CSF1R Ligands Expressed by Murine Gliomas Promote M-MDSCs to Suppress CD8+ T Cells in a NOS-Dependent Manner.

Glioblastoma (GBM) is the most common malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a subset of myeloid cells, expressing monocytic (M)-MDSC markers and dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate the TME. This study evaluated the mechanism of CCR2+/CX3CR1+ M-MDSC differentiation and T cell suppressive function in murine glioma models. We determined that bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Glioma-secreted CSF1R ligands M-CSF and IL-34 were identified as key drivers of M-MDSC differentiation while adenosine and iNOS pathways were implicated in the M-MDSC suppression of T cells. Mining a human GBM spatial RNAseq database revealed a variety of different pathways that M-MDSCs utilize to exert their suppressive function that is driven by complex niches within the microenvironment. These data provide a more comprehensive understanding of the mechanism of M-MDSCs in glioblastoma.

Errors associated with co-names of medicines: The nomenclature of combination medicinal products.

In comparison to the efforts required to bring a new drug or formulation to the clinic, bestowing a name on a medicine is relatively simple. However, if the name we choose causes confusion-by making its contents ambiguous or if it is too alike another drug-it can precipitate clinical errors. This prompted the World Health Organization to set up the International Nonproprietary Naming Committee in the 1970s to select unambiguous names for drugs. Unfortunately, multidrug products-which are becoming increasingly popular-do not fall under the remit of conventional International Non-proprietary Nomenclature. We have identified 26 combination formulations that have been historically named with the co-drug format in the United Kingdom. Most of them have also been prescribed in the United Kingdom in the past year, and although several of them are not prescribed very often, 11 were prescribed more than 2000 times. In this paper, we have explored the literature to identify prescribing errors with co-drug products and found several idiosyncrasies that have caused drug errors in the past. We advocate for a standard nomenclature (state the international nonproprietary name [INN] of each component followed by dose information in the x + y format) for these products on the box and in prescribing resources. We hope that this will enhance clarity and safety during prescribing and administration, particularly for high-volume drugs like paracetamol + codeine (co-codamol), amoxicillin + clavulanic acid (co-amoxiclav) and trimethoprim + sulfamethoxazole (co-trimoxazole).

Association Between Social Vulnerability and Gastrointestinal Cancer Mortality in the United States Counties.

Background and Aims: Social determinants of health contribute to disparities in gastrointestinal (GI) cancer mortality between individuals in the US. Their effects on count-level mortality rates remain uncertain. We aimed to assess the association between county social vulnerability and GI cancer mortality. Methods: In this ecological study (2016-2020), we obtained US county Social Vulnerability Index (SVI) from the Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry and age-adjusted mortality rates (AAMRs) for GI cancers from Centers for Disease Control and Prevention WONDER (Wide-Ranging Online Data for Epidemiological Research). SVI ranges from 0 to 1, with higher indices indicating greater vulnerability. We presented AAMRs by quintiles of SVIs. We used Poisson regression through generalized estimating equation to calculate rate ratios (RRs) and 95% confidence intervals (CIs) for GI cancer mortality by quintiles of SVI. Results: There were 799,968 deaths related to GI cancers from 2016 to 2020, resulting in an AAMR (95% CI) of 39.9 (41.4-51.2) deaths per 100,000 population. The largest concentration of counties with greater SVI and GI cancer mortality was clustered in the southern US. Counties with greater SVI had higher mortality related to all GI cancers (RRQ5 vs Q1, 1.19 [95% CI, 1.14-1.24]), gastric cancer (1.58 [1.48-1.69]), liver cancer (1.54 [1.36-1.73]), and colorectal cancer (RRQ5 vs Q1, 1.23 [95% CI, 1.15-1.31]). RRs for overall GI cancers were greater among individuals <45 years (1.24 [1.15-1.32]), men (1.22 [1.16-1.27]), Hispanic individuals (1.33 [1.18-1.50]), and rural counties (1.21 [1.14-1.27]) compared with their counterparts. Conclusion: Socially disadvantaged counties face a disproportionately high burden of GI cancer mortality in the US. Targeted public health interventions should aim to address social inequities faced by underserved communities.

Dynamics of microRNA secreted via extracellular vesicles during the maturation of embryonic stem cell-derived retinal pigment epithelium.

Retinal pigment epithelial (RPE) cells are exclusive to the retina, critically multifunctional in maintaining the visual functions and health of photoreceptors and the retina. Despite their vital functions throughout lifetime, RPE cells lack regenerative capacity, rendering them vulnerable which can lead to degenerative retinal diseases. With advancements in stem cell technology enabling the differentiation of functional cells from pluripotent stem cells and leveraging the robust autocrine and paracrine functions of RPE cells, extracellular vesicles (EVs) secreted by RPE cells hold significant therapeutic potential in supplementing RPE cell activity. While previous research has primarily focused on the trophic factors secreted by RPE cells, there is a lack of studies investigating miRNA, which serves as a master regulator of gene expression. Profiling and defining the functional role of miRNA contained within RPE-secreted EVs is critical as it constitutes a necessary step in identifying the optimal phenotype of the EV-secreting cell and understanding the biological cargo of EVs to develop EV-based therapeutics. In this study, we present a comprehensive profile of miRNA in small extracellular vesicles (sEVs) secreted during RPE maturation following differentiation from human embryonic stem cells (hESCs); early-stage hESC-RPE (20-21 days in culture), mid-stage hESC-RPE (30-31 days in culture) and late-stage hESC-RPE (60-61 days in culture). This exploration is essential for ongoing efforts to develop and optimize EV-based intraocular therapeutics utilizing RPE-secreted EVs, which may significantly impact the function of dysfunctional RPE cells in retinal diseases.

The RNA binding protein HNRNPA2B1 regulates RNA abundance and motor protein activity in neurites.

RNA molecules are localized to subcellular regions through interactions between localization-regulatory cis-elements and trans-acting RNA binding proteins (RBPs). However, the identities of RNAs whose localization is regulated by a specific RBP as well as the impacts of that RNA localization on cell function have generally remained unknown. Here, we demonstrate that the RBP HNRNPA2B1 acts to keep specific RNAs out of neuronal projections. Using subcellular fractionation, high-throughput sequencing, and single molecule RNA FISH, we find that hundreds of RNAs demonstrate markedly increased abundance in neurites in HNRNPA2B1 knockout cells. These RNAs often encode motor proteins and are enriched for known HNRNPA2B1 binding sites and motifs in their 3' UTRs. The speed and processivity of microtubule-based transport is impaired in these cells, specifically in their neurites. HNRNPA2B1 point mutations that increase its cytoplasmic abundance relative to wildtype lead to stronger suppression of RNA mislocalization defects than seen with wildtype HNRNPA2B1. We further find that the subcellular localizations of HNRNPA2B1 target RNAs are sensitive to perturbations of RNA decay machinery, suggesting that it is HNRNPA2B1's known role in regulating RNA stability that may explain these observations. These findings establish HNRNPA2B1 as a negative regulator of neurite RNA abundance and link the subcellular activities of motor proteins with the subcellular abundance of the RNAs that encode them.

Progressive Thickening of Retinal Nerve Fiber and Ganglion Cell Complex Layers Following SDM Laser Vision Protection Therapy in Open-Angle Glaucoma.

INTRODUCTION: This work aims to determine the effect on nerve fiber layer (NFL) and ganglion cell complex (GCC) thickness trends in eyes with open-angle glaucoma (OAG) treated with Vision Protection Therapy™ (VPT). METHODS: A retrospective analysis of spectral-domain optical coherence tomography (OCT) measured NFL and GCC thickness trends was performed, excluding eyes with poor-quality scans and principal diagnoses other than OAG. This study compares eyes with OAG managed conventionally with IOP control alone (controls) to eyes managed with the addition of VPT (VPT eyes). The direction (+ or -) and magnitude (microns/year) of the OCT trends were the study endpoints. RESULTS: Seventy-eight control eyes of 40 patients and 61 VPT-treated eyes of 39 patients were included in the study. Positive NFL trends were noted in 5% of control eyes vs. 71% of VPT eyes (p < 0.0001). Positive GCC trends were noted in 8% of control eyes vs. 43% of VPT eyes (p < 0.0001). Mean NFL trends (µm/year) were - 0.692 for controls vs. 0.347 for VPT (p < 0.0001). Mean GCC trends (µm/year) were - 0.554 for controls vs. - 0.148 for VPT (p = 0.0175). CONCLUSIONS: The addition of VPT to the conventional management of OAG resulted in highly significant improvements in NFL and GCC trends, indicating a reversal of key indicators of glaucoma severity and progression.