Francisco Ruiz-cabello - Academia.edu (original) (raw)

Papers by Francisco Ruiz-cabello

Clinical Pharmacology & Therapeutics, 2021

The identification of specific HLA risk alleles in drug‐induced liver injury (DILI) points toward... more The identification of specific HLA risk alleles in drug‐induced liver injury (DILI) points toward an important role of the adaptive immune system in DILI development. In this study, we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n = 12), acute viral hepatitis (VH; n = 13), acute autoimmune hepatitis (AIH; n = 9), and acute liver injury of unknown etiology (n = 15) at day 1 (recognition), day 7, and day >30. Blood samples from patients with nonalcoholic fatty liver disease (NAFLD; n = 20) and healthy liver controls (HLCs; n = 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA‐4 that was determined intracellularly, using flow cytometry. At recognition, DILI demonstrated significantly higher levels of activated helpe...

International Journal of Molecular Sciences

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, inc... more Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignanc...

Pharmaceutics, 2022

Breast cancer is the most common type of malignancy and leading cause of cancer death among women... more Breast cancer is the most common type of malignancy and leading cause of cancer death among women worldwide. Despite the current revolutionary advances in the field of cancer immunotherapy, clinical response in breast cancer is frequently below expectations, in part due to various mechanisms of cancer immune escape that produce tumor variants that are resistant to treatment. Thus, a further understanding of the molecular events underlying immune evasion in breast cancer may guarantee a significant improvement in the clinical success of immunotherapy. Furthermore, nanomedicine provides a promising opportunity to enhance the efficacy of cancer immunotherapy by improving the delivery, retention and release of immunostimulatory agents in targeted cells and tumor tissues. Hence, it can be used to overcome tumor immune escape and increase tumor rejection in numerous malignancies, including breast cancer. In this review, we summarize the current status and emerging trends in nanomedicine-b...

Frontiers in Immunology, 2020

The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate respons... more The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most ...

Immunological Investigations, 2019

ABSTRACT Inflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We ... more ABSTRACT Inflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We hypothesized that changes in the function of key components of the inflammatory cascade, caused by genetic polymorphisms, could determine the development and/or severity of AP. We studied the following polymorphisms in 269 patients: IL23R rs11209026, TNF rs1800629, RIPK2 rs42490, NOD2 rs9302752, MCP1 rs1024611 and NFKB1 rs28362491. The rs11209026 A allele was related to the presence of AP (p = 0.007261; OR = 1 .523). Epistasis analysis revealed that AP susceptibility was increased by interaction between IL23R rs11209026 and TNF rs1800629 (p = 1.205 × 10−5; ORinteraction = 4.031). The rs42490-G allele was associated with an increased risk of severe pancreatitis (p = 0.01583; OR = 2.736), severe or moderately severe pancreatitis (p = 0.04206; OR = 1.609), and death (p = 0.03226; OR = 3.010). In conclusion, these results point to a plausible role for genetic polymorphisms in IL23R and RIPK2 in the development and severity of AP.

Immunogenetics, 2018

HLA class I (HLA-I) molecules play a crucial role in the presentation of tumor antigenic peptides... more HLA class I (HLA-I) molecules play a crucial role in the presentation of tumor antigenic peptides to CD8+ T cells. Tumor HLA-I loss provides a route of immune escape from T cell-mediated killing. We analyzed HLA-I expression in 98 cryopreserved breast cancer tissues using a broad panel of anti-HLA-I antibodies. Genomic HLA-I typing was performed using DNA obtained from autologous normal breast tissue. Analysis of the loss of heterozygosity (LOH) in the HLA-I region of chromosome 6 (LOH-6) and in the β2-microglobulin (B2M) region of chromosome 15 (LOH-15) was done by microsatellite amplification of DNA isolated from microdissected tumor areas. B2M gene sequencing was done using this DNA form HLA-I-negative tumors. Immunohistological analysis revealed various types of HLA-I alterations in 79 tumors (81%), including total HLA-I loss in 53 cases (54%) and partial loss in 16 samples (14%). In 19 cases (19%), HLA-I expression was positive. Using microsatellite analysis, we detected LOH in...

Oncotarget, Jan 25, 2015

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whos... more Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56- phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outc...

Human Immunology, 2008

Four experimental results, which seem to contradict the established ideas about the Bose-Einstein... more Four experimental results, which seem to contradict the established ideas about the Bose-Einstein correlations in multiple particle production precesses, are briefly presented and discussed.

Cancer Immunology, Immunotherapy, 2011

Aim We compared the expression of genes related to inXammatory and cytotoxic functions between MS... more Aim We compared the expression of genes related to inXammatory and cytotoxic functions between MSI and MSS (HLA-class I-negative and HLA-class I-positive) colorectal cancers (CRCs), seeking evidence of diVerences in inXammatory mediators and cytotoxic T-cell responses. Twenty-two CRCs were divided into three study groups as a function of HLA class I expression and MSI phenotype: 8 MSI tumours, 6 MSS/HLA¡ tumours and 6 MSS/HLA+ tumours (controls). Findings A Wrst comparison between eight MSI and six MSS/HLA-positive (control) cancers, based on microarray analysis on an AVymetrix ® HG-U133-Plus-PM plate, iden-tiWed 1974 diVerentially expressed genes (P < 0.05). We grouped genes in Gene Ontology functional categories: apoptotic programme (72 genes, P = 5.5•10 ¡3), leucocyte activation (43 genes, P = 1.8•10 ¡5), T-cell activation (24 genes, P = 6.3•10 ¡4), inXammatory response (40 genes, 2.3•10 ¡2) and cytokine production (10 genes, P = 1.9•10 ¡2). Real-time PCR and immunohistochemical evaluation were used to validate the data, Wnding that increased mRNA levels of pro-inXammatory cytokines and cytotoxic mediators were associated with greater inWltration by CD8+T lymphocytes in the MSI group (P < 0.001). Finally, HLA-class I-negative tumours were not grouped together but rather in accordance with features of the gene expression proWle of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-class I-negative CRCs (n = 6) in comparison to controls. Conclusions In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and diVerentiate MSI from MSS cancers. The two types of tumour, MSI/HLA-class I-negative and MSS/HLA-class I-negative, showed marked diVerences in the composition and intensity of inWltrating leucocytes, suggesting that their immune escape strategies involve distinct pathways.

British Journal of Pharmacology, 2007

Background and purpose: The general view on the pathogenesis of drug-induced idiosyncratic liver ... more Background and purpose: The general view on the pathogenesis of drug-induced idiosyncratic liver injury (DILI) is that parent compounds are rendered hepatotoxic by metabolism, mainly by cytochrome (CYP) 450, although other metabolic pathways can contribute. Anecdotal reports suggest a role of CYP 450 polymorphisms in DILI. We aimed to assess in a series of Spanish DILI patients the prevalence of important allelic variants of CYP2C9 and CYP2C19, known to be involved in the metabolism of several hepatotoxic drugs. Experimental approach: Genotyping of CYP2C9 (*2, *3) and CYP2C19 (*2 and *3), was carried out in a total of 28 and 32 patients with a well established diagnosis of DILI. CYP2C9 and CYP2C19 variants were analysed in genomic DNA by means of PCR-FRET and compared with previous findings in other Caucasian populations. Key results: CYP2C9 and CYP2C19 allele and genotype frequencies were in agreement with Hardy-Weinberg equilibrium. Fourteen patients (50%) were heterozygous and 1(4%) found to be compound heterozygous for the CYP2C9 allele. Seven (22%) were found to carry one and 1(3%) carried two CYP2C19 mutated alleles. No patients were homozygous for *3 allele. The distribution of both CYP2C9 and CYP2C19 allelic variants in DILI patients were similar to those in other Caucasian populations. Patients with variant and those with wild-type alleles did not differ in regard to clinical presentation of DILI, type of injury and outcome. Conclusions and Implications: We find no evidence to support CYP2C9 and CYP2C19 genetic polymorphisms as predictable potential risk factors for DILI.

Blood, 2008

Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of m... more Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of monoclonal T-cell receptor (TCR)–αβ+/CD4+/NKa+/CD8−/+dim T-large granular lymphocyte (LGL) lymphocytosis. Because healthy persons show (oligo)clonal expansions of human cytomegalovirus (hCMV)–specific TCRVβ+/CD4+/cytotoxic/memory T cells, we investigate the potential involvement of hCMV in the origin and/or expansion of monoclonal CD4+ T-LGL. Peripheral blood samples from patients with monoclonal TCR-αβ+/CD4+ T-LGL lymphocytosis and other T-chronic lymphoproliferative disorders were evaluated for the specific functional response against hCMV and hEBV whole lysates as well as the “MQLIPDDYSNTHSTRYVTVK” hCMV peptide, which is specifically loaded in HLA-DRB1*0701 molecules. A detailed characterization of those genes that underwent changes in T-LGL cells responding to hCMV was performed by microarray gene expression profile analysis. Patients with TCR-αβ+/CD4+ T-LGL displayed a strong and cha...

Biochemical and Biophysical Research Communications, 1980

Monoclonal antibodies against cardiac myosin from chicken (18d embryos) and rabbit were produced ... more Monoclonal antibodies against cardiac myosin from chicken (18d embryos) and rabbit were produced in vitro by fusion of mouse myeloma cells (P3-X63-Ag8) with spleen cells from immunized BALB/c mice and Lewis rats. Three antibodies were examined and found to react with different antigenic determinants in the myosin heavy chain subunit. Antibody RCM-79 reacted specifically with heavy meromyosin. Antibodies CCM-13 and RCM-79 reacted with equal affinities to cardiac myosin from chicken, rabbit, rat, and man, but with lower affinities to skeletal muscle myosins from chicken and rabbit. Antibody CCM-31A reacted only to chicken cardiac myosin and not to other cardiac or skeletal myosins tested. Our results show that monoclonal antibodies can be produced that are either specific for sequences common to all of the cardiac myosins examined or unique to the immunizing type.

The American Journal of Pathology, 2010

Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for reconstituting the h... more Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for reconstituting the hematopoietic microenvironment by improving engraftment in stem cell transplantation. However, the availability of conventional bone marrow (BM)-derived MSCs (BMSCs) is limited. Recent studies showed that a large number of MSCs can be easily isolated from fat tissue (adipose tissue-derived MSCs [ADSCs]). In this study , we extensively evaluated the hematopoiesis-supporting properties of ADSCs , which are largely unknown. In vitro coculture and progenitor assays showed that ADSCs generated significantly more granulocytes and progenitor cells from human hematopoietic stem cells (HSCs) than BMSCs. We found that ADSCs express the chemokine CXCL12 , a critical regulator of hematopoiesis , at levels that are three fold higher than those with BMSCs. The addition of a CXCL12 receptor antagonist resulted in a lower yield of granulocytes from ADSC layers , whereas the addition of recombinant CXCL12 to BMSC cocultures promoted the growth of granulocytes. In vivo cell homing assays showed that ADSCs facilitated the homing of mouse HSCs to the BM better than BMSCs. ADSCs injected into the BM cavity of fatally irradiated mice reconstituted hematopoiesis more promptly than BM-SCs and subsequently rescued mice that had received a low number of HSCs. Secondary transplantation experiments showed that ADSCs exerted favorable effects on long-term HSCs. These results suggest that ADSCs can be a promising therapeutic alternative to BMSCs.

Vaccines, 2022

The vaccines designed against the SARS-CoV-2 coronavirus are based on the spike (S) protein. Proc... more The vaccines designed against the SARS-CoV-2 coronavirus are based on the spike (S) protein. Processing of the S protein by antigen-presenting cells (APC) and its subsequent presentation to T cells is an essential part of the development of a humoral response. HLA-class II alleles are considered immune response genes because their codified molecules, expressed on the surface of APCs (macrophages, dendritic, and B cells) present antigenic peptides to T cell via their T cell receptor (TCR). The HLA-class II genes are highly polymorphic, regulating what specific peptides induce follicular helper T cells (TFH) and promote B lymphocyte differentiation into plasma or memory B cells. This work hypothesizes that the presence of certain HLA-class II alleles could be associated with the intensity of the humoral response (amount, length) to the SARS-CoV2 mRNA 1273 vaccine. We have studied the relationship between the HLA-class II typing of 87 health workers and the level of antibodies produced...

Cancers

Total or partial loss of HLA class I antigens reduce the recognition of specific tumor peptides b... more Total or partial loss of HLA class I antigens reduce the recognition of specific tumor peptides by cytotoxic T lymphocytes favoring cancer immune escape during natural tumor evolution. These alterations can be caused by genomic defects, such as loss of heterozygosity at chromosomes 6 and 15 (LOH-6 and LOH-15), where HLA class I genes are located. There is growing evidence indicating that LOH in HLA contributes to the immune selection of HLA loss variants and influences the resistance to immunotherapy. Nevertheless, the incidence and the mechanism of this chromosomal aberration involving HLA genes has not been systematically assessed in different types of tumors and often remains underestimated. Here, we used SNP arrays to investigate the incidence and patterns of LOH-6 and LOH-15 in a number of human cancer cell lines and tissues of different histological types. We observed that LOH in HLA is a common event in cancer samples with a prevalence of a copy neutral type of LOH (CN-LOH) t...

Cancers

Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive ... more Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing the transcriptomic signatures of tumoral and non-tumoral samples. We identified 48 lncRNAs that were differentially expressed between pediatric B-ALL and healthy bone marrow samples. The most relevant lncRNA/mRNA pair was AL133346.1/CCN2 (previously known as RP11-69I8.3/CTGF), whose expression was positively correlated and increased in B-ALL samples. Their differential expression pattern and their strong correlation were validated in external B-ALL datasets (Therapeutically Applicable Research to Generate Effective Treatments, Cancer Cell Line Encyclopedia). Survival curve analysis demonstrated that patients with “high” expression levels of CCN2 had...

Annals of hematology, 2017

Clinical Pharmacology & Therapeutics, 2021

The identification of specific HLA risk alleles in drug‐induced liver injury (DILI) points toward... more The identification of specific HLA risk alleles in drug‐induced liver injury (DILI) points toward an important role of the adaptive immune system in DILI development. In this study, we aimed to corroborate the role of an adaptive immune response in DILI through immunophenotyping of leukocyte populations and immune checkpoint expressions. Blood samples were collected from adjudicated DILI (n = 12), acute viral hepatitis (VH; n = 13), acute autoimmune hepatitis (AIH; n = 9), and acute liver injury of unknown etiology (n = 15) at day 1 (recognition), day 7, and day >30. Blood samples from patients with nonalcoholic fatty liver disease (NAFLD; n = 20) and healthy liver controls (HLCs; n = 54) were extracted at one time point. Leukocyte populations and immune checkpoint expressions were determined based on cell surface receptors, except for CTLA‐4 that was determined intracellularly, using flow cytometry. At recognition, DILI demonstrated significantly higher levels of activated helpe...

International Journal of Molecular Sciences

Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, inc... more Cancer eradication and clinical outcome of immunotherapy depend on tumor cell immunogenicity, including HLA class I (HLA-I) and PD-L1 expression on malignant cells, and on the characteristics of the tumor microenvironment, such as tumor immune infiltration and stromal reaction. Loss of tumor HLA-I is a common mechanism of immune escape from cytotoxic T lymphocytes and is linked to cancer progression and resistance to immunotherapy with the inhibitors of PD-L1/PD-1 signaling. Here we observed that HLA-I loss in bladder tumors is associated with T cell exclusion and tumor encapsulation with stromal elements rich in FAP-positive cells. In addition, PD-L1 upregulation in HLA-I negative tumors demonstrated a correlation with high tumor grade and worse overall- and cancer-specific survival of the patients. These changes define common immuno-morphological signatures compatible with cancer immune escape and acquired resistance to therapeutic interventions across different types of malignanc...

Pharmaceutics, 2022

Breast cancer is the most common type of malignancy and leading cause of cancer death among women... more Breast cancer is the most common type of malignancy and leading cause of cancer death among women worldwide. Despite the current revolutionary advances in the field of cancer immunotherapy, clinical response in breast cancer is frequently below expectations, in part due to various mechanisms of cancer immune escape that produce tumor variants that are resistant to treatment. Thus, a further understanding of the molecular events underlying immune evasion in breast cancer may guarantee a significant improvement in the clinical success of immunotherapy. Furthermore, nanomedicine provides a promising opportunity to enhance the efficacy of cancer immunotherapy by improving the delivery, retention and release of immunostimulatory agents in targeted cells and tumor tissues. Hence, it can be used to overcome tumor immune escape and increase tumor rejection in numerous malignancies, including breast cancer. In this review, we summarize the current status and emerging trends in nanomedicine-b...

Frontiers in Immunology, 2020

The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate respons... more The severity of SARS-CoV-2 infection has been related to uncontrolled inflammatory innate responses and impaired adaptive immune responses mostly due to exhausted T lymphocytes and lymphopenia. In this work we have characterized the nature of the lymphopenia and demonstrate a set of factors that hinder the effective control of virus infection and the activation and arming of effector cytotoxic T CD8 cells and showing signatures defining a high-risk population. We performed immune profiling of the T helper (Th) CD4+ and T CD8+ cell compartments in peripheral blood of 144 COVID-19 patients using multiparametric flow cytometry analysis. On the one hand, there was a consistent lymphopenia with an overrepresentation of non-functional T cells, with an increased percentage of naive Th cells (CD45RA+, CXCR3-, CCR4-, CCR6-, CCR10-) and persistently low frequency of markers associated with Th1, Th17, and Th1/Th17 memory-effector T cells compared to healthy donors. On the other hand, the most ...

Immunological Investigations, 2019

ABSTRACT Inflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We ... more ABSTRACT Inflammation plays a central role in the pathophysiology of acute pancreatitis (AP). We hypothesized that changes in the function of key components of the inflammatory cascade, caused by genetic polymorphisms, could determine the development and/or severity of AP. We studied the following polymorphisms in 269 patients: IL23R rs11209026, TNF rs1800629, RIPK2 rs42490, NOD2 rs9302752, MCP1 rs1024611 and NFKB1 rs28362491. The rs11209026 A allele was related to the presence of AP (p = 0.007261; OR = 1 .523). Epistasis analysis revealed that AP susceptibility was increased by interaction between IL23R rs11209026 and TNF rs1800629 (p = 1.205 × 10−5; ORinteraction = 4.031). The rs42490-G allele was associated with an increased risk of severe pancreatitis (p = 0.01583; OR = 2.736), severe or moderately severe pancreatitis (p = 0.04206; OR = 1.609), and death (p = 0.03226; OR = 3.010). In conclusion, these results point to a plausible role for genetic polymorphisms in IL23R and RIPK2 in the development and severity of AP.

Immunogenetics, 2018

HLA class I (HLA-I) molecules play a crucial role in the presentation of tumor antigenic peptides... more HLA class I (HLA-I) molecules play a crucial role in the presentation of tumor antigenic peptides to CD8+ T cells. Tumor HLA-I loss provides a route of immune escape from T cell-mediated killing. We analyzed HLA-I expression in 98 cryopreserved breast cancer tissues using a broad panel of anti-HLA-I antibodies. Genomic HLA-I typing was performed using DNA obtained from autologous normal breast tissue. Analysis of the loss of heterozygosity (LOH) in the HLA-I region of chromosome 6 (LOH-6) and in the β2-microglobulin (B2M) region of chromosome 15 (LOH-15) was done by microsatellite amplification of DNA isolated from microdissected tumor areas. B2M gene sequencing was done using this DNA form HLA-I-negative tumors. Immunohistological analysis revealed various types of HLA-I alterations in 79 tumors (81%), including total HLA-I loss in 53 cases (54%) and partial loss in 16 samples (14%). In 19 cases (19%), HLA-I expression was positive. Using microsatellite analysis, we detected LOH in...

Oncotarget, Jan 25, 2015

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whos... more Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico-biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56- phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outc...

Human Immunology, 2008

Four experimental results, which seem to contradict the established ideas about the Bose-Einstein... more Four experimental results, which seem to contradict the established ideas about the Bose-Einstein correlations in multiple particle production precesses, are briefly presented and discussed.

Cancer Immunology, Immunotherapy, 2011

Aim We compared the expression of genes related to inXammatory and cytotoxic functions between MS... more Aim We compared the expression of genes related to inXammatory and cytotoxic functions between MSI and MSS (HLA-class I-negative and HLA-class I-positive) colorectal cancers (CRCs), seeking evidence of diVerences in inXammatory mediators and cytotoxic T-cell responses. Twenty-two CRCs were divided into three study groups as a function of HLA class I expression and MSI phenotype: 8 MSI tumours, 6 MSS/HLA¡ tumours and 6 MSS/HLA+ tumours (controls). Findings A Wrst comparison between eight MSI and six MSS/HLA-positive (control) cancers, based on microarray analysis on an AVymetrix ® HG-U133-Plus-PM plate, iden-tiWed 1974 diVerentially expressed genes (P < 0.05). We grouped genes in Gene Ontology functional categories: apoptotic programme (72 genes, P = 5.5•10 ¡3), leucocyte activation (43 genes, P = 1.8•10 ¡5), T-cell activation (24 genes, P = 6.3•10 ¡4), inXammatory response (40 genes, 2.3•10 ¡2) and cytokine production (10 genes, P = 1.9•10 ¡2). Real-time PCR and immunohistochemical evaluation were used to validate the data, Wnding that increased mRNA levels of pro-inXammatory cytokines and cytotoxic mediators were associated with greater inWltration by CD8+T lymphocytes in the MSI group (P < 0.001). Finally, HLA-class I-negative tumours were not grouped together but rather in accordance with features of the gene expression proWle of MSI or MSS tumours. As expected, genes associated with antigen processing machinery and MHC class I molecules (TAP2, B2m) were downregulated in MSS/HLA-class I-negative CRCs (n = 6) in comparison to controls. Conclusions In conclusion, microarray and immunohistochemical data may be useful to comprehensively assess tumour-host interactions and diVerentiate MSI from MSS cancers. The two types of tumour, MSI/HLA-class I-negative and MSS/HLA-class I-negative, showed marked diVerences in the composition and intensity of inWltrating leucocytes, suggesting that their immune escape strategies involve distinct pathways.

British Journal of Pharmacology, 2007

Background and purpose: The general view on the pathogenesis of drug-induced idiosyncratic liver ... more Background and purpose: The general view on the pathogenesis of drug-induced idiosyncratic liver injury (DILI) is that parent compounds are rendered hepatotoxic by metabolism, mainly by cytochrome (CYP) 450, although other metabolic pathways can contribute. Anecdotal reports suggest a role of CYP 450 polymorphisms in DILI. We aimed to assess in a series of Spanish DILI patients the prevalence of important allelic variants of CYP2C9 and CYP2C19, known to be involved in the metabolism of several hepatotoxic drugs. Experimental approach: Genotyping of CYP2C9 (*2, *3) and CYP2C19 (*2 and *3), was carried out in a total of 28 and 32 patients with a well established diagnosis of DILI. CYP2C9 and CYP2C19 variants were analysed in genomic DNA by means of PCR-FRET and compared with previous findings in other Caucasian populations. Key results: CYP2C9 and CYP2C19 allele and genotype frequencies were in agreement with Hardy-Weinberg equilibrium. Fourteen patients (50%) were heterozygous and 1(4%) found to be compound heterozygous for the CYP2C9 allele. Seven (22%) were found to carry one and 1(3%) carried two CYP2C19 mutated alleles. No patients were homozygous for *3 allele. The distribution of both CYP2C9 and CYP2C19 allelic variants in DILI patients were similar to those in other Caucasian populations. Patients with variant and those with wild-type alleles did not differ in regard to clinical presentation of DILI, type of injury and outcome. Conclusions and Implications: We find no evidence to support CYP2C9 and CYP2C19 genetic polymorphisms as predictable potential risk factors for DILI.

Blood, 2008

Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of m... more Recent studies suggest the potential involvement of common antigenic stimuli on the ontogeny of monoclonal T-cell receptor (TCR)–αβ+/CD4+/NKa+/CD8−/+dim T-large granular lymphocyte (LGL) lymphocytosis. Because healthy persons show (oligo)clonal expansions of human cytomegalovirus (hCMV)–specific TCRVβ+/CD4+/cytotoxic/memory T cells, we investigate the potential involvement of hCMV in the origin and/or expansion of monoclonal CD4+ T-LGL. Peripheral blood samples from patients with monoclonal TCR-αβ+/CD4+ T-LGL lymphocytosis and other T-chronic lymphoproliferative disorders were evaluated for the specific functional response against hCMV and hEBV whole lysates as well as the “MQLIPDDYSNTHSTRYVTVK” hCMV peptide, which is specifically loaded in HLA-DRB1*0701 molecules. A detailed characterization of those genes that underwent changes in T-LGL cells responding to hCMV was performed by microarray gene expression profile analysis. Patients with TCR-αβ+/CD4+ T-LGL displayed a strong and cha...

Biochemical and Biophysical Research Communications, 1980

Monoclonal antibodies against cardiac myosin from chicken (18d embryos) and rabbit were produced ... more Monoclonal antibodies against cardiac myosin from chicken (18d embryos) and rabbit were produced in vitro by fusion of mouse myeloma cells (P3-X63-Ag8) with spleen cells from immunized BALB/c mice and Lewis rats. Three antibodies were examined and found to react with different antigenic determinants in the myosin heavy chain subunit. Antibody RCM-79 reacted specifically with heavy meromyosin. Antibodies CCM-13 and RCM-79 reacted with equal affinities to cardiac myosin from chicken, rabbit, rat, and man, but with lower affinities to skeletal muscle myosins from chicken and rabbit. Antibody CCM-31A reacted only to chicken cardiac myosin and not to other cardiac or skeletal myosins tested. Our results show that monoclonal antibodies can be produced that are either specific for sequences common to all of the cardiac myosins examined or unique to the immunizing type.

The American Journal of Pathology, 2010

Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for reconstituting the h... more Mesenchymal stem cells (MSCs) have emerged as a new therapeutic modality for reconstituting the hematopoietic microenvironment by improving engraftment in stem cell transplantation. However, the availability of conventional bone marrow (BM)-derived MSCs (BMSCs) is limited. Recent studies showed that a large number of MSCs can be easily isolated from fat tissue (adipose tissue-derived MSCs [ADSCs]). In this study , we extensively evaluated the hematopoiesis-supporting properties of ADSCs , which are largely unknown. In vitro coculture and progenitor assays showed that ADSCs generated significantly more granulocytes and progenitor cells from human hematopoietic stem cells (HSCs) than BMSCs. We found that ADSCs express the chemokine CXCL12 , a critical regulator of hematopoiesis , at levels that are three fold higher than those with BMSCs. The addition of a CXCL12 receptor antagonist resulted in a lower yield of granulocytes from ADSC layers , whereas the addition of recombinant CXCL12 to BMSC cocultures promoted the growth of granulocytes. In vivo cell homing assays showed that ADSCs facilitated the homing of mouse HSCs to the BM better than BMSCs. ADSCs injected into the BM cavity of fatally irradiated mice reconstituted hematopoiesis more promptly than BM-SCs and subsequently rescued mice that had received a low number of HSCs. Secondary transplantation experiments showed that ADSCs exerted favorable effects on long-term HSCs. These results suggest that ADSCs can be a promising therapeutic alternative to BMSCs.

Vaccines, 2022

The vaccines designed against the SARS-CoV-2 coronavirus are based on the spike (S) protein. Proc... more The vaccines designed against the SARS-CoV-2 coronavirus are based on the spike (S) protein. Processing of the S protein by antigen-presenting cells (APC) and its subsequent presentation to T cells is an essential part of the development of a humoral response. HLA-class II alleles are considered immune response genes because their codified molecules, expressed on the surface of APCs (macrophages, dendritic, and B cells) present antigenic peptides to T cell via their T cell receptor (TCR). The HLA-class II genes are highly polymorphic, regulating what specific peptides induce follicular helper T cells (TFH) and promote B lymphocyte differentiation into plasma or memory B cells. This work hypothesizes that the presence of certain HLA-class II alleles could be associated with the intensity of the humoral response (amount, length) to the SARS-CoV2 mRNA 1273 vaccine. We have studied the relationship between the HLA-class II typing of 87 health workers and the level of antibodies produced...

Cancers

Total or partial loss of HLA class I antigens reduce the recognition of specific tumor peptides b... more Total or partial loss of HLA class I antigens reduce the recognition of specific tumor peptides by cytotoxic T lymphocytes favoring cancer immune escape during natural tumor evolution. These alterations can be caused by genomic defects, such as loss of heterozygosity at chromosomes 6 and 15 (LOH-6 and LOH-15), where HLA class I genes are located. There is growing evidence indicating that LOH in HLA contributes to the immune selection of HLA loss variants and influences the resistance to immunotherapy. Nevertheless, the incidence and the mechanism of this chromosomal aberration involving HLA genes has not been systematically assessed in different types of tumors and often remains underestimated. Here, we used SNP arrays to investigate the incidence and patterns of LOH-6 and LOH-15 in a number of human cancer cell lines and tissues of different histological types. We observed that LOH in HLA is a common event in cancer samples with a prevalence of a copy neutral type of LOH (CN-LOH) t...

Cancers

Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive ... more Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing the transcriptomic signatures of tumoral and non-tumoral samples. We identified 48 lncRNAs that were differentially expressed between pediatric B-ALL and healthy bone marrow samples. The most relevant lncRNA/mRNA pair was AL133346.1/CCN2 (previously known as RP11-69I8.3/CTGF), whose expression was positively correlated and increased in B-ALL samples. Their differential expression pattern and their strong correlation were validated in external B-ALL datasets (Therapeutically Applicable Research to Generate Effective Treatments, Cancer Cell Line Encyclopedia). Survival curve analysis demonstrated that patients with “high” expression levels of CCN2 had...

Annals of hematology, 2017