sistemas de interpretación, itinerarios y repertorios terapéuticos de pacientes con lepra en un país con baja prevalencia / Interpretation systems, therapeutic itineraries and repertoires of leprosy patients in a low prevalence country

RESUMEN Objetivos: En Perú, a pesar del escaso número de casos, existe evidencia de un diagnóstico tardío y prevalencia oculta de la lepra. En este contexto el objetivo del estudio fue conocer los sistemas de inter pretación sobre la lepra, itinerarios y repertorios terapéuticos de pacientes con diagnóstico de lepra que se encuentren en tratamiento o con tratamiento culminado. Materiales y métodos: Se realizó un estudio cualitativo, aplicando entrevistas semiestructuradas a pacientes con diagnóstico de lepra de las regiones de Loreto y Ucayali. Resultados: Se entrevistaron a 30 pacientes. La mayoría no conocía el mecanismo de transmisión de la lepra. En relación con los itinerarios terapéuticos, los pacientes generalmente acudie ron a los establecimientos de salud por recomendación de terceros que conocían la enfermedad. En al gunos casos, el personal de salud realizó un mal diagnóstico. Se reconoce la importancia del tratamiento indicado por el Ministerio de Salud; sin embargo, factores económicos y la distancia a los establecimien tos de salud afectan de forma negativa la adherencia al tratamiento. Además, se evidenció que persiste el estigma de la enfermedad. Conclusiones: Los pacientes reconocen la importancia del tratamiento, sin embargo, manifiestan ideas equivocadas sobre la patogenia de la lepra, además se identifican debilidades en el sistema de salud. Estos problemas conllevarían al retraso en el diagnóstico y tratamiento. Se reco mienda fortalecer las estrategias de control y descentralizar la atención de la lepra con la participación de la comunidad, pacientes, personal de salud y curanderos, considerando las barreras identificadas y un probable infradiagnóstico en la mujer.

ABSTRACT Objectives: In Peru, despite the small number of cases, there is evidence of late diagnosis and hidden prevalence of leprosy. In this context the objective of the study was to know the interpretation systems on leprosy, itineraries and therapeutic repertoires of patients diagnosed with leprosy who are in treatment or who have finished treatment. Materials and methods: A qualitative study was carried out, applying se mi-structured interviews to patients diagnosed with leprosy from the Loreto and Ucayali regions. Results: 30 patients were interviewed. Most did not know the mechanism of leprosy transmission. In relation to therapeutic itineraries, patients generally went to health facilities on the recommendation of third parties who knew the disease. In some cases, health personnel made a bad diagnosis. The importance of the treatment indicated by the "Ministerio de Salud" (Ministry of Health) is recognized; however, economic factors and the distance to health facilities negatively affect adherence to treatment. In addition, it was evidenced that stigma persists towards the disease. Conclusions: Patients recognize the importance of treatment; however, they express misconceptions about the pathogenesis of leprosy, and weaknesses in the health system are also identified. These problems would lead to delay in diagnosis and treatment. It is recommended to strengthen control strategies and decentralize the care of leprosy with the participa tion of the community, patients, health personnel and healers, considering the identified barriers and a probable underdiagnosis in women.

Photobacterium lucens sp. nov., Isolated from a Cultured Shrimp Penaeus vannamei.

Two bacterial strains were isolated from the hepatopancreas of a cultured shrimp (Penaeus vannamei) in Sinaloa, México. Their partial 16S rRNA gene sequences clustered within those of the genus Photobacterium, showing high similarity to the type strains of Photobacterium angustum and Photobacterium leiognathi, were 87.1% and 97.5%, respectively. Multilocus sequence analysis using eight housekeeping genes (ftsZ, gapA, gyrB, mreB, pyrH, recA, rpoA, topA and 16S rRNA) and phylogenetic analysis with 139 single-copy genes showed that the new strains form an independent branch whole genome sequencing and genomic analyses (average nucleotide identity, average amino acid identity, and in silico DNA-DNA hybridization) produced values well below the thresholds for species delineation with all methods tested. In addition, a phenotypic characterization was performed to support the description and differentiation of the novel strains from related taxa. The results obtained demonstrate that the two strains represent a novel species for which the name Photobacterium lucens sp. nov. is proposed.

Effect on nutritional markers of a model of aberrant crypt foci induced by azoxymethane and sodium dextran sulfate in Sprague Dawley rats / Efecto sobre marcadores nutricionales de un modelo de focos de criptas aberrantes inducidos por azoximetano y dextrano de sulfato sódico en ratas Sprague Dawley

Introduction: aberrant crypt foci (ACF) are colon preneoplastic lesions that can be used as a tool to study preventive processes for colorectal cancer (CRC). This model consists of initiation induced by azoxymethane (AOM) and promoted by sodium dextran sulfate (DSS), simulating human colonic carcinogenesis in a rat model. There is no direct information on the effects of this process on nutritional markers. Objective: to determine the effect on nutritional markers after the induction of ACF by AOM/DSS in a rat model. Methods: ACF were induced in 24 four-week-old Sprague Dawley male rats by administration of 2 AOM injections (10 mg/kg) and 7 days of 2% DSS in their drinking water. Body weight gain, food and fluid intake, weight of sacrificial organs, nutritional biochemical profiles, liver and kidney toxicity were evaluated. Cell counts in blood were also performed and histological sections evaluated in specific organs. The model was confirmed with identification and counts of ACF. Half of the rats were sacrificed at the sub-chronic stage and the rest at the chronic stage. Results: at the sub-chronic stage, changes in the liver and colon weight, and in the lymphocyte count were observed. For both stages, histopathological damage was observed in liver, kidney and colon, along with alterations in serum glucose levels. Conclusions: the model for proposed ACF can be used at the sub-chronic stage without the need for observation at the chronic stage. More research is needed to determine the mechanism of the observed effects

Introducción: los focos de criptas aberrantes (ACF) son lesiones preneoplásicas en colon que pueden ser utilizados como herramienta para estudiar procesos preventivos para el cáncer colorectal (CCR). Este modelo consiste en la iniciación inducida por azoximetano (AOM) y promovida por dextrano sulfato sódico (DSS) simulando una carcinogénesis colónica humana en un modelo de rata. No existe información directa de los efectos sobre marcadores nutricios para este proceso. Objetivo: determinar el efecto sobre marcadores nutricios tras la inducción de ACF por AOM/DSS en un modelo de rata. Métodos: se utilizaron veinticuatro ratas machos Sprague Dawley de 4 semanas para la inducción de ACF por administración de 2 inyecciones de AOM (10 mg/kg) y 7 días de DSS al 2% en el agua para beber. Se evaluó la ganancia de peso corporal, el consumo de alimento y de líquidos, el peso de órganos al sacrificio, perfiles bioquímicos nutricios, de toxicidad hepática y renal. Asimismo, se realizaron conteos celulares en sangre y se evaluaron cortes histológicos en órganos específicos. El modelo se confirmó con la identificación y conteos de ACF. Se sacrificó la mitad de las ratas en etapa subcrónica y las demás en etapa crónica. Resultados: en la etapa subcrónica se observaron cambios entre grupos en el peso del hígado y colon, y en el conteo de linfocitos. En ambas etapas se observaron daños histopatológicos en hígado, riñón y colon, así como alteraciones en los niveles de glucosa sérica. Conclusiones: el modelo para ACF propuesto puede ser utilizado en etapa subcrónica sin necesidad de llevarlo a tiempo crónico. Es necesaria más investigación para determinar el mecanismo de los efectos observados

Effect on nutritional markers of a model of aberrant crypt foci induced by azoxymethane and sodium dextran sulfate in Sprague Dawley rats.

INTRODUCTION: Introduction: aberrant crypt foci (ACF) are colon preneoplastic lesions that can be used as a tool to study preventive processes for colorectal cancer (CRC). This model consists of initiation induced by azoxymethane (AOM) and promoted by sodium dextran sulfate (DSS), simulating human colonic carcinogenesis in a rat model. There is no direct information on the effects of this process on nutritional markers. Objective: to determine the effect on nutritional markers after the induction of ACF by AOM/DSS in a rat model. Methods: ACF were induced in 24 four-week-old Sprague Dawley male rats by administration of 2 AOM injections (10 mg/kg) and 7 days of 2% DSS in their drinking water. Body weight gain, food and fluid intake, weight of sacrificial organs, nutritional biochemical profiles, liver and kidney toxicity were evaluated. Cell counts in blood were also performed and histological sections evaluated in specific organs. The model was confirmed with identification and counts of ACF. Half of the rats were sacrificed at the sub-chronic stage and the rest at the chronic stage. Results: at the sub-chronic stage, changes in the liver and colon weight, and in the lymphocyte count were observed. For both stages, histopathological damage was observed in liver, kidney and colon, along with alterations in serum glucose levels. Conclusions: the model for proposed ACF can be used at the sub-chronic stage without the need for observation at the chronic stage. More research is needed to determine the mechanism of the observed effects.

INTRODUCCIÓN: Introducción: los focos de criptas aberrantes (ACF) son lesiones preneoplásicas en colon que pueden ser utilizados como herramienta para estudiar procesos preventivos para el cáncer colorectal (CCR). Este modelo consiste en la iniciación inducida por azoximetano (AOM) y promovida por dextrano sulfato sódico (DSS) simulando una carcinogénesis colónica humana en un modelo de rata. No existe información directa de los efectos sobre marcadores nutricios para este proceso. Objetivo: determinar el efecto sobre marcadores nutricios tras la inducción de ACF por AOM/DSS en un modelo de rata. Métodos: se utilizaron veinticuatro ratas machos Sprague Dawley de 4 semanas para la inducción de ACF por administración de 2 inyecciones de AOM (10 mg/kg) y 7 días de DSS al 2% en el agua para beber. Se evaluó la ganancia de peso corporal, el consumo de alimento y de líquidos, el peso de órganos al sacrificio, perfiles bioquímicos nutricios, de toxicidad hepática y renal. Asimismo, se realizaron conteos celulares en sangre y se evaluaron cortes histológicos en órganos específicos. El modelo se confirmó con la identificación y conteos de ACF. Se sacrificó la mitad de las ratas en etapa subcrónica y las demás en etapa crónica. Resultados: en la etapa subcrónica se observaron cambios entre grupos en el peso del hígado y colon, y en el conteo de linfocitos. En ambas etapas se observaron daños histopatológicos en hígado, riñón y colon, así como alteraciones en los niveles de glucosa sérica. Conclusiones: el modelo para ACF propuesto puede ser utilizado en etapa subcrónica sin necesidad de llevarlo a tiempo crónico. Es necesaria más investigación para determinar el mecanismo de los efectos observados.

Autophagy Promotes Survival of CHP-212 Neuroblastoma Cells Treated With Casiopeínas®.

BACKGROUND: Neuroblastoma is the main solid extracranial tumor of childhood. The amplification of N-myc oncogene (MYCN) and 1p deletion are the main molecular alterations. These features are what make treatment impossible, especially in high-risk patients with metastases. MATERIALS AND METHODS: Our study investigated the processes undergone by CHP-212 neuroblastoma cells, after being treated with Casiopeínas® (Cas) IIgly, IIIEa, and IIIia for 2, 10, and 24 h. RESULTS: At 2 h, all the treatments Ied to apoptosis [defined by the presence of B-cell lymphoma 2 (BCL2), BCL2-associated X protein, cytochrome c, and caspase-3]. In addition, autophagy with specific molecules beclin-1 and microtubule-associated protein 1A/1B-light chain 3 (LC3)-II/LC3-I (ratio >1). Later at 10 h, autophagy-associated proteins were observed, and at 24 h, only survival proteins nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), and extracellular signal-regulated kinases (ERK)2/ERK1>1 were found. Another relevant finding was the presence of caspase-10 throughout the study, especially in cells treated with CasIIgly and CasIIIEa. CONCLUSION: These relationships indicate a possible mechanism of action of Casiopeínas on neuroblastoma.

Preventive Effect of an Infusion of the Aqueous Extract of Chaya Leaves (Cnidoscolus aconitifolius) in an Aberrant Crypt Foci Rat Model Induced by Azoxymethane and Dextran Sulfate Sodium.

Aberrant crypt foci (ACF) is the precursor lesion of colorectal carcinogenesis (CRC), one of the most common malignancies in the world. Many studies have reported that people with higher phytochemical intake are at a reduced risk of developing ACF. One example of the botanical potential of preventive plant products is Cnidoscolus aconitifolius (CA), commonly known as Chaya. This study evaluated the phenolic profile of CA and the effects of the daily consumption of CA leaf infusion on the formation of ACF, histopathological lesions, and molecular biomarkers after azoxymethane (AOM) and dextran sulfate sodium (DSS) induced premalignant colon lesions in rats treated with for 16 and 32 weeks. The phenolic composition of the CA infusion was identified by reversed phase-high performance liquid chromatography-diode array detection (RP-HPCC-DAD). After sacrifice, a 4 cm segment was collected from the distal part of the colon and stained with methylene blue to look for ACF. Furthermore, 4 µm of colon, liver, and kidney was collected and stained with hematoxylin and eosin for histopathological analysis, along with 7 µm of colon for immunohistochemistry analysis. Eleven phenolic compounds were identified in the infusions, and ACF formation was reduced by 29.5% at the subchronic and by 64.6% at chronic stages. Lesions on kidney, liver, and colon tissue were also reduced. Our data suggest that CA treatment has preventive effects against AOM-/DSS-induced premalignant colon lesions in colon rats at the promotion level, inhibiting the cell proliferation of early neoplastic lesions and colonic inflammation through the decrease of ß-catenin by 41.8% at the subchronic stage and 29% at the chronic stage, along with a 46.2% reduction of cyclooxygenase 2 (COX-2) at long term, despite a high expression of NF-κB (30.3% at the subchronic stage and 22.8% at the chronic stage).

Phaseolus acutifolius Lectin Fractions Exhibit Apoptotic Effects on Colon Cancer: Preclinical Studies Using Dimethilhydrazine or Azoxi-Methane as Cancer Induction Agents.

Phaseolus acutifolius (Tepary bean) lectins have been studied as cytotoxic molecules on colon cancer cells. The toxicological profile of a Tepary bean lectin fraction (TBLF) has shown low toxicity in experimental animals; exhibiting anti-nutritional effects such as a reduction in body weight gain and a decrease in food intake when using a dose of 50 mg/kg on alternate days for six weeks. Taking this information into account, the focus of this work was to evaluate the effect of the TBLF on colon cancer using 1,2-dimethylhydrazine (DMH) or azoxy-methane/dextran sodium sulfate (AOM/DSS) as colon cancer inductors. Rats were treated with DMH or AOM/DSS and then administered with TBFL (50 mg/kg) for six weeks. TBLF significantly decreased early tumorigenesis triggered by DMH by 70%, but without any evidence of an apoptotic effect. In an independent experiment, AOM/DSS was used to generate aberrant cryptic foci, which decreased by 50% after TBLF treatment. TBLF exhibited antiproliferative and proapoptotic effects related to a decrease of the signal transduction pathway protein Akt in its activated form and an increase of caspase 3 activity, but not to p53 activation. Further studies will deepen our knowledge of specific apoptosis pathways and cellular stress processes such as oxidative damage.

Synergistic effects between a copper-based metal Casiopeína III-ia and cisplatin.

Additive, subadditive or superadditive interactions observed in combination therapy play an important role in several treatments, particularly for cancer. The isobolographic analysis allows to establish the pharmacological interactions that exist between two drugs that are administered together in equieffective doses. In order to identify if the combination of two compounds presents synergistic interaction, the antiproliferative activity of CasIII-ia with analogue compounds or cisplatin in different molar ratios was evaluated. Results showed that this compound exhibited additive, subadditive or antagonic and superadditive or synergistic interactions, depending on the compound that accompanies it and the proportion of the compounds in the combination. One of the combinations increased the antiproliferative activity from 50 to 77% when the cells were exposed to 4.59 and 9.70 µM to CasIII-ia and cisplatin, respectively. Further studies of the toxicity and biochemical level of the interactions still remain to be studied on a in-vivo xenographed model.

The mitochondrial apoptotic pathway is induced by Cu(II) antineoplastic compounds (Casiopeínas®) in SK-N-SH neuroblastoma cells after short exposure times.

The family of Copper(II) coordination compounds Casiopeínas® (Cas) has shown antiproliferative activity in several tumour lines by oxidative cellular damage and mitochondrial dysfunction that lead to cell death through apoptotic pathways. The goal of this work is looking for the functional mechanism of CasIIgly, CasIIIia and CasIIIEa in neuroblastoma metastatic cell line SK-N-SH, a paediatric extra-cranial tumour which is refractory to several anti-carcinogenic agents. All Cas have shown higher antiproliferative activity than cisplatin (IC50 = 123 µM) with IC50 values of 18, 22 and 63 µM for CasIIgly, CasIIIEa and CasIIIia, respectively. At low concentrations and early times (4 h), these compounds cause a disruption of the mitochondrial transmembrane potential (Δψm). Concomitantly, an important depletion of intracellular glutathione and an increase of reactive oxygen species (ROS) hydrogen peroxide and radical superoxide were observed. On the other side, the lower cytotoxic effect of Casiopeínas on cultures of human peripheral blood lymphocytes (IC50CasIIgly  = 1720 µM, IC50 CasIIIEa  = 3860 µM and IC50 CasIIIia  = 4700 µM) show the selectivity of these compounds over the tumour cells compared with the non-transformed cells. Chemically, glutathione (GSH) interacts with Casiopeínas® through the coordination of sulphur atom to the metal centre, process which facilitates the electron transfer to get Cu(I), GSSG and the posterior production of ROS. Additionally, the molecular structure of CasIIIia as nitrate is reported. These results have shown that the anticarcinogenic activity of Casiopeínas® on neuroblastoma SK-N-SH is through mitochondrial apoptosis due to the enhanced pro-oxidant environment promoted by the presence of the coordination copper compounds.

Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma.

BACKGROUND: Thyroid cancer (TC) is the most common malignant cancer of the Endocrine System. Histologically, there are three main subtypes of TC: follicular, papillary and anaplastic. Diagnosing a thyroid tumor subtype with a high level of accuracy and confidence is still a difficult task because genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumors are not well understood. A genome-wide analysis of these three subtypes of thyroid carcinoma was carried out in order to identify significant differences in expression levels as well as enriched pathways for non-shared molecular and cellular features between subtypes. RESULTS: Inhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis. This pathway is drastically altered in ATC while in FTC and PTC, the most important pathways are related to DNA-repair activation or cell to cell signaling events. CONCLUSION: A progression from FTC to PTC and then to ATC was detected and validated on two independent datasets. Moreover, PTX3, COLEC12 and PDGFRA genes were found as possible candidates for biomarkers of ATC while GPR110 could be tested to distinguish PTC over other tumor subtypes. The genome-wide analysis emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.

Network Analysis Shows Novel Molecular Mechanisms of Action for Copper-Based Chemotherapy.

The understanding of the mechanisms associated with the action of chemotherapeutic agents is fundamental to assess and account for possible side-effects of such treatments. Casiopeínas have demonstrated a cytotoxic effect by activation of pro-apoptotic processes in malignant cells. Such processes have been proved to activate the apoptotic intrinsic route, as well as cell cycle arrest. Despite this knowledge, the whole mechanism of action of Casiopeínas is yet to be completely understood. In this work we implement a systems biology approach based on two pathway analysis tools (Over-Representation Analysis and Causal Network Analysis) to observe changes in some hallmarks of cancer, induced by this copper-based chemotherapeutic agent in HeLa cell lines. We find that the metabolism of metal ions is exacerbated, as well as cell division processes being globally diminished. We also show that cellular migration and proliferation events are decreased. Moreover, the molecular mechanisms of liver protection are increased in the cell cultures under the actions of Casiopeínas, unlike the case in many other cytotoxic drugs. We argue that this chemotherapeutic agent may be promising, given its protective hepatic function, concomitant with its cytotoxic participation in the onset of apoptotic processes in malignant cells.

Copper(II) mixed chelate compounds induce apoptosis through reactive oxygen species in neuroblastoma cell line CHP-212.

In the present work we report the antiproliferative activity of Cu(II) coordination compounds, CasIIgly ([Cu(4,7-dimethyl-1,10-phenanthroline) (glycinato) (H2O)]NO3), CasIIIia ([Cu(4,4'-dimethyl-2,2'-bipyridine) (glycinato) (H2O)]NO3), and CasIIIEa ([Cu(4,7-dimethyl-1,10-phenanthroline) (acetylacetonato) (H2O)]NO3), against human tumoral cell line CHP-212 (estromal neuroblastoma). Additionally, the molecular structure of CasIIIEa was reported. The IC50 values obtained for the evaluated compounds are in the range 18 to 47 µM, representing an inhibition potency increase of 5 to 12 times compared with cisplatin (IC50=226.7 µM). After 2h of incubation with the evaluated compounds, cells showed high levels of reactive oxygen species and a considerable GSH depletion, besides an important disruption of the mitochondrial membrane with release of cytochrome C and besides the presence of caspase-3, an effector caspase that is activated in the last step of apoptosis cascade. The results confirm that cell death in neuroblastoma CHP-212 treated with Casiopeínas occurs via apoptosis. Due to the lack of expression of caspase-8, cell death is principally by the mitochondrial pathway. Thus, one of the most interesting findings of this work is the identification of a very important damage in neuroblastoma cells induced by Cu(II) coordination compounds in a very short exposition times.

Recomendaciones para la prevención de la transmisión perinatal del virus de la inmunodeficiencia humana en Costa Rica / Recommendations for prevention of perinatal transmission of the human immunodeficiency virus in Costa Rica

Se conoce que la transmisión perinatal del VIH es prevenible con la toma de algunas medidas generales y otras específicas. La acción fundamental para lograr esta prevención es identificar temprano durante el embarazo, cuáles mujeres embarazadas están infectadas por VIH. Para conseguir este objetivo es necesario realizar la prueba del ELISA para VIH, a toda embarazada, en su primera consulta prenatal. Las guías para la prevención de la transmisión perinatal de VIH se desarrollaron con el fin de facilitar la aplicación de todas las acciones necesarias para prevenir la transmisión perinatal de VIH en Costa Rica, brindando una óptima atención médica a la madre y al recién nacido. Los elementos fundamentales de estas guías incluyen: tratamiento con 3 antirretrovirales a las mujeres embarazadas VIH+, a apartir de la 12ava semana de gestación, uso intravenoso de Zidovudina en labor, vía de parto por cesárea, suspensión de la lactancia materna, profilaxis con Zidovudina al recién nacido a partir de las 8 horas de edad. Las guías proveen también recomendaciones para proceder en situaciones especiales relacionadas con la embarazada VIH+ y su hijo...