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Leptomeningeal dissemination (LMD) is the primary cause of treatment failure in children with group 3 medulloblastoma (MB). Building on our previous work on protein phosphatase 2A (PP2A) activation in MB, here we present preclinical and molecular data on the effects of two novel classes of PP2A activators on disease processes of LMD in group 3 MB. The PP2A activators used in this study are ATUX-6156 and ATUX-6954 (diarylmethylcycloamine sulfonylureas), and ATUX-1215 and ATUX-5800 (diarylmethyl-4-aminotetrahydropyran-sulfonamides). Treatment with these compounds led to suppression of the endogenous PP2A inhibitor, cancerous inhibitor of PP2A (CIP2A), enhanced phosphatase activity (10-60%), and reduced MB viability, migration, and invasion, prerequisites for MB cells to access the cerebrospinal fluid, affecting the initiation stage of LMD. PP2A activator treatment of MB cells led to apoptosis mediated via caspase 9/PARP signaling due to decreased phosphorylation of Bad, impeding the dispersal stage of LMD. Cell proliferation and LMD-driving cellular traits and molecules pertinent to the third stage, colonization, were also affected. Treatment with ATUX-1215 or ATUX-5800 prevented LMD in an intraventricular murine model of MB, possibly mediated by disruption of the CCL2-CCR2 axis by altered NF-kB phosphorylation via disrupted AKT signaling. The present investigation offers proof-of-principle data for PP2A-based reactivation therapy for Group 3 MB and provides the first indications that PP2A reactivation may challenge the current paradigm in targeting the 3-stage process of MB LMD. Further investigations of PP2A activators are warranted as these compounds may prove beneficial as therapeutics for MB., Competing Interests: Conflict of interest Patent applications WO2023/023594 and WO2021/188949, inventor MO, are assigned to Atux Iskay LLC. The other authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Neuroblastoma is the most common extracranial solid tumor in children and accounts for 15% of pediatric cancer related deaths. Targeting neuroblastoma with immunotherapies has proven challenging due to a paucity of immune cells in the tumor microenvironment and the release of immunosuppressive cytokines by neuroblastoma tumor cells. We hypothesized that combining an oncolytic Herpes Simplex Virus (oHSV) with natural killer (NK) cells might overcome these barriers and incite tumor cell death., Methods: We utilized MYCN amplified and non-amplified neuroblastoma cell lines, the IL-12 expressing oHSV, M002, and the human NK cell line, NK-92 MI. We assessed the cytotoxicity of NK cells against neuroblastoma with and without M002 infection, the effects of M002 on NK cell priming, and the impact of M002 and priming on the migratory capacity and CD107a expression of NK cells. To test clinical applicability, we then investigated the effects of M002 and NK cells on neuroblastoma in vivo., Results: NK cells were more attracted to neuroblastoma cells that were infected with M002. There was an increase in neuroblastoma cell death with the combination treatment of M002 and NK cells both in vitro and in vivo. Priming the NK cells enhanced their cytotoxicity, migratory capacity and CD107a expression., Conclusions: To the best of our knowledge, these investigations are the first to demonstrate the effects of an oncolytic virus combined with self-maintaining NK cells in neuroblastoma and the priming effect of neuroblastoma on NK cells. The current studies provide a deeper understanding of the relation between NK cells and neuroblastoma and these data suggest that oHSV increases NK cell cytotoxicity towards neuroblastoma., (© 2024. The Author(s).)

Hepatoblastoma is the most common primary pediatric liver tumor. Children with pulmonary metastases at diagnosis experience survival rates as low as 25%. We have shown PIM kinases play a role in hepatoblastoma tumorigenesis. In this study, we assessed the role of PIM kinases in metastatic hepatoblastoma. We employed the metastatic hepatoblastoma cell line, HLM_2. PIM kinase inhibition was attained using PIM3 siRNA and the pan-PIM inhibitor, AZD1208. Effects of PIM inhibition on proliferation were evaluated via growth curve. Flow cytometry determined changes in cell cycle. AlamarBlue assay assessed effects of PIM kinase inhibition and cisplatin treatment on viability. The lethal dose 50% (LD 50 ) of each drug and combination indices (CI) were calculated and isobolograms constructed to determine synergy. PIM kinase inhibition resulted in decreased HLM_2 proliferation, likely through cell cycle arrest mediated by p21. Combination therapy with AZD1208 and cisplatin resulted in synergy, potentially through downregulation of the ataxia-telangiectasia mutated (ATM) kinase DNA damage response pathway. When assessing the combined effects of pharmacologic PIM kinase inhibition with cisplatin on HLM_2 cells, we found the agents to be synergistic, potentially through inhibition of the ATM pathway. These findings support further exploration of PIM kinase inhibition as a therapeutic strategy for metastatic hepatoblastoma.

Background: There is limited and conflicting data available regarding the cardiovascular disease outcomes associated with inflammatory bowel disease (IBD)., Objective: We aim to perform a systematic review to evaluate the cardiovascular outcomes and mortality associated with IBD patients., Methods: A systematic literature search has been performed on PubMed, Embase, Cochrane, and Scopus from inception till May 2022 without any language restrictions., Results: A total of 2,029,941 patients were included in the analysis from 16 studies. The mean age of the patients was 45.6 years. More females were found compared with males (57% vs 43%). The most common risk factors for cardiovascular disease (CVD) included smoking (24.19%) and alcohol (4.60%). The most common comorbidities includes hypertension (30%), diabetes mellitus (14.41%), dyslipidemia (18.42%), previous CVD (22%), and renal disease (10%). Among outcomes, all-cause mortality among IBD patients was 1.66%; ulcerative colitis (UC): 15.92%; and Crohn disease (CD): 0.30%. Myocardial Infarction (MI) among IBD patients were 1.47%, UC: 30.96%; and CD: 34.14%. CVD events among IBD patients were 1.95%. Heart failure events among IBD patients were 5.49%, stroke events among IBD patients were 0.95%, UC: 2.63%, and CD: 2.41%, respectively., Conclusion: IBD patients are at higher risk for adverse cardiovascular outcomes, especially in women. Although there remains a lack of concrete treatment algorithms and assessment parameters that better characterize IBD risk factors, nutritional modifications and physical activity should be at the forefront of CVD prevention in IBD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

[This corrects the article DOI: 10.1016/j.ijcha.2022.101073.]., (© 2022 The Author(s).)

Background: Sarcoidosis is a chronic inflammatory disorder of unknown etiology associated with high morbidity and mortality. Its association with cardiovascular outcomes is under-documented., Aim: The aim of this study was to assess the adverse cardiovascular outcomes in patients with sarcoidosis compared with that of non-sarcoidosis., Methodology: Online databases including PubMed, Embase and Scopus were queried from inception until March 2022. The outcomes assessed included all-cause mortality (ACM) and incidence of ventricular tachycardia (VT), heart failure (HF) and atrial arrhythmias (AA)., Result: A total of 6 studies with 22,539,096 participants (42,763 Sarcoidosis, 22,496,354 Non-Sarcoidosis) were included in this analysis. The pooled prevalence of sarcoidosis was 13.1% (95% CI 1% to 70%). The overall mean age was 47 years. The most common comorbidities were hypertension (12.7% vs 12.5%), and diabetes mellitus (5.5% vs 4%) respectively. The pooled analysis of primary endpoints showed that all-cause mortality (RR, 2.08; 95% CI: 1.17 to 3.08; p = 0.01) was significantly increased in sarcoidosis patients. The pooled analysis of secondary endpoints showed that the incidence of VT (RR, 15.3; 95% CI: 5.39 to 43.42); p < 0.001), HF (RR, 4.96; 95% CI: 2.02 to 12.14; p < 0.001) and AA (RR, 2.55; 95% CI: 1.47 to 4.44); p = 0.01) were significantly higher with sarcoidosis respectively compared to non-sarcoidosis., Conclusion: Incidence of VT, HF and AA was significantly higher in patients with CS. Clinicians should be aware of these adverse cardiovascular events associated with sarcoidosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)