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1.
Nat Immunol ; 16(6): 609-17, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25915731

RESUMEN

Tumor-associated eosinophilia is frequently observed in cancer. However, despite numerous studies of patients with cancer and mouse models of cancer, it has remained uncertain if eosinophils contribute to tumor immunity or are mere bystander cells. Here we report that activated eosinophils were essential for tumor rejection in the presence of tumor-specific CD8(+) T cells. Tumor-homing eosinophils secreted chemoattractants that guided T cells into the tumor, which resulted in tumor eradication and survival. Activated eosinophils initiated substantial changes in the tumor microenvironment, including macrophage polarization and normalization of the tumor vasculature, which are known to promote tumor rejection. Thus, our study presents a new concept for eosinophils in cancer that may lead to novel therapeutic strategies.


Asunto(s)
Vasos Sanguíneos/inmunología , Linfocitos T CD8-positivos/inmunología , Factores Quimiotácticos/inmunología , Eosinófilos/inmunología , Melanoma/inmunología , Neoplasias Cutáneas/inmunología , Animales , Diferenciación Celular , Movimiento Celular , Citotoxicidad Inmunológica , Melanoma/irrigación sanguínea , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Neovascularización Patológica/inmunología , Neovascularización Fisiológica , Neoplasias Cutáneas/irrigación sanguínea , Carga Tumoral/inmunología , Microambiente Tumoral
2.
AIDS Behav ; 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38963568

RESUMEN

Scientific reports on the association between human immunodeficiency virus (HIV) in patients with COVID-19 and mortality have not been in agreement. In this nationwide study, we described and analyzed the demographic and clinical characteristics of people living with HIV (PLWH) and established that HIV infection is a risk factor for mortality in patients hospitalized due to COVID-19. We collected data from the National Hospital Data Information System at Hospitalization between 2020 and 2022. We included patients admitted to the hospital with a diagnosis of COVID-19. We established a cohort of patients with PLWH and compared them to patients without HIV (non-PLWH). For multivariate analyses, we performed binary logistic regression, using mortality as the dependent variable. To improve the interpretability of the results we also applied penalized regression and random forest, two well-known machine-learning algorithms. A broad range of comorbidities, as well as sex and age data, were included in the final model as adjusted estimators. Our data of 1,188,160 patients included 6,973 PLWH. The estimated hospitalization rate in this set was between 1.43% and 1.70%, while the rate among the general population was 0.83%. Among patients with COVID-19, HIV infection was a risk factor for mortality with an odds ratio (OR) of 1.25 (95% CI, 1.14-1.37, p < 0.001). PLWH are more likely to be hospitalized due to COVID-19 than are non-PLWH. PLWH are 25% more likely to die due to COVID-19 than non-PLWH. Our results highlight that PLWH should be considered a population at risk for both hospitalization and mortality.

4.
BMC Infect Dis ; 23(1): 476, 2023 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-37464303

RESUMEN

BACKGROUND: Spain had some of Europe's highest incidence and mortality rates for coronavirus disease 2019 (COVID-19). Here we describe the epidemiology and trends in hospitalizations, the number of critical patients, and deaths in Spain in 2020 and 2021. METHODS: We performed a descriptive, retrospective, nationwide study using an administrative database, the Minimum Basic Data Set at Hospitalization, which includes 95-97% of discharge reports for patients hospitalized in Spain in 2020 and 2021. We analyzed the number of hospitalizations, admissions to intensive care units, and deaths and their geographic distribution across regions of Spain. RESULTS: As of December 31, 2021, a total of 498,789 patients (1.04% of the entire Spanish population) had needed hospitalization. At least six waves of illness were identified. Men were more prone to hospitalization than women. The median age was 66. A total of 54,340 patients (10.9% of all hospitalizations) had been admitted to the intensive care unit. We identified 71,437 deaths (mortality rate of 14.3% among hospitalized patients). We also observed important differences among regions, with Madrid being the epicenter of hospitalizations and mortality. CONCLUSIONS: We analyzed Spain's response to COVID-19 and describe here its experiences during the pandemic in terms of hospitalizations, critical illness, and deaths. This research highlights changes over several months and waves and the importance of factors such as vaccination, the predominant variant of the virus, and public health interventions in the rise and fall of the outbreaks.


Asunto(s)
COVID-19 , Masculino , Humanos , Femenino , Anciano , COVID-19/epidemiología , Pandemias , España/epidemiología , Estudios Retrospectivos , Hospitalización
5.
Adv Skin Wound Care ; 34(5): 255-260, 2021 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-33852462

RESUMEN

OBJECTIVE: To assess the effectiveness of a dimethicone- and zinc-based barrier cream compared with hyperoxygenated fatty acids in preventing pressure injuries (PIs) in patients at high or very high risk. METHODS: Researchers conducted a retrospective noninferiority study in an inpatient acute care hospital in Spain that included hospitalized patients in nonsurgical departments with impaired mobility. RESULTS: The study authors reviewed 522 patients in a control group (hyperoxygenated fatty acids) and an experimental group (barrier cream) over a period of 7 days. The incidence of PI was 31% in the control group and 31.1% in the experimental group. The hazard ratio for developing PI was 0.84 (confidence interval, 0.61-1.17; P = .32) in the experimental group compared with the control group, meeting the criteria for noninferiority. The Kaplan-Meier estimator indicated no statistically significant difference between groups (log-rank = 0.654). CONCLUSIONS: Dimethicone- and zinc-based barrier cream was not inferior to hyperoxygenated fatty acids in preventing PIs in hospitalized patients at high or very high risk of developing them during their hospital stay.


Asunto(s)
Accesibilidad Arquitectónica/normas , Úlcera por Presión/tratamiento farmacológico , Crema para la Piel/uso terapéutico , Adulto , Accesibilidad Arquitectónica/estadística & datos numéricos , Estudios de Cohortes , Estudios de Equivalencia como Asunto , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Úlcera por Presión/epidemiología , Úlcera por Presión/fisiopatología , Estudios Retrospectivos , Crema para la Piel/normas , España/epidemiología
6.
Entropy (Basel) ; 23(6)2021 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-34204225

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is the most common cause of chronic liver disease in developed countries. Certain conditions, including mild inflammation biomarkers, dyslipidemia, and insulin resistance, can trigger a progression to nonalcoholic steatohepatitis (NASH), a condition characterized by inflammation and liver cell damage. We demonstrate the usefulness of machine learning with a case study to analyze the most important features in random forest (RF) models for predicting patients at risk of developing NASH. We collected data from patients who attended the Cardiovascular Risk Unit of Mostoles University Hospital (Madrid, Spain) from 2005 to 2021. We reviewed electronic health records to assess the presence of NASH, which was used as the outcome. We chose RF as the algorithm to develop six models using different pre-processing strategies. The performance metrics was evaluated to choose an optimized model. Finally, several interpretability techniques, such as feature importance, contribution of each feature to predictions, and partial dependence plots, were used to understand and explain the model to help obtain a better understanding of machine learning-based predictions. In total, 1525 patients met the inclusion criteria. The mean age was 57.3 years, and 507 patients had NASH (prevalence of 33.2%). Filter methods (the chi-square and Mann-Whitney-Wilcoxon tests) did not produce additional insight in terms of interactions, contributions, or relationships among variables and their outcomes. The random forest model correctly classified patients with NASH to an accuracy of 0.87 in the best model and to 0.79 in the worst one. Four features were the most relevant: insulin resistance, ferritin, serum levels of insulin, and triglycerides. The contribution of each feature was assessed via partial dependence plots. Random forest-based modeling demonstrated that machine learning can be used to improve interpretability, produce understanding of the modeled behavior, and demonstrate how far certain features can contribute to predictions.

7.
J Med Syst ; 44(1): 16, 2019 Dec 09.
Artículo en Inglés | MEDLINE | ID: mdl-31820120

RESUMEN

Few studies have addressed the predictive value of arterial stiffness determined by pulse wave velocity (PWV) in a high-risk population with no prevalent cardiovascular disease and with obesity, hypertension, hyperglycemia, and preserved kidney function. This longitudinal, retrospective study enrolled 88 high-risk patients and had a follow-up time of 12.4 years. We collected clinical and laboratory data, as well as information on arterial stiffness parameters using arterial tonometry and measurements from ambulatory blood pressure monitoring. We considered nonfatal, incident cardiovascular events as the primary outcome. Given the small size of our dataset, we used survival analysis (i.e., Cox proportional hazards model) combined with a machine learning-based algorithm/penalization method to evaluate the data. Our predictive model, calculated with Cox regression and least absolute shrinkage and selection operator (LASSO), included body mass index, diabetes mellitus, gender (male), and PWV. We recorded 16 nonfatal cardiovascular events (5 myocardial infarctions, 5 episodes of heart failure, and 6 strokes). The adjusted hazard ratio for PWV was 1.199 (95% confidence interval: 1.09-1.37, p < 0.001). Arterial stiffness was a predictor of cardiovascular disease development, as determined by PWV in a high-risk population. Thus, in obese, hypertensive, hyperglycemic patients with preserved kidney function, PWV can serve as a prognostic factor for major adverse cardiac events.


Asunto(s)
Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus , Aprendizaje Automático , Estado Prediabético , Análisis de la Onda del Pulso , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión
8.
Diabetes Metab Res Rev ; 33(2)2017 02.
Artículo en Inglés | MEDLINE | ID: mdl-27253149

RESUMEN

BACKGROUND: Complexity analysis of glucose profile may provide valuable information about the gluco-regulatory system. We hypothesized that a complexity metric (detrended fluctuation analysis, DFA) may have a prognostic value for the development of type 2 diabetes in patients at risk. METHODS: A total of 206 patients with any of the following risk factors (1) essential hypertension, (2) obesity or (3) a first-degree relative with a diagnosis of diabetes were included in a survival analysis study for a diagnosis of new onset type 2 diabetes. At inclusion, a glucometry by means of a Continuous Glucose Monitoring System was performed, and DFA was calculated for a 24-h glucose time series. Patients were then followed up every 6 months, controlling for the development of diabetes. RESULTS: In a median follow-up of 18 months, there were 18 new cases of diabetes (58.5 cases/1000 patient-years). DFA was a significant predictor for the development of diabetes, with ten events in the highest quartile versus one in the lowest (log-rank test chi2 = 9, df = 1, p = 0.003), even after adjusting for other relevant clinical and biochemical variables. In a Cox model, the risk of diabetes development increased 2.8 times for every 0.1 DFA units. In a multivariate analysis, only fasting glucose, HbA1c and DFA emerged as significant factors. CONCLUSIONS: Detrended fluctuation analysis significantly performed as a harbinger of type 2 diabetes development in a high-risk population. Complexity analysis may help in targeting patients who could be candidates for intensified treatment. Copyright © 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.


Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/diagnóstico , Hipertensión/complicaciones , Monitoreo Fisiológico/métodos , Obesidad/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Estudios de Seguimiento , Hemoglobina Glucada/análisis , Humanos , Masculino , Persona de Mediana Edad , Modelos Teóricos , Prevalencia , Pronóstico , Factores de Riesgo , España/epidemiología
9.
Int J Cancer ; 136(5): E326-39, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25230579

RESUMEN

L1 cell adhesion molecule (L1CAM) is overexpressed in many human cancers, confers bad prognosis and augments cell motility, invasion and metastasis. Results from xenograft mouse models suggested that L1CAM antibodies might be promising tools for cancer therapy. Here, we generated human L1CAM-transgenic mice to study therapeutic efficacy and putative side effects in a model system. We established three transgenic lines (M2, M3 and F4) expressing the human L1CAM transgene in brain, kidney and colon with decreasing intensity (M2, M3 > F4). The expression pattern was similar to that of L1CAM in humans. No interference of the transgene with the expression of endogenous L1CAM was observed. Immunohistochemical analysis revealed correct expression of the transgene in mouse cortex and collective duct of the kidney. Injection of (125)I-labeled L1CAM antibodies resulted in specific enrichment in the kidney but not in the brain. The injection of the therapeutic anti-human L1CAM mAb L1-9.3/2a into transgenic mice even at high doses did not cause behavioral changes or other side effects. Similar results were obtained using a mouse specific L1CAM mAb in normal mice. Tumor therapy experiments were performed using syngeneic mouse tumor cells (RET melanoma and Panc02 pancreatic adenocarcinoma) transduced with human L1CAM. MAb L1-9.3/2a efficiently and specifically attenuated local tumor growth in both model systems without apparent side effects. The therapeutic effect was dependent on immune effector mechanisms. Analysis of Panc02-huL1CAM tumors after therapy showed elevated levels of EGF and evidence of immune-induced epithelial-mesenchymal transition. The results suggest that our transgenic mice are valuable tools to study L1CAM-based antibody therapy.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal , Melanoma/terapia , Molécula L1 de Adhesión de Célula Nerviosa/antagonistas & inhibidores , Neoplasias Pancreáticas/terapia , Adenocarcinoma/genética , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adenocarcinoma/terapia , Animales , Western Blotting , Movimiento Celular , Proliferación Celular , Femenino , Humanos , Técnicas para Inmunoenzimas , Radioisótopos de Yodo/uso terapéutico , Melanoma/genética , Melanoma/inmunología , Melanoma/patología , Ratones , Ratones Transgénicos , Molécula L1 de Adhesión de Célula Nerviosa/inmunología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , ARN Mensajero/genética , Radioinmunoterapia , Ratas , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales Cultivadas
10.
Mol Cell Proteomics ; 12(8): 2111-25, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23625662

RESUMEN

Bone metastasis is the most common distant relapse in breast cancer. The identification of key proteins involved in the osteotropic phenotype would represent a major step toward the development of new prognostic markers and therapeutic improvements. The aim of this study was to characterize functional phenotypes that favor bone metastasis in human breast cancer. We used the human breast cancer cell line MDA-MB-231 and its osteotropic BO2 subclone to identify crucial proteins in bone metastatic growth. We identified 31 proteins, 15 underexpressed and 16 overexpressed, in BO2 cells compared with parental cells. We employed a network-modeling approach in which these 31 candidate proteins were prioritized with respect to their potential in metastasis formation, based on the topology of the protein-protein interaction network and differential expression. The protein-protein interaction network provided a framework to study the functional relationships between biological molecules by attributing functions to genes whose functions had not been characterized. The combination of expression profiles and protein interactions revealed an endoplasmic reticulum-thiol oxidoreductase, ERp57, functioning as a hub that retained four down-regulated nodes involved in antigen presentation associated with the human major histocompatibility complex class I molecules, including HLA-A, HLA-B, HLA-E, and HLA-F. Further analysis of the interaction network revealed an inverse correlation between ERp57 and vimentin, which influences cytoskeleton reorganization. Moreover, knockdown of ERp57 in BO2 cells confirmed its bone organ-specific prometastatic role. Altogether, ERp57 appears as a multifunctional chaperone that can regulate diverse biological processes to maintain the homeostasis of breast cancer cells and promote the development of bone metastasis.


Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias de la Mama/metabolismo , Metástasis de la Neoplasia , Proteína Disulfuro Isomerasas/metabolismo , Animales , Neoplasias Óseas/secundario , Neoplasias de la Mama/patología , Línea Celular Tumoral , Femenino , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Ratones , Ratones SCID , Mapeo de Interacción de Proteínas , Proteoma , Transcriptoma , Vimentina/metabolismo
11.
Wien Klin Wochenschr ; 136(3-4): 101-109, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37814058

RESUMEN

BACKGROUND: Metabolic syndrome refers to the association among several cardiovascular risk factors: obesity, dyslipidemia, hyperglycemia, and hypertension. It is associated with increased cardiovascular risk and the development of type 2 diabetes mellitus. Insulin resistance is the underlying mechanism of metabolic syndrome, although its role in increased cardiovascular risk has not been directly identified. OBJECTIVE: We investigated the association between insulin resistance and increased cardiovascular risk in hypertensive adults without diabetes mellitus. DESIGN AND PARTICIPANTS: We enrolled participants without diabetes from an outpatient setting in a retrospective, longitudinal study. Several demographic, clinical, and laboratory parameters were recorded during the observation period. Plasma insulin and homeostatic model assessment for insulin resistance (HOMA-IR) were used to determine insulin resistance and four cardiovascular events (acute coronary disease, acute cerebrovascular disease, incident heart failure, and cardiovascular mortality) were combined into a single outcome. Logistic regression and Cox proportional hazards models were fitted to evaluate the association between covariates and outcomes. RESULTS: We included 1899 hypertensive adults without diabetes with an average age of 53 years (51.3% women, 23% had prediabetes, and 64.2% had metabolic syndrome). In a logistic regression analysis, male sex (odds ratio, OR = 1.66) having high levels of low-density lipoprotein (LDL, OR = 1.01), kidney function (OR = 0.97), and HOMA-IR (OR = 1.06) were associated with the incidence of cardiovascular events; however, in a survival multivariate analysis, only HOMA-IR (hazard ratio, HR 1.4, 95% confidence interval, CI: 1.05-1.87, p = 0.02) and body mass index (HR 1.05, 95% CI: 1.02-1.08, p = 0.002) were considered independent prognostic variables for the development of incident cardiovascular events. CONCLUSION: Insulin resistance and obesity are useful for assessing cardiovascular risk in hypertensive people without diabetes but with preserved kidney function. This work demonstrates the predictive value of the measurement of insulin, and therefore of insulin resistance, in an outpatient setting and attending to high-risk patients.


Asunto(s)
Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensión , Resistencia a la Insulina , Síndrome Metabólico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Factores de Riesgo de Enfermedad Cardiaca , Hipertensión/epidemiología , Hipertensión/complicaciones , Insulina , Estudios Longitudinales , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Obesidad , Estudios Retrospectivos , Factores de Riesgo
12.
Metab Syndr Relat Disord ; 21(8): 443-452, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37669018

RESUMEN

Aim: Conditions linked to metabolic syndrome, such as obesity, hypertension, insulin resistance, and dyslipidemia, are common in patients with severe coronavirus disease 2019 (COVID-19). These conditions can act synergistically to contribute to negative outcomes. We describe and analyze the relationship between metabolic syndrome and COVID-19 severity in terms of risk of hospitalization. Methods: We designed a retrospective, cross-sectional study, including patients with confirmed COVID-19 diagnosis. Clinical and laboratory parameters regarding metabolic syndrome were collected. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was used to assess insulin resistance. The outcome was needed for hospitalization. Logistic regression was used to calculate odds ratios, and to determine the association between variables and risk of hospitalization. Advanced approaches using machine learning were also used to identify and interpret the effects of predictors on the proposed outcome. Results: We included 2716 COVID-19 patients with a mean age of 61.8 years. Of these, 48.9% were women, 28.9% had diabetes, and 50.6% were diagnosed with metabolic syndrome. Overall, 212 patients required hospitalization. Patients with metabolic syndrome had a 58% greater chance of hospitalization if they were men, 32% if they had metabolic syndrome, and 23% if they were obese. Machine learning methods identified body mass index, metabolic syndrome, systolic blood pressure, and HOMA-IR as the most relevant features for our predictive model. Conclusion: Metabolic syndrome and its related biomarkers increase the odds for a severe clinical course of COVID-19 and the need for hospitalization. Machine learning methods can aid understanding of the effects of single features when assessing risks for a given outcome.


Asunto(s)
COVID-19 , Resistencia a la Insulina , Síndrome Metabólico , Masculino , Humanos , Femenino , Persona de Mediana Edad , Síndrome Metabólico/complicaciones , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/epidemiología , Proyectos Piloto , Estudios Retrospectivos , Estudios Transversales , Prueba de COVID-19 , COVID-19/complicaciones , COVID-19/epidemiología , Factores de Riesgo , Obesidad/complicaciones , Obesidad/diagnóstico , Obesidad/epidemiología , Índice de Masa Corporal , Hospitalización
13.
Infect Dis Ther ; 12(1): 143-156, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36348228

RESUMEN

INTRODUCTION: Herpes zoster (HZ) and its complications still represent a significant burden for patients and health care systems. In Spain, vaccination is progressively being introduced and recommended for patients between 65 and 80 years old and patients > 18 years of age suffering from certain immunosuppression conditions. The aim of this study is to estimate the number of hospital admissions related to HZ from 2016 to 2019 in Spain. METHODS: Data were collected from the Minimum Basic DataSet (MBDS) and codified according to the Spanish version of the 10th International Classification of Disease (ICD-10-CM codes B02-B02.9). Among others, variables such as sex, age and presence of complications were included. RESULTS: A total of 27,642 hospitalizations were identified (90% in patients > 50 and 45.8% in patients > 80). Women represented 51.2% of the patients, and 59.9% of patients presented complications related to HZ. The hospitalization rate was 17.74, the mortality rate was 1.2, and the case fatality rate was 6.75%. All rates were significantly higher with age, among men and in complicated HZ. Immunosuppression status for which vaccination had been recommended represented 22.7% of the total cases, affecting mostly individuals > 65 and causing more deaths in those > 80 years. The estimated annual cost of hospitalization for herpes zoster was €35,738,285, and the mean cost per patient was €5172. CONCLUSION: The hospitalization burden for HZ is still important in Spain. Data on the current epidemiology are important to evaluate future vaccination strategies.

14.
Exp Hematol Oncol ; 12(1): 29, 2023 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-36906639

RESUMEN

Melanoma is the deadliest form of skin cancer showing rising incidence over the past years. New insights into the mechanisms of melanoma progression contributed to the development of novel treatment options, such as immunotherapies. However, acquiring resistance to treatment poses a big problem to therapy success. Therefore, understanding the mechanisms underlying resistance could improve therapy efficacy. Correlating expression levels in tissue samples of primary melanoma and metastases revealed that secretogranin 2 (SCG2) is highly expressed in advanced melanoma patients with poor overall survival (OS) rates. By conducting transcriptional analysis between SCG2-overexpressing (OE) and control melanoma cells, we detected a downregulation of components of the antigen presenting machinery (APM), which is important for the assembly of the MHC class I complex. Flow cytometry analysis revealed a downregulation of surface MHC class I expression on melanoma cells that showed resistance towards the cytotoxic activity of melanoma-specific T cells. IFNγ treatment partially reversed these effects. Based on our findings, we suggest that SCG2 might stimulate mechanisms of immune evasion and therefore be associated with resistance to checkpoint blockade and adoptive immunotherapy.

15.
Viruses ; 15(7)2023 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-37515302

RESUMEN

Spain had some of Europe's highest incidence and mortality rates for coronavirus disease 2019 (COVID-19). This study highlights the impact of the COVID-19 pandemic on daily health care in terms of incidence, critical patients, and mortality. We describe the characteristics and clinical outcomes of patients, comparing variables over the different waves. We performed a descriptive, retrospective study using the historical records of patients hospitalized with COVID-19. We describe demographic characteristics, admissions, and occupancy. Time series allowed us to visualize and analyze trends and patterns, and identify several waves during the 27-month period. A total of 3315 patients had been hospitalized with confirmed COVID-19. One-third of these patients were hospitalized during the first weeks of the pandemic. We observed that 4.6% of all hospitalizations had been admitted to the intensive care unit, and we identified a mortality rate of 9.4% among hospitalized patients. Arithmetic- and semi-logarithmic-scale charts showed how admissions and deaths rose sharply during the first weeks, increasing by 10 every few days. We described a single hospital's response and experiences during the pandemic. This research highlights certain demographic profiles in a population and emphasizes the importance of identifying waves when performing research on COVID-19. Our results can extend the analysis of the impact of COVID-19 and can be applied in other contexts, and can be considered when further analyzing the clinical, epidemiological, or demographic characteristics of populations with COVID-19. Our findings suggest that the pandemic should be analyzed not as a whole but rather in different waves.


Asunto(s)
COVID-19 , Humanos , COVID-19/epidemiología , Pandemias , SARS-CoV-2 , Estudios Retrospectivos , Hospitalización , Hospitales
16.
J Immunother Cancer ; 11(11)2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37963637

RESUMEN

BACKGROUND: The metabolism of tryptophan to kynurenines (KYN) by indoleamine-2,3-dioxygenase or tryptophan-2,3-dioxygenase is a key pathway of constitutive and adaptive tumor immune resistance. The immunosuppressive effects of KYN in the tumor microenvironment are predominantly mediated by the aryl hydrocarbon receptor (AhR), a cytosolic transcription factor that broadly suppresses immune cell function. Inhibition of AhR thus offers an antitumor therapy opportunity via restoration of immune system functions. METHODS: The expression of AhR was evaluated in tissue microarrays of head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). A structure class of inhibitors that block AhR activation by exogenous and endogenous ligands was identified, and further optimized, using a cellular screening cascade. The antagonistic properties of the selected AhR inhibitor candidate BAY 2416964 were determined using transactivation assays. Nuclear translocation, target engagement and the effect of BAY 2416964 on agonist-induced AhR activation were assessed in human and mouse cancer cells. The immunostimulatory properties on gene and cytokine expression were examined in human immune cell subsets. The in vivo efficacy of BAY 2416964 was tested in the syngeneic ovalbumin-expressing B16F10 melanoma model in mice. Coculture of human H1299 NSCLC cells, primary peripheral blood mononuclear cells and fibroblasts mimicking the human stromal-tumor microenvironment was used to assess the effects of AhR inhibition on human immune cells. Furthermore, tumor spheroids cocultured with tumor antigen-specific MART-1 T cells were used to study the antigen-specific cytotoxic T cell responses. The data were analyzed statistically using linear models. RESULTS: AhR expression was observed in tumor cells and tumor-infiltrating immune cells in HNSCC, NSCLC and CRC. BAY 2416964 potently and selectively inhibited AhR activation induced by either exogenous or endogenous AhR ligands. In vitro, BAY 2416964 restored immune cell function in human and mouse cells, and furthermore enhanced antigen-specific cytotoxic T cell responses and killing of tumor spheroids. In vivo, oral application with BAY 2416964 was well tolerated, induced a proinflammatory tumor microenvironment, and demonstrated antitumor efficacy in a syngeneic cancer model in mice. CONCLUSIONS: These findings identify AhR inhibition as a novel therapeutic approach to overcome immune resistance in various types of cancers.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Dioxigenasas , Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Humanos , Ratones , Animales , Triptófano , Receptores de Hidrocarburo de Aril/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Leucocitos Mononucleares/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Quinurenina/metabolismo , Inmunoterapia , Factores Inmunológicos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Microambiente Tumoral
17.
Int J Cancer ; 131(2): 387-95, 2012 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-21964766

RESUMEN

We present the results of a comparative gene expression analysis of 15 metastases (10 regressing and 5 progressing) obtained from 2 melanoma patients with mixed response following different forms of immunotherapy. Whole genome transcriptional analysis clearly indicate that regression of melanoma metastases is due to an acute immune rejection mediated by the upregulation of genes involved in antigen presentation and interferon mediated response (STAT-1/IRF-1) in all the regressing metastases from both patients. In contrast, progressing metastases showed low transcription levels of genes involved in these pathways. Histological analysis showed T cells and HLA-DR positive infiltrating cells in the regressing but not in the progressing metastases. Quantitative expression analysis of HLA-A,B and C genes on microdisected tumoral regions indicate higher HLA expression in regressing than in progressing metastases. The molecular signature obtained in melanoma rejection appeared to be similar to that observed in other forms of immune-mediated tissue-specific rejection such as allograft, pathogen clearance, graft versus host or autoimmune disease, supporting the immunological constant of rejection. We favor the idea that the major factor determining the success or failure of immunotherapy is the nature of HLA Class I alterations in tumor cells and not the type of immunotherapy used. If the molecular alteration is reversible by the immunotherapy, the HLA expression will be upregulated and the lesion will be recognized and rejected. In contrast, if the defect is structural the MHC Class I expression will remain unchanged and the lesion will progress.


Asunto(s)
Presentación de Antígeno/genética , Inmunoterapia , Melanoma/inmunología , Melanoma/terapia , Metástasis de la Neoplasia , Presentación de Antígeno/inmunología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Antígenos HLA-DR/análisis , Humanos , Factor 1 Regulador del Interferón/genética , Melanoma/genética , Melanoma/secundario , Factor de Transcripción STAT1/genética , Linfocitos T/inmunología , Transcripción Genética , Activación Transcripcional
18.
Sci Immunol ; 7(71): eabh1873, 2022 05 27.
Artículo en Inglés | MEDLINE | ID: mdl-35622904

RESUMEN

T cells become functionally exhausted in tumors, limiting T cell-based immunotherapies. Although several transcription factors regulating the exhausted T (Tex) cell differentiation are known, comparatively little is known about the regulators of Tex cell survival. Here, we reported that the regulator of G protein signaling 16 (Rgs-16) suppressed Tex cell survival in tumors. By performing lineage tracing using reporter mice in which mCherry marked Rgs16-expressing cells, we identified that Rgs16+CD8+ tumor-infiltrating lymphocytes (TILs) were terminally differentiated, expressed low levels of T cell factor 1 (Tcf1), and underwent apoptosis as early as 6 days after the onset of Rgs16 expression. Rgs16 deficiency inhibited CD8+ T cell apoptosis and promoted antitumor effector functions of CD8+ T cells. Furthermore, Rgs16 deficiency synergized with programmed cell death protein 1 (PD-1) blockade to enhance antitumor CD8+ T cell responses. Proteomics revealed that Rgs16 interacted with the scaffold protein IQGAP1, suppressed the recruitment of Ras and B-Raf, and inhibited Erk1 activation. Rgs16 deficiency enhanced antitumor CD8+ TIL survival in an Erk1-dependent manner. Loss of function of Erk1 decreased antitumor functions of Rgs16-deficient CD8+ T cells. RGS16 mRNA expression levels in CD8+ TILs of patients with melanoma negatively correlated with genes associated with T cell stemness, such as SELL, TCF7, and IL7R, and predicted low responses to PD-1 blockade. This study uncovers Rgs16 as an inhibitor of Tex cell survival in tumors and has implications for improving T cell-based immunotherapies.


Asunto(s)
Linfocitos T CD8-positivos , Receptor de Muerte Celular Programada 1 , Proteínas RGS/inmunología , Animales , Diferenciación Celular , Humanos , Inmunoterapia , Linfocitos Infiltrantes de Tumor , Ratones
19.
Oncoimmunology ; 11(1): 2008110, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35141051

RESUMEN

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), a cell surface receptor, is expressed on normal epithelial tissue and highly expressed in cancers of high unmet medical need, such as non-small cell lung, pancreatic, and colorectal cancer. CEACAM receptors undergo homo- and heterophilic interactions thereby regulating normal tissue homeostasis and angiogenesis, and in cancer, tumor invasion and metastasis. CEACAM6 expression on malignant plasma cells inhibits antitumor activity of T cells, and we hypothesize a similar function on epithelial cancer cells. The interactions between CEACAM6 and its suggested partner CEACAM1 on T cells were studied. A humanized CEACAM6-blocking antibody, BAY 1834942, was developed and characterized for its immunomodulating effects in co-culture experiments with T cells and solid cancer cells and in comparison to antibodies targeting the immune checkpoints programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and T cell immunoglobulin mucin-3 (TIM-3). The immunosuppressive activity of CEACAM6 was mediated by binding to CEACAM1 expressed by activated tumor-specific T cells. BAY 1834942 increased cytokine secretion by T cells and T cell-mediated killing of cancer cells. The in vitro efficacy of BAY 1834942 correlated with the degree of CEACAM6 expression on cancer cells, suggesting potential in guiding patient selection. BAY 1834942 was equally or more efficacious compared to blockade of PD-L1, and at least an additive efficacy was observed in combination with anti-PD-1 or anti-TIM-3 antibodies, suggesting an efficacy independent of the PD-1/PD-L1 axis. In summary, CEACAM6 blockade by BAY 1834942 reactivates the antitumor response of T cells. This warrants clinical evaluation.


Asunto(s)
Antígenos CD , Neoplasias , Receptor de Muerte Celular Programada 1 , Antígenos CD/inmunología , Antígeno B7-H1/inmunología , Moléculas de Adhesión Celular/inmunología , Proteínas Ligadas a GPI/inmunología , Humanos , Neoplasias/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T
20.
Int J Cancer ; 129(4): 839-46, 2011 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-20957629

RESUMEN

Bacillus Calmette-Guerin (BCG) immunotherapy is a standard treatment for high-risk non-muscle-infiltrating bladder cancer patients. Although the outcomes are good, cancer relapse is observed in around 40% of patients. We present the comparative analysis of human leukocyte antigen (HLA) class I expression in recurrent bladder tumors in patients treated with mitomycin or BCG. HLA class I expression was analyzed by RT-Q-PCR and immunohistochemical techniques. Loss of heterozygosity (LOH) was determined by microsatellite amplification of markers in chromosome 6 and 15. More profound alterations in HLA class I expression were found in post-BCG recurrent tumors than in pre-BCG lesions, whereas mitomycin treatment did not change the HLA class I expression pattern. Post-BCG recurrent tumors also showed a higher incidence of structural defects underlying altered HLA class I expression. We hypothesize that the immunotherapy-activated immune system recognizes and eliminates tumor cells with reversible ("soft") HLA class I changes but not transformed cells with additional, irreversible ("hard") alterations. To our knowledge, this is the first clinical evidence of immunotherapy-induced immunoselection of HLA class I loss tumor variants in bladder cancer, although the study involved a small number of patients.


Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Vacuna BCG/administración & dosificación , Antígenos de Histocompatibilidad Clase I/metabolismo , Inmunoterapia , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/terapia , Adulto , Anciano , Antibióticos Antineoplásicos/uso terapéutico , Vacuna BCG/inmunología , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Técnicas para Inmunoenzimas , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Mitomicina/uso terapéutico , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/metabolismo , Valor Predictivo de las Pruebas , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Resultado del Tratamiento
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