Anticuerpos monoclonales inmunoestimulantes para el tratamiento del hepatocarcinoma. Avances y perspectivas

Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and isthe main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablationcan only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy foradvanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specificpotent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunologicalmicroenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors suchas nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regionaltreatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.El hepatocarcinoma (HCC) es la segunda causa de muerte relacionada con el cáncer en el mundo y es la principal causa de muerte en pacientes cirróticos. Desafortunadamente, la incidencia de HCC ha crecido significativamente en la última década. Los tratamientos curativos como la cirugía, el trasplante de hígado o la ablación solo pueden aplicarse en menos del 30% de los casos. El sorafenib es el tratamiento de primera línea para el HCC avanzado, mientras que el regorafenib se reserva como segunda línea. Sin embargo, todavía son necesarios nuevos enfoques terapéuticos potentes y más específicos para el HCC avanzado. El hígado constituye un microambiente inmunológico único, aunque la inmunidad antitumoral parece ser factible mediante el uso de inhibidores de punto de control como nivolumab. La eficacia puede aumentarse adicionalmente combinando inhibidores de puntos de control inmunitario o aplicando tratamientos loco-regionales. En este sentido, el éxito del uso de anticuerpos monoclonales, que bloquean el control inmunitario, ha renovado el interés en la inmunoterapia para el HCC.Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentin

Alcohol consumption leads to loss of healthy life, but the ADH1B*2 allele may still protect from NASH

Nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease worldwide, affecting almost a quarter of the world population (1,2), and is a main cause of severe hepatic complications such as cirrhosis and liver cancer. In histological assessment NAFLD and alcoholic liver disease (ALD) are difficult to distinguish; NAFLD diagnosis thus requires a limit of alcohol intake. However, NAFLD and ALD very frequently coexist in the same patient, making it difficult to identify the exact cause of liver complications. Almost 5?6% of all worldwide deaths (~3 million) are caused by the harmful use of alcohol (https://www.who.int/publications/i/item/9789241565639), therefore alcohol represents a major health problem at a global scale. There is an association between the amount of alcohol consumption and ALD, however, only 30% of chronic drinkers develop alcoholic hepatitis, and 10?20% progress to advanced fibrosis or cirrhosis (3), underscoring the role of genetic factors involved in disease severity and progression. Any level of alcohol consumption, regardless of the amount, leads to loss of healthy life. The recommendation in clinical practice should be to avoid alcohol intake, particularly in the presence of any liver disease. Moderate alcohol consumption has been reported by many studies to be associated with less severe NAFLD, although some of these cross-sectional studies may be affected by selection bias (4-6). In contrast a longitudinal analysis of liver biopsies from patients with NAFLD showed that modest alcohol consumption was associated with lower NASH resolution in comparison with nondrinkers (7). Recently, Chang et al. showed that the risk of liver steatosis in low and moderate alcohol consumers (MACs) was lower in comparison with nondrinkers (8); however, the proportion of hepatic steatosis plus fibrosis was higher in drinkers. The exact mechanism of the deleterious effect of alcohol consumption on NAFLD in obese patients is still unclear. When combined with free fatty acids the polyphenol resveratrol resulted in the stimulation of profibrogenic effects in hepatic stellate cells (key cells for induction and propagation of hepatic fibrosis) instead of any protective role (9). Therefore, it is important to shed light on the exact role of alcohol intake in addition to NAFLD to solve the currently rather conflicting data on this issue. The work published by Vilar-Gomez et al. in Gastroenterology (10) clarifies some knowledge gaps about alcohol metabolism and consumption, and the severity of NAFLD by studying the role of alcohol dehydrogenase (ADH)-1B, in particular ADH1B*2, in this context. The authors started from a finding generated in a previous work by Sookoian et al., where they observed that patients with low alcohol intake and the ADH1B*2 allele showed a less severe NAFLD by histology compared to other patients studied (11). Vilar-Gomez et al. studied 1,697 patients enrolled into various studies conducted by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) over a period of 10 years [2009?2019]; the NASH CRN Pathology committee reviewed all liver biopsies, and comprehensive alcohol consumption was obtained by AUDIT and LDH questionnaire, binge and heavy drinkers were excluded (170 patients). Remarkably, the frequency of ADH1B*2 carriage varied across race being high in Asians/Pacific Islanders/Hawaiians (86%) and low in non-Hispanic whites (8%), Hispanics (14%), and Blacks (4%), but the study was focused on the 1,153 non-Hispanic whites, which were mainly female, obese, and hypertensive. Among the 1,153 patients, 30% had advanced fibrosis, and 60% had definite NASH. The cohort included 720 non-drinkers and 433 moderate drinkers, but no heavy alcohol consumers. ADH1B*2 carriers were more likely to be male, and moderate alcohol consumption was similar between ADH1B*1 and ADH1B*2 carriersFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Canbay, Ali. Ruhr Universität Bochum; Alemani

Dendritic cell-based therapeutic cancer vaccines

En los últimos años la inmunoterapia ha revolucionado el tratamiento de pacientes con cáncer avanzado. El mayor conocimiento de la biología tumoral y de la inmunología ha permitido desarrollar tratamientos racionales manipulando el sistema inmunitario con importante impacto clínico. Entre otras estrategias de inmunoterapia contra el cáncer se ha explorado el uso de vacunas terapéuticas basadas en células dendríticas (CD). Las CD son células de origen hematopoyético, que expresan constitutivamente moléculas presentadoras de antígeno, y son funcionalmente las inductoras más potentes de la activación y proliferación de linfocitos T a los que presentan antígenos. Los linfocitos T CD8+ proliferan y adquieren capacidad citotóxica cuando reconocen su antígeno específico presentado en la superficie de CD, aunque solo algunos tipos de CD pueden presentar antígenos internalizados desde el exterior celular a precursores de linfocitos T citotóxicos (a esta función se la llama presentación cruzada). Explotar la inducción de una respuesta inmunitaria adaptativa eficaz se considera una buena opción por su especificidad y prolongada duración de la respuesta. Las CD, gracias a su particular capacidad de presentación antigénica y de estimulación linfocitaria, son capaces de revertir la respuesta inmunitaria antitumoral deficiente que presentan algunos pacientes con cáncer. Las CD se pueden obtener a partir de distintas fuentes, empleando diversos protocolos para generar diferenciación y maduración, y se administran por diversas vías como son subcutánea, intravenosa o intranodal. La gran variedad de protocolos en los que se aplican las CD explica los resultados clínicos tan heterogéneos que se han comunicado hasta la fecha.In recent years immunotherapy has revolutionized the treatment of patients with advanced cancer. The increased knowledge in the tumor immune-biology has allowed developing rational treatments by manipulation of the immune system with significant clinical impact. This rapid development has significantly changed the prognosis of many tumors without treatment options up to date. Other strategies have explored the use of therapeutic vaccines based on dendritic cells (DC) by inducing antitumor immunity. DC are cells of hematopoietic origin, constitutively expressing molecules capable to present antigens, that are functionally the most potent inducers of the activation and proliferation of antigen specific T lymphocytes. The CD8+ T cells proliferate and acquire cytotoxic capacity after recognizing their specific antigen presented on the surface of DC, although only some types of DC can present antigens internalized from outside the cell to precursors of cytotoxic T lymphocytes (this function is called cross-presentation) requiring translocation mechanisms of complex antigens. The induction of an effective adaptive immune response is considered a good option given its specificity, and prolonged duration of response. The DC, thanks to its particular ability of antigen presentation and lymphocyte stimulation, are able to reverse the poor antitumor immune response experienced by patients with cancer. The DC can be obtained from various sources, using different protocols to generate differentiation and maturation, and are administered by various routes such as subcutaneous, intravenous or intranodal. The wide variety of protocols resulted in heterogeneous clinical responses.Fil: Rizzo, Manglio Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Investigaciones Médicas Aplicadas. Laboratorio de Terapia Génica y Celular; ArgentinaFil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires. Universidad Nacional del Noroeste de la Provincia de Buenos Aires. Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Instituto de Investigaciones Médicas Aplicadas. Laboratorio de Terapia Génica y Celular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Hepatokines and adipokines in NASH-related hepatocellular carcinoma

Summary The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non- alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD- related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, pre- ventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipo- kines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors – in particular, angiopoietin-like proteins, fi broblast growth factors, and apelin – for detection or even as therapeutic targets in NAFLD-related HCC.Supported by the German Research Foundation (DFG CA267/13-3; CA267/14-1) and the Wilhelm Laupitz Foundation (A.C. and O.K.)

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.This research was funded by the German Research Foundation (DFG CA267/13-3; CA267/14-1 to A.C.) and by the Wilhelm Laupitz Foundation (A.C. and O.K.)

The liver, liver metastasis and liver cancer: A special case for immunotherapy with cytokines and immunostimulatory monoclonal antibodies

"The immunologic outcome of liver transplantations tells us that this organ is somehow specialized as a tolerogenic organ under steady state conditions."Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ochoa, María C. Universidad de Navarra; EspañaFil: Morales Kastresana, Aizea. Universidad de Navarra; EspañaFil: Sanmamed, Miguel F.. Universidad de Navarra; EspañaFil: Melero, Ignacio. Universidad de Navarra; Españ

Overexpression of SPARC obliterates the in vivo tumorigenicity of human hepatocellular carcinoma cells

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related death worldwide. Current treatments are extremely disappointing. SPARC (Secreted protein, acidic and rich in cysteine) is a matricellular glycoprotein with differential expression in several tumors, including HCC, which significance remains unclear. We infected HCC cells (HepG2, Hep3B and Huh7) with an adenovirus expressing SPARC (AdsSPARC) to examine the role of SPARC expression on HCC cells and its effect on tumor aggressiveness. The in vitro HCC cells substrate-dependent proliferation and cell cycle profile were unaffected; however, SPARC overexpression reduced HCC proliferation when cells were grown in spheroids. A mild induction of cellular apoptosis was observed upon SPARC overexpression. SPARC overexpression resulted in spheroid growth inhibition in vitro while no effects were found when recombinant SPARC was exogenously applied. Moreover, the clonogenic and migratory capabilities were largely decreased in SPARC-overexpressing HCC cells, altogether suggesting a less aggressive HCC cell phenotype. Consistently, AdsSPARC-transduced cells showed increased E-cadherin expression and a concomitant decrease in N-cadherin expression. Furthermore, SPARC overexpression was found to reduce HCC cell viability in response to 5-FU-based chemotherapy in vitro, partially through induction of apoptosis. In vivo experiments revealed that SPARC overexpression in HCC cells inhibited their tumorigenic capacity and increased animal survival through a mechanism that partially involves host macrophages. Our data suggest that SPARC overexpression in HCC cells results in a reduced tumorigenicity partially through the induction of mesenchymal-to-epithelial transition (MET). These evidences point to SPARC as a novel target for HCC treatment.Fil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Malvicini, Mariana. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Aquino, Jorge Benjamin. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Alaniz, Laura Daniela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bolontrade, Marcela Fabiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Rizzo, Manglio Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Laboratorio de Terapia Genética; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Sowa, Jan Peter. Ruhr Universität Bochum; AlemaniaFil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Kücükoglu, Özlem. Otto-von-Guericke-Universität Magdeburg; AlemaniaFil: Syn, Wing Kin. Universidad del País Vasco; España. Medical University of South Carolina; Estados Unidos. University of the Basque Country; EspañaFil: Canbay, Ali. Ruhr Universität Bochum; Alemani

Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies

Cell-based therapies for acute and chronic liver diseases are under continuous progress. Mesenchymal stem/stromal cells (MSCs) are multipotent cells able to migrate selectively to damaged tissue and contribute to its healing and regeneration. The MSC pro-regenerative effect occurs due to their immunomodulatory capacity and their ability to produce factors that promote cell protection and survival. Likewise, it has been observed that part of their paracrine effect is mediated by MSC-derived extracellular vesicles (EVs). EVs contain proteins, lipids and nucleic acids (DNA, mRNA, miRNA, lncRNA) from the cell of origin, allowing for intercellular communication. Recently, different studies have demonstrated that MSC-derived EVs could reproduce, at least in part, the biological effects obtained by MSC-based therapies. Moreover, due to EVs’ stability for long periods of time and easy isolation methods they have become a therapeutic option to MSCs treatments. This review summarizes the latest results achieved in clinical trials using MSCs as cell therapy for liver regeneration, the role of EVs in liver physiopathology and the potential of MSC-derived EVs as intercellular mediators and therapeutic tools in liver diseases.Fil: Fiore, Esteban Juan. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Domínguez, Luciana María. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Bayo Fina, Juan Miguel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: García, Mariana Gabriela. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentin

Single low-dose cyclophosphamide combined with interleukin-12 gene therapy is superior to a metronomic schedule in inducing immunity against colorectal carcinoma in mice

The use of conventional cytotoxic agents at metronomic schedules, alone or in combination with targeted agents or immunotherapy, is being explored as a promising anticancer strategy. We previously reported a potent antitumor effect of a single low-dose cyclophosphamide and interleukin-12 (IL-12) gene therapy against advanced gastrointestinal carcinoma, in mice. Here, we assessed whether the delivery of IL-12 by gene therapy together with metronomic cyclophosphamide exerts antitumor effects in a murine model of colorectal carcinoma. This combination therapy was able, at least in part, to reverse immunosuppression, by decreasing the number of regulatory T cells (Tregs) as well as of splenic myeloid-derived suppressor cells (MDSC s). However, metronomic cyclophosphamide plus IL-12 gene therapy failed to increase the number of tumor-infiltrating T lymphocytes and, more importantly, to induce a specific antitumor immune response. With respect to this, cyclophosphamide at a single low dose displayed a superior anticancer profile than the same drug given at a metronomic schedule. Our results may have important implications in the design of new therapeutic strategies against colorectal carcinoma using cyclophosphamide in combination with immunotherapy.Fil: Malvicini, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Alaniz, Laura Daniela. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Bayo Fina, Juan Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: García, Mariana Gabriela. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Piccioni, Flavia Valeria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Fiore, Esteban Juan. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Atorrasagasti, María Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Aquino, Jorge Benjamin. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; ArgentinaFil: Matar, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Rosario. Facultad de Ciencias Medicas. Instituto de Genetica Experimental; ArgentinaFil: Mazzolini Rizzo, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Austral; Argentin