Casein kinase II controls TBK1/IRF3 activation in IFN response against viral infection.

By sensing viral nucleic acids, host innate receptors elicit signaling pathways converging on TBK1-IFN regulatory factor (IRF)3 axis in mediating IFN-αß induction and defense mechanisms. In contrast, viruses have evolved with diverse immune evasion/interference mechanisms to undermine innate receptor signaling and IFN response. In this regard, approaches enabling host to overcome such immune evasion/interference mechanisms are urgently needed to combat infections by epidemic/pandemic viruses. In this study, we report that protein kinase CK2 serves as a key component controlling TBK1 and IRF3 activation in IFN-inducing TLR, RIG-I-like receptors, and cGAS/STING signaling pathways. Accordingly, knocking down of CK2 expression or genetic ablation of its kinase activity resulted in elevated IFN-αß response in response to infection by DNA and RNA viruses. Moreover, PP2A was identified as one of the intermediate phosphatases responsible for CK2-regulated IFN response, suggesting that CK2 may regulate TBK1 and IRF3 activation indirectly. Importantly, blockade of CK2 activity by small molecule inhibitor was able to activate TBK1, whereby eliciting effective host defense mechanisms against hepatitis C virus infection. Taken together, our results identify CK2 as a novel regulator of TBK1 and IRF3 and suggest that targeting CK2 by small molecular inhibitor may be a viable approach to prevent and treat viral infections.

Stereotactic body radiotherapy for spinal metastases: a review.

To evaluate the efficacy and safety of stereotactic body radiotherapy (SBRT) in treating spinal metastases. Two reviewers performed independent literature searches of the PubMed database, searching literatures of the efficacy and safety of SBRT in metastatic spinal diseases. A total of 67 studies were included in the review. Regarding SBRT for de novo spinal metastases, the 1- and 2-year local control (LC) rates were 51-100% and 56-96%, respectively. The local failure rate was 10.5-47.5%, with most studies reporting a local failure rate of < 30%. The 1- and 2-year overall survival (OS) rates were 25.7-80% and 25-60.7%, respectively. The pain relief rate was 41.6-100%. In the postoperative scenario, the LC rate was 70-100%, and the local failure rate was 11.7-33%. Regarding the reirradiated setting, the 1-year LC rate was 71-83%, the local failure rate was 6.0-25.5%, and the 1-year OS rate was 28-68%. The pain relief rate was approximately 35.7-77%. Between studies on single- and multi-fraction SBRT, the 1- and 2-year LC rates with single-fraction SBRT were 71-95% and 70-96%, respectively; the 1- and 2-year OS rates with single-fraction SBRT were 43.5-46% and 43.5-49%, respectively. For the management of spinal metastases, it appears that regardless of the clinical scenario in which SBRT is applied, a high rate of LC is achieved, particularly with single-fraction SBRT, regardless of histology. Additionally, spinal SBRT can establish durable pain palliation with acceptable toxicities.

Survival Benefits of Anti-PD-1 Therapy in Combination With Radiotherapy in Chinese Melanoma Patients With Brain Metastasis.

Limited data reported the synergistic anti-tumor effect of anti-PD-1 (programmed death 1) therapy and radiotherapy on melanoma BM (brain metastasis). And the efficacy in the Chinese population is unclear. This study aimed to evaluate the efficacy of anti-PD-1 therapy and radiotherapy in Chinese melanoma patients with BM. We retrospectively reviewed 96 consecutive melanoma patients with BM treated at Sun Yat-Sen University Cancer Center. Patient demographics, BM characteristics and treatment details were carefully collected. The intracranial PFS (progression free survival) and OS (overall survival) were estimated using the Kaplan-Meier method. Twenty-five patients were treated with anti-PD-1 therapy and radiotherapy. Eighteen (72.0%) patients had SBRT (stereotactic body radiation therapy) or SRS (stereotactic radiosurgery) for BM, 1 (4.0%) patient had WBRT (whole brain radiation therapy), 6 (24.0%) patients had SBRT/SRS and WBRT. The median treatment period of anti-PD-1 therapy was 10.77 months. Objective intracranial response was observed in 15 (60%) patients, and 5 (20%) patients achieved CR (complete response). After a median follow-up of 16 months, 11 (44%) patients experienced intracranial PD (progressive disease), and 15 (60%) patients died. The median intracranial PFS and OS were 10.73 months (range, 1.67-38.83 months) and 15.87 months (range, 2.47-41.50 months), respectively. The 1-year intracranial PFS and OS were 61.9% (95% CI, 44.1-86.9%) and 62.5% (95%CI, 45.8-85.2%), respectively. Patients with BM can benefit from a combination of anti-PD-1 therapy and radiotherapy. It merits further investigation in melanoma patients with BM.

Long Non-Coding RNA PITPNA-AS1 Accelerates the Progression of Colorectal Cancer Through miR-129-5p/HMGB1 Axis.

BACKGROUND: Long non-coding RNAs (lncRNAs) are essential regulators in colorectal cancer (CRC) progression. This work aimed to delve into the characteristics of lncRNA PITPNA-AS1 in CRC. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was adopted to examine PITPNA-AS1, miR-129-5p, high-mobility group box-1 (HMGB1) mRNA expressions in CRC tissues and cell lines. Functionally, cell counting kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) incorporation assays were employed to examine cell proliferation; wound healing assay was utilized to detect cell migration; and flow cytometry was used to detect the cell apoptosis. Luciferase reporter assay, RNA immunoprecipitation assay and Western blot were conducted to detect the regulatory relationships among PITPNA-AS1, miR-129-5p and HMGB1. RESULTS: PITPNA-AS1 and HMGB1 mRNA expressions were observably elevated in CRC tissues and cell lines. Knocking down PITPNA-AS1 could significantly inhibit cell proliferation and migration, and promote apoptosis of CRC cells. PITPNA-AS1 could serve as a competitive endogenous RNA, and up-regulate HMGB1 expression by adsorbing miR-129-5p. CONCLUSION: PITPNA-AS1 can expedite CRC cell proliferation and migration, and inhibit apoptosis through miR-129-5p/HMGB1 axis.

Exploring the Optimal Chemotherapy Strategy for Locoregionally Advanced Children and Adolescent Nasopharyngeal Carcinoma Based on Pretreatment Epstein-Barr Virus DNA Level in the Era of Intensity Modulated Radiotherapy.

BACKGROUND: The present study aimed to explore the optimal chemotherapy strategy for locoregionally advanced children and adolescent nasopharyngeal carcinoma (LcaNPC), based on the level of pretreatment plasma Epstein-Barr virus DNA (pEBV-DNA) in the era of intensity modulated radiation therapy (IMRT). METHODS: This real-world, retrospective study consecutively reviewed locoregionally advanced nasopharyngeal carcinoma patients younger than 22 years old from 2006 to 2016 in the Sun Yat-sen University Cancer Center. The Kaplan-Meier method with the log-rank test and the Cox regression model were used to investigate the survival outcomes of different chemotherapy intensities and pEBV-DNA. Treatment-related toxicity was also evaluated using the chi-squared test or Fisher's exact test. RESULTS: A total of 179 patients were enrolled, including 86 patients in the high-risk group (pEBV-DNA ≥7,500 copies/ml) and 93 patients in the low-risk group (pEBV-DNA <7,500 copies/ml). Among all patients, those receiving low intensity induction chemotherapy (IC courses = 2) had a better 5-year overall survival (OS) than those receiving no IC (P = 0.025) and high intensity IC (IC courses >2) (P = 0.044). In the high-risk group, receipt of low intensity IC showed significant 5-year OS (P = 0.032), progression-free survival (PFS) (P = 0.027), and 5-year distant metastasis-free survival (DMFS) (P = 0.008) benefits compared with not receiving IC. Multivariate analyses identified that not receiving IC was a risk factor compared with low intensity IC for OS (hazard ratio (HR) = 10.933, P = 0.038) among all patients. Moreover, in the high-risk group, not receiving IC was a risk factor for 5-year OS (HR = 10.878, P = 0.038), 5-year PFS (HR = 5.705, P = 0.041), and 5-year DMFS (HR = 10.290, P = 0.040) compared to low intensity IC. There were no differences in survival for patients treated with or without concurrent chemotherapy. CONCLUSION: Two courses of platinum-based IC might be the optimal induction chemotherapy intensity to reduce risk of death, progression, and distant metastasis in patients with high pEBV-DNA levels.

mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines.

Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte (CTL) responses, Toll-like receptor (TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3K, ERK, and mTOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates mTOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, mTOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, mTOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of mTOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which mTOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.

Expression of interleukin 6 in brain and colon of rats with TNBS-induced colitis.

AIM: To characterise expression of interleukin 6 (IL-6), a potent proinflammatory cytokine, in the occurrence and development of inflammatory bowel disease (IBD) and investigate its effect on neuroimmunomodulation and immune homeostasis regulation. METHODS: In this study, rats with colitis induced by trinitrobenzene sulfonic acid (TNBS) were sacrificed on days 3, 7, 14, 21 and 28 after induction. In the controls, the TNBS was just replaced by equivalent amount of phosphate buffered solution (PBS, 0.01 mol/L). IL-6 mRNA expression in brain and colon tissues in each phase was evaluated by real-time reverse transcription-polymerase chain reaction, and cellular localisation and protein level of IL-6 was determined by immunohistochemistry. RESULTS: At day 7, mRNA expression of IL-6 was significantly higher in the colon and brain of IBD rats than that of the controls. The protein level was also significantly higher in colon, hypothalamus and cerebral cortex of IBD rats compared with the controls. So there are similar temporal trends in IL-6 mRNA expression and protein levels in all positions with a persistent increase to a peak at day 7, followed by a decline and gradual return to normal levels. CONCLUSION: These results revealed that changes in IL-6 expression in brain and colon tissues occur in different phases of IBD. Therefore, we propose that the nerve centre regulates and controls the occurrence and development of IBD via IL-6.