TACkling Cancer by Targeting Selective Protein Degradation.

Targeted protein degradation has emerged as an alternative therapy against cancer, offering several advantages over traditional inhibitors. The new degrader drugs provide different therapeutic strategies: they could cross the phospholipid bilayer membrane by the addition of specific moieties to extracellular proteins. On the other hand, they could efficiently improve the degradation process by the generation of a ternary complex structure of an E3 ligase. Herein, we review the current trends in the use of TAC-based technologies (TACnologies), such as PROteolysis TArgeting Chimeras (PROTAC), PHOtochemically TArgeting Chimeras (PHOTAC), CLIck-formed Proteolysis TArgeting Chimeras (CLIPTAC), AUtophagy TArgeting Chimeras (AUTAC), AuTophagosome TEthering Compounds (ATTEC), LYsosome-TArgeting Chimeras (LYTAC), and DeUBiquitinase TArgeting Chimeras (DUBTAC), in experimental development and their progress towards clinical applications.

Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer.

The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.

Transcriptomic Mapping of Non-Small Cell Lung Cancer K-RAS p.G12C Mutated Tumors: Identification of Surfaceome Targets and Immunologic Correlates.

Targeting K-RAS-mutant non-small cell lung cancer (NSCLC) with novel inhibitors has shown promising results with the recent approval of sotorasib in this indication. However, progression to this agent is expected, as it has previously been observed with other inhibitors. Recently, new immune therapeutics, including vectorized compounds with antibodies or modulators of the host immune response, have demonstrated clinical activity. By interrogating massive datasets, including TCGA, we identified genes that code for surface membrane proteins that are selectively expressed in K-RAS mutated NSCLC and that could be used to vectorize novel therapies. Two genes, CLDN10 and TMPRSS6, were selected for their clear differentiation. In addition, we discovered immunologic correlates of outcome that were clearly de-regulated in this particular tumor type and we matched them with immune cell populations. In conclusion, our article describes membrane proteins and immunologic correlates that could be used to better select and optimize current therapies.

Checkpoint Kinase 1 Pharmacological Inhibition Synergizes with DNA-Damaging Agents and Overcomes Platinum Resistance in Basal-Like Breast Cancer.

Basal-like breast cancer is an incurable disease with limited therapeutic options, mainly due to the frequent development of anti-cancer drug resistance. Therefore, identification of druggable targets to improve current therapies and overcome these resistances is a major goal. Targeting DNA repair mechanisms has reached the clinical setting and several strategies, like the inhibition of the CHK1 kinase, are currently in clinical development. Here, using a panel of basal-like cancer cell lines, we explored the synergistic interactions of CHK1 inhibitors (rabusertib and SAR020106) with approved therapies in breast cancer and evaluated their potential to overcome resistance. We identified a synergistic action of these inhibitors with agents that produce DNA damage, like platinum compounds, gemcitabine, and the PARP inhibitor olaparib. Our results demonstrated that the combination of rabusertib with these chemotherapies also has a synergistic impact on tumor initiation, invasion capabilities, and apoptosis in vitro. We also revealed a biochemical effect on DNA damage and caspase-dependent apoptosis pathways through the phosphorylation of H2AX, the degradation of full-length PARP, and the increase of caspases 3 and 8 activity. This agent also demonstrated synergistic activity in a platinum-resistant cell line, inducing an increase in cell death in response to cisplatin only when combined with rabusertib, while no toxic effect was found on non-tumorigenic breast tissue-derived cell lines. Lastly, the combination of CHK1 inhibitor with cisplatin and gemcitabine resulted in more activity than single or double combinations, leading to a higher apoptotic effect. In conclusion, in our study we identify therapeutic options for the clinical development of CHK1 inhibitors, and confirm that the inhibition of this kinase can overcome acquired resistance to cisplatin.

Modulation of hepatic ABC transporters by Eruca vesicaria intake: Potential diet-drug interactions.

The aim of this work was to evaluate whether oral administration of Eruca vesicaria, a species of rocket cultivated in Argentina, could modify cyclophosphamide (CP)-induced genotoxicity through modulation of hepatic ABC transporters. Daily oral administration of E. vesicaria fresh leaves juice (1.0, 1.4 and 2.0  g/kg) for 14 days did not alter genotoxicity biomarkers -alkaline comet assay and micronucleus test -in neither male nor female mice. Instead, repeated intake of this cruciferous decreased CP-induced DNA damage dose-dependently and it caused hepatic overexpression of P-glycoprotein (P-gp; 1.4 and 2.0  g/kg) and multidrug resistance protein 2 (MRP2; 2.0  g/kg), but not breast cancer resistance protein (Bcrp). The antigenotoxic effect of E. vesicaria was prevented by 50 mg/kg verapamil (P-gp inhibitor) or 10 mg/kg indomethacin (MRP2 inhibitor). In turn, CP-induced cytotoxicity (10 mM, 24 h) on human hepatoma cells (HepG2/C3A) was significantly reduced by preincubation with E. vesicaria (1.4 mg/ml; 48 h); this effect was absent when CP was coincubated with 35 µM verapamil, 80 µM indomethacin or 10 µM KO-143 (BCRP inhibitor). Altogether, these results allow us to demonstrate that repeated intake of E. vesicaria exhibited antigenotoxicity, at least in part, by induction of hepatic ABC transporters in vivo in mice as well as in vitro in human liver cells. This could account for other diet-drug interactions.

Genomic Signatures of Immune Activation Predict Outcome in Advanced Stages of Ovarian Cancer and Basal-Like Breast Tumors.

There is an unmet need for new therapies in metastatic ovarian cancer and basal-like breast cancer since no curative therapies are currently available. Immunotherapy has shown to be active in several solid tumors, but particularly more in those where a pre-activated immune state does exist. In this work, we aim to identify biomarkers that could distinguish immune-activated tumors and predict response to therapies in ovarian and basal-like breast cancer, as well as their association with the level of tumor immune infiltration. We found that the combined expression of IFNG, CD30, CXCL13, and PRF1 correlated with better overall survival (OS) in advanced stage ovarian cancer. This was confirmed using an independent dataset from TCGA. Interestingly, we observed that this gene combination also predicted for better prognosis in ovarian tumors with low mutational load, which typically respond less to immunotherapy. Expression of IFNG, CD30, CXCL13, and PRF1 was associated with increased level of immune infiltrates (CD8+ T cells, dendritic cells, and neutrophils) within the tumor. Moreover, we found that these gene signature also correlated with an increased OS and with a higher level of tumor immune infiltrates (B cells, CD8+ T cells, CD4+ T cells, neutrophils, and dendritic cells) in basal-like breast cancer. In conclusion, our analysis identifies genes signatures with potential to recognize immune activated ovarian and basal-like breast cancers with favorable prognosis and with a remarkable predictive capacity in tumors with low mutational burden. The presented results led to a hypothesis being formulated, but prospective clinical studies are needed to support a potential clinical application.

Transcriptome evolution from breast epithelial cells to basal-like tumors.

In breast cancer, it is unclear the functional modifications at a transcriptomic level that are associated with the evolution from epithelial cells and ductal carcinoma in situ (DCIS) to basal-like tumors. By applying weighted gene co-expression network analysis (WGCNA), we identified 17 gene co-expression modules in normal, DCIS and basal-like tumor samples. We then correlated the expression pattern of these gene modules with disease progression from normal to basal-like tumours and found eight modules exhibiting a high and statistically significant correlation. M4 included genes mainly related to cell cycle/division and DNA replication like CCNA2 or CDK1. The M7 module included genes linked with the immune response showing top hub genes such as CD86 or PTPRC. M10 was found specifically correlated to DCIS, but not to basal-like tumor samples, and showed enrichment in ubiquitination or ubiquitin-like processes. We observed that genes in some of these modules were associated with clinical outcome and/or represented druggable opportunities, including AURKA, AURKB, PLK1, MCM2, CDK1, YWHAE, HSP90AB1, LCK, or those targeting ubiquitination. In conclusion, we describe relevant gene modules related to biological functions that can influence survival and be targeted pharmacologically.

DNA-damage related genes and clinical outcome in hormone receptor positive breast cancer.

BACKGROUND: Control of DNA damage is frequently deregulated in solid tumors. Upregulation of genes within this process can be indicative of a more aggressive phenotype and linked with worse outcome. In the present article we identify DNA damage related genes associated with worse outcome in breast cancer. RESULTS: 2286 genes were differentially expressed between normal breast tissue and basal-like tumors, and 62 included in the DNA metabolic process function. Expression of RAD51, GINS1, TRIP13 and MCM2 were associated with detrimental relapse free survival (RFS) and overall survival (OS) in luminal tumors. The combined analyses of TRIP13+RAD51+MCM2 showed the worse association for RFS (HR 2.25 (1.51-3.35) log rank p= 4.1e-05) and TRIP13+RAD51 for OS (HR 5.13 (0.6-44.17) log rank p=0.098) in ER+/HER2- tumors. TRIP13 is amplified in 3.1% of breast cancers. METHODS: Transcriptomic analyses using public datasets evaluating expression values between normal breast tissue and TNBC identified upregulated genes. Genes included in the DNA metabolic process were selected and confirmed using data contained at oncomine (www.oncomine.org). Evaluation of the selected genes with RFS and OS was performed using the KM Plotter Online Tool (http://www.kmplot.com). Evaluation of molecular alterations was performed using cBioportal (www.cbioportal.org). CONCLUSIONS: Expression of DNA metabolic related genes RAD51, GINS1, TRIP13 and MCM2 are associated with poor outcome. Combinations of some of these genes are linked to poor RFS or OS in luminal A, B and ER+HER2- tumors. Evaluation of its predictive capacity in prospective studies is required.

Synthetic Lethality Interaction Between Aurora Kinases and CHEK1 Inhibitors in Ovarian Cancer.

Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair genes, so they rely on DNA-damage checkpoint proteins, like the checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic aurora kinase A (AURKA) inhibitors. Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1, and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot analysis. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes that belonged to cell cycle, including AURKA/B, TTK kinase, and CHEK1. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models. Combination of alisertib and LY2603618 triggered apoptosis, reduced the stem cell population, and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describe a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting. Mol Cancer Ther; 16(11); 2552-62. ©2017 AACR.

Mitotic read-out genes confer poor outcome in luminal A breast cancer tumors.

Luminal breast tumors have been classified into A and B subgroups, with the luminal A being associated with a more favorable clinical outcome. Unfortunately, luminal A tumors do not have a universally good prognosis. We used transcriptomic analyses using public datasets to evaluate the differential expression between normal breast tissue and breast cancer, focusing on upregulated genes included in cell cycle function. Association of selected genes with relapse free survival (RFS) and overall survival (OS) was performed using the KM Plotter Online Tool (http://www.kmplot.com). Seventy-seven genes were differentially expressed between normal and malignant breast tissue. Only five genes were associated with poor RFS and OS. The mitosis-related genes GTSE1, CDCA3, FAM83D and SMC4 were associated with poor outcome specifically in Luminal A tumors. The combination of FAM83D and CDCA3 for RFS and GTSE1 alone for OS showed the better prediction for clinical outcome. CDCA3 was amplified in 3.4% of the tumors, and FAM83D and SMC4 in 2.3% and 2.2%, respectively. In conclusion, we describe a set of genes that predict detrimental outcome in Luminal A tumors. These genes may have utility for stratification in trials of antimitotic agents or cytotoxic chemotherapy, or as candidates for direct target inhibition.

Targeting basal-like breast tumors with bromodomain and extraterminal domain (BET) and polo-like kinase inhibitors.

Metastatic triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options, and no targeted therapies available. Triple negative tumors and the basal-like genomic subtype, are both characterized by a high proliferation rate and an increase in cell division. In this context, protein kinases involved in the mitotic formation have a relevant role in this tumor subtype. Recently, Bromodomain and extraterminal domain (BET) inhibitors have shown to be active in this disease by modulating the expression of several transcription factors. In this article, by using an "in silico" approach, we identified genomic functions that can be inhibited pharmacologically in basal-like tumors. Functional annotation analyses identified "cell division" and "regulation of transcription" as upregulated functions. When focus on cell division, we identified the polo-like kinase 1 (PLK) as an upregulated kinase. The PLK inhibitor Volasertib had the strongest anti-proliferative effect compared with other inhibitors against mitotic kinases. Gene expression analyses demonstrated that the BET inhibitor JQ1 reduced the expression of kinases involved in cell division, and synergized with Volasertib in a panel of triple negative cell lines. Combination of both agents augmented cell death. Similarly, combination of both compounds reduced the expression of stem cell markers. Globally, this data demonstrates the synergistic interaction between BET and PLK inhibitors, paving the way for their future clinical development.

In silico analyses identify gene-sets, associated with clinical outcome in ovarian cancer: role of mitotic kinases.

INTRODUCTION: Accurate assessment of prognosis in early stage ovarian cancer is challenging resulting in suboptimal selection of patients for adjuvant therapy. The identification of predictive markers for cytotoxic chemotherapy is therefore highly desirable. Protein kinases are important components in oncogenic transformation and those relating to cell cycle and mitosis control may allow for identification of high-risk early stage ovarian tumors. METHODS: Genes with differential expression in ovarian surface epithelia (OSE) and ovarian cancer epithelial cells (CEPIs) were identified from public datasets and analyzed with dChip software. Progression-free (PFS) and overall survival (OS) associated with these genes in stage I/II and late stage ovarian cancer was explored using the Kaplan Meier Plotter online tool. RESULTS: Of 2925 transcripts associated with modified expression in CEPIs compared to OSE, 66 genes coded for upregulated protein kinases. Expression of 9 of these genes (CDC28, CHK1, NIMA, Aurora kinase A, Aurora kinase B, BUB1, BUB1ßB, CDKN2A and TTK) was associated with worse PFS (HR:3.40, log rank p<0.001). The combined analyses of CHK1, CDKN2A, AURKA, AURKB, TTK and NEK2 showed the highest magnitude of association with PFS (HR:4.62, log rank p<0.001). Expression of AURKB predicted detrimental OS in stage I/II ovarian cancer better than all other combinations Conclusion: Genes linked to cell cycle control are associated with worse outcome in early stage ovarian cancer. Incorporation of these biomarkers in clinical studies may help in the identification of patients at high risk of relapse for whom optimizing adjuvant therapeutic strategies is needed.

Evolución y respuesta al tratamiento de los pacientes pediátricos diagnósticados con hepatitis autoinmune / Prognosis and Treatment Response in pediatric patients with Autoimmune Hepatitis

Introducción: La Hepatitis Autoinmune (HAI) es una hepatopatía inflamatoria crónica y progresiva, de etiología desconocida, con presencia de autoanticuerpos circulantes e hipergammaglobulinemia. La mayoría de los pacientes responden adecuadamente al tratamiento inmunosupresor, pero si no se instaura se produce destrucción progresiva del parénquima hepático evolucionando a cirrosis e insuficiencia hepática. La interrupción temprana de la terapia puede causar recaídas y aumentar el riesgo de progresión a cirrosis.Objetivo: evaluar la evolución y la respuesta al tratamiento de los pacientes pediátricos con HAI. Materiales y métodos: estudio descriptivo, retrospectivo y transversal de 51 pacientes atendidos en el servicio de Gastroenterología Pediátrica del Hospital JM de los Ríos, de abril de 1996 a septiembre de 2010. De 51 pacientes con diagnóstico de HAI se incluyeron 48 pacientes con más de un año de tratamiento para evaluar evolución y respuesta.Resultados: 79, % de los pacientes presentaron remisión a los 20,4 ± 13,8 meses, 25 % tuvo recaídas. 10/48 (20,8 %) mostraron respuesta incompleta y 38,5 % de ellos no tuvo adherencia al tratamiento (p=0,001). 33/48 (68,8 %) presentaron complicaciones, siendo las más frecuentes: 64,6 % hipertensión portal, 27,2 % osteosporosis/osteopenia y 18,8 % evolucionaron a cirrosis hepática.3 (8,5 %) pacientes presentaron remisión con biopsia hepática normal, luego de aproximadamente 7 años, por lo que se les suspendió el tratamiento, manteniéndose la remisión durante 3,5 años de seguimiento. Dos pacientes requirieron trasplante hepático.Conclusiones: La mayoría de los pacientes respondieron adecuadamente al tratamiento inmunosupresor. La cuarta parte sufrió recaídas. La respuesta incompleta se relacionó significativamente con la falta de adherencia al tratamiento.

Introduction: Autoimmune hepatitis (AIH) is a progressive, chronic disease of unknown etiology, characterized for the presence of circulating autoantibodies and hyper gammaglobulinemia. Most patients respond to immunosuppressive treatment, otherwise, liver parenchimal is progressively destroyed leading to cirrhosis and liver failure. Early withdrawal of therapy might cause relapses and increased risk to cirrhosis.Objective: To assess HAI outcome and treatment response in pediatric patients.Methods: By a retrospective and descriptive analysis we evaluated 51 patients who attended the Pediatric Gastroenterology Department at the “J.M de Los Rios” Children Hospital from April 1996 to September 2010. 48 of these 51 patients have been on immunosuppressive treatment for more than one year.Results: 79.2 % of patients experienced remission at 20.4 ± 13.8 months, 25 % relapsed. 10/48 (20.8 %) showed incomplete response and 38.5 % had no adherence to treatment (p = 0.001). 33/48 (68.8 %) had complications, being the most frequent portal hypertension 64.6 %, following by osteoporosis and osteopenia 27,2 %, and 18.8 % developed cirrhosis.3 (8.5 %) patients had remission with normal liver biopsy after approximately 7 years, so treatment was discontinued, maintaining remission for 3.5 years. Two patients required liver transplantation.Conclusions: Most patients responded well to immunosuppressive therapy. 25 % suffered relapses. The incomplete response was significantly associated to non-adherence to treatment.

¿Pensar en hepatitis autoinmune precozmente evita la cirrosis? / Does early autoimmune hepatitis diagnose prevent from cirrhosis?

La hepatitis autoinmune (HAI) es una hepatopatía inflamatoria crónica y progresiva, que afecta predominantemente al sexo femenino y se caracteriza por la presencia de autoanticuerpos, elevación de aminotransferasas e hipergammaglobulinemia. Evoluciona rápidamente a cirrosis en pacientes no tratados, por lo que su diagnóstico precoz es indispensable. El propósito de este estudio es evaluar el tiempo promedio entre el inicio de los síntomas y el diagnóstico, así como su correlación con la presencia de cirrosis. Se realizó un estudio analítico, retrospectivo, no experimental. Se revisaron las historias clínicas de 51 pacientes que acudieron a la consulta de gastroenterología del hospital de niños J.M. de los Ríos desde abril de 1996 hasta septiembre de 2010 diagnosticados de HAI según criterios clínicos, serológicos e histológicos. Se excluyeron 3 pacientes por presentar patologías asociadas o estar recibiendo tratamiento inmunosupresor previo. La edad varió entre 2 y 15 años (media 8,3±3,2 DE); prevaleciendo el sexo femenino (72,9%). La clínica predominante fue ictericia (81,3%), coluria (47,9%) y dolor abdominal (39,5%). El diagnóstico se realizó en promedio 8,4 ± 7,3 meses luego del inicio de los síntomas. 50% se diagnosticó en los primeros 6 meses, de éstos 54,2% presentó cirrosis y 33,3% fibrosis. La HAI debe considerarse en pacientes pediátricos con clínica de hepatopatía inflamatoria a fin de realizar un diagnóstico oportuno y precoz debido a su rápida evolución a cirrosis

Autoimmune hepatitis (HAI) is a progressive chronic inflammatory hepatopathy with higher prevalence in females characterized by autoantibodies presence, elevation of aminotransferases and hipergammaglobulinemia. Another important characteristic is that it can develop into a rapid cirrhosis, so early diagnosis is vital. The purpose of our study is to evaluate the time spent between initial symptoms and final diagnosis, and it relation with the presence of cirrhosis. An analytic, retrospective non experimental study was performed. We reviewed the clinical records of 51 patients from April 1996 to September 2010 who attended the consultation of gastroenterology in the J. M. de los Ríos Children's Hospital with the diagnose of HAI according to clinical criteria, serological and histological. We excluded 3 patients for two reasons. 1. They were presenting associated pathologies 2. They were receiving immunosuppressive treatment. The ages vary from 2 to 15 years old (mean 8.3±3.2 ED); female prevail with (72.9%). The predominant symptoms were jaundice (81.3%), coluria (47.9%) and abdominal pain (39.5%). The diagnosis was made on average 8.4 ± 7.3 months after the beginning of the symptoms. 50% were diagnosed in the first 6 months, from these 54.2% presented with cirrhosis and 33,3% with fibrosis. HAI must be considered in pediatric patients with inflammatory hepatopathy clinical history in order to make an early and opportune diagnosis due to its rapid evolution to cirrhosis

Síndrome de Eisenmenger y embarazo / The Eisenmenger's syndrome and the pregnancy

El síndrome de Eisenmenger se define como una enfermedad vascular pulmonar de tipo obstructivo que se desarrolla a partir de la existencia previa de una comunicación entre la circulación sistémica y pulmonar, con desviación de la corriente sanguínea de izquierda a derecha. Durante el embarazo conlleva una mortalidad fetal y materna superior al 50 por ciento. El objetivo de este trabajo es describir un caso clínico de una paciente con síndrome de Eisenmenger asociado al embarazo. Se presenta el caso clínico de una paciente de 16 años de edad, primigesta, con antecedentes de síndrome de Eisenmenger que acude al servicio de Cardiopatía y embarazo con una gestación de 20 sem. Se mantiene hospitalizada con evaluación de la calidad de vida fetal por sospecha de retardo del crecimiento y se utilizan inductores de la madurez pulmonar fetal en las sem 30 y 33 de gestación. A las 34,4 sem se le practica una cesárea electiva y esterilización quirúrgica. Se obtiene un recién nacido masculino, peso 1 958 g, apgar 9/9 sin incidentes anestÚsicos ni quirúrgicos durante el procedimiento. La evolución del puerperio inmediato y mediato es satisfactoria y egresa a los 36 días. El síndrome de Eisenmenger implica un alto riesgo de morbilidad y mortalidad materno-perinatal y el manejo multidisciplinario optimiza los resultados(AU)

Eisenmenger's syndrome is defined as a obstructive pulmonary vascular disease developed from the previous existence of a communication between the systemic and the pulmonary circulation with a deviation of blood stream from left to right. During pregnancy entails a mother and fetus mortality higher than 50 percent. The objective of present paper is to describe a clinical case of a patient presenting with Eisenmenger's syndrome seen in the Heart Disease service and a 20 weeks pregnancy. Remains admitted with an evaluation of the fetal quality of life due to suspicion of growth retardation using inductors of the fetal pulmonary maturity at 30 and 33 weeks of pregnancy. At 34.4 weeks she undergoes an elective cesarean section and surgical sterilization. She give birth a male newborn weighing 1 958 g, Apgar 9/9 without surgical and anesthetic backgrounds during procedure. Immediate puerperium evolution is satisfactory and is discharged at 36 days. The Eisenmenger's syndrome entails a high risk of morbidity and mortality for mother and for fetus, and the multidisciplinary management optimizes the results(AU)

Síndrome de Eisenmenger y embarazo / The Eisenmenger's syndrome and the pregnancy

El síndrome de Eisenmenger se define como una enfermedad vascular pulmonar de tipo obstructivo que se desarrolla a partir de la existencia previa de una comunicación entre la circulación sistémica y pulmonar, con desviación de la corriente sanguínea de izquierda a derecha. Durante el embarazo conlleva una mortalidad fetal y materna superior al 50 por ciento. El objetivo de este trabajo es describir un caso clínico de una paciente con síndrome de Eisenmenger asociado al embarazo. Se presenta el caso clínico de una paciente de 16 años de edad, primigesta, con antecedentes de síndrome de Eisenmenger que acude al servicio de Cardiopatía y embarazo con una gestación de 20 sem. Se mantiene hospitalizada con evaluación de la calidad de vida fetal por sospecha de retardo del crecimiento y se utilizan inductores de la madurez pulmonar fetal en las sem 30 y 33 de gestación. A las 34,4 sem se le practica una cesárea electiva y esterilización quirúrgica. Se obtiene un recién nacido masculino, peso 1 958 g, apgar 9/9 sin incidentes anestÚsicos ni quirúrgicos durante el procedimiento. La evolución del puerperio inmediato y mediato es satisfactoria y egresa a los 36 días. El síndrome de Eisenmenger implica un alto riesgo de morbilidad y mortalidad materno-perinatal y el manejo multidisciplinario optimiza los resultados

Eisenmenger's syndrome is defined as a obstructive pulmonary vascular disease developed from the previous existence of a communication between the systemic and the pulmonary circulation with a deviation of blood stream from left to right. During pregnancy entails a mother and fetus mortality higher than 50 percent. The objective of present paper is to describe a clinical case of a patient presenting with Eisenmenger's syndrome seen in the Heart Disease service and a 20 weeks pregnancy. Remains admitted with an evaluation of the fetal quality of life due to suspicion of growth retardation using inductors of the fetal pulmonary maturity at 30 and 33 weeks of pregnancy. At 34.4 weeks she undergoes an elective cesarean section and surgical sterilization. She give birth a male newborn weighing 1 958 g, Apgar 9/9 without surgical and anesthetic backgrounds during procedure. Immediate puerperium evolution is satisfactory and is discharged at 36 days. The Eisenmenger's syndrome entails a high risk of morbidity and mortality for mother and for fetus, and the multidisciplinary management optimizes the results

Factores psicosociales de riesgo asociados a conductas problemáticas en jóvenes infractores y no infractores / Psychosocial risk factors associated with problem behaviors in young offenders and non offenders

El presente trabajo estudia los factores de riesgo asociados con la conducta antisocial y delictiva en dos grupos de adolescentes. Un grupo está conformado por adolescentes que se encuentran recluidos en dos instituciones privadas para menores infractores, y el grupo control, de adolescentes no infractores, que asisten a una institución educativa pública. La muestra estuvo conformada por 179 adolescentes con edades entre 12 y 18 años. La edad media de la muestra fue de 15 años. Para analizar la información sociodemográfica y las puntuaciones de las pruebas se utilizó el paquete estadístico SPSS versión 15.0. Los resultados muestran que los adolescentes que se encuentran recluidos en dos instituciones para menores infractores presentan una mayor frecuencia de exposición a los factores de riesgo, asociados con la conducta antisocial y delictiva, en comparación con los adolescentes no infractores que asisten a una institución pública, en los niveles exosistema, microsistema y macrosistema. Los dos grupos de adolescentes se encuentran expuestos al maltrato, el consumo y abuso de alcohol en proporciones similares, y constituyen los factores de riesgo que más se asocian a la generación del comportamiento antisocial y el comportamiento delictivo.

The present study examines the risk factors associated with antisocial and criminal behavior in two groups of adolescents. A group consists of teenagers who are being held in two private institutions for juvenile offenders, and the control group of adolescent's offenders, attending a public school. The sample consisted of 179 adolescents aged between 12 and 18. The sample mean age was 15 years. The results were analyzed with SPSS 15.0. To analyze demographic information and test scores. The results show that adolescents who are being held in two institutions for juvenile offenders have an increased frequency of exposure to risk factors associated with antisocial and criminal behavior in adolescents compared with offenders who attend a public institution, exosystem levels, micro and macro. Abuse, alcohol use and abuse are factors that are exposed in similar proportions the two groups of adolescents and risk factors are most associated with the generation of antisocial behavior and criminal behavior.

Conductas antisociales y delictivas en adolescentes infractores y no infractores

Se estudian las manifestaciones de la conducta antisocial y delictiva en dos grupos de adolescentes hombres y mujeres, entre los 12 y los 18 años de edad. La muestra estuvo conformada por 179 adolescentes, 72 infractores de ley y 107 no infractores. La edad promedio de la muestra fue de 15.0años, con una desviación estándar de 1.828. Los resultados muestran que existen diferencias en la frecuencia de comportamientos antisociales y delictivos entre los dos grupos de adolescentes. Los adolescentes no infractores informaron una mayor frecuencia de conductas antisociales y delictivas en comparación con los infractores. En cuanto a la edad, se observa que existen diferencias significativas entre los adolescentes de 12 a 13 años y los de 16 a 17 años y 18 años, siendo los últimos quienes más presentaron estos comportamientos; datos que muestran el inicio temprano y progresivo del comportamiento. Los varones adolescentes presentan una media mayor en la conducta antisocial yen la conducta delictiva comparada con las mujeres, diferencias estadísticamente significativas. Sesugiere tener en cuenta, en estudios similares, las diferencias biológicas y evolutivas que puedan estarinfluyendo en la manifestación de estos tipos de comportamientos, y en consecuencia, la generación de programas que puedan prevenir su manifestación, teniendo en cuenta su carácter progresivo y, en algunos grupos, persistente en el tiempo.

Expressions of anti-social and criminal conduct with two groups of adolescent males and females between 12 and 18 years of age are studied. The sample was made up of 179 adolescents, 72 of whom were law-breakers and 107 who were not. The average age of the sample was 15, with a standarddeviation of 1.828. The results showed that that there were differences in the frequency of antisocial and criminal behavior between the two adolescent groups. The non-law-breaking adolescents reported a higher frequency of antisocial and criminal conduct in comparison with the law-breakers.With reference to age, there were significant differences between the 12-13 year-old adolescents, andthose of 16, 17 and 18, the latter being the group with the highest incidence of this type of behavior. These results showed the early commencement and progressive nature of this behavior. Adolescent males showed a higher average of antisocial conduct and criminal behavior compared with females, which are statistically significant differences. We suggest that similar future studies take account of biological and evolutionary differences which could be affecting the expression of this type of behavior and therefore the preparation of prevention programs, bearing in mind its progressive natureand some groups which are persistent over time.

Se estudam as manifestações da conduta anti-social e delitiva em dois grupos de adolescentes homense mulheres entre os 12 e os 18 anos de idade. A mostra esteve conformada por 179 adolescentes, 72 infratores de lei e 107 não infratores. A idade média da amostra foi de 15.0 anos, com um desviostandard de 1.828. Os resultados mostram que existem diferenças na freqüência de comportamentosanti-sociais e comportamentos delitivos entre os dois grupos de adolescentes. Os adolescentes não infratores informaram uma maior freqüência de condutas anti-sociais e delitivas em comparação com os infratores. Quanto à idade se observa que existem diferenças significativas entre os adolescentesde 12 a 13 anos e os adolescentes de 16 a 17 anos e 18 anos, sendo os últimos que mais apresentaram estes comportamentos; dados que mostram o início cedo e progressivo do comportamento. Os varõesadolescentes apresentam uma meia maior na conduta anti-social e na conduta delitiva comparada com as mulheres, com diferenças estatisticamente significativas. Se sugere levar em conta em estudos similares diferenças biológicas e evolutivas que possam estar influindo na manifestação destes tipos de comportamentos e em conseqüência a geração de programas que possam prevenir sua manifestação, levando em conta seu caráter progressivo e em alguns grupos persistente no tempo.

Descripción de los conocimientos, actitudes, susceptibilidad y autoeficacia frente al VIH/SIDA en un grupo de adolescentes colombianos

La presente investigación tiene como objetivo describir y comparar los conocimientos correctos,las ideas erróneas, las actitudes, la susceptibilidad y autoeficacia frente al VIH/SIDA en un grupode adolescentes colombianos. La muestra está conformada por 222 adolescentes de ambos sexos,entre los 10 y 18 años (media 14.10 y desviación típica 1.925) que pertenecen a una instituciónpública de la ciudad de Cali. Es una investigación descriptivo-correlacional (Montero y León, 2005).La información se recogió mediante la aplicación de la Adaptación Colombiana de la escala VIH-65 (Bermúdez, Buela-Casal y Uribe (2005), que mide conocimientos, actitudes, susceptibilidad yautoeficacia frente al VIH/SIDA. Los resultados evidencian que la escala que obtuvo mayor puntuaciónes la de conocimientos erróneos, lo que indica que aún persisten conceptos errados y mitos frente alVIH/SIDA. Igualmente, se encontró que existen diferencias significativas en función de la edad, laescolaridad y el sexo...

The objective of this research is to describe and compare correct knowledge, incorrect ideas, attitudes,susceptibility and self-efficacy in cases of HIV/AIDS in a group of Colombian adolescents. Thesample consists of 222 adolescents of both sexes between the ages of 10 and 18. (Average 14.10 anda typical deviation of 1.925), who belong to a public institution in the city of Cali. This is descriptivecorrelationalresearch (Montero and León, 2005). The information was gathered by the applicationof the Colombian adaptation of the HIV-65 scale (Bermúdez, Buela-Casal and Uribe (2005), whichmeasures knowledge, attitudes, susceptibility, and self-efficacy in cases of HIV/AIDS. The results show that the scale obtaining the highest score is that of incorrect knowledge, which suggests thatthere are still erroneous and mythical concepts about HIV/AIDS. It was also found that there aredifferent meanings depending on age, academic level and sex...

A presente investigação tem como objetivo descrever e comparar os conhecimentos corretos, asidéias errôneas, as atitudes, a suscetibilidade e auto-eficácia contra o HIV/AIDS em um grupo deadolescentes colombianos. A mostra está conformada por 222 adolescentes de ambos sexos, entre os10 e 18 anos (meia 14.10 e desvio típica 1.925) que pertencem a uma instituição pública da cidade deCali. É uma investigação descritivo-correlacional (Montero y León, 2005). A informação se recolheumediante a aplicação da Adaptação Colombiana da escala HIV-65 (Bermúdez, Buela-Casal y Uribe(2005), que mede conhecimentos, atitudes, suscetibilidade e auto-eficácia contra o HIV/AIDS. Osresultados evidenciam que a escala que obteve maior pontuação é a de conhecimentos errôneos, o queindica que ainda persistem conceitos errados e mitos contra o HIV/AIDS. Igualmente se encontrouque existem diferenças significativas em função da idade, a escolaridade e o sexo...

Efecto biológico de la resonancia magnética sobre la mosca de la fruta drosophila malanogaster

En este artículo se describre la investigación en la cual fueron sometidas moscas de la fruta D. Melanogaster de las cepas White y vestigial a un campo de Resonancia Magnética por 171 horas con el fin de determinar, posibles alteraciones en el nivel genético