Search

Merkel cell polyomavirus (MCPyV) is the causative agent of the majority of Merkel cell carcinomas (MCC). The virus has limited coding capacity, with its early viral proteins, large T (LT) and small T (sT), being multifunctional and contributing to infection and transformation. A fundamental difference in early viral gene expression between infection and MCPyV-driven tumorigenesis is the expression of a truncated LT (LTtr) in the tumor. In contrast, sT is expressed in both conditions and contributes significantly to oncogenesis. Here, we identified novel functions of early viral proteins by performing genome-wide transcriptome and chromatin studies in primary human fibroblasts. Due to current limitations in infection and tumorigenesis models, we mimic these conditions by ectopically expressing sT, LT or LTtr, individually or in combination, at different time points. In addition to its known function in cell cycle and inflammation modulation, we reveal a fundamentally new function of sT. We show that sT regulates the type I interferon (IFN) response downstream of the type I interferon receptor (IFNAR) by interfering with the interferon-stimulated gene factor 3 (ISGF3)-induced interferon-stimulated gene (ISG) response. Expression of sT leads to a reduction in the expression of interferon regulatory factor 9 (IRF9) which is a central component of the ISGF3 complex. We further show that this function of sT is conserved in BKPyV. We provide a first mechanistic understanding of which early viral proteins trigger and control the type I IFN response, which may influence MCPyV infection, persistence and, during MCC progression, regulation of the tumor microenvironment. Author summary: Merkel cell polyomavirus (MCPyV) is the only human polyomavirus that causes cancer in humans. As with all human polyomaviruses, the available infection models are limited. Thus, many processes such as the host response to infection and its regulation by the virus to establish infection and persistence are poorly understood. To better understand this interplay of viral MCPyV proteins, we performed genome-wide transcriptome and chromatin studies in primary human fibroblasts and simulated infection and tumorigenesis conditions by ectopically expressing the early viral proteins individually or in combination at different time points. This allowed us to uncover a novel, previously undescribed function of polyomavirus sT, namely the reduction of the ISG response by affecting the ISGF3 complex, specifically by reducing IRF9 protein levels. This work sheds light on how early viral proteins influence the type I IFN response and how their interplay may affect MCPyV infection, persistence, and MCC progression. [ABSTRACT FROM AUTHOR]

Previous studies have established the relationship between behavioral problems and specific learning disorders (SLD); however, the exact mechanism by which behavioral disorders impact SLD remains unclear. This longitudinal study used the Child Behavior Checklist (CBCL) to investigate how parents' judgment of children's behavioral problems changed from kindergarten to fifth grade in children diagnosed with or without specific learning disorders in reading and spelling (SLD[subscript rs]) (N = 196). Growth component model analyses showed differential development of behavior problems between children with and without SLD[subscript rs]. The groups did not differ before school entrance in externalizing behavior, internalizing behavior or any sub-scale of the CBCL. Parents reported their children with SLD[subscript rs] as having higher overall levels of behavioral problems after school entrance, especially in first and fourth grade. Comorbid ADHD appears to be the explanatory factor of differential problem behavior ratings between children with and without SLD[subscript rs].

Background: In patients with prostate cancer (PCa), imaging with gastrin-releasing peptide receptor (GRPR) ligands is an alternative to PSMA-targeted tracers, particularly if PSMA expression is low or absent. [99mTc]Tc-N4-BTG is a newly developed GRPR-directed probe for conventional scintigraphy and single photon emission computed tomography (SPECT) imaging. The current study aims to investigate the safety, biodistribution and dosimetry of [99mTc]Tc-N4-BTG in patients with biochemical recurrence (BCR) of PCa. Results: No adverse pharmacologic effects were observed. Injection of [99mTc]Tc-N4-BTG resulted in an effective dose of 0.0027 ± 0.0002 mSv/MBq. The urinary bladder was the critical organ with the highest mean absorbed dose of 0.028 ± 0.001 mGy/MBq, followed by the pancreas with 0.0043 ± 0.0015 mGy/MBq, osteogenic cells with 0.0039 ± 0.0005 mGy/MBq, the kidneys with 0.0034 ± 0.0003 mGy/MBq, and the liver with 0.0019 ± 0.0004 mGy/MBq, respectively. No focal tracer uptake suggestive of PCa recurrence could be revealed for any of the patients. Conclusion: [99mTc]Tc-N4-BTG appears to be a safe diagnostic agent. Compared to GRPR-targeted PET tracers, this 99mTc-labelled SPECT agent could contribute to a broader application and better availability of this novel approach. Further research to assess its clinical value is warranted. [ABSTRACT FROM AUTHOR]