The usefulness of mesocosms for ecotoxicity testing with lacertid lizards

Mesocosms (i.e., outdoor, man-made representations of natural ecosystems) have seldom been used to study the impact of contaminants on terrestrial ecosystems. However, mesocosms can be a useful tool to provide a link between field and laboratory studies. We exposed juvenile lacertid lizards for a period of over one year to pesticides (herbicides and insecticides) in mesocosm enclosures with the intention of validating field observations obtained in a previous study that examined the effects of corn pesticides in Podarcis bocagei. Our treatments replicated field conditions and consisted of a control, an herbicides only treatment (alachlor, terbuthylazine, mesotrione and glyphosate) and an herbicides and insecticide treatment (including chlorpyrifos). We used a multi-biomarker approach that examined parameters at an individual and sub-individual level, including growth, locomotor performance, standard metabolic rate, biomarkers of oxidative stress, esterases and liver histopathologies. Although mortality over the course of the exposures was high (over 60%), surviving individuals prospered relatively well in the mesocosms and displayed a broad range of natural behaviours. The low numbers of replicate animals compromised many of the statistical comparisons, but in general, surviving lizards exposed to pesticides in mesocosm enclosures for over one year, thrived, and displayed few effects of pesticide exposure. Despite the difficulties, this work acts as an important stepping-stone for future ecotoxicology studies using lizards.publishe

Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma:Systematic Review and Meta-Analysis

The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers. In this systematic review and meta-analysis, we investigated the prognostic value of TIL in laryngeal squamous cell carcinoma (LSCC). We performed a systematic search in PubMed for publications that investigated the prognostic value of TIL in LSCC. A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS). The pooled meta-analysis showed a favorable prognostic role for stromal TIL in HE sections for OS (HR 0.57, 95% CI 0.36-0.91, p = 0.02), and for DFS (HR 0.56, 95% CI 0.34-0.94, p = 0.03). High CD8+ TIL were associated with a prolonged OS (HR 0.62, 95% CI 0.4-0.97, p = 0.04) and DFS (HR 0.73, 95% CI 0.34-0.94, p = 0.002). High CD3+/CD4+ TIL demonstrated improved OS (HR 0.32, 95% CI 0.16-0.9, p = 0.03) and DFS (HR 0.23, 95% CI 0.10-0.53, p = 0.0005). This meta-analysis confirmed the favorable prognostic significance of TIL in LSCC. High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome

Evaluating Earthworms’ Potential for Remediating Soils Contaminated with Olive Mill Waste Sediments

The olive-oil industry generates large amounts of residues that, in the past, were accumulated in evaporating ponds in many Mediterranean countries. Currently, these open-air ponds pose a serious environmental hazard because of toxic chemicals that concentrate in their sediments. Bioremediation of olive mill waste (OMW) sediments has emerged as a viable option for managing this environmentally problematic residue. Here, we postulate that inoculation of an OMW-soil mixture with earthworms may be a complementary bioremediation strategy to that using native microorganisms only. A laboratory study assessed the ecotoxicity of OMW-amended soils (10%, 20%, 40% and 80% w/w) combining earthworm biomarker responses and soil enzyme activities. The doses of 40% and 80% were toxic to earthworms, as evidenced by the high mortality rate, loss of body weight and signs of oxidative stress after 30 d of soil incubation. Conversely, doses ≤ 20% w/w were compatible with earthworm activity, as indicated by the significant increase of soil enzyme activities. Total concentrations of phenolic compounds decreased by more than 70% respect to initial concentrations in 10% and 20% OMW treatments. These results suggest that OMW sediments intentionally mixed with soils in an up to 20% proportion is a workable bioremediation strategy, where earthworms can be inoculated to facilitate the OMW degradation

Getting Ahead: A Resident Led Quality Improvement Project to Increase Diabetic Nephropathy Screening in an Underserved Hispanic-Predominant Population

Introduction: Diabetes is the leading cause of end-stage renal disease (ESRD) in the United States (US), with 37 million having chronic kidney disease. Despite national guidelines recommendations for diabetic nephropathy screening with urine albumin-to-creatinine ratio (UACR), less than 50% receive full screening. Our Internal Medicine residents led a quality improvement project to increase diabetic nephropathy screening rate with UACR in our resident clinic by 50% in one academic year. Methods: We conducted the resident-led quality improvement project from July 2021 to April 2022. We reviewed the electronic medical records (EMR) from our clinic pre-intervention July 2020 to June 2021 and compared this to post intervention July 2021 to March 2022 determining the nephropathy screening rates in patients with diabetes. Our interventions included resident education, pre and post surveys to test foundational knowledge, adding UACR in the affordable laboratory order form and establishing normal reference range of UACR in the EMR. Results: We collected 217 patients with diabetes, 27% were uninsured, 38% had Medicare/Medicaid and 90% identified as Hispanic. Comparing pre to post intervention, there was a significant change of 45 (20.7%) vs 71 (32.7%) patients screened for diabetic nephropathy with a UACR. The correct average score of knowledge-based questions was 82% on the pre survey, which increased to 88% in the post survey. Conclusion: Our study showed promising results on improving diabetic nephropathy screening. The comprehensive approach including resident education about diabetic nephropathy screening with UACR and more so facilitating the order set in the EMR were key to achieve this goal

Physiological lentiviral vectors for the generation of improved CAR-T cells

Anti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms. However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%-50% of the treated patients. Most CAR-T cells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor alpha (EF1 alpha)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-alpha) and interferon (IFN)-gamma after efficient destruction of CD19(+) lymphoma cells, both in vitro and in vivo. Moreover, we also showed their improved efficiency using an in vitro CD19(+) pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AWLVs for the generation of improved CAR-T products

Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction

AIM: Experimental animal studies suggest that the use of skeletal myoblast in patients with myocardial infarction may result in improved cardiac function. The aim of the study was to assess the feasibility and safety of this therapy in patients with myocardial infarction. METHODS AND RESULTS: Twelve patients with old myocardial infarction and ischaemic coronary artery disease underwent treatment with coronary artery bypass surgery and intramyocardial injection of autologous skeletal myoblasts obtained from a muscle biopsy of vastus lateralis and cultured with autologous serum for 3 weeks. Global and regional cardiac function was assessed by 2D and ABD echocardiogram. 18F-FDG and 13N-ammonia PET studies were used to determine perfusion and viability. Left ventricular ejection fraction (LVEF) improved from 35.5+/-2.3% before surgery to 53.5+/-4.98% at 3 months (P=0.002). Echocardiography revealed a marked improvement in regional contractility in those cardiac segments treated with skeletal myoblast (wall motion score index 2.64+/-0.13 at baseline vs 1.64+/-0.16 at 3 months P=0.0001). Quantitative 18F-FDG PET studies showed a significant (P=0.012) increased in cardiac viability in the infarct zone 3 months after surgery. No statistically significant differences were found in 13N-ammonia PET studies. Skeletal myoblast implant was not associated with an increase in adverse events. No cardiac arrhythmias were detected during early follow-up. CONCLUSIONS: In patients with old myocardial infarction, treatment with skeletal myoblast in conjunction with coronary artery bypass is safe and feasible and is associated with an increased global and regional left ventricular function,improvement in the viability of cardiac tissue in the infarct area and no induction of arrhythmias

Gene-environment interaction analysis of redox-related metals and genetic variants with plasma metabolic patterns in a general population from Spain: The Hortega Study

Background: Limited studies have evaluated the joint influence of redox-related metals and genetic variation on metabolic pathways. We analyzed the association of 11 metals with metabolic patterns, and the interacting role of candidate genetic variants, in 1145 participants from the Hortega Study, a population-based sample from Spain. Methods: Urine antimony (Sb), arsenic, barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), molybdenum (Mo) and vanadium (V), and plasma copper (Cu), selenium (Se) and zinc (Zn) were measured by ICP-MS and AAS, respectively. We summarized 54 plasma metabolites, measured with targeted NMR, by estimating metabolic principal components (mPC). Redox-related SNPs (N = 291) were measured by oligo-ligation assay. Results: In our study, the association with metabolic principal component (mPC) 1 (reflecting non-essential and essential amino acids, including branched chain, and bacterial co-metabolism versus fatty acids and VLDL subclasses) was positive for Se and Zn, but inverse for Cu, arsenobetaine-corrected arsenic (As) and Sb. The association with mPC2 (reflecting essential amino acids, including aromatic, and bacterial co-metabolism) was inverse for Se, Zn and Cd. The association with mPC3 (reflecting LDL subclasses) was positive for Cu, Se and Zn, but inverse for Co. The association for mPC4 (reflecting HDL subclasses) was positive for Sb, but inverse for plasma Zn. These associations were mainly driven by Cu and Sb for mPC1; Se, Zn and Cd for mPC2; Co, Se and Zn for mPC3; and Zn for mPC4. The most SNP-metal interacting genes were NOX1, GSR, GCLC, AGT and REN. Co and Zn showed the highest number of interactions with genetic variants associated to enriched endocrine, cardiovascular and neurological pathways. Conclusions: Exposures to Co, Cu, Se, Zn, As, Cd and Sb were associated with several metabolic patterns involved in chronic disease. Carriers of redox-related variants may have differential susceptibility to metabolic alterations associated to excessive exposure to metals.This work was supported by the Strategic Action for Research in Health sciences [CP12/03080, PI15/00071, PI10/0082, PI13/01848, PI14/00874, PI16/01402, PI21/00506 and PI11/00726], CIBER Fisio patología Obesidad y Nutrición (CIBEROBN) (CIBER-02-08-2009, CB06/03 and CB12/03/30,016), the State Agency for Research (PID2019-108973RB- C21 and C22), the Valencia Government (GRUPOS 03/101; PROMETEO/2009/029 and ACOMP/2013/039, IDI FEDER/2021/072 and GRISOLIAP/2021/119), the Castilla-Leon Government (GRS/279/A/08) and European Network of Excellence Ingenious Hypercare (EPSS-037093) from the European Commission. The Strategic Action for Research in Health sciences, CIBERDEM and CIBEROBN are initiatives from Carlos III Health Institute Madrid and cofunded with European Funds for Regional Development (FEDER). The State Agency for Research and Carlos III Health Institute belong to the Spanish Ministry of Science and Innovation. ADR received the support of a fellowship from “la Caixa” Foundation (ID 100010434) (fellowship code “LCF/BQ/DR19/11740016”). MGP received the support of a fellowship from “la Caixa” Foundation (ID 100010434, fellowship code LCFLCF/BQ/DI18/11660001). The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.S

Oceanographic processes and products around the Iberian margin: a new multidisciplinary approach

Our understanding of the role of bottom currents and associated oceanographic processes (e.g, overflows, barotropic tidal currents) including intermittent processes (e.g, vertical eddies, deep sea storms, horizontal vortices, internal waves and tsunamis) is rapidly evolving. Many deep-water processes remain poorly understood due to limited direct observations, but may generate significant depositional and erosional features on both short-and long-term time scales. This paper describes these oceanographic processes and examines their potential role in the sedimentary features around the Iberian margin. The paper explores the implications of the processes studied, given their secondary role relative to other factors such as mass-transport and turbiditic processes. An integrated interpretation of these oceanographic processes requires an understanding of contourites, sea-floor features, their spatial and temporal evolution, and the near-bottom flows that form them. Given their complex, three-dimensional and temporally-variable nature, integration of these processes into sedimentary, oceanographic and climatological frameworks will require a multidisciplinary approach that includes Geology, Physical Oceanography, Paleoceanography and Benthic Biology. This approach will synthesize oceanographic data, seafloor morphology, sediments and seismic images to improve our knowledge of permanent and intermittent processes around Iberia, and evaluate their conceptual and regional role in the sedimentary evolution of the margin. © 2015, Instituto Geologico y Minero de Espana. All rights reservedEl conocimiento del papel de las corrientes de fondo y los procesos oceanográficos asociados (overflows, corrientes de marea barotrópicas, etc), incluyendo procesos intermitentes (eddies, tormentas profundas, ondas internas, tsunamis, etc), está evolucionando rápidamente. Muchos de estos procesos son poco conocidos, en parte debido a que las observaciones directas son limitadas, si bien pueden generar importantes rasgos deposicionales y/o erosivos a escalas temporales de corto o largo periodo. Este artículo describe dichos procesos oceanográficos y examina su influencia en la presencia de rasgos sedimentarios alrededor del margen Ibérico. El trabajo discute las implicaciones de dichos procesos y el papel secundario que juegan en relación a otros factores tales como los procesos de transporte gravitacionales en masa y los turbidíticos. Para un mejor conocimiento de la sedimentación marina profunda, y en concreto de los sistemas contorníticos, se requiere de una interpretación de estos procesos oceanográficos, cuál es su evolución espacial y temporal, cómo afectan a las corrientes de fondo y cómo se ven afectados por la topografía submarina. Sin embargo, dada su complejidad y su variable naturaleza tridimensional y temporal, es necesario que estos procesos se integren en un marco sedimentológico, oceanográfico y climatológico con un enfoque multidisciplinar que incluyan la Geología, la Oceanografía Física, la Paleoceanografía y la Biología bentónica. Esta integración requiere de una mayor compilación de datos oceanográficos, de un mejor conocimiento de la morfología del fondo marino, y de una mejor caracterización de los sedimentos en ambientes profundos. Todo ello permitirá mejorar nuestro conocimiento de los procesos permanentes e intermitentes alrededor de Iberia y evaluar su verdadero efecto en la evolución sedimentaria delos márgenes continentales que le rodeanPostprint0,000