Proximity-dependent labeling identifies dendritic cells that drive the tumor-specific CD4+ T cell response.

Dendritic cells (DCs) are uniquely capable of transporting tumor antigens to tumor-draining lymph nodes (tdLNs) and interact with effector T cells in the tumor microenvironment (TME) itself, mediating both natural antitumor immunity and the response to checkpoint blockade immunotherapy. Using LIPSTIC (Labeling Immune Partnerships by SorTagging Intercellular Contacts)-based single-cell transcriptomics, we identified individual DCs capable of presenting antigen to CD4+ T cells in both the tdLN and TME. Our findings revealed that DCs with similar hyperactivated transcriptional phenotypes interact with helper T cells both in tumors and in the tdLN and that checkpoint blockade drugs enhance these interactions. These findings show that a relatively small fraction of DCs is responsible for most of the antigen presentation in the tdLN and TME to both CD4+ and CD8+ tumor-specific T cells and that classical checkpoint blockade enhances CD40-driven DC activation at both sites.

An efficient regioconvergent synthesis of 3-aza-obeticholic acid.

Bile acids (BAs) are steroidal molecules that play important roles in nutrient absorption, distribution, and excretion. They also act on specific receptors implicated in various metabolic and inflammatory diseases demonstrating their importance as potential drug candidates. Accordingly, there has been a concerted effort to develop new BA derivatives to probe structure-activity relationships with the goal of discovering BA analogues with enhanced pharmacological properties. Among the many steroidal derivatisations reported, the formation of endocyclic azasteroids appeals due to their potential to deliver altered biological responses with minimal change to the steroidal superstructure. Here, we report the synthesis of 3-aza-obeticholic acid (6) via a regioconvergent route. Ammoniolysis of lactones, formed from an m-CPBA-mediated Baeyer-Villiger reaction on a 3-keto-OCA derivative, furnished protected intermediate amido-alcohols which were separately elaborated to amino-alcohols via Hofmann degradation with BAIB. Upon individual N-Boc-protection, these underwent annulation to the 3-aza-A-ring when subjected to either mesylation or a Dess-Martin oxidation/hydrogenation sequence. Global deprotection of the 3-aza-intermediate delivered 3-aza-OCA in ten steps and an overall yield of up to 19%.

Protocol for Designing a Model to Predict the Likelihood of Psychosis From Electronic Health Records Using Natural Language Processing and Machine Learning.

INTRODUCTION: Rapid identification of individuals developing a psychotic spectrum disorder (PSD) is crucial because untreated psychosis is associated with poor outcomes and decreased treatment response. Lack of recognition of early psychotic symptoms often delays diagnosis, further worsening these outcomes. METHODS: The proposed study is a cross-sectional, retrospective analysis of electronic health record data including clinician documentation and patient-clinician secure messages for patients aged 15-29 years with ≥ 1 primary care encounter between 2017 and 2019 within 2 Kaiser Permanente regions. Patients with new-onset PSD will be distinguished from those without a diagnosis if they have ≥ 1 PSD diagnosis within 12 months following the primary care encounter. The prediction model will be trained using a trisourced natural language processing feature extraction design and validated both within each region separately and in a modified combined sample. DISCUSSION: This proposed model leverages the strengths of the large volume of patient-specific data from an integrated electronic health record with natural language processing to identify patients at elevated chance of developing a PSD. This project carries the potential to reduce the duration of untreated psychosis and thereby improve long-term patient outcomes.

Body Composition, Vascular Health, Cardiorespiratory Fitness, Lung Function, Muscle Architecture, and Physical Activity in People with Young Onset Dementia: A Case-Control Study.

BACKGROUND: Body composition, blood pressure, estimated maximal oxygen uptake (VO2max), lung function, physical activity, muscle architecture, and endothelial function had not previously been examined in people with young onset dementia. Therefore, the study measured these variables in a young onset dementia group, compared them to age-matched controls. METHODS: Estimated VO2max (via the Astrand-Rhyming test), body composition, blood pressure, lung function (via spirometry), muscle architecture (via ultrasonography) and endothelial function (via flow mediated dilation) were assessed. Physical activity was measured using ActiGraph accelerometers for 7 days. RESULTS: We recruited 33 participants (16 young onset dementia, 17 controls). The young onset dementia group had shorter fascicle lengths of the vastus lateralis, were sedentary for longer over a seven-day period, and completed less moderate-vigorous physical activity than controls (p=0.028, d=0.81; large effect, p=0.029, d=0.54; moderate effect, and p=0.014, d=0.97; large effect, respectively for pairwise comparisons). Pairwise comparisons suggest no differences at the p<0.05 level between young onset dementia and controls for estimated VO2max (despite a moderate effect size [d=0.66]), height, body mass, BMI, blood pressure, light physical activity, lung function, muscle thickness, pennation angle, or endothelial function. CONCLUSION: This study highlights differences between people with young onset dementia and controls, underscoring the need for multicomponent exercise interventions. Future interventions should target muscle architecture, increase moderate-vigorous physical activity, and reduce sedentariness, with the goal of improving quality of life and promoting functional independence.

Sclerotic prostate cancer bone metastasis: woven bone lesions with a twist.

Bone metastases are the most severe and prevalent consequences of prostate cancer (PC), affecting more than 80% of patients with advanced PC. PCBMs generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences. Radiographically, PCBMs are predominantly osteosclerotic, but the mechanisms of abnormal bone formation and how this pathological increase in bone density is related to fractures are unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM specimens and 12 cancer-free specimens as controls. We used micro-computed tomography to determine 3D organization and quantify bone characteristics, quantitative backscattering electron microscopy to characterize mineral content and details in bone structure, nanoindentation to determine mechanical properties, and histological and immunohistochemical analysis of bone structure and composition. We define 4 PCBM phenotypes: osteolytic, mixed lytic-sclerotic, and 2 subgroups of osteosclerotic lesions-those with residual trabeculae, and others without residual trabeculae. The osteosclerotic lesions are characterized by the presence of abnormal bone accumulated on trabeculae surfaces and within intertrabecular spaces. This abnormal bone is characterized by higher lacunae density, abnormal lacunae morphology, and irregular lacunae orientation. However, mineral content, hardness, and elastic modulus at micron-scale were indistinguishable between this irregular bone and residual trabeculae. The collagen matrix of this abnormal bone presents with irregular organization and a prominent collagen III composition. These characteristics suggest that osteosclerotic PCBMs initiate new bone deposition as woven bone; however, the lack of subsequent bone remodeling, absence of lamellar bone deposition on its surface, and presence of collagen III distinguish this pathologic matrix from conventional woven bone. Although the mineralized matrix retains normal bone hardness and stiffness properties, the lack of fibril anisotropy presents a compromised trabecular structure, which may have clinical implications.

Australian Youth Self-Harm Atlas: spatial modelling and mapping of self-harm prevalence and related risk and protective factors to inform youth suicide prevention strategies.

AIMS: Suicide prevention strategies have shifted in many countries, from a national approach to one that is regionally tailored and responsive to local community needs. Previous Australian studies support this approach. However, most studies have focused on suicide deaths which may not fully capture a complete understanding of prevention needs, and few have focused on the priority population of youth. This was the first nationwide study to examine regional variability of self-harm prevalence and related factors in Australian young people. METHODS: A random sample of Australian adolescents (12-17-year-olds) were recruited as part of the Young Minds Matter (YMM) survey. Participants completed self-report questions on self-harm (i.e., non-suicidal self-harm and suicide attempts) in the previous 12 months. Using mixed effects regressions, an area-level model was built with YMM and Census data to produce out-of-sample small area predictions for self-harm prevalence. Spatial unit of analysis was Statistical Area Level 1 (average population 400 people), and all prevalence estimates were updated to 2019. RESULTS: Across Australia, there was large variability in youth self-harm prevalence estimates. Northern Territory, Western Australia, and South Australia had the highest estimated state prevalence. Psychological distress and depression were factors which best predicted self-harm at an individual level. At an area-level, the strongest predictor was a high percentage of single unemployed parents, while being in an area where ≥30% of parents were born overseas was associated with reduced odds of self-harm. CONCLUSIONS: This study identified characteristics of regions with lower and higher youth self-harm risk. These findings should assist governments and communities with developing and implementing regionally appropriate youth suicide prevention interventions and initiatives.

Repurposing metabolic regulators: antidiabetic drugs as anticancer agents.

Drug repurposing in cancer taps into the capabilities of existing drugs, initially designed for other ailments, as potential cancer treatments. It offers several advantages over traditional drug discovery, including reduced costs, reduced development timelines, and a lower risk of adverse effects. However, not all drug classes align seamlessly with a patient's condition or long-term usage. Hence, repurposing of chronically used drugs presents a more attractive option. On the other hand, metabolic reprogramming being an important hallmark of cancer paves the metabolic regulators as possible cancer therapeutics. This review emphasizes the importance and offers current insights into the repurposing of antidiabetic drugs, including metformin, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), thiazolidinediones (TZD), and α-glucosidase inhibitors, against various types of cancers. Antidiabetic drugs, regulating metabolic pathways have gained considerable attention in cancer research. The literature reveals a complex relationship between antidiabetic drugs and cancer risk. Among the antidiabetic drugs, metformin may possess anti-cancer properties, potentially reducing cancer cell proliferation, inducing apoptosis, and enhancing cancer cell sensitivity to chemotherapy. However, other antidiabetic drugs have revealed heterogeneous responses. Sulfonylureas and TZDs have not demonstrated consistent anti-cancer activity, while SGLT2 inhibitors and DPP-4 inhibitors have shown some potential benefits. GLP-1RAs have raised concerns due to possible associations with an increased risk of certain cancers. This review highlights that further research is warranted to elucidate the mechanisms underlying the potential anti-cancer effects of these drugs and to establish their efficacy and safety in clinical settings.

Crime-related perceptions and walking for recreation inside and outside one's home neighborhood.

It is widely assumed crime and related concerns, including neighborhood incivilities and fear of crime, are barriers to physical activity (PA). Past studies reveal mixed evidence. Studies of impacts for crime-protective factors are less common but have similarly mixed results. This paper evaluates a comprehensive transdisciplinary conceptual framework of cross-sectional associations between crime-related perceptions and reported minutes/week of recreational walking inside and outside one's home neighborhood. Safe and Fit Environments Study (SAFE) recruited and surveyed 2302 participants from adolescents to older adults from four U.S. metropolitan areas. A zero-inflated model estimated two components of each outcome: whether the respondent walked, and minutes/week walked. Correlates of recreational walking were location-specific, differing based on walking location. Fear of crime, risk evaluation, victimization, and incivilities were not consistently associated with walking for recreation inside one's neighborhood. People with crime concerns about their own neighborhoods, however, more commonly walked for recreation outside their neighborhoods. Protective crime-related perceptions that seldom have been studied in relation to PA, such as street efficacy (i.e., the perceived ability to avoid and manage danger), were strongly associated with recreational walking in both locations, indicating the additional heuristic value of the SAFE conceptual framework. Crime-related perceptions and walking for recreation: Evaluating a conceptual model.

Structure, biosynthesis and regulation of the T1 antigen, a phase-variable surface polysaccharide conserved in many Salmonella serovars.

The bacterial genus Salmonella includes diverse isolates with multiple variations in the structure of the main polysaccharide component (O antigen) of membrane lipopolysaccharides. In addition, some isolates produce a transient (T) antigen, such as the T1 polysaccharide identified in the 1960s in an isolate of Salmonella enterica Paratyphi B. The structure and biosynthesis of the T1 antigen have remained enigmatic. Here, we use biophysical, biochemical and genetic methods to show that the T1 antigen is a complex linear glycan containing tandem homopolymeric domains of galactofuranose and ribofuranose, linked to lipid A-core, like a typical O antigen. T1 is a phase-variable antigen, regulated by recombinational inversion of the promoter upstream of the T1 genetic locus through a mechanism not observed for other bacterial O antigens. The T1 locus is conserved across many Salmonella isolates, but is mutated or absent in most typhoidal serovars and in serovar Enteritidis.

Per- and polyfluoroalkyl substances (PFAS) fate and transport across a groundwater-surface water interface.

Per- and polyfluoroalkyl substances (PFAS) are emerging contaminants of concern whose fate and transport in environmental media are incompletely understood. In the 1960s, PFAS were dumped in the House Street Disposal Site, an unlined landfill on the crest of a glacial end moraine near Rockford, Michigan, USA. In 2017, PFAS were discovered in groundwater and subsequently, a network of monitoring wells delineated a 2 mi (3 km) PFAS plume migrating downgradient toward the Rogue River. Today, the Michigan Department of Natural Resources (MDNR) operates fish-rearing ponds in the area where the plume intersects the groundwater-surface water interface (GSI). Each year, the MDNR fills these man-made ponds using water from a nearby creek. Springs in the ponds prevent them from draining completely at the end of fish-rearing each fall. We sampled surface water and modeled groundwater flow to investigate PFAS transport across the GSI. Numerical models constructed with and without the fishponds did not substantially change MODFLOW model calibration curves or predicted MODPATH flow lines, indicating that PFAS transport is dominated by the regional flow system with limited influence from semiannual changes to boundary conditions at the GSI. Surface water samples collected from five locations within and adjacent to the fishponds were analyzed using EPA Draft Method 1633. PFAS were detected at all locations with the highest total PFAS >60 ng/L in the fishponds. Mixing models based on total PFAS indicate that approximately 10 % of the fishpond water is sourced by groundwater. However, similar analyses with perfluoroalkyl carboxylic acids (PFCA) and perfluoroalkyl sulfonic acids (PFSA) imply that groundwater comprises as much as 30 % of water in the ponds, suggesting differential movement of individual PFAS across the groundwater-surface water interface. Additional investigation of PFAS within the pond sediments is needed to better understand partitioning and differential transport behavior across the GSI.

Single-cell analysis of treatment-resistant prostate cancer: Implications of cell state changes for cell surface antigen-targeted therapies.

Targeting cell surface molecules using radioligand and antibody-based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)-a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single-cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate-resistant PRAD and NEPC than previously anticipated but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene-regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to current and future antigen-directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.

Axially swept open-top light-sheet microscopy for densely labeled clinical specimens.

Open-top light-sheet (OTLS) microscopy offers rapid 3D imaging of large optically cleared specimens. This enables nondestructive 3D pathology, which provides key advantages over conventional slide-based histology including comprehensive sampling without tissue sectioning/destruction and visualization of diagnostically important 3D structures. With 3D pathology, clinical specimens are often labeled with small-molecule stains that broadly target nucleic acids and proteins, mimicking conventional hematoxylin and eosin (H&E) dyes. Tight optical sectioning helps to minimize out-of-focus fluorescence for high-contrast imaging in these densely labeled tissues but has been challenging to achieve in OTLS systems due to trade-offs between optical sectioning and field of view. Here we present an OTLS microscope with voice-coil-based axial sweeping to circumvent this trade-off, achieving 2 µm axial resolution over a 750 × 375 µm field of view. We implement our design in a non-orthogonal dual-objective (NODO) architecture, which enables a 10-mm working distance with minimal sensitivity to refractive index mismatches, for high-contrast 3D imaging of clinical specimens.

Reproductive genetic carrier screening in pregnancy: improving health outcomes and expanding access.

Reproductive genetic carrier screening (RGCS) serves to screen couples for their risk of having children affected by monogenic conditions. The included conditions are mostly autosomal recessive or X-linked with infantile or early-childhood onset. Cystic fibrosis, spinal muscular atrophy, and hemoglobinopathies are now recommended by the American College of Obstetricians and Gynecologists (ACOG) for universal screening. Recommendations for further RGCS remain ethnicity based. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors in recent years have recommended universal expanded-panel RGCS and moving towards a more equitable approach. ACOG guidelines state that offering RGCS is an acceptable option, however it has not provided clear guidance on standard of care. Positive results on RGCS can significantly impact reproductive plans for couples, including pursuing in vitro fertilization with preimplantation genetic testing, prenatal genetic testing, specific fetal or neonatal treatment, or adoption. RGCS is a superior approach compared to ethnicity-based carrier screening and moves away from single race-based medical practice. We urge the obstetrics and gynecology societies to adopt the guidelines for RGCS put forward by multiple societies and help reduce systemic inequalities in medicine in our new genetic age. Having national societies such as ACOG and the Society for Maternal-Fetal Medicine officially recommend and endorse RGCS would bolster insurance coverage and financial support by employers for RGCS. The future of comprehensive reproductive care in the age of genomic medicine entails expanding access so patients and families can make the reproductive options that best fit their needs.

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

Bivalent Omicron BA.4/BA.5 BNT162b2 Vaccine in 6-Month- to <12-Year-Olds.

BACKGROUND: With the future epidemiology and evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uncertain, the use of safe and effective coronavirus disease 2019 (COVID-19) vaccines in pediatric populations remains important. METHODS: We report data from two open-label substudies of an ongoing phase 1/2/3 master study (NCT05543616) investigating the safety and immunogenicity of a variant-adapted bivalent COVID-19 vaccine encoding ancestral and Omicron BA.4/BA.5 spike proteins (bivalent BNT162b2). The open-label groups presented here evaluate dose 4 with bivalent BNT162b2 in 6-month- to <12-year-olds who previously received three original (monovalent) BNT162b2 doses. In 6-month- to <5-year-olds, primary immunogenicity objectives were to demonstrate superiority (neutralizing titer) and noninferiority (seroresponse rate) to Omicron BA.4/BA.5 and noninferiority (neutralizing titer and seroresponse rate) to SARS-CoV-2 ancestral strains in participants who received bivalent BNT162b2 dose 4 compared with a matched group who received three doses of original BNT162b2 in the pivotal pediatric study (NCT04816643). In 5- to <12-year-olds, primary immunogenicity comparisons were descriptive. Reactogenicity and safety following vaccination were evaluated. RESULTS: In 6-month- to <5-year-olds, dose 4 with bivalent BNT162b2 met predefined immunogenicity superiority and noninferiority criteria against Omicron BA.4/BA.5 and ancestral strains when compared with dose 3 of original BNT162b2. In 5- to <12-year-olds, bivalent BNT162b2 induced robust Omicron BA.4/BA.5 and ancestral strain neutralizing titers comparable with dose 3 of original BNT162b2. The safety profile for dose 4 of bivalent BNT162b2 given as dose 4 was consistent with that of original BNT162b2 in 6-month- to <12-year-olds. Reactogenicity events were generally mild to moderate. No adverse events led to discontinuation. CONCLUSIONS: These safety and immunogenicity data support a favorable benefit-risk profile for a variant-adapted BNT162b2 in children <12 years old.

Analysis of 3D pathology samples using weakly supervised AI.

Human tissue, which is inherently three-dimensional (3D), is traditionally examined through standard-of-care histopathology as limited two-dimensional (2D) cross-sections that can insufficiently represent the tissue due to sampling bias. To holistically characterize histomorphology, 3D imaging modalities have been developed, but clinical translation is hampered by complex manual evaluation and lack of computational platforms to distill clinical insights from large, high-resolution datasets. We present TriPath, a deep-learning platform for processing tissue volumes and efficiently predicting clinical outcomes based on 3D morphological features. Recurrence risk-stratification models were trained on prostate cancer specimens imaged with open-top light-sheet microscopy or microcomputed tomography. By comprehensively capturing 3D morphologies, 3D volume-based prognostication achieves superior performance to traditional 2D slice-based approaches, including clinical/histopathological baselines from six certified genitourinary pathologists. Incorporating greater tissue volume improves prognostic performance and mitigates risk prediction variability from sampling bias, further emphasizing the value of capturing larger extents of heterogeneous morphology.

The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate.

During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises that the antiviral effector Protein Kinase RNA-activated (PKR) suppresses glucose breakdown within the pentose phosphate pathway (PPP). This pathway runs parallel to central glycolysis and is critical to producing NADPH and pentose precursors for nucleotides. Changes in metabolite levels between wild-type and PKR-ablated macrophages show that PKR controls the generation of ribose 5-phosphate, in a manner distinct from its established function in gene expression but dependent on its kinase activity. PKR phosphorylates and inhibits the Ribose 5-Phosphate Isomerase A (RPIA), thereby preventing interconversion of ribulose- to ribose 5-phosphate. This activity preserves redox control but decreases production of ribose 5-phosphate for nucleotide biosynthesis. Accordingly, the PKR-mediated immune response to RNA suppresses nucleic acid production. In line, pharmacological targeting of the PPP during infection decreases the replication of the Herpes simplex virus. These results identify an immune response-mediated control of host cell metabolism and suggest targeting the RPIA as a potential innovative antiviral treatment.

Outcome Analysis of a Series of Mixed-Grade, Non-muscle Invasive, Papillary Carcinomas of the Bladder.

Introduction. Papillary urothelial carcinomas are currently graded as either low- or high-grade tumors based on World Health Organization (WHO) 2022 guidelines for genitourinary tumors. However, a minority of tumors are mixed-grade tumors, composed predominantly of low-grade cancer with a minor high-grade component. In the 2022 WHO these cancers are recognized as having outcomes comparable to low-grade cancers, although data to date has been limited. Methods. The pathology records of a large academic institution were searched for mixed-grade, non-muscle invasive papillary carcinomas of the bladder and ureter in order to characterize prognosis of these cancers. Results. Of 136 cancers, the majority (n = 104, 76.5%) were solitary, mixed-grade tumors, while 21 (15.4%) had a concurrent low-grade cancer and 11 (8.1%) had multiple mixed-grade tumors at the time of diagnosis. At follow-up (median 48.3 months, range = 1.3 months-18.1 years), 71 cancers recurred (52.2%): 52 (38.2%) as low- or mixed-grade cancers and 18 (13.2%) as high-grade cancers. There were no instances of stage-progression to >pT2. Conclusions. The clinical outcome of mixed-grade carcinomas was similar to what has been reported for low-grade carcinomas. Based on our results, and prior congruent studies of mixed-grade lesions, these lesions may be regarded as a distinct sub-category with a better prognosis than high-grade tumors.