Dual-target car-ts with on-and off-tumour activity may override immune suppression in solid cancers: A mathematical proof of concept

Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on-and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatmentsThis work has been funded by the James S. Mc. Donnell Foundation (USA) 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (Collaborative award 220020450), Ministerio de Ciencia e Innovación, Spain (grant number PID2019-110895RB-I00), and Junta de Comunidades de Castilla-La Mancha (grant number SBPLY/17/180501/000154). OLT is supported by a PhD Fellowship from the University of Castilla-La Mancha research pla

Análisis dogmático del derecho penal ambiental chileno, a la luz del derecho comparado y las obligaciones contraídas por Chile en el ámbito del derecho internacional. Conclusiones y propuesta legislativa

Indexación: ScieloEl presente artículo corresponde al Informe Final del Proyecto FONDECYT 1010206­2001, sobre tratamiento penal de los delitos contra el medio ambiente en Chile. Sus conclusiones se exponen en siete partes: la primera aborda la cuestión de la necesidad de un derecho penal protector del medio ambiente, ante los riesgos a que se encuentra sometido en las sociedades contemporáneas; la segunda, la necesidad de su regulación desde el punto de vista del Derecho Internacional y las obligaciones contraídas en la materia; la tercera, una descripción sucinta de los modelos de regulación de la protección penal del medio ambiente en el derecho comparado; la cuarta, una explicación acerca de las normas de derecho penal ambiental vigentes en Chile; la quinta, el por qué de la insuficiencia legislativa penal para la protección del medio ambiente, a la luz de las obligaciones internacionales contraídas en la materia, el estado del derecho comparado y la necesidad de evitar la burla del Sistema de Evaluación de Impacto Ambiental; la sexta, una reseña y crítica científica de los proyectos de ley en materia penal ambiental presentados al Congreso Nacional; y la séptima, las ideas matrices de las soluciones de lege ferenda que se ofrecen a los problemas de las insuficiencias del Derecho nacional en la materia y el texto de la propuesta de Proyecto de Ley elaborado, producto final de nuestras investigaciones.http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S0718-00122003000200002&nrm=is

A Mathematical Description of the Bone Marrow Dynamics during CAR T-Cell Therapy in B-Cell Childhood Acute Lymphoblastic Leukemia

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients' experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T-cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells, and CAR T-cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T-cells, and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T-cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load, and leukemia burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model.This work was partially supported by the Fundacion Espanola para la Ciencia y la Tecnologia (UCA PR214), the Asociacion Pablo Ugarte (APU, Spain), Junta de Comunidades de Castilla-La Mancha (SBPLY/17/180501/000154), Ministry of Science and Technology, Spain (PID2019110895RB-I00), and Inversion Territorial Integrada de la Provincia de Cadiz (ITI-0038-2019)

Increased hypothalamic anti‐inflammatory mediators in non‐diabetic insulin receptor substrate 2‐deficient mice

© 2021 by the authors.Insulin receptor substrate (IRS) 2 is a key mediator of insulin signaling and IRS-2 knockout (IRS2−/−) mice are a preclinical model to study the development of diabetes, as they develop peripheral insulin resistance and beta-cell failure. The differential inflammatory profile and insulin signaling in the hypothalamus of non-diabetic (ND) and diabetic (D) IRS2−/− mice might be implicated in the onset of diabetes. Because the lipid profile is related to changes in inflammation and insulin sensitivity, we analyzed whether ND IRS2−/− mice presented a different hypothalamic fatty acid metabolism and lipid pattern than D IRS2−/− mice and the relationship with inflammation and markers of insulin sensitivity. ND IRS2−/− mice showed elevated hypothalamic anti-inflammatory cytokines, while D IRS2−/− mice displayed a proinflammatory profile. The increased activity of enzymes related to the pentose-phosphate route and lipid anabolism and elevated polyunsaturated fatty acid levels were found in the hypothalamus of ND IRS2−/− mice. Conversely, D IRS2−/− mice have no changes in fatty acid composition, but hypothalamic energy balance and markers related to anti-inflammatory and insulin-sensitizing properties were reduced. The data suggest that the concurrence of an anti-inflammatory profile, increased insulin sensitivity and polyunsaturated fatty acids content in the hypothalamus may slow down or delay the onset of diabetes.This work was supported by the Spanish Ministry of Science and Innovation with the help of European FEDER funding (grant numbers FIS PI19/00166, BFU 2017-82565-C2-1-R, and RTI2018-094052-B-100), Comunidad de Madrid, Spain (S2017/BMD-3684) and the Network Center for Biomedical Research on Obesity and Nutrition (CIBEROBN) and Diabetes (CIBERDEM) Instituto Carlos III. S.C. was supported by CIBEROBN and A.G.M. by Fundación para la Investigación Biomédica Hospital Infantil Universitario Niño Jesús

Origin, distribution, and potential risk factors associated with influenza A virus in swine in two production systems in Guatemala

Background: Guatemala is the country with the largest swine production in Central America; however, evidence of influenza A virus (IAV) in pigs has not been clearly delineated. Objectives: In this study, we analyzed the presence and spatial distribution of IAV in commercial and backyard swine populations. Methods: Samples from two nationwide surveys conducted in 2010 and 2011 were tested using virological (rRT-PCR and virus isolation) and serological (ELISA and hemagglutination inhibition) assays to detect IAV. Results: Influenza A virus was detected in 15.7% of the sampled pigs (30.6% of herds) in 2010 and in 11.7% (24.2% of herds) in 2011. The percentage of seropositive pigs was 10.6% (16.1% of herds) and 1.4% (3.1% of herds) for each year, respectively. Three pandemic H1N1 and one seasonal human-like H3N2 viruses were isolated. Antibodies against viruses from different genetic clusters were detected. No reassortant strains with swine viruses were detected. The H3N2 virus was closely related to human viruses that circulated in Central America in 2010, distinct to the most recent human seasonal vaccine lineages. Spatial clusters of rRT-PCR positive herds were detected each year by scan statistics. Conclusions: Our results demonstrate circulation of IAV throughout Guatemala and identify commercial farms, animal health status, and age as potential risk factors associated with IAV infection and exposure. Detection of human-origin viruses in pigs suggests a role for humans in the molecular epidemiology of IAV in swine in Guatemala and evidences gaps in local animal and human surveillance

Association of oxidative stress and inflammatory metabolites with Alzheimer’s disease cerebrospinal fluid biomarkers in mild cognitive impairment

Background: Isoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects. Methods: Targeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression. Results: Increased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression. Conclusions: Oxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype

High-Dimensional Analysis of Single-Cell Flow Cytometry Data Predicts Relapse in Childhood Acute Lymphoblastic Leukaemia

B-cell Acute Lymphoblastic Leukaemia is one of the most common cancers in childhood, with 20% of patients eventually relapsing. Flow cytometry is routinely used for diagnosis and follow-up, but it currently does not provide prognostic value at diagnosis. The volume and the high-dimensional character of this data makes it ideal for its exploitation by means of Artificial Intelligence methods. We collected flow cytometry data from 56 patients from two hospitals. We analysed differences in intensity of marker expression in order to predict relapse at the moment of diagnosis. We finally correlated this data with biomolecular information, constructing a classifier based on CD38 expression. Artificial intelligence methods may help in unveiling information that is hidden in high-dimensional oncological data. Flow cytometry studies of haematological malignancies provide quantitative data with the potential to be used for the construction of response biomarkers. Many computational methods from the bioinformatics toolbox can be applied to these data, but they have not been exploited in their full potential in leukaemias, specifically for the case of childhood B-cell Acute Lymphoblastic Leukaemia. In this paper, we analysed flow cytometry data that were obtained at diagnosis from 56 paediatric B-cell Acute Lymphoblastic Leukaemia patients from two local institutions. Our aim was to assess the prognostic potential of immunophenotypical marker expression intensity. We constructed classifiers that are based on the Fisher's Ratio to quantify differences between patients with relapsing and non-relapsing disease. We also correlated this with genetic information. The main result that arises from the data was the association between subexpression of marker CD38 and the probability of relapse

Computational approaches to Explainable Artificial Intelligence:Advances in theory, applications and trends

Deep Learning (DL), a groundbreaking branch of Machine Learning (ML), has emerged as a driving force in both theoretical and applied Artificial Intelligence (AI). DL algorithms, rooted in complex and non-linear artificial neural systems, excel at extracting high-level features from data. DL has demonstrated human-level performance in real-world tasks, including clinical diagnostics, and has unlocked solutions to previously intractable problems in virtual agent design, robotics, genomics, neuroimaging, computer vision, and industrial automation. In this paper, the most relevant advances from the last few years in Artificial Intelligence (AI) and several applications to neuroscience, neuroimaging, computer vision, and robotics are presented, reviewed and discussed. In this way, we summarize the state-of-the-art in AI methods, models and applications within a collection of works presented at the 9th International Conference on the Interplay between Natural and Artificial Computation (IWINAC). The works presented in this paper are excellent examples of new scientific discoveries made in laboratories that have successfully transitioned to real-life applications.</p

Salud de los trabajadores

Actividad f&iacute;sica y su relaci&oacute;n con los factores de riesgo cardiovascular de carteros chilenosAn&aacute;lisis de resultados: riesgos psicosociales en el trabajo Suceso-Istas 21 en Cesfam Quell&oacute;nAusentismo laboral por enfermedades oftalmol&oacute;gicas, Chile 2009Brote de diarreas por norovirus, posterremoto-tsunami, Constituci&oacute;n, Regi&oacute;n del MauleCalidad de vida en profesionales de la salud p&uacute;blica chilenaCaracterizaci&oacute;n del reposo laboral en personal del SSMN durante el primer semestre de 2010Concentraci&oacute;n de nicotina en pelo en trabajadores no fumadores expuestos a humo de tabaco ambientalCondiciones de trabajo y bienestar/malestar docente en profesores de ense&ntilde;anza media de SantiagoDisfunci&oacute;n auditiva inducida por exposici&oacute;n a xilenoErgonom&iacute;a aplicada al estudio del s&iacute;ndrome de dolor lumbar en el trabajoEstimaci&oacute;n de la frecuencia de factores de riesgo cardiovascular en trabajadores de una empresa mineraExposici&oacute;n a plaguicidas inhibidores de la acetilcolinesterasa en Colombia, 2006-2009Factores de riesgo y da&ntilde;os de salud en conductores de una empresa peruana de transporte terrestre, 2009Las consecuencias de la cultura en salud y seguridad ocupacional en una empresa mineraPercepci&oacute;n de cambios en la pr&aacute;ctica m&eacute;dica y estrategias de afrontamientoPercepci&oacute;n de la calidad de vida en la Universidad del Biob&iacute;oPesos m&aacute;ximos aceptables para tareas de levantamiento manual de carga en poblaci&oacute;n laboral femeninaRiesgo coronario en trabajadores mineros seg&uacute;n la funci&oacute;n de Framingham adaptada para la poblaci&oacute;n chilenaTrastornos emocionales y riesgo cardiovascular en trabajadores de la salu

Clonal heterogeneity and rates of specific chromosome gains are risk predictors in childhood high-hyperdiploid B-cell acute lymphoblastic leukemia

B-cell acute lymphoblastic leukemia (B-ALL) is the commonest childhood cancer. High hyperdiploidy (HHD) identifies the most frequent cytogenetic subgroup in childhood B-ALL. Although hyperdiploidy represents an important prognostic factor in childhood B-ALL, the specific chromosome gains with prognostic value in HHD-B-ALL remain controversial, and the current knowledge about the hierarchy of chromosome gains, clonal heterogeneity and chromosomal instability in HHD-B-ALL remains very limited. We applied automated sequential-iFISH coupled with single-cell computational modeling to identify the specific chromosomal gains of the eight typically gained chromosomes in a large cohort of 72 primary diagnostic (DX, n = 62) and matched relapse (REL, n = 10) samples from HHD-B-ALL patients with either favorable or unfavorable clinical outcome in order to characterize the clonal heterogeneity, specific chromosome gains and clonal evolution. Our data show a high degree of clonal heterogeneity and a hierarchical order of chromosome gains in DX samples of HHD-B-ALL. The rates of specific chromosome gains and clonal heterogeneity found in DX samples differ between HHD-B-ALL patients with favorable or unfavorable clinical outcome. In fact, our comprehensive analyses at DX using a computationally defined risk predictor revealed low levels of trisomies +18+10 and low levels of clonal heterogeneity as robust relapse risk factors in minimal residual disease (MRD)-negative childhood HHD-B-ALL patients: relapse-free survival beyond 5 years: 22.1% versus 87.9%, P < 0.0001 and 33.3% versus 80%, P < 0.0001, respectively. Moreover, longitudinal analysis of matched DX-REL HHD-B-ALL samples revealed distinct patterns of clonal evolution at relapse. Our study offers a reliable prognostic sub-stratification of pediatric MRD-negative HHD-B-ALL patients