Deep learning system for malignancy risk prediction in cystic renal lesions: a multicenter study.

OBJECTIVES: To develop an interactive, non-invasive artificial intelligence (AI) system for malignancy risk prediction in cystic renal lesions (CRLs). METHODS: In this retrospective, multicenter diagnostic study, we evaluated 715 patients. An interactive geodesic-based 3D segmentation model was created for CRLs segmentation. A CRLs classification model was developed using spatial encoder temporal decoder (SETD) architecture. The classification model combines a 3D-ResNet50 network for extracting spatial features and a gated recurrent unit (GRU) network for decoding temporal features from multi-phase CT images. We assessed the segmentation model using sensitivity (SEN), specificity (SPE), intersection over union (IOU), and dice similarity (Dice) metrics. The classification model's performance was evaluated using the area under the receiver operator characteristic curve (AUC), accuracy score (ACC), and decision curve analysis (DCA). RESULTS: From 2012 to 2023, we included 477 CRLs (median age, 57 [IQR: 48-65]; 173 men) in the training cohort, 226 CRLs (median age, 60 [IQR: 52-69]; 77 men) in the validation cohort, and 239 CRLs (median age, 59 [IQR: 53-69]; 95 men) in the testing cohort (external validation cohort 1, cohort 2, and cohort 3). The segmentation model and SETD classifier exhibited excellent performance in both validation (AUC = 0.973, ACC = 0.916, Dice = 0.847, IOU = 0.743, SEN = 0.840, SPE = 1.000) and testing datasets (AUC = 0.998, ACC = 0.988, Dice = 0.861, IOU = 0.762, SEN = 0.876, SPE = 1.000). CONCLUSION: The AI system demonstrated excellent benign-malignant discriminatory ability across both validation and testing datasets and illustrated improved clinical decision-making utility. CRITICAL RELEVANCE STATEMENT: In this era when incidental CRLs are prevalent, this interactive, non-invasive AI system will facilitate accurate diagnosis of CRLs, reducing excessive follow-up and overtreatment. KEY POINTS: The rising prevalence of CRLs necessitates better malignancy prediction strategies. The AI system demonstrated excellent diagnostic performance in identifying malignant CRL. The AI system illustrated improved clinical decision-making utility.

Epstein-Barr Virus Envelope Glycoprotein gp110 Inhibits IKKi-Mediated Activation of NF-κB and Promotes the Degradation of ß-Catenin.

Epstein-Barr virus (EBV) infects host cells and establishes a latent infection that requires evasion of host innate immunity. A variety of EBV-encoded proteins that manipulate the innate immune system have been reported, but whether other EBV proteins participate in this process is unclear. EBV-encoded envelope glycoprotein gp110 is a late protein involved in virus entry into target cells and enhancement of infectivity. Here, we reported that gp110 inhibits RIG-I-like receptor pathway-mediated promoter activity of interferon-ß (IFN-ß) as well as the transcription of downstream antiviral genes to promote viral proliferation. Mechanistically, gp110 interacts with the inhibitor of NF-κB kinase (IKKi) and restrains its K63-linked polyubiquitination, leading to attenuation of IKKi-mediated activation of NF-κB and repression of the phosphorylation and nuclear translocation of p65. Additionally, gp110 interacts with an important regulator of the Wnt signaling pathway, ß-catenin, and induces its K48-linked polyubiquitination degradation via the proteasome system, resulting in the suppression of ß-catenin-mediated IFN-ß production. Taken together, these results suggest that gp110 is a negative regulator of antiviral immunity, revealing a novel mechanism of EBV immune evasion during lytic infection. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous pathogen that infects almost all human beings, and the persistence of EBV in the host is largely due to immune escape mediated by its encoded products. Thus, elucidation of EBV's immune escape mechanisms will provide a new direction for the design of novel antiviral strategies and vaccine development. Here, we report that EBV-encoded gp110 serves as a novel viral immune evasion factor, which inhibits RIG-I-like receptor pathway-mediated interferon-ß (IFN-ß) production. Furthermore, we found that gp110 targeted two key proteins, inhibitor of NF-κB kinase (IKKi) and ß-catenin, which mediate antiviral activity and the production of IFN-ß. gp110 inhibited K63-linked polyubiquitination of IKKi and induced ß-catenin degradation via the proteasome, resulting in decreased IFN-ß production. In summary, our data provide new insights into the EBV-mediated immune evasion surveillance strategy.

Epstein-Barr virus envelope glycoprotein 110 inhibits NF-κB activation by interacting with NF-κB subunit p65.

Epstein-Barr virus (EBV) is a member of the lymphotropic virus family and is highly correlated with some human malignant tumors. It has been reported that envelope glycoprotein 110 (gp110) plays an essential role in viral fusion, DNA replication, and nucleocapsid assembly of EBV. However, it has not been established whether gp110 is involved in regulating the host's innate immunity. In this study, we found that gp110 inhibits tumor necrosis factor α-mediated NF- κB promoter activity and the downstream production of NF- κB-regulated cytokines under physiological conditions. Using dual-luciferase reporter assays, we showed that gp110 might impede the NF-κB promoter activation downstream of NF-κB transactivational subunit p65. Subsequently, we used coimmunoprecipitation assays to demonstrate that gp110 interacts with p65 during EBV lytic infection, and that the C-terminal cytoplasmic region of gp110 is the key interaction domain with p65. Furthermore, we determined that gp110 can bind to the N-terminal Rel homologous and C-terminal domains of p65. Alternatively, gp110 might not disturb the association of p65 with nontransactivational subunit p50, but we showed it restrains activational phosphorylation (at Ser536) and nuclear translocation of p65, which we also found to be executed by the C-terminal cytoplasmic region of gp110. Altogether, these data suggest that the surface protein gp110 may be a vital component for EBV to antagonize the host's innate immune response, which is also helpful for revealing the infectivity and pathogenesis of EBV.

The Molecular Mechanism of Herpes Simplex Virus 1 UL31 in Antagonizing the Activity of IFN-ß.

Virus infection triggers intricate signal cascade reactions to activate the host innate immunity, which leads to the production of type I interferon (IFN-I). Herpes simplex virus 1 (HSV-1), a human-restricted pathogen, is capable of encoding over 80 viral proteins, and several of them are involved in immune evasion to resist the host antiviral response through the IFN-I signaling pathway. Here, we determined that HSV-1 UL31, which is associated with nuclear matrix and is essential for the formation of viral nuclear egress complex, could inhibit retinoic acid-inducible gene I (RIG-I)-like receptor pathway-mediated interferon beta (IFN-ß)-luciferase (Luc) and (PRDIII-I)4-Luc (an expression plasmid of IFN-ß positive regulatory elements III and I) promoter activation, as well as the mRNA transcription of IFN-ß and downstream interferon-stimulated genes (ISGs), such as ISG15, ISG54, ISG56, etc., to promote viral infection. UL31 was shown to restrain IFN-ß activation at the interferon regulatory factor 3 (IRF3)/IRF7 level. Mechanically, UL31 was demonstrated to interact with TANK binding kinase 1 (TBK1), inducible IκB kinase (IKKi), and IRF3 to impede the formation of the IKKi-IRF3 complex but not the formation of the IRF7-related complex. UL31 could constrain the dimerization and nuclear translocation of IRF3. Although UL31 was associated with the CREB binding protein (CBP)/p300 coactivators, it could not efficiently hamper the formation of the CBP/p300-IRF3 complex. In addition, UL31 could facilitate the degradation of IKKi and IRF3 by mediating their K48-linked polyubiquitination. Taken together, these results illustrated that UL31 was able to suppress IFN-ß activity by inhibiting the activation of IKKi and IRF3, which may contribute to the knowledge of a new immune evasion mechanism during HSV-1 infection. IMPORTANCE The innate immune system is the first line of host defense against the invasion of pathogens. Among its mechanisms, IFN-I is an essential cytokine in the antiviral response, which can help the host eliminate a virus. HSV-1 is a double-stranded DNA virus that can cause herpes and establish a lifelong latent infection, due to its possession of multiple mechanisms to escape host innate immunity. In this study, we illustrate for the first time that the HSV-1-encoded UL31 protein has a negative regulatory effect on IFN-ß production by blocking the dimerization and nuclear translocation of IRF3, as well as promoting the K48-linked polyubiquitination and degradation of both IKKi and IRF3. This study may be helpful for fully understanding the pathogenesis of HSV-1.