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Background: Hyperglycemia and hypoglycemia are associated with undesirable clinical outcomes. Patients receiving parenteral nutrition (PN) are at increased risk due to the intravascular administration of dextrose. Lipid injectable emulsion (ILE) is also a component of PN, however, administration practices for ILE vary widely, with unknown implications for blood glucose control. Research Objective: This cross-sectional study explored the incidence of hyper- and hypoglycemia in hospitalized patients before and after a clinical practice change designed to base ILE on patients weight (i.e., 50 gm/day for< 75 kg, 100 gm/day for >/= 75 kg). Methods: Patients with weight >/= 75 kg with sole PN support at a goal rate for >/= 3 days were included based on the ILE dosing guideline in Nebraska Medicine. Baseline demographic, clinical, nutritional, and blood glucose-related data were collected and analyzed in the first 24 and 24-48 hours. Results: 112 patients were included (58 NWBD and 54 WBD). The adjusted ORs (aOR) from the multivariate logistic regression model showed hyperglycemia risk in the first 24 hours after PN at the goal rate decreased by 67% for the WBD compared to the NWBD (P = 0.022, aOR = 0.330 [95%CI: 0.127, 0.854]). Additionally, patients with type 1 or type 2 diabetes were more likely to have hyperglycemia events in the first 24 hours of PN initiation (P< 0.0001, aOR = 13.075 [95%CI: 4.297, 39.789]). The risk of hypoglycemia between the two groups was not significant. Discussion: The WBD ILE can improve hyperglycemia events in hospitalized patients with PN support, especially when they have been diagnosed with diabetes. We recommend dosing 100 g/d ILE for patients of weight >/= 75 kg to meet the daily lipid requirements and improve glycemic control.

All higher plants produce polyphenols, for defence against above-ground herbivory. These polyphenols also influence the soil micro- and macro-fauna that break down plant leaf litter. Polyphenols therefore indirectly affect the fluxes of soil nutrients and, ultimately, carbon turnover and ecosystem functioning in soils. It is unknown how earthworms, the major component of animal biomass in many soils, cope with high-polyphenol diets. Here, we show that earthworms possess a class of unique surface-active metabolites in their gut, which we term ‘drilodefensins’. These compounds counteract the inhibitory effects of polyphenols on earthworm gut enzymes, and high-polyphenol diets increase drilodefensin concentrations in both laboratory and field populations. This shows that drilodefensins protect earthworms from the harmful effects of ingested polyphenols. We have identified the key mechanism for adaptation to a dietary challenge in an animal group that has a major role in organic matter recycling in soils worldwide. Little is known about how detritivorous invertebrates cope with high levels of defensive plant polyphenols. Here, Liebeke et al . identify a new class of surface-active metabolites in earthworms exposed to high-polyphenol diets, and show that they play a protective role against precipitation of proteins.

Student-centered instruction allows students to take ownership over their learning in the classroom. However, these settings do not always promote productive engagement. Using discourse analysis, student engagement can be analyzed based on how they are interacting with each other while completing in-class group activities. Previous analyses of student engagement in science settings have used methods that do not capture the intricacies of student group interactions such as the flow of conversation and nature of student utterances outside of argumentation or reasoning. However, these features are important to accurately assess student engagement. This study proposes a tiered analytical framework and visualization scheme for analyzing group discussion patterns that allow for a detailed analysis of student discourse moves while discussing scientific topics. This framework allows a researcher to see the flow of an entire conversation within a single schematic. The Student Interaction Discourse Moves framework can be used to extend studies using discourse analysis to determine how student groups work through problems.

BackgroundGlioblastoma (GBM), the most common malignant primary brain tumor, remains incurable despite aggressive multi-modal therapies. Immunotherapy, while effective for many solid tumors, has not shown benefits against GBM. Limited T cell infiltration and an immunosuppressive tumor microenvironment (TME) are among the main barriers to successful immunotherapy. Evidence from extracranial solid tumors suggests that the chemokine CXCL-12 regulates immune cell trafficking and promotes an immunosuppressive TME.1–7 We hypothesized that the brain’s unique tissue environment creates a distinct immune response compared to extracranial tissues. This work aimed to test whether blocking CXCL12, using the spiegelmer NOX-A12, modulates the immune TME to enhance immunotherapy response in GBM, and whether the immune response differs between intracranial and extracranial environments.MethodsUsing B6 immunocompetent mice, we established a subcutaneous (s.c.) SB28 GBM model representing an extracranial tissue environment and compared it to orthotopic (intracranial) SB28. Tumor-bearing mice were treated with either vehicle, NOX-A12, anti-PD1 and anti-CTLA4 (immune-check-point blockade, ICB), or NOX-A12 + ICB (combination). Immune cells from tumor and blood were analyzed using high-dimensional flow cytometry. Statistical analysis used ANOVA with post-hoc Tuckey`s multiple comparison test. Survival was analyzed using the log-rank test.ResultsTreatment with ICB increased overall survival in s.c. SB28, but not in intracranial (i.c.) SB28 model. While ICB increased circulating CD8 and CD4 T cell subsets in both s.c. and i.c. models, it increased antigen-experienced CD8 and CD4 T cells only in the TME of the s.c. tumors. To enhance T cell migration into i.c. tumors, we targeted CXCL12 with NOX-A12. As expected, combining NOX-A12 with ICB significantly increased antigen-experienced CD8 T cells in i.c. and s.c. SB28 compared to ICB or NOX-A12 monotherapy. Additionally, the combination treatment increased antigen-experienced CD4 T cells only in the i.c tumor, indicating a tissue-specific treatment effect. These treatment effects were not evident in the blood, indicating a local mechanism of action within the TME. However, the increase in intra-tumoral T-cells induced by the combination treatment was not translated into increased median overall survival.ConclusionsThe distinct survival benefit of s.c. SB28 tumors in response to ICB was consistent with an increase in T cell subsets, which was absent in i.c SB28 tumors. However, an increase in T cells by CXCL12 inhibition was not translated into increased survival, suggesting that additional factors in the brain tissue contribute to treatment resistance. Elucidating those factors is imperative for the development of innovative strategies to augment immunotherapy efficacy in GBM.AcknowledgementsWe acknowledge TME Pharma AG for providing of Nox-A12ReferencesDe Filippo K, Rankin SM, CXCR4, the master regulator of neutrophil trafficking in homeostasis and disease. Eur J Clin Invest, 2018;48(Suppl 2):e12949.Mercurio L, et al. Targeting CXCR4 by a selective peptide antagonist modulates tumor microenvironment and microglia reactivity in a human glioblastoma model. J Exp Clin Cancer Res. 2016;35:55.Wang Z, et al. Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack. Proc Natl Acad Sci U S A, 2022;119(4).Seo YD, et al. Mobilization of CD8(+) T cells via CXCR4 blockade facilitates PD-1 checkpoint therapy in human pancreatic cancer. Clin Cancer Res. 2019;25(13):3934–3945.Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol Res. 2014;2(3):187–93.Feig C, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–7.Yang J, et al. Loss of CXCR4 in myeloid cells enhances antitumor immunity and reduces melanoma growth through NK cell and FASL mechanisms. Cancer Immunol Res. 2018;6(10):1186–1198.Ethics ApprovalAll animal experiments and protocols were reviewed and approved by National Cancer Institute

BackgroundThe aggressive nature and dismal prognosis of glioblastoma may partly be due to its limited ability to induce anti-tumor T cell responses within the brain. Using vaccines to generate tumor-specific T cells may be beneficial to patients if the T cells can traffic to the brain and maintain functionality within the immunosuppressive tumor microenvironment. Heterologous prime-boost vaccination with chimpanzee adenovirus (ChAdOx1) and modified vaccinia Ankara (MVA) viral vectors can generate high frequencies of CD8+ T cells specific for tumor antigens,1 but this has not been studied in glioblastoma. Therefore, we used preclinical models to determine whether this vaccination strategy could induce effective T cell responses in the brain.MethodsWe tested this vaccination strategy against the poorly immunogenic, syngeneic, orthoptic SB28 glioblastoma model. As endogenous SB28 antigens were unknown, we created a transgenic SB28.P1A model expressing P1A, a murine tumor-associated antigen (TAA), which we targeted with ChAdOx1/MVA-P1A vaccines. Furthermore, we developed a pipeline to identify novel SB28 TAAs, which we screened for off-target expression, immunogenicity, and therapeutic targetability by creating TAA-encoding ChAdOx1/MVA vaccines.ResultsProphylactic ChAdOx1/MVA vaccination significantly prolonged the survival of mice challenged with tumors compared to controls in the context of P1A and a novel TAA (n=15-20/group, p=0.0034, p<0.0001), with 30% and 50% showing complete remission, respectively. A significant survival benefit was also observed in the therapeutic setting, with vaccination starting 7 days post-tumor implantation, following confirmation of tumor establishment (n=15-20/group, P1A: p=0.0047, TAA: p=0.0119). The tumor-bearing brains of vaccinated mice were enriched for antigen-specific CD8+ T cells (25% of CD8+ T cells vs. 5% in blood), of which 50% had a CD103+CD69+T resident memory-like (TRM) phenotype. Long-term surviving mice maintained consistent levels of antigen-specific TRM in their brains 70 and 175 days post-tumor challenge, despite a three-fold decrease in circulating antigen-specific T cells, indicating parenchymal TRM durability. Furthermore, survivors were protected against orthotopic but not subcutaneous rechallenge, demonstrating tissue-specific memory. Adoptive transfer of P1A-specific TRM cells derived from vaccinated tumor-bearing mice into the brains of naïve mice protected mice from later tumor challenge (n=10/group, p=0.0233), while P1A-specific non-TRM cells or non-P1A-specific brain-derived CD8+ T cells did not, demonstrating that antigen-specific TRMs are sufficient to mediate anti-glioblastoma immunity.ConclusionsChAdOx1/MVA vaccination induced high frequencies of antigen-specific TRMs with functional memory and long-term durability in the brain. These TRMs were sufficient to protect against glioblastoma, making this vaccination strategy an attractive candidate for translation into clinical trials.ReferenceMcAuliffe J, Chan HF, Noblecourt L, Ramirez-Valdez RA, Pereira-Almeida V, Zhou Y, Pollock E, Cappuccini F, Redchenko I, Hill AV, Leung CSK, Van den Eynde BJ. Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy. J Immunother Cancer. 2021 Sep;9(9):e003218Ethics ApprovalAll animal work was approved by either the University of Oxford Animal Care and Ethical Review Committee and experimental procedures were carried out in accordance with the terms of the UK Animals (Scientific Procedures) Act Project Licenses P0D369534 and PB050649E; or by the National Cancer Institute-Bethesda Animal Care and Use Committee and experimental procedures were carried out in accordance with the terms of Protocol NOB-024.

BackgroundGlioblastoma (GBM) is the most common primary brain tumor, with a poor prognosis of 14-17 months median survival. The standard of care, consisting of surgery, chemotherapy, and radiation has not changed in over 20 years, and no phase III immunotherapy clinical trial has been successful. Recent studies determined that in GBM, tumor cells integrate into neural networks, forming synapses with neurons, enhancing neuronal firing and facilitating tumor growth. However, the impact of neuronal activity on the tumor microenvironment remains poorly understood and may have therapeutic importance. We sought to understand if neuronal activity alters the function of immune cells in GBM using both murine models and freshly acquired human GBM tissue from surgical specimens.Methods and ResultsWe first used chemogenetic stimulation (AAV5-SYN1-hM3Dq) of an RCAS-tva mouse glioblastoma model (Ntv-a Ink4a-Arf-/-) to identify which tumor immune populations are impacted by enhanced neuronal firing in vivo. Using high-dimensional spectral flow cytometry, we found an increase in microglia percentages following stimulation. We then used human GBM tissue to study the putative neuron-myeloid interaction. Immunofluorescent staining of these tumors showed that approximately 50% of the Iba1+ myeloid cells co-localized with the presynaptic neuronal marker synapsin 1, confirming the neuron-myeloid interaction. We then sorted CD11b+ myeloid cells from these patient samples. Bulk RNA-seq revealed high expression of neurotransmitter receptors, predominantly the Gi protein-coupled P2Y12 receptor for ADP. Calcium fluorescence imaging and calcium flow cytometry showed that the cells were primarily responsive to ADP among the neurotransmitters examined, including glutamate, GABA, norepinephrine, acetylcholine, and dopamine. Furthermore, the phagocytic ability of these cells improved with the addition of ADP. Analysis of bulk RNA-seq from 286 brain tumor patients found that P2Y12 had a clear positive correlation with M1-like markers and a negative correlation with M2-like markers greater than all other neurotransmitter receptor genes and others such as ADRB2, CX3CR1, TMEM119, TREM2, and CSF1R. To understand how the ADP-P2Y12 axis affects myeloid phenotypic function in vivo, we conducted flow cytometry on our SB28 mouse brain tumor tissues. Based on functional marker expression, we found that, compared to P2Y12-negative microglia, P2Y12-positive microglia had an increased M1-like and decreased M2-like phenotype.ConclusionsOur findings strongly suggest that neuronal excitation impacts microglia in the GBM microenvironment, primarily through an ADP-P2Y12 axis. Furthermore, our data suggests that P2Y12 may play a role in promoting an M1-like phenotype in microglia and could be an important target for enhancing response to immunotherapy.Ethics ApprovalAll human tissue samples and experiments were conducted according to the approved protocols by the University of Cambridge under REC reference 23/EE/0241 and IRAS project ID 335210. Each participant was given informed consent prior to taking part in any research studies. All animal work was performed according to the National Cancer Institute-Bethesda Animal Care and Use Committee’s protocols NOB-024 and NOB-026.