Consideraciones de diseño de equipo prototipo para el trozado de neumáticos fuera de uso provenientes de la explotación minera

Los neumáticos fuera de uso utilizados por vehículos de gran porte en los yacimientos mineros de Argentina y otros países de Latinoamérica se descartan y acumulan en zonas aledañas a los lugares de explotación. Es decir, no se reciclan lo cual provoca un problema creciente de contaminación ambiental. Este texto se basa en un proyecto que partió del análisis exhaustivo de la macroestructura de los NFU (neumáticos fuera de uso) de minería y el estudio de las propiedades físico-químicas del acero que lo conforma. Los valores de dureza obtenida y la evidencia de tratamiento térmico en el estudio metalográfico del acero demostraron que éste es elástico. Todos estos aspectos resultan fundamentales en el diseño de trozado. Los criterios de diseño referidos al equipamiento necesario para proceder a la etapa de trozado de los NFU provenientes de la actividad minera y la observación del requerimiento de un equipo que, en una primera instancia, debería tener la propiedad de ser móvil para poder ser trasladado a los diferentes lugares donde se acumulan este tipo de NFU, permitirían hacer una primera selección de los componentes del NFU y reducir considerablemente el volumen del material para ser trasladado hasta la planta de procesamiento final.The used tyres left by the commercial vehicles in the mining industry in Argentina and other Latin American countries are discarded and accumulated in some strip mining nearby areas. That is to say, they are not recycled, which causes a growing environmental pollution problem. This text is based on a project which started on the exhaustive analysis of the structure of the off-theroad (OTR) used tyres left in the mining industry and the study of the physical and chemical properties of the steel involved in them. The hardness values obtained and the evidence of the heat treatment in the metallographic study of the steel have shown that It presents elastic characteristics. All these aspects are fundamental in the cutup design. This is necessary to define the design criteria relating to the cutting stages equipment for the mining activity tires. In the first instance, the device should have the property of being mobile in order to be placed to different locations where such tires accumulate. This would make a first selection of the tire components and significantly reduce the volume of material to be moved to the final processing plant

A specific N-terminal extension of the 8 kDa domain is required for DNA end-bridging by human Polµ and Polλ

Human DNA polymerases mu (Polµ) and lambda (Polλ) are X family members involved in the repair of double-strand breaks in DNA during non-homologous end joining. Crucial abilities of these enzymes include bridging of the two 3′ single-stranded overhangs and trans-polymerization using one 3′ end as primer and the other as template, to minimize sequence loss. In this context, we have studied the importance of a previously uncharacterised sequence (‘brooch’), located at the N-terminal boundary of the Polß-like polymerase core, and formed by Tyr141, Ala142, Cys143, Gln144 and Arg145 in Polµ, and by Trp239, Val240, Cys241, Ala242 and Gln243 in Polλ. The brooch is potentially implicated in the maintenance of a closed conformation throughout the catalytic cycle, and our studies indicate that it could be a target of Cdk phosphorylation in Polµ. The brooch is irrelevant for 1 nt gap filling, but of specific importance during end joining: single mutations in the conserved residues reduced the formation of two ended synapses and strongly diminished the ability of Polµ and polymerase lambda to perform non-homologous end joining reactions in vitro

Avances de diseño de prototipo de equipo de trozado de neumáticos fuera de uso provenientes de la explotaciòn minera

Los neumáticos fuera de uso (NFU) fueron y son motivo de preocupación, pues si bien se trata de un residuo no peligroso, presenta una alta capacidad calorífica, que dificulta su extinción en caso de incendios, y no es degradable. En Argentina existe una planta procesadora de NFU provenientes del parque automotor particular que se encuentra instalada en el partido de San Martín (Buenos Aires) y pertenece a la firma REGOMAX. Actualmente cuenta con la asistencia y auditoría técnica de INTI-Caucho y funciona en terrenos cedidos por CEAMSE, donde llegan los neumáticos de desecho. En ésta el tratamiento de los NFU se realiza en dos etapas: Trozado y Molido. Para ello se utiliza equipamiento importado. El producto final es un polvo metal-nylon-caucho de granulometría fina. El caucho, una vez separado de los otros componentes, es utilizado por REGOMAX en la fabricación de pisos, pavimentos deportivos, canchas sintéticas y mezclas con asfalto para pavimentos, recuperando el acero y los restos de tela/nylon de la estructura. Sin embargo, los neumáticos fuera de uso utilizados por vehículos de gran porte en los yacimientos mineros de Argentina y otros países de Latinoamérica se descartan y acumulan en zonas aledañas a los lugares de explotación. Es decir, no se reciclan provocando un problema creciente de contaminación ambiental. La primera etapa de nuestro proyecto se basó en el análisis exhaustivo de la macroestructura de los NFU de minería y el estudio de las propiedades físico-químicas del acero que lo conforma (elemento de mayor resistencia del conjunto). Los valores de dureza obtenida y la evidencia de tratamiento térmico en el estudio metalográfico del acero, demostraron que éste es elástico. Todos estos aspectos resultan fundamentales en el diseño de trozado. El presente trabajo avanza sobre los criterios de diseño referidos al equipamiento necesario para proceder a la primera etapa (Trozado) de los NFU provenientes de la actividad minera (dimensiones, tecnología de corte, potencias requeridas, sistema de montaje). Teniendo en cuenta el requerimiento de un equipo que, en una primera instancia, debería tener la propiedad de ser móvil para poder ser trasladado a los diferentes lugares donde se acumulan este tipo de NFU. Esto permitiría hacer una primera selección de los componentes del NFU y reducir considerablemente el volumen del material para ser trasladado hasta la planta de procesamiento final

Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy

INTRODUCTION: Chronic low-grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)-based first-line therapies. MATERIALS AND METHODS: Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV-infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first-line ART with either ATV/r or EFV, had a baseline biobank sample and a follow-up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein-associated Phospholipase A2 (Lp-PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests. RESULTS: 145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp-PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp-PLA2 (estimated difference -16.3 [CI 95%: -31.4, -1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference -21.8 [-38.0, -5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated. CONCLUSIONS: In virologically suppressed patients on stable ART, OS was lower in ATV/r-based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels.S

Comparison of oxidative stress markers in HIV-infected patients on efavirenz or atazanavir/ritonavir-based therapy

Introduction Chronic low‐grade inflammation and immune activation may persist in HIV patients despite effective antiretroviral therapy (ART). These abnormalities are associated with increased oxidative stress (OS). Bilirubin (BR) may have a beneficial role in counteracting OS. Atazanavir (ATV) inhibits UGT1A1, thus increasing unconjugated BR levels, a distinctive feature of this drug. We compared changes in OS markers in HIV patients on ATV/r versus efavirenz (EFV)‐based first‐line therapies. Materials and Methods Cohort of the Spanish Research Network (CoRIS) is a multicentre, open, prospective cohort of HIV‐infected patients naïve to ART at entry and linked to a biobank. We identified hepatitis C virus/hepatitis B virus (HCV/HBV) negative patients who started first‐line ART with either ATV/r or EFV, had a baseline biobank sample and a follow‐up sample after at least nine months of ART while maintaining initial regimen and being virologically suppressed. Lipoprotein‐associated Phospholipase A2 (Lp‐PLA2), Myeloperoxidase (MPO) and Oxidized LDL (OxLDL) were measured in paired samples. Marker values at one year were interpolated from available data. Multiple imputations using chained equations were used to deal with missing values. Change in the OS markers was modelled using multiple linear regressions adjusting for baseline marker values and baseline confounders. Correlations between continuous variables were explored using Pearson's correlation tests. Results 145 patients (97 EFV; 48 ATV/r) were studied. Mean (SD) baseline values for OS markers in EFV and ATV/r groups were: Lp‐PLA2 [142.2 (72.8) and 150.1 (92.8) ng/mL], MPO [74.3 (48.2) and 93.9 (64.3) µg/L] and OxLDL [76.3 (52.3) and 82.2 (54.4) µg/L]. After adjustment for baseline variables patients on ATV/r had a significant decrease in Lp‐PLA2 (estimated difference −16.3 [CI 95%: −31.4, −1.25; p=0.03]) and a significantly lower increase in OxLDL (estimated difference −21.8 [−38.0, −5.6; p<0.01] relative to those on EFV, whereas no differences in MPO were found. Adjusted changes in BR were significantly higher for the ATV/r group (estimated difference 1.33 [1.03, 1.52; p<0.01]). Changes in BR and changes in OS markers were significantly correlated. Conclusions In virologically suppressed patients on stable ART, OS was lower in ATV/r‐based regimens compared to EFV. We hypothesize these changes could be in part attributable to increased BR plasma levels

Evaluation of Dram Score as a Predictor of Poor Postoperative Outcome in Spine Surgery

[EN] The Distress Risk Assessment Method (DRAM) was presented by Main, Wood and Hillis in 1992 as a simple means of assessing the risk of failure due to psychosocial factors in spine surgery. To our knowledge, it has not been used in our setting. The aim of this study was to analyse the usefulness of the Spanish translation of this instrument to predict poor outcomes. Methods: A prospective blind study was conducted including 65 patients undergoing spine surgery. We created two groups of patients based on DRAM score: not distressed (NDRAM) or distressed (DDRAM). A visual analogue scale for pain and the 12-Item Short Form Health Survey (SF-12) were used at baseline, 6 weeks and 6 months. Results: 24 patients were classified as DDRAM and 38 as NDRAM, with 3 patients not completing the questionnaires. The analysis found no significant differences in the demographic or clinical variables at baseline. At 6 weeks and 6 months, the NDRAM group showed improvements in low back pain (p < 0.001; p = 0.005), leg pain (p < 0.001; p = 0.017), physical health (p = 0.031; p = 0.003) and mental health (p = 0.137; p = 0.049). In contrast, in the DDRAM group, though leg pain score improved (p < 0.001; p = 0.002), there was no improvement at 6 weeks or 6 months in low back pain (p = 0.108; p = 0.287), physical health (p = 0.620; p = 0.263) or mental health (p = 0.185; p = 0.329). Conclusions: In our setting, the DRAM is a useful screening tool, and it has allowed the creation of a program between psychiatry and spine surgeryS

Cutting-edge: preclinical and clinical development of the first approved LAG-3 inhibitor

Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in oncology since the FDA approval of the first ICI 11 years ago. In light of this, Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important next-generation immune checkpoint molecules, playing a similar role as Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical trials which are demonstrating positive results, including promising bispecific molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA) as the first LAG-3 blocking antibody combination for unresectable or metastatic melanoma. This novel immunotherapy combination more than doubled median progression-free survival (PFS) when compared to nivolumab monotherapy (10.1 months versus 4.6 months). Here, we analyze the large clinical trial responsible for this historical approval (RELATIVITY-047), and discuss the preclinical and clinical developments that led to its jump into clinical practice. We will also summarize results achieved by other LAG-3 targeting molecules with promising anti-tumor activities currently under clinical development in phases I, I/II, II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules into clinical practice, supporting the accumulating evidence highlighting the pivotal role of LAG-3 in cancer.The OncoImmunology group is funded by the Spanish Association against Cancer (AECC) [grant number PROYE16001ESCO]; Instituto de Salud Carlos III (ISCIII)-FEDER project grants [grant numbers FIS PI17/02119, FIS PI20/00010, COV20/00000, TRANSPOCART ICI19/00069]; a Biomedicine Project grant from the Department of Health of the Government of Navarre [grant number BMED 050-2019]; strategic projects from the Department of Industry, Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Project Horizon 2020 Improved Vaccination for Older Adults (ISOLDA; ID: 848166); Crescendo Biologics Ltd. supported the OncoImmunology group for the development and testing of PD-1 and LAG-3 bispecifics

Clinical landscape of LAG-3-targeted therapy

Lymphocyte-activated gene 3 (LAG-3) is a cell surface inhibitory receptor and a key regulator of immune homeostasis with multiple biological activities related to T-cell functions. LAG-3 is considered a next-generation immune checkpoint of clinical importance, right next to programmed cell death protein 1 (PD-1) and cytotoxic T-cell lymphocyte antigen-4 (CTLA-4). Indeed, it is the third inhibitory receptor to be exploited in human anticancer immunotherapies. Several LAG-3-antagonistic immunotherapies are being evaluated at various stages of preclinical and clinical development. In addition, combination therapies blocking LAG-3 together with other immune checkpoints are also being evaluated at preclinical and clinical levels. Indeed, the co-blockade of LAG-3 with PD-1 is demonstrating encouraging results. A new generation of bispecific PD-1/LAG-3-blocking agents have also shown strong capacities to specifically target PD-1+ LAG-3+ highly dysfunctional T cells and enhance their proliferation and effector activities. Here we identify and classify preclinical and clinical trials conducted involving LAG-3 as a target through an extensive bibliographic research. The current understanding of LAG-3 clinical applications is summarized, and most of the publically available data up to date regarding LAG-3-targeted therapy preclinical and clinical research and development are reviewed and discussed.The OncoImmunology group is funded by the Spanish Association against Cancer ( AECC ) [grant number PROYE16001ESCO ]; Instituto de Salud Carlos III (ISCIII)-FEDER project grants [grant numbers FIS PI17/02119, FIS PI20/00010, COV20/00000, TRANSPOCART ICI19/00069]; a Biomedicine Project grant from the Department of Health of the Government of Navarre [grant number BMED 050-2019 ]; strategic projects from the Department of Industry, Government of Navarre (AGATA, Ref. 0011-1411-2020-000013; LINTERNA, Ref. 0011-1411-2020-000033; DESCARTHES, 0011-1411-2019-000058); European Project Horizon 2020 Improved Vaccination for Older Adults (ISOLDA; ID: 848166); Crescendo Biologics Ltd. supported the OncoImmunology group for the development and testing of PD-1 and LAG-3 bispecifics