Immune Checkpoint Blockade: Subjugation of the Masses

Osteosarcoma remains the most common form of bone cancer in adolescents. Standard of care treatment for osteosarcoma includes chemotherapy combined with limb-salvage surgery or amputation. Survival rates for compliant patients are 60–80% for those with localized tumors and 15–30% if the tumor metastasizes or reoccurs. Given the successes of monoclonal antibody blockades in other cancers, clinical trials for applying immunotherapies to osteosarcoma are underway. Antibody blockades reinvigorate T cells to eliminate cancer cells thereby leading to decreased tumor burden and long-term regression. Single monoclonal antibody therapy has shown modest efficacy compared to standard of care. However, treating with only a single antibody can ultimately result in immune evasion by heterogeneous tumors via selection of cells expressing other inhibitory ligands. Hence, combination immunotherapies have yielded the most promising results for eliminating tumors or preventing reoccurrence in other cancer types and will likely be the most efficacious strategy for treating osteosarcoma. Here, we review current immunotherapies for other cancers and their potential application to osteosarcoma

12 Museum Theorists at Play

Introduction by Lauren Appel1. Learning by Do-weyan, by Marian Howard, with Nicole Ferrin2: Dewey Defines Himself and Education, by David Vining 3. Benjamin Ives Gilman: Arts in People’s Lives, by Katherine Hillman 4. John Cotton Dana: The Social Construction of Museums, by Marissa Corwin 5. Piaget in the Art Museum: Constructing Knowledge Through Active Engagement, by Berry Stein 6. Lev Vygotsky: The Social Aspects of Learning, by Nicole Keller 7. Paulo Freire: Literacy, Democracy, and Context, by Nicole Keller 8. Maxine Greene: Aesthetic Education, by Lauren Appel 9. Howard Gardner and Multiple Intelligence Theory: A Practical Application of Entry Points in Museum Programming, by Bill Elliston 10. Mihaly Csikszentmihalyi: Finding the Flow, by David Bowles 11. George Hein: Metaconstructivist, by Lauren Appel 12. David Carr: A Poetics of Questions, by Tiffany Reedy 13. David Sobel: Please in My Backyard, by Kathryn Eliza Harris 14. Connecting the Dots, by Liat Olenickhttps://educate.bankstreet.edu/faculty-staff/1009/thumbnail.jp

Production of Infectious Genotype 1b Virus Particles in Cell Culture and Impairment by Replication Enhancing Mutations

With the advent of subgenomic hepatitis C virus (HCV) replicons, studies of the intracellular steps of the viral replication cycle became possible. These RNAs are capable of self-amplification in cultured human hepatoma cells, but save for the genotype 2a isolate JFH-1, efficient replication of these HCV RNAs requires replication enhancing mutations (REMs), previously also called cell culture adaptive mutations. These mutations cluster primarily in the central region of non-structural protein 5A (NS5A), but may also reside in the NS3 helicase domain or at a distinct position in NS4B. Most efficient replication has been achieved by combining REMs residing in NS3 with distinct REMs located in NS4B or NS5A. However, in spite of efficient replication of HCV genomes containing such mutations, they do not support production of infectious virus particles. By using the genotype 1b isolate Con1, in this study we show that REMs interfere with HCV assembly. Strongest impairment of virus formation was found with REMs located in the NS3 helicase (E1202G and T1280I) as well as NS5A (S2204R), whereas a highly adaptive REM in NS4B still allowed virus production although relative levels of core release were also reduced. We also show that cells transfected with the Con1 wild type genome or the genome containing the REM in NS4B release HCV particles that are infectious both in cell culture and in vivo. Our data provide an explanation for the in vitro and in vivo attenuation of cell culture adapted HCV genomes and may open new avenues for the development of fully competent culture systems covering the therapeutically most relevant HCV genotypes

Experiencia COIL en el Grado en Enfermería. Percepción de los estudiantes

[ES] Objetivo: Realizar una experiencia intercultural remota entre los estudiantes de enfermería de la Universidad de Washington y de León centrada en el abordaje de contenidos relacionados con la salud mental. Co-aprender sobre los sistemas de salud de Estados Unidos y de España, centrándose específicamente en el abordaje de la salud mental en los distintos países. Conocer la percepción de los estudiantes tras realizar la experiencia innovadora. Descripción de la innovación: Se lleva a cabo un proyecto de innovación docente siguiendo la metodología COIL durante el segundo semestre del curso académico 2021/2022 entre los estudiantes de la Universidad de Washington y de la Universidad de León del grado en enfermería. Esta experiencia siguió la metodología COIL. Principales resultados: Los estudiantes, obtuvieron la máxima calificación posible en las entregas de los trabajos. Las expectativas tras la realización de esta actividad son elevadas y manifiestan utilidad en esta experiencia dentro de la asignatura y para su futuro desarrollo profesional. Conclusiones: El aprendizaje internacional colaborativo en línea es un método innovador que ofrece a los estudiantes de enfermería la oportunidad de desarrollar conciencia intercultural, necesaria en su formación y en su futura práctica como enfermeros. Los estudiantes señalan un beneficio a la hora de atender a pacientes con problemas de salud mental tras la realización de esta experiencia de innovación

Human Umbilical Cord Blood Treatment in a Mouse Model of ALS: Optimization of Cell Dose

Amyotrophic Lateral Sclerosis (ALS) is a multicausal disease characterized by motor neuron degeneration in the spinal cord and brain. Cell therapy may be a promising new treatment for this devastating disorder. We recently showed that a single low dose (10(6) cells) of mononuclear human umbilical cord blood (MNC hUCB) cells administered intravenously to G93A mice delayed symptom progression and modestly prolonged lifespan. The aim of this pre-clinical translation study is to optimize the dose of MNC hUCB cells to retard disease progression in G93A mice. Three different doses of MNC hUCB cells, 10x10(6), 25x10(6) and 50x10(6), were administered intravenously into pre-symptomatic G93A mice. Motor function tests and various assays to determine cell effects were performed on these mice.Our results showed that a cell dose of 25x10(6) cells significantly increased lifespan of mice by 20-25% and delayed disease progression by 15%. The most beneficial effect on decreasing pro-inflammatory cytokines in the brain and spinal cord was found in this group of mice. Human Th2 cytokines were found in plasma of mice receiving 25x10(6) cells, although prevalent human Th1 cytokines were indicated in mice with 50x10(6) cells. High response of splenic cells to mitogen (PHA) was indicated in mice receiving 25x10(6) (mainly) and 10x10(6) cells. Significantly increased lymphocytes and decreased neutrophils in the peripheral blood were found only in animals receiving 25x10(6) cells. Stable reduction in microglia density in both cervical and lumbar spinal cords was also noted in mice administered with 25x10(6) cells.These results demonstrate that treatment for ALS with an appropriate dose of MNC hUCB cells may provide a neuroprotective effect for motor neurons through active involvement of these cells in modulating the host immune inflammatory system response

The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics

Schons M, Pilgram L, Reese J-P, et al. The German National Pandemic Cohort Network (NAPKON): rationale, study design and baseline characteristics. European Journal of Epidemiology . 2022.The German government initiated the Network University Medicine (NUM) in early 2020 to improve national research activities on the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. To this end, 36 German Academic Medical Centers started to collaborate on 13 projects, with the largest being the National Pandemic Cohort Network (NAPKON). The NAPKON's goal is creating the most comprehensive Coronavirus Disease 2019 (COVID-19) cohort in Germany. Within NAPKON, adult and pediatric patients are observed in three complementary cohort platforms (Cross-Sectoral, High-Resolution and Population-Based) from the initial infection until up to three years of follow-up. Study procedures comprise comprehensive clinical and imaging diagnostics, quality-of-life assessment, patient-reported outcomes and biosampling. The three cohort platforms build on four infrastructure core units (Interaction, Biosampling, Epidemiology, and Integration) and collaborations with NUM projects. Key components of the data capture, regulatory, and data privacy are based on the German Centre for Cardiovascular Research. By April 01, 2022, 34 university and 40 non-university hospitals have enrolled 5298 patients with local data quality reviews performed on 4727 (89%). 47% were female, the median age was 52 (IQR 36-62-) and 50 pediatric cases were included. 44% of patients were hospitalized, 15% admitted to an intensive care unit, and 12% of patients deceased while enrolled. 8845 visits with biosampling in 4349 patients were conducted by April 03, 2022. In this overview article, we summarize NAPKON's design, relevant milestones including first study population characteristics, and outline the potential of NAPKON for German and international research activities.Trial registration https://clinicaltrials.gov/ct2/show/NCT04768998 . https://clinicaltrials.gov/ct2/show/NCT04747366 . https://clinicaltrials.gov/ct2/show/NCT04679584. © 2022. The Author(s)

Genome-wide associations for birth weight and correlations with adult disease

Birth weight (BW) is influenced by both foetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease1. These lifecourse associations have often been attributed to the impact of an adverse early life environment. We performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where foetal genotype was associated with BW (P <5x10-8). Overall, ˜15% of variance in BW could be captured by assays of foetal genetic variation. Using genetic association alone, we found strong inverse genetic correlations between BW and systolic blood pressure (rg-0.22, P =5.5x10-13), T2D (rg-0.27, P =1.1x10-6) and coronary artery disease (rg-0.30, P =6.5x10-9) and, in large cohort data sets, demonstrated that genetic factors were the major contributor to the negative covariance between BW and future cardiometabolic risk. Pathway analyses indicated that the protein products of genes within BW-associated regions were enriched for diverse processes including insulin signalling, glucose homeostasis, glycogen biosynthesis and chromatin remodelling. There was also enrichment of associations with BW in known imprinted regions (P =1.9x10-4). We have demonstrated that lifecourse associations between early growth phenotypes and adult cardiometabolic disease are in part the result of shared genetic effects and have highlighted some of the pathways through which these causal genetic effects are mediated

Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation.

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets