La inmunidad más allá de las ciencias médicas y biológicas / Immunity beyond the medical and biological sciences

El contexto socio-cultural actual, con su vertiginoso indi¬vidualismo y cada vez más alejado de lo colectivo, nos exige ejercitar la bioética y reflexionar sobre la lógica inmunitaria y la teoría del sistema inmunitario. La división siempre fue igual: blanco/negro, el bien/el mal, anticuerpo/antígeno, normal/patológico, occidente/oriente, civilización/barbarie, gen/proteína, y la lista es inagotable. Desde la lógica inmunitaria estas asociaciones se sintetizan en el par dicotómico vertical lo propio/lo no propio, donde el cuerpo humano biologizado (o biomedicalizado) representaría lo propio, que debe protegerse de lo considerado no propio, como podría ser un microorganismo o un cáncer. ¿De qué hablamos cuando hablamos de inmunidad? Depende. En la sinopsis del libro de divulgación científica Qué es el sistema inmune, escrito por Gabriel Rabinovich y Jorge Geffner, se anuncia (2014): "Sin que nos demos cuenta, nuestro organismo es un territorio en el que día y noche se desarrollan batallas épicas. Se producen en la intimidad de nuestros tejidos, y con armas más versátiles y efectivas que ninguna de las diseñadas por la industria bélica. Las protagoniza el sistema inmune, que distingue lo propio de lo extraño, nos protege de microorganis¬mos patógenos y descarta errores en la cadena de producción de las células (1)". En otro sentido, en la solapa del libro Immunitas. Protec¬ción y negación de la vida de Roberto Espósito se lee (2009): "La inmunidad preserva la comunidad al tiempo que la debilita". La fisiología del sistema inmunológico obedece a una lógica contradictoria: "la vida busca afirmase en aquello que la niega" (2). Es decir, para sobrevivir, conservar, proliferar y potenciar lo propio, se necesita de lo extraño. ¿Quién se puede negar a proteger lo que es de uno (tu cuerpo, tu casa, tu renta, tu país)? "Lo no propio" representa la esencia de la categoría "enfermedad" y se establece como ejemplar predilecto del discurso inmunitario, habiendo evo¬lucionado en sentido común. El sentido común, la obviedad vacía, materializa las re¬presentaciones del vulgo y produce un ethos mediado por el discurso biomédico con el objetivo de cosificar y colocar a las personas bajo la órbita comercial, donde "lo no propio" y la "enfermedad" funcionan como dispositivo espectacular de valor agregado. En este sentido, Donna Haraway sostiene: "Dirijo mi atención principalmente hacia ese polimorfo y poderosos objeto de fe, conocimiento y práctica llamado sistema inmunitario. Mi tesis es que el Sistema Inmunitario es un elaborado ícono para sistemas clave de "diferenciación" simbólica y material en el capitalismo tardío. Preeminente¬mente un objeto del siglo veinte, el Sistema Inmunitario es un mapa dibujado para guiar el reconocimiento y el desconoci¬miento del sí mismo y del otro en la dialéctica de la política occidental (Haraway en Esposito, 2009)." Este rasgo esencial del Sistema Inmune (lo no propio) se encuadra en el hábito de designar a las instituciones y a los eventos culturales como conceptos médico-biológicos y calificarlos en términos de moralidad, siempre en pares dicotómicos verticales, donde lo "mejor/peor" o "superior/inferior" es el sustrato favorito para fabricar conceptos aso¬ciados a ellos, en este caso "lo propio/lo no propio" (3, 4). La naturaleza del mecanismo inmunitario es una teoría, devenida verdad, cuya atracción para el estudiantado y su facilidad para estudiarla y comprenderla proviene de la dicotomía axiológica "lo propio y lo no propio" y desde la metáfora bélica. El problema surge cuando ­televisión de por medio­ se produce el pasaje de verdades (conceptos) médicas a la comunidad, porque la sociedad y el espectáculo encuentran en el fascinante discurso médico su argumentación teórica (5). Ahora bien, imaginemos la siguiente definición: El Sistema Inmunitario se encarga de reconocer e incluir lo no propio, para interactuar con lo propio y fortalecerse. El contenido y el mecanismo fisiológico es el mismo; sólo cambió el discurso y, por ende, el significado. Lamentablemente, para que "la cosa funcione" el discurso inmunitario debe ser el de siempre: el de una batalla, y si es épica mejor.

Bioética y asignación de recursos críticos en Pandemia: una reflexión sobre el principio del ciclo de vida en adultos y la vulnerabilidad social / Bioethics and critical resource allocation in pandemic: a reflection on the life-cycle principle in adults and the social vulnerability

Introducción: en el presente artículo se reflexiona sobre el uso del principio del ciclo de vida en adultos y la selección por lotería en la asignación de recursos críticos en el contexto de pandemia, tomando como referencia lo publicado y sugerido en las "Guías éticas para la atención durante la pandemia COVID-19. Recomendaciones multisocietarias para asignación de recursos" (Maglio et al, 2020). Desarrollo: son numerosas las guías que han decidido aplicar el principio del ciclo de vida (edad) al momento de asignar recursos críticos. Algunas sugieren utilizarlo como criterio independiente, mientras que otras proponen aplicarlo como criterio dependiente del pronóstico de supervivencia a corto plazo (score SOFA) y del pronóstico de supervivencia a largo plazo (evaluación médica de comorbilidades). La selección aleatoria es un criterio de asignación de recursos sanitarios que, según varias guías, solo se aplicaría ante dos o más pacientes con similares condiciones médicas y del mismo rango etario. Los comités de bioética hospitalarios juegan un rol clave en el monitorio ético de las guías establecidas en cada hospital. No obstante, durante lo que va de la pandemia, ha emergido una confusión (al menos teórica) entre monitoreo, reflexión y responsabilidad en la toma de decisiones. Comentarios finales: una decisión médica en un caso clínico particular debería estar sustentada por decisiones éticas globales (políticas, sanitarias y ciudadanas). La bioética ya tiene 50 años de existencia. Sin embargo, recién ahora el mundo se acuerda de ella.

Eugenética y procreación humana. Un aporte desde la bioética / Eugenics and human procreation. A contribution from bioethics

La revolución biológica constituye una de las raíces que, según José Alberto Mainetti, origina la crisis bioética como síndrome de la posmodernidad. El desarrollo de la genómica, como técnica vanguardia de esta revolución, conlleva varias cuestiones que merecen su abordaje bioético. En este trabajo se intentará reflexionar sobre una de ellas: la eugenesia (y el derecho a no nacer) en torno a las nuevas formas de procrear.

The biological revolution constitutes one of the roots that, according to José Alberto Mainetti, originates the bioethical crisis as a post-modernity syndrome. The development of genomics, as the vanguard technique of this revolution, involves several issues that deserve a bioethical approach. In this work we will try to reflect on one of them: eugenics, and the right not to be born , around the new forms of procreation.

Heme Oxygenase-1 Has an Antitumor Role in Breast Cancer.

Aims: Heme oxygenase-1 (HO-1) is an enzyme involved in cellular responses to oxidative stress and has also been shown to regulate processes related to cancer progression. In this regard, HO-1 has been shown to display a dual effect with either antitumor or protumor activity, which is also true for breast cancer (BC). In this work, we address this discrepancy regarding the role of HO-1 in BC. Results: HO-1 was detected in human BC tissues, and its protein levels correlated with reduced tumor size and longer overall survival time of patients, thus suggesting the clinical importance of HO-1 in this type of cancer. Contrariwise, nuclear localization of HO-1 correlated with higher tumor grade suggesting that the effect of HO-1 is dependent on its cellular localization. In vivo experiments showed that both pharmacological activation and genetic overexpression of HO-1 reduce the tumor burden in two different animal models of BC. Furthermore, the pharmacological and genetic activation of HO-1 in several BC cell lines reduce the cellular viability by inducing apoptosis and cell cycle arrest and decrease the cellular migration and invasion rates by modulating pathways involved in the epithelial-mesenchymal transition. Furthermore, HO-1 activation impaired in vivo the metastatic dissemination. Innovation and Conclusion: By using various BC cell lines and animal models as well as human tumor samples, we demonstrated that total HO-1 displays antitumor activities in BC. Furthermore, our study suggests that HO-1 subcellular localization may explain the differential effects observed for the protein in different tumor types.

Antitumoral Effects of D-Fraction from Grifola Frondosa (Maitake) Mushroom in Breast Cancer.

D-Fraction is protein-bound ß-1,6 and ß-1,3 glucans (proteoglucan) extracted from the edible and medicinal mushroom Grifola frondosa (Maitake). The antitumoral effect of D-Fraction has long been exclusively attributed to their immunostimulatory capacity. However, in recent years increasing evidence showed that D-Fraction directly affects the viability of canine and human tumor cells, independent of the immune system. Previously, we have reported that D-Fraction modulates the expression of genes associated with cell proliferation, cell death, migration, invasion, and metastasis in MCF7 human breast cancer cells. Therefore, the purpose of the current study is to investigate if this modulation of gene expression by Maitake D-Fraction really modulates tumor progression. In the present work, we demonstrate for the first time that Maitake D-Fraction is able to act directly on mammary tumor cells, modulating different cellular processes involved in the development and progression of cancer. We demonstrate that D-Fraction decreases cell viability, increases cell adhesion, and reduces the migration and invasion of mammary tumor cells, generating a less aggressive cell behavior. In concordance with these results, we also demonstrate that D-Fraction decreases tumor burden and the number of lung metastases in a murine model of breast cancer.

The UVB1 Vitamin D analogue inhibits colorectal carcinoma progression.

Vitamin D has been shown to display a wide variety of antitumour effects, but their therapeutic use is limited by its severe side effects. We have designed and synthesized a Gemini vitamin D analogue of calcitriol (UVB1) which has shown to display antineoplastic effects on different cancer cell lines without causing hypercalcemia. The aim of this work has been to investigate, by employing in silico, in vitro, and in vivo assays, whether UVB1 inhibits human colorectal carcinoma progression. We demonstrated that UVB1 induces apoptotic cell death and retards cellular migration and invasion of HCT116 colorectal carcinoma cells. Moreover, the analogue reduced the tumour volume in vivo, and modulated the expression of Bax, E-cadherin and nuclear ß-catenin in tumour animal tissues without producing toxic effects. In silico analysis showed that UVB1 exhibits greater affinity for the ligand binding domain of vitamin D receptor than calcitriol, and that several characteristics in the three-dimensional conformation of VDR may influence the biological effects. These results demonstrate that the Gemini vitamin D analogue affects the growth of the colorectal cancer and suggest that UVB1 is a potential chemotherapeutic agent for treatment of this disease.

Inhibition of p300 suppresses growth of breast cancer. Role of p300 subcellular localization.

There is evidence that p300, a transcriptional co-factor and a lysine acetyl-transferase, could play a role both as an oncoprotein and as a tumor suppressor, although little is known regarding its role in breast cancer (BC). First we investigated the role p300 has on BC by performing pharmacological inhibition of p300 acetyl-transferase function and analyzing the effects on cell count, migration and invasion in LM3 murine breast cancer cell line and on tumor progression in a syngeneic murine model. We subsequently studied p300 protein expression in human BC biopsies and evaluated its correlation with clinical and histopathological parameters of the patients. We observed that inhibition of p300 induced apoptosis and reduced migration and invasion in cultured LM3 cells. Furthermore, a significant reduction in tumor burden, number of lung metastases and number of tumors invading the abdominal cavity was observed in a syngeneic tumor model of LM3 following treatment with the p300 inhibitor. This reduction in tumor burden was accompanied by a decrease in the mitotic index and Ki-67 levels and an increase in Bax expression. Moreover, the analysis of p300 expression in human BC samples showed that p300 immunoreactivity is significantly higher in the cancerous tissues than in the non-malignant mammary tissues and in the histologically normal adjacent tissues. Interestingly, p300 was observed in the cytoplasm, and the rate of cytoplasmic p300 was higher in BC than in non-tumor tissues. Importantly, we found that cytoplasmic localization of p300 is associated with a longer overall survival time of the patients. In conclusion, we demonstrated that inhibition of the acetylase function of p300 reduces both cell count and invasion in LM3 cells, and decreases tumor progression in the animal model. In addition, we show that the presence of p300 in the cytoplasm correlates with increased survival of patients suggesting that its nuclear localization is necessary for the pro-tumoral effects.

Vitamin D receptor expression is associated with improved overall survival in human glioblastoma multiforme.

Vitamin D and its analogs have been shown to display anti-proliferative effects in a wide variety of cancer types including glioblastoma multiforme (GBM). These anticancer effects are mediated by its active metabolite, 1α, 25-dihydroxyvitamin D3 (calcitriol) acting mainly through vitamin D receptor (VDR) signaling. In addition to its involvement in calcitriol action, VDR has also been demonstrated to be useful as a prognostic factor for some types of cancer. However, to our knowledge, there are no studies evaluating the expression of VDR protein and its association with outcome in gliomas. Therefore, we investigated VDR expression by using immunohistochemical analysis in human glioma tissue microarrays, and analyzed the association between VDR expression and clinico-pathological parameters. We further investigated the effects of genetic and pharmacologic modulation of VDR on survival and migration of glioma cell lines. Our data demonstrate that VDR is increased in tumor tissues when compared with VDR in non-malignant brains, and that VDR expression is associated with an improved outcome in patients with GBM. We also show that both genetic and pharmacologic modulation of VDR modulates GBM cellular migration and survival and that VDR is necessary for calcitriol-mediated effects on migration. Altogether these results provide some limited evidence supporting a role for VDR in glioma progression.

Heme oxygenase-1 expression in human gliomas and its correlation with poor prognosis in patients with astrocytoma.

In human glioma tumors, heme oxygenase-1 (HO-1) has been shown to be upregulated both when compared with normal brain tissues and also during oligodendroglioma progression. The cell types that express HO-1 have been shown to be mainly macrophages/microglia and T cells. However, many other reports also demonstrated that cell lines derived from glioma tumors and astrocytes express HO-1 after the occurrence of a wide variety of cell injuries and stressors. In addition, the significance of HO-1 upregulation in glioma had not, so far, been addressed. We therefore aimed at investigating the expression and significance of HO-1 in human glial tumors. For this purpose, we performed a wide screening of HO-1 expression in gliomas by using tissue microarrays containing astrocytomas, oligodendrogliomas, mixed tumors, and normal brain tissues. We subsequently correlated protein expression with patient clinicopathological data. We found differences in HO-1 positivity rates between non-malignant brain (22 %) and gliomas (54%, p = 0.01). HO-1 was expressed by tumor cells and showed cytoplasmic localization, although 19% of tumor samples also depicted nuclear staining. Importantly, a significant decrease in the overall survival time of grade II and III astrocytoma patients with HO-1 expression was observed. This result was validated at the mRNA level in a cohort of 105 samples. However, no association of HO-1 nuclear localization with patient survival was detected. In vitro experiments aimed at investigating the role of HO-1 in glioma progression showed that HO-1 modulates glioma cell proliferation, but has no effects on cellular migration. In conclusion, our results corroborate the higher frequency of HO-1 protein expression in gliomas than in normal brain, demonstrate that HO-1 is expressed by glial malignant cells, and show an association of HO-1 expression with patients' shorter survival time.

Assessing health system performance: a model-based approach.

It is difficult to assess countries' relative success in addressing issues of public health because countries are subject to very different background conditions. To address this problem we offer a model-based approach for assessing health system performance. Specifically, an index of public health is regressed against a vector of variables intended to capture economic, educational, cultural, geographic, and epidemiological endowments. The residual from this model is regarded as a plausible measure of public health performance at the national level. We argue that a model-based approach to performance is informative for policymakers and academics as it focuses attention on those aspects of a country's health profile that are not constrained by structural factors. This sharpens comparisons across countries and through time, and also allows one to evaluate the degree to which health systems have lived up to their potential.

Enteropatía grado II. Revisión diagnóstica de 12 años / Grade II Entheropathy. 12 year diagnostic review

Introducción: El diagnóstico de enteropatía grado II presenta amplias discrepancias entre los distintos observadores. Objetivo: Realizar una revisión de las biopsias de mucosa duodeno-yeyunal diagnosticadas como enteropatía grado II en el H.I.G.A. «Dr. José Penna¼ de Bahía Blanca entre 1997 y 2009. Materiales y Métodos: Se reevaluaron 22 casos utilizando los criterios histológicos propuestos por Drut y col. (2004) que clasifican la enteropatía en 4 grados según el compromiso de la relación vellosidad/cripta. Resultados: De los 22 casos reevaluados, concordamos que 13 de ellos eran enteropatía grado II. En los 9 casos restantes surgieron nuevas interpretaciones. Conclusión: Coincidimos con el diagnóstico previo en un 59,1% de los casos. Creemos que la falta de concordancia en el 40,9% restante se debió a la utilización de varios criterios, que al superponerlos generan gran variación interobservador.

Introduction: Grade II entheropathy diagnosis presents marked differences depending on the observers. Objective: This work aims at reviewing the biopsies of duodenal­jejunal mucosa biopsies diagnosed as grade II entheropathy at the Hospital «Dr. José Penna¼ of Bahía Blanca, between the years 1997 and 2009. Materials and Methods: 22 cases of grade II entheropathy were re-assessed using the histological criteria proposed by Drut and collaborators (2004), who classify entheropathy into 4 degrees according to crypt/villus ratio involvement. Results: Out of the 22 re-assessed cases, we agree that 13 corresponded to grade II entheropathy. In the 9 remaining cases there were new interpretations. Conclusions: We agree with the previous diagnosis in 59.1% of the cases. We believe that the lack of agreement in the remaining 40.9% of cases is due to the use of several overlapping criteria that create a great interobserver variation.