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Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma
Objective
Natural killer (NK) cells play a critical role in the innate antitumor immune response. Recently, NK cell dysfunction has been verified in various malignant tumors, including hepatocellular carcinoma (HCC). However, the molecular biological mechanisms of NK cell dysfunction in human HCC are still obscure.
Methods
The expression of circular ubiquitin-like with PHD and ring finger domain 1 RNA (circUHRF1) in HCC tissues, exosomes, and cell lines was detected by qRT-PCR. Exosomes were isolated from the culture medium of HCC cells and plasma of HCC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit and then characterized by transmission electronic microscopy, NanoSight and western blotting. The role of circUHRF1 in NK cell dysfunction was assessed by ELISA. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the molecular mechanisms of circUHRF1 in NK cells. In a retrospective study, the clinical characteristics and prognostic significance of circUHRF1 were determined in HCC tissues.
Results
Here, we report that the expression of circUHRF1 is higher in human HCC tissues than in matched adjacent nontumor tissues. Increased levels of circUHRF1 indicate poor clinical prognosis and NK cell dysfunction in patients with HCC. In HCC patient plasma, circUHRF1 is predominantly secreted by HCC cells in an exosomal manner, and circUHRF1 inhibits NK cell-derived IFN-γ and TNF-α secretion. A high level of plasma exosomal circUHRF1 is associated with a decreased NK cell proportion and decreased NK cell tumor infiltration. Moreover, circUHRF1 inhibits NK cell function by upregulating the expression of TIM-3 via degradation of miR-449c-5p. Finally, we show that circUHRF1 may drive resistance to anti-PD1 immunotherapy in HCC patients.
Conclusions
Exosomal circUHRF1 is predominantly secreted by HCC cells and contributes to immunosuppression by inducing NK cell dysfunction in HCC. CircUHRF1 may drive resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for patients with HCC.
Journal Article
Cryoablation, high-intensity focused ultrasound, irreversible electroporation, and vascular-targeted photodynamic therapy for prostate cancer: a systemic review and meta-analysis
Cryoablation (CA), high-intensity focused ultrasound (HIFU), irreversible electroporation (IRE), and vascular-targeted photodynamic therapy (VTP) have been evaluated as novel strategies for selected patients with prostate cancer (PCa). We aim to determine the current status of literature regarding the clinical outcomes among these minimally invasive therapies. A systematic search of PubMed, EMBASE, and the Cochrane Library for all English literature published from January 2001 to December 2019 was conducted to identify studies evaluating outcomes of CA, HIFU, IRE or VTP on PCa. Proportionality with 95% confidence intervals (CIs) was performed using STATA version 14.0. 56 studies consisting of 7383 participants were found to report data of interest and fulfilled the inclusion criteria in the final meta-analysis. The pooled proportions of positive biopsy after procedure were 20.0%, 24.3%, 24.2%, and 36.2% in CA, HIFU, IRE and VTP, respectively. The pooled proportions of BRFS were 75.7% for CA and 74.4% for HIFU. The pooled proportions of CSS were 96.1%, 98.2%, and 97.9% for CA, HIFU, and IRE, respectively. The pooled proportions of OS were 92.8% for CA and 85.2% for HIFU. The pooled proportions of FFS were 64.7%, 90.4%, and 76.7% for CA, IRE and VTP, respectively. The pooled proportions of MFS were 92.8% for HIFU and 99.1% for IRE. This meta-analysis shows that CA, HIFU, IRE, and VTP are promising therapies for PCa patients with similar clinical outcomes. However, further larger, well-designed randomized controlled trials are required to confirm this assertion.
Journal Article
Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial
Background
Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
Methods
We conducted exploratory analyses in the FUSCC cohort to characterize a novel patient selection method and actionable targets for TNBC immunotherapy. We investigated this in vivo and launched a phase 2 trial to assess the clinical value of such criteria and combination regimen. Furthermore, we collected clinicopathological and next-generation sequencing data to illustrate biomarkers for patient outcomes.
Results
CD8-positivity could identify an immunomodulatory subpopulation of TNBCs with higher possibilities to benefit from immunotherapy, and angiogenesis was an actionable target to facilitate checkpoint blockade. We conducted the phase II FUTURE-C-Plus trial to assess the feasibility of combining famitinib (an angiogenesis inhibitor), camrelizumab (a PD-1 monoclonal antibody) and chemotherapy in advanced immunomodulatory TNBC patients. Within 48 enrolled patients, the objective response rate was 81.3% (95% CI, 70.2–92.3), and the median progression-free survival was 13.6 months (95% CI, 8.4–18.8). No treatment-related deaths were reported. Patients with CD8- and/or PD-L1- positive tumors benefit more from this regimen.
PKD1
somatic mutation indicates worse progression-free and overall survival.
Conclusion
This study confirms the efficacy and safety of the triplet regimen in immunomodulatory TNBC and reveals the potential of combining CD8, PD-L1 and somatic mutations to guide clinical decision-making and treatments.
Trial registration
ClinicalTrials.gov:
NCT04129996
. Registered 11 October 2019.
Journal Article
Amplification of spatially isolated adenosine pathway by tumor–macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma
Background
Immune checkpoint blockade resistance narrows the efficacy of cancer immunotherapies, but the underlying mechanism remains elusive. Delineating the inherent mechanisms of anti-PD1 resistance is important to improve outcome of patients with advanced HCC.
Method
The level of cricTMEM181 was measured in HCC patients with anti-PD1 therapy by RNA sequencing and then confirmed by qPCR and Sanger sequencing. Immune status in tumor microenvironment of HCC patients or mice models was evaluated by flow cytometry and IHC. Exosomes from HCC cell lines were isolated by ultracentrifugation, and their internalization by macrophage was confirmed by immunofluorescence. The underlying mechanism of HCC-derived exosomal circTMEM181 to macrophage was confirmed by SILAC, RNA FISH and RNA immunoprecipitation. The ATP–ADO pathway amplified by HCC–macrophage interaction was evaluated through ATP, AMP and ADO measurement and macrophage-specific CD39 knockout mice. The role of circTMEM181 in anti-PD1 therapy and its clinical significance were also determined in our retrospective HCC cohorts.
Results
Here, we found that circTMEM181 was elevated in hepatocellular carcinoma (HCC) patients responding poorly to anti-PD1 therapy and in HCC patients with a poor prognosis after operation. Moreover, we also found that high exosomal circTMEM181 favored the immunosuppressive microenvironment and endowed anti-PD1 resistance in HCC. Mechanistically, exosomal circTMEM181 sponged miR-488-3p and upregulated CD39 expression in macrophages. Using macrophage-specific CD39 knockout mice and pharmacologic approaches, we revealed a novel mode of anti-PD1 resistance in HCC. We discovered that cell-specific CD39 expression in macrophages and CD73 expression in HCC cells synergistically activated the eATP–adenosine pathway and produced more adenosine, thereby impairing CD8
+
T cell function and driving anti-PD1 resistance.
Conclusion
In summary, HCC-derived exosomal circTMEM181 contributes to immunosuppression and anti-PD1 resistance by elevating CD39 expression, and inhibiting the ATP–adenosine pathway by targeting CD39 on macrophages can rescue anti-PD1 therapy resistance in HCC.
Graphical Abstract
Journal Article
One Health: a key element in the WHO Pandemic Agreement
The ongoing threats of pandemics, such as COVID-19, underscore the urgency of rethinking outdated models, as pathogens spill over from animals to humans due to ecological changes and human–animal interactions. 2 The One Health framework proposed in the WHO Pandemic Agreement is a promising, although not flawless, response. Academic institutions play a critical role in providing tools for rigorous economic evaluations of One Health investments. 3 These studies can quantify the cost–benefit dynamics of pandemic preparedness interventions, enhancing the willingness of policy makers to adopt One Health strategies despite resource constraints. Participatory disease monitoring and citizen science initiatives can improve data timeliness and coverage, bridging gaps left by traditional official monitoring systems. 5 Additionally, community health education can reduce high-risk behaviours that facilitate zoonotic transmission.
Journal Article