Acquired cancer cell resistance to T cell bispecific antibodies and CAR T targeting HER2 through JAK2 down-modulation.

Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression.

Enhanced antitumor efficacy of an oncolytic adenovirus armed with an EGFR-targeted BiTE using menstrual blood-derived mesenchymal stem cells as carriers.

Poor tumor targeting of oncolytic adenoviruses (OAdv) after systemic administration is considered a major limitation for virotherapy of disseminated cancers. The benefit of using mesenchymal stem cells as cell carriers for OAdv tumor targeting is currently evaluated not only in preclinical models but also in clinical trials. In this context, we have previously demonstrated the enhanced antitumor efficacy of OAdv-loaded menstrual blood-derived mesenchymal stem cells (MenSCs). However, although significant, the antitumor efficacy obtained was modest, and we hypothesized that a greater antitumor efficacy could be obtained arming the OAdv with a therapeutic transgene. Here we show that combining MenSCs with ICOVIR15-cBiTE, an OAdv expressing an epidermal growth factor receptor (EGFR)-targeting bispecific T-cell engager (cBiTE), enhances the antitumor efficacy compared to MenSCs loaded with the unarmed virus ICOVIR15. We found that MenSCs properly produce cBiTE after viral infection leading to a greater antitumor potency both in vitro and in vivo. These findings indicate the mutual benefit of combining MenSCs and armed OAdv and support the combination of ICOVIR15-cBiTE and MenSCs as a cancer treatment.

Los textos hipocráticos y su vigencia: elementos para la formación humanística del médico en el siglo XXI / Hippocratic Writings and their Relevance: Elements for the Humanistic Education of Doctors in the 21st Century / Os textos hipocráticos e sua validade: elementos para a formação humanística do médico no século XXI

Resumen Se presentan comentarios, a modo de apostillas, sobre la actualidad de algunos textos hipocráticos desde la perspectiva del aprendizaje y la práctica del quehacer médico en las primeras décadas del siglo XXI, en plena expansión de una civilización técnico-científica e informática. Se destaca la afirmación de verdades perennes -con valor para todos los tiempos- extractadas de una selección de los escritos hipocráticos, los cuales expresan el espíritu de la medicina clásica griega entendida como tekhne iatrike, concebida originalmente como una actividad de carácter racional, humana, filantrópica y científica, dirigida al servicio del bien de los pacientes, con la puesta en marcha de un ethos, unos principios y valores éticos de rango, validez y aplicación universales. Se propone que la asimilación de estos conceptos añade calidad humana, dignidad, crecimiento moral e intelectual al estudiante de medicina, así como mejoramiento de sus actitudes y aptitudes, habilidades y destrezas, para la comprensión y el enfrentamiento de las múltiples situaciones existenciales que impregnan la práctica clínica diaria, la cual no solo exige competencias técnicas profesionales, sino también cualidades humanísticas para un mejor enfoque de las relaciones interpersonales y las actitudes ante el paciente y sus familiares. Estas ideas se presentan como un aporte de la bioética, caracterizada por su tarea de integración de humanidades-ciencia-tecnología y su misión educativa en la formación de conciencias críticas en la civilización tecno-científica, a fin de fomentar una actitud de respeto y apertura ante los diferentes aspectos de la realidad.

Abstract By way of notes, comments are made on the validity of some Hippocratic works from the perspective of the learning and practice of medicine in the first decades of the 21st century, amidst a expanding technical-scientific and computer civilization. The paper highlights the affirmation of perennial truths -valid at all times- extracted from a selection of Hippocratic writings, which express the spirit of classic Greek medicine understood as tekhne iatrike. It was originally conceived as an activity of a rational, human, philanthropic and scientific nature aimed at serving the good of patients, following an ethos and some ethical principles and values of universal range, validity and application. It is proposed that taking in these concepts provides the medicine student with humanity, dignity, moral and intellectual growth, and improves their attitudes and aptitudes, skills and abilities to understand and face multiple existential situations that permeate daily clinical practice. This not only requires professional technical skills, but also humane attributes for better approaching interpersonal relationships with and attitudes towards the patient and their families. These ideas are introduced as a contribution of bioethics, characterized by its humanities-science-technology integration and educational mission of training critical consciences within the techno-scientific civilization, in order to foster respect for and openness towards diverse aspects of reality.

Resumo São apresentados comentários com objetivos didáticos sobre a atualidade de alguns textos hipocráticos sob a perspectiva da aprendizagem e da prática do fazer médico nas primeiras décadas do século XXI, em plena expansão de uma civilização técnico-científica e informática. Destaca-se a afirmação de verdades perenes extraídas de uma seleção dos textos hipocráticos, os quais expressam o espírito da medicina clássica grega entendida como tekhne iatrike, concebida, originalmente, como atividade de caráter racional, humana, filantrópica e científica, dirigida ao serviço do bem dos pacientes, com a instauração de um ethos, de princípios e valores éticos de rango, validade e aplicação universais. Propõe-se que a assimilação desses conceitos agregue qualidade humana, dignidade, crescimento moral e intelectual ao estudante de Medicina, bem como melhore suas atitudes e aptidões, habilidades e destrezas, para compreender e enfrentar as múltiplas situações existenciais presentes na prática clínica diária, a qual não só exige competências técnicas profissionais, mas também qualidades humanas para uma melhor abordagem das relações interpessoais e melhores atitudes para com o paciente e seus familiares. Essas ideias são apresentadas como uma contribuição da Bioética, caracterizada por sua tarefa de integração de ciências humanas-ciência-tecnologia e sua missão educativa na formação de consciências críticas na civilização técnico-científica, a fim de fomentar uma atitude de respeito e abertura ante os diferentes aspectos da realidade.

Determinants for Neoantigen Identification.

All tumors accumulate genetic alterations, some of which can give rise to mutated, non-self peptides presented by human leukocyte antigen (HLA) molecules and elicit T-cell responses. These immunogenic mutated peptides, or neoantigens, are foreign in nature and display exquisite tumor specificity. The correlative evidence suggesting they play an important role in the effectiveness of various cancer immunotherapies has triggered the development of vaccines and adoptive T-cell therapies targeting them. However, the systematic identification of personalized neoantigens in cancer patients, a critical requisite for the success of these therapies, remains challenging. A growing amount of evidence supports that only a small fraction of all tumor somatic non-synonymous mutations (NSM) identified represent bona fide neoantigens; mutated peptides that are processed, presented on the cell surface HLA molecules of cancer cells and are capable of triggering immune responses in patients. Here, we provide an overview of the existing strategies to identify candidate neoantigens and to evaluate their immunogenicity, two factors that impact on neoantigen identification. We will focus on their strengths and limitations to allow readers to rationally select and apply the most suitable method for their specific laboratory setting.

Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager.

BACKGROUND: Oncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor-associated stroma limits the efficacy of oncolytic viruses by forming a barrier that blocks efficient viral penetration and spread. The stroma also plays a critical role in progression, immunosuppression and invasiveness of cancer. Fibroblast activation protein-α (FAP) is highly overexpressed in cancer-associated fibroblasts (CAFs), the main cellular component of tumor stroma, and in this study we assessed whether arming oncolytic adenovirus (OAd) with a FAP-targeting Bispecific T-cell Engager (FBiTE) could retarget infiltrated lymphocytes towards CAFs, enhancing viral spread and T cell-mediated cytotoxicity against the tumor stroma to improve therapeutic activity. METHODS: The bispecific T-cell Engager against FAP was constructed using an anti-human CD3 single-chain variable fragment (scFv) linked to an anti-murine and human FAP scFv. This FBiTE was inserted in the oncolytic adenovirus ICOVIR15K under the control of the major late promoter, generating the ICO15K-FBiTE. ICO15K-FBiTE replication and potency were assessed in HT1080 and A549 tumor cell lines. The expression of the FBiTE and the activation and proliferation of T cells that induced along with the T cell-mediated cytotoxicity of CAFs were evaluated by flow cytometry in vitro. In vivo, T-cell biodistribution and antitumor efficacy studies were conducted in NOD/scid/IL2rg-/- (NSG) mice. RESULTS: FBiTE expression did not decrease the infectivity and replication potency of the armed virus. FBiTE-mediated binding of CD3+ effector T cells and FAP+ target cells led to T-cell activation, proliferation, and cytotoxicity of FAP-positive cells in vitro. In vivo, FBiTE expression increased intratumoral accumulation of T cells and decreased the level of FAP, a marker of CAFs, in tumors. The antitumor activity of the FBiTE-armed adenovirus was superior to the parental virus. CONCLUSIONS: Combination of viral oncolysis of cancer cells and FBiTE-mediated cytotoxicity of FAP-expressing CAFs might be an effective strategy to overcome a key limitation of oncolytic virotherapy, encouraging its further clinical development.

Enhanced Antitumor Efficacy of Oncolytic Adenovirus-loaded Menstrual Blood-derived Mesenchymal Stem Cells in Combination with Peripheral Blood Mononuclear Cells.

Several studies have evaluated the efficacy of using human oncolytic adenovirus (OAdv)-loaded mesenchymal stem cells (MSC) for cancer treatment. For example, we have described the antitumor efficacy of CELYVIR, autologous bone marrow-mesenchymal stem cells infected with the OAdv ICOVIR-5, for treatment of patients with neuroblastoma. Results from this clinical trial point out the role of the immune system in the clinical outcome. In this context, a better understanding of the immunophenotypic changes of human MSCs upon adenoviral infection and how these changes affect human autologous or allogeneic peripheral blood mononuclear cells (PBMC) could guide strategies to improve the antitumor efficacy of infected MSCs. In this work, we show how infection by an OAdv induces toll-like receptor 9 overexpression and activation of the NFĸB pathway in menstrual blood-derived MSCs, leading to a specific cytokine secretion profile. Moreover, a proinflammatory environment, mainly mediated by monocyte activation that leads to the activation of both T cells and natural killer cells (NK cell), is generated when OAdv-loaded MSCs are cocultured with allogeneic PBMCs. This combination of allogeneic PBMCs and OAdv-loaded MSCs enhances antitumor efficacy both in vitro and in vivo, an effect partially mediated by monocytes and NK cells. Altogether our results demonstrate not only the importance of the immune system for the OAdv-loaded MSCs antitumor efficacy, but in particular the benefits of using allogeneic MSCs for this therapy.

Evidence of Anti-tumoral Efficacy in an Immune Competent Setting with an iRGD-Modified Hyaluronidase-Armed Oncolytic Adenovirus.

To enhance adenovirus-mediated oncolysis, different approaches that tackle the selectivity, tumor penetration, and spreading potential of oncolytic adenoviruses have been reported. We have previously demonstrated that insertion of the internalizing Arginine-Glycine-Aspartic (iRGD) tumor-penetrating peptide at the C terminus of the fiber or transgenic expression of a secreted hyaluronidase can improve virus tumor targeting and spreading. Here we report a new oncolytic adenovirus ICOVIR17K-iRGD in which both modifications have been incorporated. In xenografted A549 tumors in nude mice, ICOVIR17K-iRGD shows higher efficacy than the non-iRGD counterpart. To gain insights into the role of the immune system in oncolysis, we have studied ICOVIR17K-iRGD in the tumor isograft mouse model CMT64.6, partially permissive to human adenovirus 5 replication, in immunodeficient or immunocompetent mice. Whereas no efficacy was observed in the immunodeficient setting due to insufficient viral replication, partial efficacy and a polymorphonuclear and CD8+ T cell infiltrate were observed in the immunocompetent mice. The results indicate that the elicitation of a virus-induced anti-tumoral immune response is responsible for the observed partial anti-tumoral effect.

Improving CART-Cell Therapy of Solid Tumors with Oncolytic Virus-Driven Production of a Bispecific T-cell Engager.

T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE-mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605-16. ©2018 AACR.

Oncolytic Adenoviral Delivery of an EGFR-Targeting T-cell Engager Improves Antitumor Efficacy.

Antiviral immune responses present a major hurdle to the efficacious use of oncolytic adenoviruses as cancer treatments. Despite the existence of a highly immunosuppressive tumor environment, adenovirus-infected cells can nonetheless be efficiently cleared by infiltrating cytotoxic T lymphocytes (CTL) without compromising tumor burden. In this study, we tested the hypothesis that tumor-infiltrating T cells could be more effectively activated and redirected by oncolytic adenoviruses that were armed with bispecific T-cell-engager (BiTE) antibodies. The oncolytic adenovirus ICOVIR-15K was engineered to express an EGFR-targeting BiTE (cBiTE) antibody under the control of the major late promoter, leading to generation of ICOVIR-15K-cBiTE, which retained its oncolytic properties in vitro cBiTE expression and secretion was detected in supernatants from ICOVIR-15K-cBiTE-infected cells, and the secreted BiTEs bound specifically to both CD3+ and EGFR+ cells. In cell coculture assays, ICOVIR-15K-cBiTE-mediated oncolysis resulted in robust T-cell activation, proliferation, and bystander cell-mediated cytotoxicity. Notably, intratumoral injection of this cBiTE-expressing adenovirus increased the persistence and accumulation of tumor-infiltrating T cells in vivo, compared with the parental virus lacking such effects. Moreover, in two distinct tumor xenograft models, combined delivery of ICOVIR-15K-cBiTE with peripheral blood mononuclear cells or T cells enhanced the antitumor efficacy achieved by the parental counterpart. Overall, our results show how arming oncolytic adenoviruses with BiTE can overcome key limitations in oncolytic virotherapy. Cancer Res; 77(8); 2052-63. ©2017 AACR.

Albumin-binding adenoviruses circumvent pre-existing neutralizing antibodies upon systemic delivery.

Recombinant adenoviruses are used as vaccines, gene therapy vectors, and oncolytic viruses. However, the efficacy of such therapies is limited by pre-existing neutralizing antibodies (NAbs), especially when the virus is administered systemically for a wider biodistribution or to reach multiple metastases. To protect adenovirus against NAbs we inserted an albumin-binding domain (ABD) in the main adenovirus capsid protein, the hexon. This domain binds serum albumin to shield the virus upon systemic administration. The ABD-modified adenoviruses bind human and mouse albumin and maintain the infectivity and replication capacity in presence of NAbs. In pre-immunized mice non-modified viruses are completely neutralized, whereas ABD-modified viruses preserve the ability to transduce target organs, induce oncolysis, or generate immune responses to expressed proteins. Our results indicate that albumin coating of the virus capsid represents an effective approach to evade pre-existing NAbs. This strategy has translational relevance in the use of adenovirus for gene therapy, cancer virotherapy, and vaccination.

Observaciones booéticas sobre el "consenso de etambul": el cientificismo y la omisión de lo humano en la embriología humana / Biothical observvations on the "istnbul consensus": scientism and omission of the human aspect in human embryology / Observações bioéticas sobre o "cnsenso de istambul": o cientificismo e a omissãão do humano na embriologia humana

El "Consenso de Estambul" presenta criterios de calificación de embriones humanos en tres categorías de "calidad" (bueno, regular, malo), según criterios morfológicos establecidos por expertos en embriología dedicados a la aplicación de tecnologías de reproducción asistida en humanos. Se propone la necesidad de un diálogo interdisciplinario que, superando el reduccionismo cientificista, comprenda y analice prudencialmente las implicaciones de diverso carácter que necesariamente están ligadas en al uso de los embriones humanos como un "objeto" de aplicación de una técnica supuestamente desprovista de implicaciones éticas, humanas, antropológicas, filosóficas y jurídicas. Se destaca el concepto de la condición personal propia de cada ser humano, independientemente de los criterios utilitarios que se pretendan asignar a estos embriones -que se encuentran bajo la voluntad y el poder de terceras personas- en una de las fases de mayor fragilidad existencial, cuando son convertidos en "material biológico" descartable. Se refuerza el concepto de la autonomía teleológica -estatuto antropológico del embrión humano- y la necesidad de una comprensión cabal del significado de lo humano, como un aporte de la bioética y del diálogo interdisciplinar en pro de una aproximación científica válida y honesta en este campo de la aplicación de la tecnociencia.

The "Istanbul Consensus" offers a set of consensus points to classify human embryos into three "quality" categories (good, fair and poor), based on morphological criteria established by experts in embryology who are dedicated to the application of assisted reproductive technology in humans. The need for an interdisciplinary dialogue is proposed in this article, particularly one that overcomes scientific reductionism and understands and prudently analyzes the diverse implications that are linked inevitably to the use of human embryos as "objects" to be applied in a technique supposedly devoid of ethical, human, anthropological, philosophical and legal implications. The concept of the personal condition particular to each human being is underscored, regardless of whatever utilitarian criteria might be assigned to these embryos, which are subject to the will and power of third persons in one of the phases of greatest existential fragility; namely, when they are turned into disposable "biological material". The concept of teleological autonomy - the anthropological status of the human embryo - is reinforced and the need for a thorough understanding of the meaning of what is human is emphasized as a contribution of bioethics and interdisciplinary dialogue on behalf of a valid and honest scientific approach in this field of techno- scientific application.

O "Consenso de Istambul" apresenta critérios de qualificação de embriões humanos em três categorias de "qualidade" (bom, regular, mau), segundo critérios morfológicos estabelecidos por especialistas em embriologia dedicados à aplicação de tecnologias de reprodução assistida em humanos. Expõe-se a necessidade de um diálogo interdisciplinar que, superando o reducionismo cientificista, compreenda e analise prudencialmente as implicações de diverso caráter que necessariamente estão ligadas ao uso dos embriões humanos como um "objeto" de aplicação de uma técnica supostamente desprovida de implicações éticas, humanas, antropológicas, filosóficas e jurídicas. Destaca-se o conceito da condição pessoal própria de cada ser humano, independentemente dos critérios utilitários que se pretendam designar a esses embriões -que se encontram sob a vontade e o poder de terceiras pessoas- em uma das fases de maior fragilidade existencial, quando são convertidos em "material biológico" descartável. Reforça-se o conceito da autonomia teleológica -estatuto antropológico do embrião humano- e a necessidade de uma compreensão cabal do significado do humano, como contribuição da bioética e do diálogo interdisciplinar em prol de uma aproximação científica válida e honesta nesse campo da aplicação da tecnociência.

Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field.

The field of adenovirology is undergoing rapid change in response to increasing appreciation of the potential advantages of adenoviruses as the basis for new vaccines and as vectors for gene and cancer therapy. Substantial knowledge and understanding of adenoviruses at a molecular level has made their manipulation for use as vaccines and therapeutics relatively straightforward in comparison with other viral vectors. In this review we summarize the structure and life cycle of the adenovirus and focus on the use of adenovirus-based vectors in vaccines against infectious diseases and cancers. Strategies to overcome the problem of preexisting antiadenovirus immunity, which can hamper the immunogenicity of adenovirus-based vaccines, are discussed. When armed with tumor-associated antigens, replication-deficient and oncolytic adenoviruses can efficiently activate an antitumor immune response. We present concepts on how to use adenoviruses as therapeutic cancer vaccines and consider some of the strategies used to further improve antitumor immune responses. Studies that explore the prospect of adenoviruses as vaccines against infectious diseases and cancer are underway, and here we give an overview of the latest developments.

CagA EPIYA polymorphisms in Colombian Helicobacter pylori strains and their influence on disease-associated cellular responses.

AIM: To investigate the influence of the CagA diversity in Helicobacter pylori (H. pylori) strains from Colombia on the host cell biology. METHODS: Eighty-four H. pylori-cagA positive strains with different Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs patterns, isolated from patients with gastritis (n = 17), atrophic gastritis (n = 17), duodenal ulcer (n = 16), intestinal metaplasia (n = 16) and gastric cancer (n = 18), were included. To determine the integrity of the cag pathogenicity island (cagPAI) we evaluated the presence of cagA, cagT, cagE, and cag10 genes by polymerase chain reaction. AGS gastric epithelial cells were infected with each strain and assayed for translocation and tyrosine phosphorylation of CagA by western blot, secretion of interleukin-8 (IL-8) by enzyme-linked immuno sorbent assay after taking supernatants from cocultures and cell elongation induction. For cell elongation quantification, coculture photographs were taken and the proportion of "hummingbird" cells (> 15 µm) was determined. RESULTS: Overall 72% (60/84) of the strains were found to harbor a functional cagPAI. Levels of phosphorylated CagA were significantly higher for isolates from duodenal ulcer than the ones in strains from gastritis, atrophic gastritis, intestinal metaplasia and gastric cancer (49.1% ± 23.1% vs 21.1% ± 19.5%, P < 0.02; 49.1% ± 23.1% vs 26.2% ± 14.8%, P < 0.045; 49.1% ± 23.1% vs 21.5% ± 19.5%, P < 0.043 and 49.1% ± 23.1% vs 29.5% ± 27.1%, P < 0.047 respectively). We observed variable IL-8 expression levels ranging from 0 to 810 pg/mL and from 8.8 to 1442 pg/mL at 6 h and 30 h post-infection, respectively. cagPAI-defective strains did not induce detectable levels of IL-8 at 6 h post-infection. At 30 h post-infection all strains induced IL-8 expression in AGS cells, although cagPAI-defective strains induced significantly lower levels of IL-8 than strains with a functional cagPAI (57.1 ± 56.6 pg/mL vs 513.6 ± 338.6 pg/mL, P < 0.0001). We did not observe differences in the extent of cell elongation induction between strains with a functional or a defective cagPAI in 6 h cocultures. At 24 h post infection strains with functional cagPAI showed high diversity in the extent of hummingbird phenotype induction ranging from 7% to 34%. cagPAI defective strains induced significantly lower levels of elongation than strains with functional cagPAI with one or more than one EPIYA-C motif (15.1% ± 5.2% vs 18.9% ± 4.7%, P < 0.03; and 15.1% ± 5.2% vs 20.0% ± 5.1%, P < 0.003 respectively). No differences were observed in cellular elongation induction or IL-8 expression among H. pylori strains bearing one and more than one EPIYA-C motifs, neither at 6 h nor at 24 h of coculture. There were no associations between the levels of induction of cell elongation or IL-8 expression and number of EPIYA motifs or pathology. CONCLUSION: The present work describes a lack of association between H. pylori CagA protein EPIYA motifs variations from Colombian isolates and disease-associated cellular responses.

Edema masivo del ovario en la adolescencia: informe de un caso y revision de la literatura / Massive edema of the ovary in adolescence: case report and review of the literature

Se presenta el caso de una paciente de 15 años de edad, remitida al Hospital Pablo Tobón Uribe de Medellín, Colombia. Su cuadro clínico consistió en dolor y masa pélvica Palpable, unilateral, con características preoperatorias propias de tumor ovárico (Teratoma). Se practicó salpingo-ooforecromía del lado comprometido. El informe definitivo de anatomía patológica fue edema masivo del ovario. La evolución postoperatoria de la paciente transcurrió sin complicaciones. Se hacen consideraciones sobre esta condición, de baja frecuencia de presentación.

Edema masivo del ovario en la adolescencia / Massive ovarian edema in adolescence

Se presenta el caso de una paciente de 15 años de edad, remitida al Hospital Pablo Tobón Uribe, en Medellín, Colombia. Su cuadro clínico consistió en dolor y masa pélvica unilateral palpable, con características preoperatorias propias de tumor ovárico (teratoma). Se practicó salpingo-ooforectomía del lado comprometido. El informe definitivo de anatomía patológica fue edema masivo del ovario. La evolución postoperatoria de la paciente transcurrió sin complicaciones. Se hacen consideraciones sobre esta condición, de baja frecuencia de presentación.

El prisionero Nariño y un concepto medico de Jose Celestino Mutis / The prisoner Nariño and a medical concept of Jose Celestino Mutis

Se presenta un breve ensayo basado en un informe escrito por el sabio José Celestino Mutis (Director de la Expedición Botánica) Y otros médicos, en 1803, sobre las condiciones de salud del prisionero Don Antonio Nariño, preso debido a su traducción de los ''Derechos del hombre y el ciudadano". Se hace un comentario sobre el pensamiento sistemático de los médicos de inicios del siglo XIX, en los años finales del virreinato de la Nueva Granada, influenciados por las enseñanzas clínicas de Herman Boerhaave.

Here we show a brief essay based on the health condition of the prisioner Don Antonio Nariño, translator ofthe "Rights of Man and Citizens". The original report was done by José Celestino Mutis (Head ofthe Botanical Expedition) and other physicians. It happened in the ending years of the viceroyalty of Nueva Granada, when a great influence wasexerted by the clinical systematic view of Herman Boerhaave.