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23. Upregulation of NKG2D ligands impairs hematopoietic stem cell function in Fanconi anemia

Author

Casado, J.A., Valeri, A., Sanchez-Dominguez, R., Vela, P., Lopez, A., Navarro, S., Alberquilla, O., Hanenberg, H., Pujol, Roser, Segovia, J. C., Minguillon, J., Surrallés i Calonge, Jordi, De Heredia, C.D., Sevilla, J., Rio, P., Bueren, J.A., Universitat Autònoma de Barcelona, Institut Català de la Salut, [Casado JA, Valeri A, Sanchez-Domínguez R, Vela P, López A, Navarro S] Division of Innovative Therapies, CIEMAT and Advanced Therapies Unit, IIS-Fundación Jimenez Diaz and Autónoma University, Madrid, Spain. Biomedical Center for Research on Rare Diseases (CIBERER), Madrid, Spain. [Díaz de Heredia C] Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
células::células de la médula ósea::células madre hematopoyéticas [ANATOMÍA], Cells::Bone Marrow Cells::Hematopoietic Stem Cells [ANATOMY], Cèl·lules mare hematopoètiques, Hemic and Lymphatic Diseases::Hematologic Diseases::Anemia::Anemia, Aplastic::Anemia, Hypoplastic, Congenital::Fanconi Anemia [DISEASES], Medizin, Genetic Phenomena::Gene Expression Regulation::Up-Regulation [PHENOMENA AND PROCESSES], Antigens, CD34, General Medicine, Hematopoietic Stem Cells, Ligands, Up-Regulation, Mice, fenómenos genéticos::regulación de la expresión génica::regulación positiva [FENÓMENOS Y PROCESOS], Fanconi Anemia, NK Cell Lectin-Like Receptor Subfamily K, Regulació genètica, Animals, Anèmia de Fanconi, enfermedades hematológicas y linfáticas::enfermedades hematológicas::anemia::anemia aplásica::anemia hipoplásica congénita::anemia de Fanconi [ENFERMEDADES]
Abstract

Cellular immune response; Immunology; Stem cells Respuesta inmune celular; Inmunología; Células madre Resposta immune cel·lular; Immunologia; Cèl·lules mare Fanconi anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage–associated stress molecules such as natural killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells, which may result in progressive HSPC depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, and these levels were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from patients with FA also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D–NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D–NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF that is characteristic of FA. This work was supported by the “Ministerio de Ciencia e Innovación y Competitividad y Fondo Europeo de Desarrollo Regional (FEDER)” (SAF2015-68073-R, SAF2015-64152-R, and RTI2018-097125-B-I00); Next Generation EU; Plan de Recuperación Transformación y Resilencia (Instituto de Salud Carlos III; TERAV) (RD12/0019/0023); Programs of the European Commission (HEALTHF5-2012-305421 and EUROFANCOLEN); the “Ministerio de Sanidad, Servicios Sociales e Igualdad” (EC11/060 and EC11/550 “Comunidad de Madrid” (AvanCell, B2017/BMD-3692); and the ICREA-Academia program.

Published
2020

27. Gefitinib and Afatinib Show Potential Efficacy for Fanconi Anemia-Related Head and Neck Cancer

Author

Montanuy, H., Martínez-Barriocanal, A., Casado, J.A., Rovirosa, L., Ramírez, M.J., Nieto, R., Carrascoso-Rubio, C., Riera, P., Gonzalez, A., Lerma, E., Lasa, A., Carreras-Puigvert, J., Helleday, T., Bueren, J.A., Arango, D., Minguillón, J., and Surrallés, J.

Subjects
hemic and lymphatic diseases
Abstract

Purpose: Fanconi anemia rare disease is characterized by bone marrow failure and a high predisposition to solid tumors, especially head and neck squamous cell carcinoma (HNSCC). Patients with Fanconi anemia with HNSCC are not eligible for conventional therapies due to high toxicity in healthy cells, predominantly hematotoxicity, and the only treatment currently available is surgical resection. In this work, we searched and validated two already approved drugs as new potential therapies for HNSCC in patients with Fanconi anemia. Experimental Design: We conducted a high-content screening of 3,802 drugs in a FANCA-deficient tumor cell line to identify nongenotoxic drugs with cytotoxic/cytostatic activity. The best candidates were further studied in vitro and in vivo for efficacy and safety. Results: Several FDA/European Medicines Agency (EMA)-approved anticancer drugs showed cancer-specific lethality or cell growth inhibition in Fanconi anemia HNSCC cell lines. The two best candidates, gefitinib and afatinib, EGFR inhibitors approved for non-small cell lung cancer (NSCLC), displayed nontumor/tumor IC50 ratios of approximately 400 and approximately 100 times, respectively. Neither gefitinib nor afatinib activated the Fanconi anemia signaling pathway or induced chromosomal fragility in Fanconi anemia cell lines. Importantly, both drugs inhibited tumor growth in xenograft experiments in immunodeficient mice using two Fanconi anemia patient-derived HNSCCs. Finally, in vivo toxicity studies in Fanca-deficient mice showed that administration of gefitinib or afatinib was well-tolerated, displayed manageable side effects, no toxicity to bone marrow progenitors, and did not alter any hematologic parameters. Conclusions: Our data present a complete preclinical analysis and promising therapeutic line of the first FDA/EMA-approved anticancer drugs exerting cancer-specific toxicity for HNSCC in patients with Fanconi anemia.

Published
2020

33. Effect of forage source (grazing vs. silage) on conjugated linoleic acid content in milk fat of Holstein-Friesian dairy cows from Galicia (NW Spain)

Author

Roca Fernández, Ana Isabel, González Rodríguez, Antonio, Fernández Casado, J.A., Vázquez Yáñez, Orlando Pablo, Roca Fernández, Ana Isabel, González Rodríguez, Antonio, Fernández Casado, J.A., and Vázquez Yáñez, Orlando Pablo

Abstract

The aim of this study was to investigate the effect of different feeding proportions of forage ?grazing vs. silage? on milk fatty acids (FA) profile and conjugated linoleic acid (CLA) content of autumn calving Holstein-Friesian cows (n = 61) at CIAM (Galicia, NW Spain). Three treatments (S, 100% silage; G/S, 50% grazing + 50% silage; G, 100% grazing) were set and milk FA profile of dairy cows was determined by gas chromatography-mass spectrometry. The G group showed a decrease in short (p < 0.05) and medium chain FA (p < 0.001), with an increase in long chain FA (p < 0.001) in comparison to the G/S and S groups, which showed the lowest levels (p < 0.001) of mono- and polyunsaturated FA. The CLA content in milk fat increased (p < 0.001) linearly in relation to the increased proportion of fresh grass in the diet of dairy cows from 0.49 and 0.82 to 1.14 g/100 g FA for the treatments S, G/S and G, respectively. During spring and summer, the levels of CLA were three times higher (p < 0.001, +0.76 g/100 g FA) in milk from dairy cows at the G group than in cows at the S group and twice higher (p < 0.001, +0.40 g/100 g FA) than in cows at the G/S group. High proportion of grass in the diet of cows increased CLA content, with the highest levels of unsaturated FA and the lowest levels of saturated FA, increasing the added value of milk on grazing systems using available farm resources.

Published
2012

34. Short communication. of forage source (grazing vs. silage) on conjugated linoleic acid content in milk fat of Holstein-Friesian dairy cows from Galicia (NW Spain)

Author

Roca Fernández, Ana Isabel, González Rodríguez, Antonio, Fernández Casado, J.A., Vázquez Yáñez, Orlando Pablo, Roca Fernández, Ana Isabel, González Rodríguez, Antonio, Fernández Casado, J.A., and Vázquez Yáñez, Orlando Pablo

Abstract

The aim of this study was to investigate the effect of different feeding proportions of forage ?grazing vs. silage? on milk fatty acids (FA) profile and conjugated linoleic acid (CLA) content of autumn calving Holstein-Friesian cows (n = 61) at CIAM (Galicia, NW Spain). Three treatments (S, 100% silage; G/S, 50% grazing + 50% silage; G, 100% grazing) were set and milk FA profile of dairy cows was determined by gas chromatography-mass spectrometry. The G group showed a decrease in short (p < 0.05) and medium chain FA (p < 0.001), with an increase in long chain FA (p < 0.001) in comparison to the G/S and S groups, which showed the lowest levels (p < 0.001) of mono- and polyunsaturated FA. The CLA content in milk fat increased (p < 0.001) linearly in relation to the increased proportion of fresh grass in the diet of dairy cows from 0.49 and 0.82 to 1.14 g/100 g FA for the treatments S, G/S and G, respectively. During spring and summer, the levels of CLA were three times higher (p < 0.001, +0.76 g/100 g FA) in milk from dairy cows at the G group than in cows at the S group and twice higher (p < 0.001, +0.40 g/100 g FA) than in cows at the G/S group. High proportion of grass in the diet of cows increased CLA content, with the highest levels of unsaturated FA and the lowest levels of saturated FA, increasing the added value of milk on grazing systems using available farm resources., El objetivo de este estudio fue investigar el efecto de utilizar diferentes proporciones de forraje, pasto vs. silo, en el perfil de ácidos grasos (AG) de la leche y en el contenido de ácido linoleico conjugado (CLA) en vacas lecheras Holstein-Friesian (n = 61) de partos de otoño. Se establecieron tres tratamientos (S, 100% ensilaje; G/S, 50% pastoreo y 50% ensilaje; G, 100% pastoreo) y se determinó el perfil de AG de la leche por cromatografía de gases-espectrometría de masas. El grupo G mostró una disminución en los AG de cadena corta (p < 0,05) y media (p < 0,001), con un aumento en los AG de cadena larga (p < 0,001) en comparación con los grupos G/S y S, que mostraron unos contenidos menores (p < 0,001) de AG mono- y poli-insaturados. El contenido de CLA en la grasa láctea aumentó linealmente con el incre-mento en la proporción de pasto fresco en la dieta de las vacas lecheras desde 0,49 y 0,82 a 1,14 g/100 g de AG para los tratamientos S, G/S y G, respectivamente. Durante la primavera y el verano, los niveles de CLA fueron tres veces superiores (p < 0,001, +0,76 g/100 gde AG) en la leche de las vacas del grupo G respecto a la del grupo S y dos veces supe-riores (p < 0,001, +0,40 g/100 g de AG) a la del grupo G/S. Una alta proporción de pasto en la dieta incrementó el conte-nido de CLA, con niveles superiores de AG insaturados y menores de saturados, lo que aumenta el valor añadido de la leche producida en los sistemas de pastoreo que aprovechan los recursos existentes en las explotaciones

Published
2012

37. A Simplified Approach to Improve the Efficiency and Safety of Ex Vivo Hematopoietic Gene Therapy in Fanconi Anemia Patients

Author

Jacome, A., primary, Navarro, S., additional, Casado, J.A., additional, Rio, P., additional, Madero, L., additional, Estella, J., additional, Sevilla, J., additional, Badell, I., additional, Ortega, J.J., additional, Olive, T., additional, Hanenberg, H., additional, Segovia, J.C., additional, and Bueren, J.A., additional

Published
2006
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44. The type of interaction with FcγR in human monocytes determines the efficiency of the generation of oxidative burst.

Author

Casado, J.A., Merino, J., Cid, J., Subika, M.L., and Sanchez-Ibarrola, A.

Subjects
*MONOCYTES, *LEUCOCYTES, *RETICULO-endothelial system, *PHAGOCYTES, *IMMUNOGLOBULINS, *GLOBULINS
Abstract

Receptors for the Fc fragment of IgG (FcγR) have a we!l-documented role in the generation of oxidative burst. It is tempting to speculate that the type of interaction with FcγR could be a mechanism of regulation of this process. Here we report on a comparative study of the induction of oxidative burst in human monocytes activated by means of different types of interaction with FcrγR. We studied non-primed monocytes obtained by centrifugal elutriation from healthy donors. These cells were submitted to FcγR interactions following two distinct models: one, using particulate material (IgG-SRBC leading to phagocytosis or rosetting), and another using soluble reagents followed by cross-linking of the receptors (monoclonal antibodies against FcγRI and FcγRII and natural ligands, namely several isotypes of murine and human IgG). Phagocytosis and oxidative burst were studied simultaneously in the monocytes, following the methodology described recently. Human non-primed monocytes were able to generate a very obvious oxidative burst response after activation of FcγR by particulate material. The same response was observed when FcγRII was blocked by monoclonal antibodies. Ingestion was not necessary for activation of the oxidative burst, since the model of rosetting induced a level of burst generation similar to the one obtained in the phagocytic process. Cross-linking of FcγRI by soluble reagents induced production of reactive oxidative intermediates (ROI) only when the ligand-binding site of the receptor was involved. These data lead to the conclusion that FcγR interaction with soluble or particulate material induces oxidative burst in non-primed human monocytes only when the binding site of natural ligands is involved. The type of interaction also determines the efficiency of the generation of ROI. This fact could represent a regulatory mechanism. [ABSTRACT FROM AUTHOR]

Published
1994

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