Biomecánica y mecanismo de producción del traumatismo cráneo-encefálico en el peatón atropellado. Evaluación de la normativa actual en la automoción

Introducción Los atropellos son una de las principales causas de muerte entre los accidentes de tráfico. Recientemente, ha aumentado el estudio de los atropellos, principalmente debido a la aplicación de la normativa europea y japonesa en protección de peatones. Esta investigación presenta un análisis del traumatismo cráneo-encefálico del peatón atropellado, asociándolo con la estructura del vehículo responsable de la lesión, su mecanismo de daño y comparando el resultado con la normativa existente. Métodos La metodología empleada ha consistido en un estudio epidemiológico descriptivo y transversal, mediante el estudio de datos de peatones atropellados recogidos en la base de datos americana (PCDS) que analiza a un total de 552 peatones atropellados y un total de 4.500 lesiones documentadas. Resultados De acuerdo con este estudio, el capó es el causante del 15,1% de las lesiones de la cabeza del peatón, mientras que el parabrisas es responsable de 41,8% de todas las lesiones. En el caso de los vehículos tipo utilitario la ubicación del impacto de la cabeza se produce por encima de lo que se espera en la regulación actual y, por lo tanto, no se aplican las contramedidas necesarias. De todas las lesiones en la cabeza sufridas por los peatones solo el 20% tiene la aceleración lineal como mecanismo de lesión, el 40% de las lesiones se deben a la aceleración rotacional. Conclusiones En esta investigación se pone de manifiesto la importancia de la aceleración rotacional como mecanismo de daño en la cabeza del peatón atropellado. En la normativa actual solo la aceleración lineal está contemplada en la formulación del principal criterio biomecánico utilizado para predecir el traumatismo cráneo-encefálico.Peer ReviewedPostprint (author's final draft

Crystal structure of {2-[4-(4-chlorophenyl)-4-hydroxy-l-piperidinylmethyl] cyclopentyl}-(4-fluorophenyl)-methanone, C24H27CIFNO2

Abstract C24H27ClFNO2, triclinic, P1̅̅̅̅ (No. 2), a = 9.494(2) Å, b = 10.769(2) Å, c = 11.377(3)Å, α = 87.18(3)°, β = 67.27(3)°, γ = 88.01(3)°, V = 1071.4 Å3, Z = 2, Rgt(F) = 0.076, wRobs(F2) = 0.302, T = 293 K

Distintos tipos de reparación quirúrgica en nervios periféricos. Estudio E. N. G

Se utilizan cuatro técnicas de reparación de nervio en perros, estudiando por medio de un analizador de ondas DIDAC, la velocidad de conducción y la morfología de los potenciales desencadenados con estímulos eléctrico-rectangulares. Se comparan los resultados con los valores hallados en animales utilizados como control

Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

Background On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic. Methods We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression. Results CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137. Conclusion sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents

Variations in platelet proteins associated with st-elevation myocardial infarction: Novel clues on pathways underlying platelet activation in acute coronary syndromes

OBJECTIVE: Our aim in this study was to provide novel information on the molecular mechanisms playing a major role in the unwanted platelet activation associated with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We compared the platelet proteome of 11 STEMI patients to a matched control group of 15 stable chronic ischemic cardiopathy patients. In addition, we did a prospective study to follow the STEMI patients over time. Proteins were separated by high-resolution 2D gel electrophoresis, identified by mass spectrometry, and validated by Western blotting. Platelets from STEMI patients on admission displayed 56 protein spot differences (corresponding to 42 unique genes) compared with the control group. The number of differences decreased with time during the patients' follow-up. Interestingly, the adapter protein CrkL and the active form of Src (phosphorylated in Tyr418) were found to be upregulated in platelets from STEMI patients. Major signaling pathways related to the proteins identified include integrin, integrin-linked kinase, and glycoprotein VI (GPVI) signaling. Interestingly, a study on an independent cohort of patients showed a higher degree of activation of GPVI signaling in STEMI patients. CONCLUSIONS: CrkL, the active form of Src, and GPVI signaling are upregulated in platelets from STEMI patients

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity

Heterogenous presence of neutrophil extracellular traps in human solid tumours is partially dependent on IL-8

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8+ T-cell density in the tumour microenvironment. Multiplex immunofluorescence panels were developed to identify NETs in human cancer tissues by co-staining with the granulocyte marker CD15, the neutrophil marker myeloperoxidase and citrullinated histone H3 (H3Cit), as well as IL-8 protein and CD8+ T cells. Three ELISA methods to detect and quantify circulating NETs in serum were optimised and utilised. Whole tumour sections and tissue microarrays from patients with non-small cell lung cancer (NSCLC; n = 14), bladder cancer (n = 14), melanoma (n = 11), breast cancer (n = 31), colorectal cancer (n = 20) and mesothelioma (n = 61) were studied. Also, serum samples collected retrospectively from patients with metastatic melanoma (n = 12) and NSCLC (n = 34) were ELISA assayed to quantify circulating NETs and IL-8. NETs were detected in six different human cancer types with wide individual variation in terms of tissue density and distribution. At least in NSCLC, bladder cancer and metastatic melanoma, NET density positively correlated with IL-8 protein expression and inversely correlated with CD8+ T-cell densities. In a series of serum samples from melanoma and NSCLC patients, a positive correlation between circulating NETs and IL-8 was found. In conclusion, NETs are detectable in formalin-fixed human biopsy samples from solid tumours and in the circulation of cancer patients with a considerable degree of individual variation. NETs show a positive association with IL-8 and a trend towards a negative association with CD8+ tumour-infiltrating lymphocytes

DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity

Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α–mediated CD8+-killing and immune-resistant lung tumors to anti–PD-1 treatment. Finally, in a series of lung cancer patients, DSTYK copy number gain predicts lack of response to the immunotherapy. In summary, we have uncovered DSTYK as new therapeutic target in lung cancer. Prioritization of this novel target for drug development and clinical testing may expand the percentage of NSCLC patients benefiting from immune-based treatments.This work was supported by Fundación para la investigación medica aplicada (FIMA), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC; CB16/12/00443), Spanish Association Against Cancer Scientific Foundation (AECC; GCB14-2170), Fundación Ramón Areces, Instituto de Salud Carlos III, and cofunded by the European Union (European Regional Development Fund, “A way to make Europe”; PI19/00098; PI19/00230; PI20/ 00419), Fundación Roberto Arnal Planelles, and International Association for the Study of Lung Cancer (IASLC) Fellowship funding (K. Valencia). M. Echepare was supported by Contratos Predoctorales de Formación en Investigación en Salud (PFIS), Instituto de Salud Carlos III, and co-funded by the European Union (European Social Fund, "Investing in your future"; FI20/00295)

Proteins Involved in Platelet Signaling Are Differentially Regulated in Acute Coronary Syndrome: A Proteomic Study

BACKGROUND: Platelets play a fundamental role in pathological events underlying acute coronary syndrome (ACS). Because platelets do not have a nucleus, proteomics constitutes an optimal approach to follow platelet molecular events associated with the onset of the acute episode. METHODOLOGY/PRINCIPAL FINDINGS: We performed the first high-resolution two-dimensional gel electrophoresis-based proteome analysis of circulating platelets from patients with non-ST segment elevation ACS (NSTE-ACS). Proteins were identified by mass spectrometry and validations were by western blotting. Forty protein features (corresponding to 22 unique genes) were found to be differentially regulated between NSTE-ACS patients and matched controls with chronic ischemic cardiopathy. The number of differences decreased at day 5 (28) and 6 months after the acute event (5). Interestingly, a systems biology approach demonstrated that 16 of the 22 differentially regulated proteins identified are interconnected as part of a common network related to cell assembly and organization and cell morphology, processes very related to platelet activation. Indeed, 14 of those proteins are either signaling or cytoskeletal, and nine of them are known to participate in platelet activation by αIIbβ3 and/or GPVI receptors. Several of the proteins identified participate in platelet activation through post-translational modifications, as shown here for ILK, Src and Talin. Interestingly, the platelet-secreted glycoprotein SPARC was down-regulated in NSTE-ACS patients compared to stable controls, which is consistent with a secretion process from activated platelets. CONCLUSIONS/SIGNIFICANCE: The present study provides novel information on platelet proteome changes associated with platelet activation in NSTE-ACS, highlighting the presence of proteins involved in platelet signaling. This investigation paves the way for future studies in the search for novel platelet-related biomarkers and drug targets in ACS

Broad sialic acid usage amongst species D human adenovirus

Human adenoviruses (HAdV) are widespread pathogens causing usually mild infections. The Species D (HAdV-D) cause gastrointestinal tract infections and epidemic keratoconjunctivitis (EKC). Despite being significant pathogens, knowledge around HAdV-D mechanism of cell infection is lacking. Sialic acid (SA) usage has been proposed as a cell infection mechanism for EKC causing HAdV-D. Here we highlight an important role for SA engagement by many HAdV-D. We provide apo state crystal structures of 7 previously undetermined HAdV-D fiber-knob proteins, and structures of HAdV-D25, D29, D30 and D53 fiber-knob proteins in complex with SA. Biologically, we demonstrate that removal of cell surface SA reduced infectivity of HAdV-C5 vectors pseudotyped with HAdV-D fiber-knob proteins, whilst engagement of the classical HAdV receptor CAR was variable. Our data indicates variable usage of SA and CAR across HAdV-D. Better defining these interactions will enable improved development of antivirals and engineering of the viruses into refined therapeutic vectors