DC-SIGN as an attachment factor mediates Japanese encephalitis virus infection of human dendritic cells via interaction with a single high-mannose residue of viral E glycoprotein

AbstractThe skin-resident dendritic cells (DCs) are thought to be the first defender to encounter incoming viruses and likely play a role in Japanese encephalitis virus (JEV) early infection. In the current study, following the demonstration of JEV productive infection in DCs, we revealed that the interaction between JEV envelope glycoprotein (E glycoprotein) and DC-SIGN was important for such infection as evidenced by antibody neutralization and siRNA knockdown experiments. Moreover, the high-mannose N-linked glycan at N154 of E glycoprotein was shown to be crucial for JEV binding to DC-SIGN and subsequent internalization, while mutation of DC-SIGN internalization motif did not affect JEV uptake and internalization. These data together suggest that DC-SIGN functions as an attachment factor rather than an entry receptor for JEV. Our findings highlight the potential significance of DC-SIGN in JEV early infection, providing a basis for further understanding how JEV exploits DC-SIGN to gain access to dendritic cells

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138(−/−) mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation

Palladium-catalyzed regiocontrollable reductive Heck reaction of unactivated aliphatic alkenes

A general Pd-catalyzed intermolecular reductive Heck reaction of both terminal and internal unactivated aliphatic alkenes has been first developed. This method affords γ- and δ-arylated alkyl carboxylic acid derivatives in high yields with complete anti-Markovnikov selectivity. Notably, the coupling process is stereoretentive for the alkyl chain. Mechanistically, alkyl palladacycle intermediates stabilized by directing group and ligand, hydride species multigenerated from PS/TFA reductant, are two key factors that successfully promote the reaction and regioselectivity.MOE (Min. of Education, S’pore

Palladium-catalyzed anti-michael reductive heck reaction of α,β-unsaturated esters

A general intermolecular anti-Michael reductive Heck reaction of α,β-unsaturated esters with organobromides has been developed. Most topical classes of aryl, heteroaryl, and vinyl bromides were found to efficiently react with a variety of internal conjugated alkenes. This protocol set up a platform toward diverse α-arylated 1,6-dicarbonyl frameworks found in natural products and drugs, which are still highly challenging targets in traditional α-arylation protocols because of competitive selectivity of enolation. A removable directing group, gram-scale reaction, and modification of complex molecules have additionally demonstrated that the anti-Michael reductive Heck reaction is a powerful complementary strategy to the classical α-arylation approaches. Preliminary mechanistic studies are consistent with our proposed mechanistic design.We gratefully acknowledge funding from the National Natural Science Foundation of China (21602104), Natural Science Foundation of Jiangsu Province, China (BK 20160986), the Starting Funding of Research (3983500176) from Nanjing Tech University. We thank Dr. Victor Gray and Dr. Sanyang Han (from Cavendish Laboratory, University of Cambridge) for proofreading

Intensity-modulated radiation therapy for definitive treatment of cervical cancer: a meta-analysis

Abstract Background To compare the efficacies and toxicities of intensity-modulated radiotherapy (IMRT) with three-dimensional conformal radiotherapy (3D-CRT) or conventional two-dimensional radiotherapy (2D-RT) for definitive treatment of cervical cancer. Methods A meta-analysis was performed using search engines, including PubMed, Cochrane Library, Web of Science, and Elsevier. In the meta-analysis, odds ratios (ORs) were compared for overall survival (OS), disease-free survival (DFS), and acute and chronic toxicities. Results Included data were analysed using RevMan 5.2 software. Six studies encompassing a total of 1008 patients who received definitive treatment (IMRT = 350, 3-DCRT/2D-RT = 658) were included in the analysis. A comparison of 3-year OS and 3-year DFS revealed no significant differences between IMRT and 3D-CRT or 2D-RT (3-year OS: OR = 2.41, 95% confidence interval [CI]: 0.62–9.39, p = 0.21; 3-year DFS: OR = 1.44, 95% CI: 0.69–3.01, p = 0.33). The incidence of acute gastrointestinal (GI) toxicity and genitourinary (GU) toxicity in patients who received IMRT was significantly lower than that in the control group (GI: Grade 2: OR = 0.5, 95% CI: 0.28–0.89, p = 0.02; Grade 3 or higher: OR = 0.55, 95% CI: 0.32–0.95, p = 0.03; GU: Grade 2: OR = 0.41, 95% CI: 0.2–0.84; p = 0.01; Grade 3 or higher: OR = 0.31, 95% CI: 0.14–0.67, p = 0.003). Moreover, the IMRT patients experienced fewer incidences of chronic GU toxicity than did the control group (Grade 3: OR = 0.09, 95% CI: 0.01–0.67, p = 0.02). Conclusion IMRT and conventional radiotherapy demonstrated equivalent efficacy in terms of 3-year OS and DFS. Additionally, IMRT significantly reduced acute GI and GU toxicities as well as chronic GU toxicity in patients with cervical cancer

Could definitive radiotherapy be a treatment option for lymphoepithelial carcinoma of major salivary gland:Comparison of clinical outcomes of upfront surgery and upfront chemoradiotherapy

Objectives: The optimal treatment and associated clinical outcomes for lymphoepithelial carcinoma of the major salivary gland (LECSG) are currently unclear. As such, the purpose of this study was to assess the survival rates of LECSG patients who received either upfront surgery or upfront chemoradiotherapy (CRT). Materials and methods: In this retrospective study, we analyzed cases of LECSG patients treated at our center from January 2010 to April 2021. The cumulative incidences of overall survival rate (OS) and locoregional failure-free survival rate (LRFFS) were evaluated using the Kaplan-Meier method. In order to balance potential risk factors between the treatment groups, we conducted propensity score matching (PSM) at a 1:1 ratio. Results: The study enrolled a total of 107 patients, among whom 24 received surgery alone, 56 underwent surgery combined with postoperative radiotherapy, and 27 underwent definitive radiotherapy. The 5-year LRFFS rate and 5-year OS rate for the entire cohort were 86.6% and 84.4%, respectively. Following PSM, the 5-year LRFFS and OS rates for the upfront CRT cases were comparable to those of upfront surgery, both before and after matching. However, the upfront surgery group showed a tendency toward more de novo facial nerve injury and post-treatment facial nerve injury. Conclusion: The results of this study suggest that upfront CRT is as effective as upfront surgery in terms of locoregional control and overall survival for LECSG patients. Therefore, upfront CRT could be considered a viable treatment option, potentially avoiding the risks associated with surgical intervention

Intermolecular reductive heck reaction of unactivated aliphatic alkenes with organohalides

A general intermolecular reductive Heck reaction of organohalides with both terminal and internal unactivated aliphatic alkenes has been first realized in high yield with complete anti-Markovnikov selectivity. The challenging vinyl bromides, aryl chlorides, and polysubstituted internal alkenes were first applied. More than 100 remote carbofunctionalized alkyl carboxylic acid derivatives were rapidly synthesized from easily accessible starting materials. The synthesis of drug molecules has further demonstrated the wide synthetic utility of this scalable strategy. Preliminary mechanistic studies are consistent with the proposed catalytic cycle.We gratefully acknowledge funding from the National Natural Science Foundation of China (21602104), Natural Science Foundation of Jiangsu Province, China (BK 20160986), and the Starting Funding of Research (3983500176) from Nanjing Tech University