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5T4 is a tumor associated antigen that is expressed on the surface of a wide spectrum of human adenocarcinomas. The highly attenuated virus, modified vaccinia Ankara, has been engineered to express human 5T4 (h5T4). In a pre-clinical murine model, the recombinant virus (TroVax) induces protection against challenge with CT26-h5T4 (a syngeneic tumor line expressing h5T4). Anti-tumor activity is long lived, with protection still evident 6 months after the final vaccination. In a therapeutic setting, injection of mice with TroVax results in a reduction in tumor burden of >90%. Depletion of CD8+ T cells has no effect upon therapy in the active treatment model, whereas depletion of CD4+ T cells completely abrogates anti-tumor activity. In a prophylactic setting, depletion of CD4+ and CD8+ T cells after the induction of a h5T4 immune response has no deleterious effect on protection following challenge with CT26-h5T4. In light of these studies, the role of antibodies in protection against tumor challenge was investigated. 5T4 specific polyclonal serum decreased tumor burden by approximately 70%. Thus, we conclude that CD4+ T cells are essential for the induction of a protective immune response and that antibodies are the likely effector moiety in this xenogeneic murine tumor model.

Although several clinical trials have shown beneficial effects by targeting tumor-associated antigens (TAAs) with monoclonal antibodies, a number of issues, including poor penetration of the tumor mass and human antimouse antibody responses, remain. The use of recombinant single-chain Fv (scFv) fragments has the potential to address these and other issues while allowing the addition of different effector functions. To develop therapeutic strategies that recruit both humoral and cellular arms of the immune response, we have constructed chimeric proteins linking either the human IgG1 Fc domain or the extracellular domain of murine B7.1 to a scFv specific for the oncofetal glycoprotein, 5T4. This TAA is expressed by a wide variety of carcinomas and is associated with metastasis and poorer clinical outcome. We have engineered retroviral constructs that produce fusion proteins able to interact simultaneously with both 5T4-positive cells and with the receptor/ligands of the immune effector moieties. Genetic delivery through a murine leukemia virus vector to 5T4-positive tumor cells results in the secreted scFv fusion protein binding to the cell surface. Furthermore, the scFv–HIgG1 fusion protein is able to direct lysis of 5T4-expressing human tumor cell lines through antibody-dependent cell cytotoxicity, indicating its potential as a gene therapy for human cancers.

Plant gene editing is typically performed by delivering reagents such as Cas9 and single guide RNAs to explants in culture. Edited cells are then induced to differentiate into whole plants by exposure to various hormones. The creation of edited plants through tissue culture is often inefficient, time-consuming, works for only limited species and genotypes, and causes unintended changes to the genome and epigenome. Here we report two methods to generate gene-edited dicotyledonous plants through de novo meristem induction. Developmental regulators and gene-editing reagents are delivered to somatic cells of whole plants. This induces meristems that produce shoots with targeted DNA modifications, and gene edits are transmitted to the next generation. The de novo induction of gene-edited meristems sidesteps the need for tissue culture and promises to overcome a bottleneck in plant gene editing. Methods to induce edited somatic plant cells to form meristems circumvent tissue culture and enable genome editing of a wider set of plant species.

Reactive oxygen species (ROS) have been extensively studied as damaging agents associated with ageing and neurodegenerative conditions. Their role in the nervous system under non-pathological conditions has remained poorly understood. Working with the Drosophila larval locomotor network, we show that in neurons ROS act as obligate signals required for neuronal activity-dependent structural plasticity, of both pre- and postsynaptic terminals. ROS signaling is also necessary for maintaining evoked synaptic transmission at the neuromuscular junction, and for activity-regulated homeostatic adjustment of motor network output, as measured by larval crawling behavior. We identified the highly conserved Parkinson’s disease-linked protein DJ-1β as a redox sensor in neurons where it regulates structural plasticity, in part via modulation of the PTEN-PI3Kinase pathway. This study provides a new conceptual framework of neuronal ROS as second messengers required for neuronal plasticity and for network tuning, whose dysregulation in the ageing brain and under neurodegenerative conditions may contribute to synaptic dysfunction.

Background and ObjectivesOptimal surgical management for gastric cancer remains controversial. We aimed to perform a network meta-analysis (NMA) of randomized clinical trials (RCTs) comparing outcomes after open gastrectomy (OG), laparoscopic-assisted gastrectomy (LAG), and robotic gastrectomy (RG) for gastric cancer.MethodsA systematic search of electronic databases was undertaken. An NMA was performed as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-NMA guidelines. Statistical analysis was performed using R and Shiny.ResultsTwenty-two RCTs including 6890 patients were included. Overall, 49.6% of patients underwent LAG (3420/6890), 46.6% underwent OG (3212/6890), and 3.7% underwent RG (258/6890). At NMA, there was a no significant difference in recurrence rates following LAG (odds ratio [OR] 1.09, 95% confidence interval [CI] 0.77–1.49) compared with OG. Similarly, overall survival (OS) outcomes were identical following OG and LAG (OS: OG, 87.0% [1652/1898] vs. LAG: OG, 87.0% [1650/1896]), with no differences in OS in meta-analysis (OR 1.02, 95% CI 0.77–1.52). Importantly, patients undergoing LAG experienced reduced intraoperative blood loss, surgical incisions, distance from proximal margins, postoperative hospital stays, and morbidity post-resection.ConclusionsLAG was associated with non-inferior oncological and surgical outcomes compared with OG. Surgical outcomes following LAG and RG superseded OG, with similar outcomes observed for both LAG and RG. Given these findings, minimally invasive approaches should be considered for the resection of local gastric cancer, once surgeon and institutional expertise allows.

In this double-blind, randomized trial, 821 asymptomatic persons with a high-risk or moderate-risk exposure to SARS-CoV-2 were assigned to receive hydroxychloroquine or placebo within 4 days after the exposure. No benefit in preventing illness compatible with Covid-19 was found.

Background/aimTo investigate the role of eccentric knee flexor strength, between-limb imbalance and biceps femoris long head (BFlh) fascicle length on the risk of future hamstring strain injury (HSI).MethodsElite soccer players (n=152) from eight different teams participated. Eccentric knee flexor strength during the Nordic hamstring exercise and BFlh fascicle length were assessed at the beginning of preseason. The occurrences of HSIs following this were recorded by the team medical staff. Relative risk (RR) was determined for univariate data, and logistic regression was employed for multivariate data.ResultsTwenty seven new HSIs were reported. Eccentric knee flexor strength below 337 N (RR=4.4; 95% CI 1.1 to 17.5) and possessing BFlh fascicles shorter than 10.56 cm (RR=4.1; 95% CI 1.9 to 8.7) significantly increased the risk of a HSI. Multivariate logistic regression revealed significant effects when combinations of age, history of HSI, eccentric knee flexor strength and BFlh fascicle length were explored. From these analyses the likelihood of a future HSI in older athletes or those with a HSI history was reduced if high levels of eccentric knee flexor strength and longer BFlh fascicles were present.ConclusionsThe presence of short BFlh fascicles and low levels of eccentric knee flexor strength in elite soccer players increases the risk of future HSI. The greater risk of a future HSI in older players or those with a previous HSI is reduced when they have longer BFlh fascicles and high levels of eccentric strength.

Exposure to natural environments offers an array of mental health benefits. Virtual reality provides simulated experiences of being in nature when outdoor access is limited. Previous studies on virtual nature have focused mainly on single \"doses\" of virtual nature. The effects of repeated exposure remain poorly understood. Motivated by this gap, we studied the influence of a daily virtual nature intervention on symptoms of anxiety, depression, and an underlying cause of poor mental health: rumination. Forty college students (58% non-Hispanic White, median age = 19) were recruited from two U.S. universities and randomly assigned to the intervention or control group. Over several weeks, anxious arousal (panic) and anxious apprehension (worry) decreased with virtual nature exposure. Participants identifying as women, past VR users, experienced with the outdoors, and engaged with the beauty in nature benefited particularly strongly from virtual nature. Virtual nature did not help symptoms of anhedonic depression or rumination. Further research is necessary to distinguish when and for whom virtual nature interventions impact mental health outcomes.

The cerebral cortex is a cellularly complex structure comprising a rich diversity of neuronal and glial cell types. Cortical neurons can be broadly categorized into two classes—excitatory neurons that use the neurotransmitter glutamate, and inhibitory interneurons that use γ-aminobutyric acid (GABA). Previous developmental studies in rodents have led to a prevailing model in which excitatory neurons are born from progenitors located in the cortex, whereas cortical interneurons are born from a separate population of progenitors located outside the developing cortex in the ganglionic eminences 1 – 5 . However, the developmental potential of human cortical progenitors has not been thoroughly explored. Here we show that, in addition to excitatory neurons and glia, human cortical progenitors are also capable of producing GABAergic neurons with the transcriptional characteristics and morphologies of cortical interneurons. By developing a cellular barcoding tool called ‘single-cell-RNA-sequencing-compatible tracer for identifying clonal relationships’ (STICR), we were able to carry out clonal lineage tracing of 1,912 primary human cortical progenitors from six specimens, and to capture both the transcriptional identities and the clonal relationships of their progeny. A subpopulation of cortically born GABAergic neurons was transcriptionally similar to cortical interneurons born from the caudal ganglionic eminence, and these cells were frequently related to excitatory neurons and glia. Our results show that individual human cortical progenitors can generate both excitatory neurons and cortical interneurons, providing a new framework for understanding the origins of neuronal diversity in the human cortex. Molecular barcoding is used to show that progenitor cells in the human cortex can produce both excitatory neurons and inhibitory interneurons, with implications for our understanding of the evolution of the human brain.