37 results on '"Ze-Qin Guo"'
Search Results
2. Interstitial pneumonitis associated with combined regimen of immunotherapy and conventional therapies—pharmacovigilance database analysis with real-world data validation
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Xue-Jun Guo, Xiao-Ting Cai, Zi-Xuan Rong, Yan-Pei Zhang, Yu-Xiang Wen, Xue Bai, Jian Wang, Qiang John Fu, Ze-Qin Guo, Li-Li Long, Si-Cong Ma, Xin-Ran Tang, Li Liu, Jian Guan, Zhong-Yi Dong, and De-Hua Wu
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Interstitial pneumonitis ,Non-small cell lung cancer ,Immune checkpoint inhibitors ,Radiation therapy ,Conventional therapy ,Medicine - Abstract
Abstract Background Immune checkpoint inhibitor (ICI) therapy combined with conventional therapies is being broadly applied in non-small cell lung cancer (NSCLC) patients. However, the risk of interstitial pneumonitis (IP) following a combined regimen is incompletely characterized. Methods A total of 46,127 NSCLC patients were extracted for disproportionality analyses of IP from the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database. A total of 1108 NSCLC patients who received ICI treatment at Nanfang Hospital of Southern Medical University were collected and utilized for real-world validation. Results Of the 46,127 patients with NSCLC, 3830 cases (8.3%; 95% confidence interval [CI], 8.05–8.56) developed IP. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with radiation (RT) was the highest (121.69; 95% CI, 83.60–184.96; P < 0.0001) among all therapies, while that of ICI combined with chemotherapy (CHEMO) or targeted therapy (TARGET) was 0.90 (95% CI, 0.78–1.04; P = 0.160) and 1.49 (95% CI, 0.95–2.23; P = 0.065), respectively, using ICI monotherapy as reference. Furthermore, analyses from our validation cohort of 1108 cases showed that the adjusted odds ratio of ICI combined with RT was the highest (12.25; 95% CI, 3.34–50.22; P < 0.01) among all the therapies, while that of ICI combined with CHEMO or TARGET was 2.32 (95% CI, 0.89–7.92; P = 0.12) and 0.66 (95% CI, 0.03–4.55; P = 0.71), respectively, using ICI monotherapy as reference. Conclusions Compared with ICI monotherapy, ICI combined with RT, rather than with CHEMO or TARGET, is associated with a higher risk of IP in NSCLC patients. Hence, patients receiving these treatments should be carefully monitored for IP.
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- 2023
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3. Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice
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Si-Cong Ma, Xue Bai, Xue-Jun Guo, Li Liu, Lu-Shan Xiao, Yan Lin, Jia-Le Tan, Xiao-Ting Cai, Yu-Xiang Wen, Hu Ma, Q. John Fu, Meng-Xin Leng, Yan-Pei Zhang, Li-Li Long, Ze-Qin Guo, De-Hua Wu, Jian-Guo Zhou, and Zhong-Yi Dong
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Metastatic-organ landscape ,Non-small cell lung cancer ,Immune checkpoint inhibitor ,Programmed death-(ligand) 1 ,Medicine - Abstract
Abstract Background Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). Methods A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. Results Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). Conclusions Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.
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- 2022
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4. Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2
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Dong-Yan Zhang, Qing-Can Sun, Xue-Jing Zou, Yang Song, Wen-Wen Li, Ze-Qin Guo, Shan-Shan Liu, Li Liu, and De-Hua Wu
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UPK1A antisense RNA 1 ,EZH2 ,Long non-coding RNA ,miR-138-5p ,Proliferation ,Hepatocellular carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. Methods Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. Results We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.
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- 2020
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5. De Novo Mutation in Non-Tyrosine Kinase Domain of ROS1 as a Potential Predictor of Immune Checkpoint Inhibitors in Melanoma
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Si-Cong Ma, Hong-Bo Zhu, Jian Wang, Yan-Pei Zhang, Xue-Jun Guo, Li-Li Long, Ze-Qin Guo, De-Hua Wu, Zhong-Yi Dong, and Xue Bai
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ROS1 mutation ,immune checkpoint inhibitor ,melanoma ,tyrosine kinase domain ,tumor mutational burden ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
PurposeDespite the success of targeted therapy in c-ros oncogene 1 (ROS1)-rearranged cancers, especially non-small cell lung cancer (NSCLC), the clinical significance of ROS1 de novo mutation has not yet been understood. We sought to elucidate the predictive effect of ROS1 mutation for immune checkpoint inhibitor (ICI) therapy in melanoma.MethodsThe Cancer Genome Atlas [TCGA (n = 10967)] and Memorial Sloan Kettering Cancer Center [MSK (n = 10,945)] datasets, as well as two clinical cohorts of melanoma received ICI [CA209-038 (n = 73) and MEL-IPI (n = 110)], were included to explore the prevalence, prognostic effect, and immunotherapeutic predictive effect of ROS1 mutation in melanoma. Overall survival (OS) was defined as the primary outcome.ResultsOverall, melanoma accounted for the highest proportion of ROS1 mutation (~20%) which made up the majority (~95%) of the ROS1-alterated cases. Remarkably, ROS1 mutation yielded longer OS from ICI than the wild-type counterpart in the MSK melanoma population [hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.30–0.74], and two external melanoma cohorts (CA209-038: HR 0.42, 95% CI 0.20–0.89; MEL-IPI: HR 0.55, 95% CI 0.34–0.91), without affecting the prognosis of patients. Elevated tumor mutational burden and enrichment of DNA damage repair was observed in ROS1 mutated patients, providing an explanation for the favorable responses to ICI therapy. Precisely, ROS1 mutation in non-protein tyrosine kinase (PTK) domain but not PTK mutation was responsible for the immunotherapy-specific responses of the ROS1 mutated patients in melanoma.ConclusionsCollectively, ROS1 mutation, specifically the non-PTK mutation, is a potential predictor of ICI therapy in melanoma, which is distinct from the well-established role of ROS1 rearrangement for targeted therapy in NSCLC.
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- 2021
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6. Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies
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Si-Cong Ma, Xin-Ran Tang, Li-Li Long, Xue Bai, Jian-Guo Zhou, Zhi-Jiao Duan, Jian Wang, Qiang John Fu, Hong-Bo Zhu, Xue-Jun Guo, Yan-Pei Zhang, Ze-Qin Guo, De-Hua Wu, and Zhong-Yi Dong
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non-small cell lung cancer ,immunotherapy ,tumor burden ,metastasis ,organ ,Immunologic diseases. Allergy ,RC581-607 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Objectives: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. Materials and Methods: We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. Results: Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. Conclusions: The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients.
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- 2021
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7. Figure S2 from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
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Relationship between CNA level and TMB in (A) MSK pan-cancer non-ICI treated cohort and (B) other three ICI-treated cohorts (MSK NSCLC, SKCM, and Dana-Farber ICI cohort). For each cancer type and each cohort, a plot is shown containing the CNA level versus tumor mutation burden. The spearman correlation coefficient and P value are shown.
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- 2023
8. Data from PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
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Zhong-Yi Dong, Xue Bai, De-Hua Wu, Xinghua Pan, Yan Lin, Xiao-Ting Cai, Jia-Le Tan, Xue-Jun Guo, Jian Wang, Meng-Xin Leng, Duan-Duan Han, Li Liu, Li-Juan Liu, Zhenzhen Fan, Yan-Pei Zhang, Ze-Qin Guo, Si-Cong Ma, and Li-Li Long
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Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.Significance:Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.
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- 2023
9. Table S1 from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
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Demographic and clinicopathologic characteristics of three cohorts treated with immune checkpoint inhibitors.
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- 2023
10. Supplementary Table 1 from PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
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Zhong-Yi Dong, Xue Bai, De-Hua Wu, Xinghua Pan, Yan Lin, Xiao-Ting Cai, Jia-Le Tan, Xue-Jun Guo, Jian Wang, Meng-Xin Leng, Duan-Duan Han, Li Liu, Li-Juan Liu, Zhenzhen Fan, Yan-Pei Zhang, Ze-Qin Guo, Si-Cong Ma, and Li-Li Long
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Sequences for qPCR primers.
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- 2023
11. Figure S4 from PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
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Zhong-Yi Dong, Xue Bai, De-Hua Wu, Xinghua Pan, Yan Lin, Xiao-Ting Cai, Jia-Le Tan, Xue-Jun Guo, Jian Wang, Meng-Xin Leng, Duan-Duan Han, Li Liu, Li-Juan Liu, Zhenzhen Fan, Yan-Pei Zhang, Ze-Qin Guo, Si-Cong Ma, and Li-Li Long
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PARP1 inhibition restores phosphorylated STAT1 from poly(ADP-ribosyl)ation and triggers synthetic lethality in LKB1-deficient cells. (a) A549 lung cancer cells were transfected with lentivirus expressing the indicated genes (LV-Ctrl, LV-LKB1-WT, and LV-LKB1-Mut) followed by treatment with olaparib (5μM) for 24 hours. The expression of pSTAT1 and PARP1 was analyzed by western blotting. (b-d) LLC1-shLkb1 and LLC1-shCtrl cells were pre-treated with olaparib (5μmol/L) for 6 hours and then stimulated with IFNγ for another 24 hours. Total pSTAT1 and STAT1 were quantified using western blot (b) and cell-surface PD-L1 was measured by flow cytometry (c). Q-PCR analysis was used to detect the expression of CXCL9 and PD-L1 (d). (e, f) The three groups of A549 cells were treated with IFNγ or IFNγ/olaparib and then refreshed the culture medium. The ratio of CD8+ T (effector cells) to A549 cells (target cell) ratio was 5:1. After 6 hours of incubation, QT-PCR analysis was used to detect the expression of indicated molecules of CD8+ T cells. (g) CD8+ T cells were treated with PBS or olaparib (5μmol/L) for 24 hours, and then the cells were collected for quantification of GZMB, PRF1, TNF, and IFNγ. CD8a was selected as the reference gene. (h) LLC-LV-Ctrl cells were treated with IFNγ/anti-PD-1 antibodies (20 μg/mL) in the absence or presence of olaparib (5 µM) or BMDCs (Tumor cells: DCs= 1:1) for 24 hours. Flow cytometry assay was used for apoptosis analysis of tumor cells. The right graph showed the quantification of tumor cell apoptosis. The data are presented as the mean ± SD of triplicate experiments. Statistical significance was determined by Student's t-test; ns, not significant; ****, P < 0.0001; ***, P < 0.001; **, P < 0.01; *, P < 0.05.
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- 2023
12. Supplementary Table 2 from PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
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Zhong-Yi Dong, Xue Bai, De-Hua Wu, Xinghua Pan, Yan Lin, Xiao-Ting Cai, Jia-Le Tan, Xue-Jun Guo, Jian Wang, Meng-Xin Leng, Duan-Duan Han, Li Liu, Li-Juan Liu, Zhenzhen Fan, Yan-Pei Zhang, Ze-Qin Guo, Si-Cong Ma, and Li-Li Long
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LKB1-interacting proteins identified by LC-MS/MS analysis.
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- 2023
13. Supplementary figure legends from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
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Supplementary figure legends
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- 2023
14. Data from Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
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Zhong-Yi Dong, Zhu Liu, Xue-Jun Guo, Qin Zeng, Ze-Qin Guo, Yuan Fang, Hong-Bo Zhu, Yao-Wei Zhang, Xiu-Ju Du, Sha-Sha Du, De-Hua Wu, Xin-Ran Tang, Jian Wang, Xue Bai, and Li Liu
- Abstract
Purpose:Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu.Experimental Design:Non-ICI–treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non–small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy.Results:TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI–treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors.Conclusions:The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.
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- 2023
15. PARP inhibition induces synthetic lethality and adaptive immunity in LKB1-mutant lung cancer
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Li-Li Long, Si-Cong Ma, Ze-Qin Guo, Yan-Pei Zhang, Zhenzhen Fan, Li-Juan Liu, Li Liu, Duan-Duan Han, Meng-Xin Leng, Jian Wang, Xue-Jun Guo, Jia-Le Tan, Xiao-Ting Cai, Yan Lin, Xinghua Pan, De-Hua Wu, Xue Bai, and Zhong-Yi Dong
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Cancer Research ,Oncology - Abstract
Contradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.Significance:Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.
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- 2022
16. UBE2T-regulated H2AX monoubiquitination induces hepatocellular carcinoma radioresistance by facilitating CHK1 activation
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Chuanhui Cao, Qingcan Sun, Li Liu, Zhenru Zhu, Jingyuan Sun, Mengying Shen, Ze-Qin Guo, Wenwen Li, and Dehua Wu
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Cancer Research ,Carcinoma, Hepatocellular ,Cell cycle checkpoint ,DNA Repair ,DNA damage ,DNA repair ,Hepatocellular carcinoma ,Mice, Nude ,Apoptosis ,Radiation Tolerance ,lcsh:RC254-282 ,Histones ,Cell cycle arrest ,Mice ,Radioresistance ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Monoubiquitination ,Phosphorylation ,H2AX monoubiquitination ,Cell Proliferation ,Radiotherapy ,biology ,Chemistry ,Research ,Cell Cycle ,Liver Neoplasms ,Ubiquitination ,Cell cycle ,Prognosis ,Ubiquitin-conjugating enzyme E2T ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Xenograft Model Antitumor Assays ,Chromatin ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Histone ,Oncology ,Checkpoint Kinase 1 ,Ubiquitin-Conjugating Enzymes ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,DNA Damage - Abstract
Background Radioresistance is the major obstacle in radiation therapy (RT) for hepatocellular carcinoma (HCC). Dysregulation of DNA damage response (DDR), which includes DNA repair and cell cycle checkpoints activation, leads to radioresistance and limits radiotherapy efficacy in HCC patients. However, the underlying mechanism have not been clearly understood. Methods We obtained 7 pairs of HCC tissues and corresponding non-tumor tissues, and UBE2T was identified as one of the most upregulated genes. The radioresistant role of UBE2T was examined by colony formation assays in vitro and xenograft tumor models in vivo. Comet assay, cell cycle flow cytometry and γH2AX foci measurement were used to investigate the mechanism by which UBE2T mediating DDR. Chromatin fractionation and immunofluorescence staining were used to assess cell cycle checkpoint kinase 1(CHK1) activation. Finally, we analyzed clinical data from HCC patients to verify the function of UBE2T. Results Here, we found that ubiquitin-conjugating enzyme E2T (UBE2T) was upregulated in HCC tissues, and the HCC patients with higher UBE2T levels exhibited poorer outcomes. Functional studies indicated that UBE2T increased HCC radioresistance in vitro and in vivo. Mechanistically, UBE2T-RNF8, was identified as the E2-E3 pair, physically bonded with and monoubiquitinated histone variant H2AX/γH2AX upon radiation exposure. UBE2T-regulated H2AX/γH2AX monoubiquitination facilitated phosphorylation of CHK1 for activation and CHK1 release from the chromatin to cytosol for degradation. The interruption of UBE2T-mediated monoubiquitination on H2AX/γH2AX, including E2-enzyme-deficient mutation (C86A) of UBE2T and monoubiquitination-site-deficient mutation (K119/120R) of H2AX, cannot effectively activate CHK1. Moreover, genetical and pharmacological inhibition of CHK1 impaired the radioresistant role of UBE2T in HCC. Furthermore, clinical data suggested that the HCC patients with higher UBE2T levels exhibited worse response to radiotherapy. Conclusion Our results revealed a novel role of UBE2T-mediated H2AX/γH2AX monoubiquitination on facilitating cell cycle arrest activation to provide sufficient time for radiation-induced DNA repair, thus conferring HCC radioresistance. This study indicated that disrupting UBE2T-H2AX-CHK1 pathway maybe a promising potential strategy to overcome HCC radioresistance.
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- 2020
17. Reciprocal regulation of HIF-1α and Uroplakin 1A promotes glycolysis and proliferation in Hepatocellular Carcinoma
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Yang Song, Hui Wang, Dehua Wu, Li Liu, Ya-Xuan Zhang, Dongyan Zhang, Xuejing Zou, and Ze-Qin Guo
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0301 basic medicine ,Hepatocellular carcinoma ,proliferation ,Cell ,HIF-1α ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,UPK1A ,medicine ,Gene silencing ,Glycolysis ,chemistry.chemical_classification ,Promoter ,Hypoxia (medical) ,glycolysis ,medicine.disease ,digestive system diseases ,030104 developmental biology ,Enzyme ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,medicine.symptom ,Research Paper - Abstract
Uroplakin 1A (UPK1A) has recently been found dysregulation in many cancers. However, the functions of UPK1A and its underlying mechanisms in hepatocellular carcinoma (HCC) remain poorly understand. In the present study, we found that UPK1A was highly expressed in HCC tumor tissues compared with adjacent non-tumor tissues. Datasets from the Cancer Genome Atlas project (TCGA) and Gene expression Omnibus confirmed that UPK1A was highly expressed in HCC. High expression of UPK1A predicted poor overall survival (OS) in patients with HCC. Univariate and multivariate analysis showed that UPK1A was a significant and independent prognostic predictor for OS of patients with HCC. Functionally, silencing UPK1A suppressed HCC cell glycolysis and proliferation. Mechanistically, hypoxia-inducible factor 1α (HIF-1α) directly bound to the hypoxia response elements (HRE) of UPK1A promoter region, which led to the up-regulation of UPK1A under hypoxia. Furthermore, downregulation of UPK1A reduced key enzyme of glycolysis via regulating HIF-1α. Taken together, these data indicates the existence of a positive feedback loop between HIF-1α and UPK1A that modulates glycolysis and proliferation under hypoxia in HCC cells.
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- 2020
18. Organ-specific metastatic landscape dissects PD-(L)1 blockade efficacy in advanced non-small cell lung cancer: applicability from clinical trials to real-world practice
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Si-Cong Ma, Xue Bai, Xue-Jun Guo, Li Liu, Lu-Shan Xiao, Yan Lin, Jia-Le Tan, Xiao-Ting Cai, Yu-Xiang Wen, Hu Ma, Q. John Fu, Meng-Xin Leng, Yan-Pei Zhang, Li-Li Long, Ze-Qin Guo, De-Hua Wu, Jian-Guo Zhou, and Zhong-Yi Dong
- Subjects
Clinical Trials as Topic ,Lung Neoplasms ,Carcinoma, Non-Small-Cell Lung ,Humans ,ddc:610 ,General Medicine ,Immunotherapy ,B7-H1 Antigen ,Progression-Free Survival - Abstract
Background Organ-specific metastatic context has not been incorporated into the clinical practice of guiding programmed death-(ligand) 1 [PD-(L)1] blockade, due to a lack of understanding of its predictive versus prognostic value. We aim at delineating and then incorporating both the predictive and prognostic effects of the metastatic-organ landscape to dissect PD-(L)1 blockade efficacy in non-small cell lung cancer (NSCLC). Methods A total of 2062 NSCLC patients from a double-arm randomized trial (OAK), two immunotherapy trials (FIR, BIRCH), and a real-world cohort (NFyy) were included. The metastatic organs were stratified into two categories based on their treatment-dependent predictive significance versus treatment-independent prognosis. A metastasis-based scoring system (METscore) was developed and validated for guiding PD-(L)1 blockade in clinical trials and real-world practice. Results Patients harboring various organ-specific metastases presented significantly different responses to immunotherapy, and those with brain and adrenal gland metastases survived longer than others [overall survival (OS), p = 0.0105; progression-free survival (PFS), p = 0.0167]. In contrast, survival outcomes were similar in chemotherapy-treated patients regardless of metastatic sites (OS, p = 0.3742; PFS, p = 0.8242). Intriguingly, the immunotherapeutic predictive significance of the metastatic-organ landscape was specifically presented in PD-L1-positive populations (PD-L1 > 1%). Among them, a paradoxical coexistence of a favorable predictive effect coupled with an unfavorable prognostic effect was observed in metastases to adrenal glands, brain, and liver (category I organs), whereas metastases to bone, pleura, pleural effusion, and mediastinum yielded consistent unfavorable predictive and prognostic effects (category II organs). METscore was capable of integrating both predictive and prognostic effects of the entire landscape and dissected OS outcome of NSCLC patients received PD-(L)1 blockade (p < 0.0001) but not chemotherapy (p = 0.0805) in the OAK training cohort. Meanwhile, general performance of METscore was first validated in FIR (p = 0.0350) and BIRCH (p < 0.0001), and then in the real-world NFyy cohort (p = 0.0181). Notably, METscore was also applicable to patients received PD-(L)1 blockade as first-line treatment both in the clinical trials (OS, p = 0.0087; PFS, p = 0.0290) and in the real-world practice (OS, p = 0.0182; PFS, p = 0.0045). Conclusions Organ-specific metastatic landscape served as a potential predictor of immunotherapy, and METscore might enable noninvasive forecast of PD-(L)1 blockade efficacy using baseline radiologic assessments in advanced NSCLC.
- Published
- 2021
19. A new strategy for non-targeted screening of phthalate metabolites using liquid chromatography-high resolution mass spectrometry
- Author
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Ze-Qin Guo, Yong-Lai Feng, and Jian-Hua Wang
- Subjects
Chromatography ,Non targeted ,010401 analytical chemistry ,Phthalate ,010402 general chemistry ,Condensed Matter Physics ,Mass spectrometry ,01 natural sciences ,Rapid detection ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Biomonitoring ,Mass spectrum ,Screening method ,Physical and Theoretical Chemistry ,Instrumentation ,Retention time ,Spectroscopy - Abstract
The ubiquity and potential toxicity of phthalates make their exposure on humans a matter of great concern. Measuring the targeted phthalate metabolites using liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a commonly used approach for human biomonitoring of phthalates. However, the targeted LC-MS/MS methods have been unable to meet the desire to comprehensively and rapidly screen and identify for as many known and potentially unknown phthalate metabolites in human samples. Instead, non-targeted screening methods, allowing the rapid detection and identification of unknown compounds in a wide variety of environmental and human samples are complementary to the targeted methods. In this study, 23 phthalate metabolites were analyzed using liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF-MS) for development of a non-targeted screening method. The fragmentation patterns of the 23 phthalate metabolites were investigated using collision-induced dissociation experiments at 10, 20, and 40 eV. And three common specific product ions at m/z 121.0297, m/z 147.0088, and m/z 165.0193 corresponding to C7H5O2-, C8H3O3-, and C8H5O4-, respectively were observed in their mass spectra. Based on the three common product ions, a new strategy was proposed for non-targeted screening of the new phthalate metabolites as exposure biomarkers for human biomonitoring. It can greatly reduce the time spent on data processing for potential precursor ions. Additionally, the correlation of the retention time and logKow of the phthalate metabolites was explored, which provides a useful tool to reduce the number of identified candidates in the non-targeted screening.
- Published
- 2019
20. Upregulated long non‑coding RNA LincIN promotes tumor progression via the regulation of nuclear factor 90/microRNA‑7/HOXB13 in esophageal squamous cell carcinoma
- Author
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Ying Wang, Yazhi Xiao, Mengying Shen, Peitao Zhou, Ze-Qin Guo, Zhibo Tan, Dehua Wu, Zhenru Zhu, and Weixi Shen
- Subjects
Male ,0301 basic medicine ,Esophageal Neoplasms ,proliferation ,non-coding RNA ,Cell ,microRNA biogenesis ,Biology ,migration ,nuclear factor 90 ,Metastasis ,esophageal carcinoma ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,microRNA ,Genetics ,medicine ,Humans ,Nuclear Factor 90 Proteins ,neoplasms ,Aged ,Homeodomain Proteins ,Oncogene ,Cell growth ,Articles ,General Medicine ,Middle Aged ,Cell cycle ,Prognosis ,invasion ,medicine.disease ,MicroRNA 7 ,digestive system diseases ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Tumor progression ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA, Long Noncoding ,Esophageal Squamous Cell Carcinoma - Abstract
Long non-coding RNA LincIN has been reported to be overexpressed and to be involved in the metastasis of breast cancer. However, the expression and role of LincIN in esophageal squamous cell carcinoma (ESCC) remain unsolved. In the present study, LincIN expression was examined in ESCC by RT-qPCR, and the roles of LincIN in ESCC were determined using cell growth, migration and invasion assays. In addition, the effects of LincIN on nuclear factor 90 (NF90) and microRNA/miR (miR)-7 were examined by RNA immunoprecipitation assay, RT-qPCR, dual-luciferase reporter assay and western blot analysis. The results revealed that LincIN expression was significantly increased in ESCC tissues and cell lines. The increased expression of LincIN was positively associated with invasion depth, lymph node metastasis, TNM stage and a poor prognosis. Functional assays revealed that the overexpression of LincIN promoted ESCC cell growth, migration and invasion. Mechanistic analysis revealed that LincIN physically bound to NF90, enhanced the binding between NF90 and primary miR-7 (pri-miR-7), and further enhanced the inhibitory effects of NF90 on miR-7 biogenesis. Therefore, LincIN downregulated miR-7 expression in ESCC. The expression of miR-7 inversely correlated with that of LincIN in ESCC tissues. By downregulating miR-7, LincIN increased the expression of HOXB13, a target of miR-7. The overexpression of miR-7 or the depletion of HOXB13 both attenuated the tumor-promoting roles of LincIN in ESCC cell growth, migration and invasion. On the whole, the findings of the present study suggest that LincIN is overexpressed and plays an oncogenic role in ESCC via the regulation of the NF90/miR-7/HOXB13 axis. Thus, LincIN may prove to be a promising prognostic biomarker and therapeutic target for ESCC.
- Published
- 2021
21. Integrative evaluation of primary and metastatic lesion spectrum to guide anti-PD-L1 therapy of non-small cell lung cancer: results from two randomized studies
- Author
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Xue Bai, Zhong-Yi Dong, Xin-Ran Tang, Si-Cong Ma, Hong-Bo Zhu, Dehua Wu, Jian-Guo Zhou, Zhi-Jiao Duan, Jian Wang, Li-Li Long, Xue-Jun Guo, Yan-Pei Zhang, Ze-Qin Guo, and Qiang John Fu
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Lung Neoplasms ,medicine.medical_treatment ,Immunology ,Docetaxel ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Non-small cell lung cancer ,Atezolizumab ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,organ ,medicine ,metastasis ,Humans ,Immunology and Allergy ,Lung cancer ,RC254-282 ,Original Research ,Retrospective Studies ,Chemotherapy ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Antibodies, Monoclonal ,Immunotherapy ,RC581-607 ,medicine.disease ,Blockade ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cohort ,immunotherapy ,Immunologic diseases. Allergy ,business ,tumor burden ,Research Article ,medicine.drug - Abstract
Objectives: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is heterogeneous in clinical practice. Materials and Methods: We retrospectively assessed the predicitive effect of the primary and metastatic lesion spectrum (baseline sum of the longest diameters [SLD], number of metastatic sites and specific organ metastases) on the efficacy of atezolizumab over docetaxel in OAK and POPLAR trial cohorts. A decision model, termed DSO (Diameter-Site-Organ), based on the spectrum was developed and validated for guiding ICB. Results: Higher SLD (>38 mm) and more metastatic sites (≥2) were characterized with pronounced overall survival (OS) benefits from atezolizumab versus docetaxel. Specifically, adrenal gland and brain metastases were identified as favorable predictors of atezolizumab treatment. The DSO model was developed in the discovery cohort to integrate the directive effect of the primary and metastatic lesion spectrum. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a significantly prolonged OS than docetaxel, whereas OS was generally similar between two treatments in patients with DSO score ≤ 0. Equivalent findings were also seen in the internal and external validation cohorts. Conclusions: The response to anti-PD-L1 therapy among patients varied with the primary and metastatic lesion spectrum. The DSO-based system might provide promising medication guidance for ICB treatment in NSCLC patients.
- Published
- 2021
22. Long noncoding RNA UPK1A-AS1 indicates poor prognosis of hepatocellular carcinoma and promotes cell proliferation through interaction with EZH2
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Xuejing Zou, Wenwen Li, Qingcan Sun, Dehua Wu, Ze-Qin Guo, Dongyan Zhang, Li Liu, Yang Song, and Shanshan Liu
- Subjects
0301 basic medicine ,Male ,Cancer Research ,Small interfering RNA ,Carcinoma, Hepatocellular ,miR-138-5p ,Hepatocellular carcinoma ,Cell ,UPK1A antisense RNA 1 ,Proliferation ,Mice, Nude ,Apoptosis ,Biology ,lcsh:RC254-282 ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Downregulation and upregulation ,Cell Movement ,medicine ,Biomarkers, Tumor ,Tumor Cells, Cultured ,Animals ,Humans ,Enhancer of Zeste Homolog 2 Protein ,RNA, Antisense ,EZH2 ,Uroplakin Ia ,Cell Proliferation ,Cell growth ,Research ,Liver Neoplasms ,RNA ,Cell cycle ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Prognosis ,Xenograft Model Antitumor Assays ,Long non-coding RNA ,Antisense RNA ,Gene Expression Regulation, Neoplastic ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,RNA, Long Noncoding - Abstract
Background Dysregulation of long non-coding RNAs (lncRNAs) is responsible for cancer initiation and development, positioning lncRNAs as not only biomarkers but also promising therapeutic targets for cancer treatment. A growing number of lncRNAs have been reported in hepatocellular carcinoma (HCC), but their functional and mechanistic roles remain unclear. Methods Gene Set Enrichment Analysis was used to investigate the molecular mechanism of UPK1A antisense RNA 1 (UPK1A-AS1). Cell Counting Kit-8 assays, EdU assays, flow cytometry, western blotting, and xenograft assays were used to confirm the role of UPK1A-AS1 in the proliferation of HCC cells in vitro and in vivo. Bioinformatics analyses and quantitative polymerase chain reaction (qRT-PCR) were performed to explore the interplay between UPK1A-AS1 and enhancer of zeste homologue 2 (EZH2). RNA immunoprecipitation (RIP), RNA pull-down assays, western blotting, and qRT-PCR were conducted to confirm the interaction between UPK1A-AS1 and EZH2. The interaction between UPK1A-AS1 and miR-138-5p was examined by luciferase reporter and RIP assays. Finally, the expression level and prognosis value of UPK1A-AS1 in HCC were analyzed using RNA sequencing data from The Cancer Genome Atlas datasets. Results We showed that UPK1A-AS1, a newly identified lncRNA, promoted cellular proliferation and tumor growth by accelerating cell cycle progression. Cell cycle-related genes, including CCND1, CDK2, CDK4, CCNB1, and CCNB2, were significantly upregulated in HCC cells overexpressing UPK1A-AS1. Furthermore, overexpression of UPK1A-AS1 could protect HCC cells from cis-platinum toxicity. Mechanistically, UPK1A-AS1 interacted with EZH2 to mediate its nuclear translocation and reinforce its binding to SUZ12, leading to increased H27K3 trimethylation. Targeting EZH2 with specific small interfering RNA impaired the UPK1A-AS1-mediated upregulation of proliferation and cell cycle progression-related genes. Moreover, miR-138-5p was identified as a direct target of UPK1A-AS1. Additionally, UPK1A-AS1 was significantly upregulated in HCC, and the upregulation of UPK1A-AS1 predicted poor prognosis for patients with HCC. Conclusions Our study revealed that UPK1A-AS1 promotes HCC development by accelerating cell cycle progression through interaction with EZH2 and sponging of miR-138-5p, suggesting that UPK1A-AS1 possesses substantial potential as a novel biomarker for HCC prognosis and therapy.
- Published
- 2020
23. Integrative Modeling of Tumor Burden and Metastatic Pattern for Guiding Anti-PD-L1 Treatment of Non–Small Cell Lung Cancer: Results From Two Randomized Studies
- Author
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Li-Li Long, Zhi-Jiao Duan, Xue Bai, Jian Wang, Dehua Wu, Si-Cong Ma, Hong-Bo Zhu, Ze-Qin Guo, Xue-Jun Guo, Xin-Ran Tang, Yan-Pei Zhang, Qiang John Fu, and Zhong-Yi Dong
- Subjects
Oncology ,Chemotherapy ,medicine.medical_specialty ,education.field_of_study ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Population ,medicine.disease ,Docetaxel ,Informed consent ,Atezolizumab ,Internal medicine ,Cohort ,medicine ,Lung cancer ,education ,business ,medicine.drug - Abstract
Background: Clinical benefits of immune-checkpoint blockade (ICB) versus standard chemotherapy have been established in unselected non-small cell lung cancer (NSCLC). However, the response to ICB therapy among patients is still heterogeneous in clinical practice. Methods: We retrospectively assessed the impact of baseline sum of the longest diameters (SLD), number of metastatic sites and specific organ metastases on the efficacy of atezolizumab versus docetaxel in the pooled population from OAK and POPLAR studies. An assistant decision model based on the machine-learning method, incorporating these indicators, termed DSO (Diameter-Site-Organ), was developed and validated in OAK and POPLAR cohorts. Findings: Higher SLD (> 38mm) and more metastatic sites (≥ 2) were characterized with pronounced OS benefits from atezolizumab versus docetaxel. Specifically, brain and adrenal gland metastases were identified as favorable predictors of atezolizumab treatment. The DSO model for guiding second-line treatment was developed based on SLD and metastatic sites and organs in the discovery cohort. Remarkably, a general pattern of enhanced efficacy of atezolizumab versus docetaxel was observed along with the increase of the DSO score. For patients with DSO score > 0, atezolizumab yielded a prolonged OS than docetaxel (hazard ratio [HR] 0.67, 95% CI 0.54-0.84; P = 0.0003), whereas OS was generally similar between two treatments in patients with DSO score ≤ 0 (HR 1.46, 95% CI 0.89-2.39; P = 0.1346). Equivalent findings were seen in the internal and external validation cohorts. Interpretation: Our study for the first time revealed that patients with higher tumor burden were more suitable for ICB compared with standard chemotherapy. More importantly, the integrative DSO decision model might provide promising medication guidance for second-line ICB treatment in unselected NSCLC patients. Funding: This study was supported by the National Natural Science Foundation for YoungScientists of China (Grant No. 81802863 and 81902353), the Natural Science Foundation of Guangdong Province (Grant No. 2018030310285), and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University (Grant No. 2017J003). Conflict of Interest: The authors have no actual or potential conflicts of interest to declare. Ethical Approval: The study was approved by theInstitutional Ethical Review Boards of Nanfang Hospital. All patients enrolled in OAK and POPLAR provided signed informed consent in accordance with the protocols of the corresponding studies.
- Published
- 2020
24. OA07.07 PARP1 Inhibitors Enhanced IFNγ-Induced PD-L1 Expression in LKB1-Mutant Lung Cancer
- Author
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Yao-Wei Zhang, Ze-Qin Guo, Zhong-Yi Dong, Xiao-Yan Bai, and Li-Li Long
- Subjects
Pulmonary and Respiratory Medicine ,PARP1 ,Oncology ,business.industry ,Mutant ,Cancer research ,Medicine ,Pd l1 expression ,business ,Lung cancer ,medicine.disease - Published
- 2021
25. OA07.04 LKB1 Deficiency Leads to an 'Adenosine-Rich' Tumor Microenvironment by Recruiting and Regulating Myeloid Derived Suppressive Cells
- Author
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Yao-Wei Zhang, Zhong-Yi Dong, Xiao-Yan Bai, Li-Li Long, and Ze-Qin Guo
- Subjects
Pulmonary and Respiratory Medicine ,Tumor microenvironment ,Myeloid ,medicine.anatomical_structure ,Oncology ,business.industry ,Cancer research ,medicine ,business ,Adenosine ,medicine.drug - Published
- 2021
26. P16.04 CDK4/6 Inhibitors Reverse Resistance to Anti-PD-1 Therapy in Lung Adenocarcinoma with LKB1 Deficiency Through pRB-ICAM1 Dependent Signaling
- Author
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Xiao-Yan Bai, Ze-Qin Guo, and Zhong-Yi Dong
- Subjects
Pulmonary and Respiratory Medicine ,Lung ,medicine.anatomical_structure ,Oncology ,business.industry ,Anti pd 1 ,Cancer research ,medicine ,Adenocarcinoma ,medicine.disease ,business - Published
- 2021
27. Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer
- Author
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Xue Bai, Xue-Jun Guo, Jian Wang, Zhong-Yi Dong, Xin-Ran Tang, Yuan Fang, Dehua Wu, Ze-Qin Guo, Qin Zeng, Yao-Wei Zhang, Zhu Liu, Sha-Sha Du, Xiu-Ju Du, Li Liu, and Hong-Bo Zhu
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,DNA Copy Number Variations ,medicine.medical_treatment ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Randomized controlled trial ,law ,Internal medicine ,Neoplasms ,medicine ,Biomarkers, Tumor ,Humans ,Neoplasm Metastasis ,Survival rate ,Aged ,business.industry ,Cancer ,Immunotherapy ,medicine.disease ,Prognosis ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cutaneous melanoma ,Cohort ,Mutation ,Biomarker (medicine) ,Female ,business - Abstract
Purpose: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. Experimental Design: Non-ICI–treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non–small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy. Results: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI–treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. Conclusions: The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.
- Published
- 2019
28. Recent advances in non-targeted screening analysis using liquid chromatography - high resolution mass spectrometry to explore new biomarkers for human exposure
- Author
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Jian-Hua Wang, Yong-Lai Feng, Sheng Huang, and Ze-Qin Guo
- Subjects
Chromatography ,Non targeted ,Chemistry ,010401 analytical chemistry ,02 engineering and technology ,021001 nanoscience & nanotechnology ,Mass spectrometry ,01 natural sciences ,Gas Chromatography-Mass Spectrometry ,Mass Spectrometry ,Chemical space ,0104 chemical sciences ,Analytical Chemistry ,Screening analysis ,Prediction algorithms ,Isomerism ,Human exposure ,Mass spectrum ,Humans ,Sample preparation ,0210 nano-technology ,Biomarkers ,Chromatography, Liquid - Abstract
Over the last decade, advances related to high-resolution mass spectrometry (HRMS) have led to improved capabilities for non-targeted chemical analyses. Important applications for these capabilities include identifying unknown xenobiotics and discovering emerging contaminants in human samples as exposure biomarkers. Despite technological advances, identifying unknown compounds by non-targeted analyses remains challenging due in part to the lack of MS spectral libraries and inherent sample complexity resulting in the generation of large amounts of MS data. While high resolution can separate nominally isobaric compounds in a mass spectrum, isomers cannot be distinguished. Much work also remains to develop models to predict both mass spectra and retention times for the unexplored regions of chemical space. In this review, we focus on recent advances and applications of non-targeted analyses using liquid chromatography - high-resolution mass spectrometry (LC-HRMS) in human biomonitoring, including sample preparation, molecular formula assignments, and prediction models for retention times and mass fragmentations, to enable and improve identifications of unknown chemicals. The purpose of this review is to improve our understanding of the applicability and limitations in both the analytical methods and data analysis aspects of non-targeted analysis in human exposure studies. We also discuss the challenges and prospects in this field for future research on sample preparation, identification confidence and accuracy, data processing tools, MS spectra comparability, liquid chromatographic retention time (RT) prediction algorithms, and quantitative capabilities.
- Published
- 2020
29. Quantitative Measurement of Melittin in Asian Honeybee Venom Using a New Method Including UPLC-QqTOF-MS
- Author
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Jianhua Wang, Yan Wang, Chundong Liu, Ze-Qin Guo, and Sheng Huang
- Subjects
Spectrometry, Mass, Electrospray Ionization ,quantitative measurement ,Chromatography ,Health, Toxicology and Mutagenesis ,lcsh:R ,lcsh:Medicine ,Reproducibility of Results ,Asian honeybee venom ,Bees ,Toxicology ,Melitten ,Honeybee venom ,High-performance liquid chromatography ,Article ,Melittin ,Bee Venoms ,chemistry.chemical_compound ,melittin ,chemistry ,Limit of Detection ,Tandem Mass Spectrometry ,ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QqTOF-MS) ,Animals ,Chromatography, Liquid - Abstract
Asian honeybee venom is widely used in traditional oriental medicine. Melittin is the main component of Asian honeybee venom. In the present study, an ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QqTOF-MS) method was used for accurate qualitative and quantitative analyses of melittin in Asian honeybee venom. The results showed that the dynamic linear range of melittin was from 0.094 to 20 &mu, g/mL, and the limit of quantification was 0.3125 &mu, g/mL. The spiking recovery of melittin in honeybee venom ranged from 84.88% to 93.05%. Eighteen Asian honeybee venom samples in eighteen batches were collected from two different zones of China, and their melittin contents were measured. The contents of melittin in Asian honeybee venom samples was 33.9&ndash, 46.23% of dry weight. This method proved a useful tool for the rapid evaluation of the authenticity and quality of Asian honeybee venom in terms of the melittin contents, and will contribute to a broader understanding of Asian honeybee venom.
- Published
- 2020
30. ATR inhibitor AZD6738 enhances the antitumor activity of radiotherapy and immune checkpoint inhibitors by potentiating the tumor immune microenvironment in hepatocellular carcinoma
- Author
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Jian Wang, Hailong Sheng, Hui Wang, Yazhi Xiao, Yan Huang, Chuanhui Cao, Ze-Qin Guo, Wanjun Zhang, Zhenru Zhu, Jingyuan Sun, Wencong Dai, Peitao Zhou, and Mengying Shen
- Subjects
tumors ,0301 basic medicine ,Cancer Research ,Indoles ,Lymphocyte ,medicine.medical_treatment ,Ataxia Telangiectasia Mutated Proteins ,CD8-Positive T-Lymphocytes ,B7-H1 Antigen ,Mice ,0302 clinical medicine ,Immunophenotyping ,Interferon ,Tumor Microenvironment ,Immunology and Allergy ,Medicine ,Immune Checkpoint Inhibitors ,RC254-282 ,Clinical/Translational Cancer Immunotherapy ,Sulfonamides ,Liver Neoplasms ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Drug Synergism ,Chemoradiotherapy ,medicine.anatomical_structure ,Oncology ,Sulfoxides ,030220 oncology & carcinogenesis ,Radioimmunotherapy ,Stimulator of interferon genes ,Molecular Medicine ,Female ,medicine.drug ,Carcinoma, Hepatocellular ,Morpholines ,Immunology ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,Cell Line, Tumor ,Animals ,Humans ,Protein Kinase Inhibitors ,radiotherapy ,Pharmacology ,business.industry ,Cell growth ,Radiation therapy ,Disease Models, Animal ,Pyrimidines ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,business ,CD8 - Abstract
BackgroundRadioimmunotherapy has a promising antitumor effect in hepatocellular carcinoma (HCC), depending on the regulatory effect of radiotherapy on tumor immune microenvironment. Ionizing radiation (IR)-induced DNA damage repair (DDR) pathway activation leads to the inhibition of immune microenvironment, thus impairing the antitumor effect of radioimmunotherapy. However, it is unclear whether inhibition of the DDR pathway can enhance the effect of radioimmunotherapy. In this study, we aim to explore the role of DDR inhibitor AZD6738 on the combination of radiotherapy and immune checkpoint inhibitors (ICIs) in HCC.MethodsC57BL/6 mouse subcutaneous tumor model was used to evaluate the ability of different treatment regimens in tumor growth control and tumor recurrence inhibition. Effects of each treatment regimen on the alterations of immunophenotypes including the quantification, activation, proliferating ability, exhaustion marker expression, and memory status were assessed by flow cytometry.ResultsAZD6738 further increased radiotherapy-stimulated CD8+T cell infiltration and activation and reverted the immunosuppressive effect of radiation on the number of Tregs in mice xenografts. Moreover, compared with radioimmunotherapy (radiotherapy plus anti-PD-L1 (Programmed death ligand 1)), the addition of AZD6738 boosted the infiltration, increased cell proliferation, enhanced interferon (IFN)-γ production ability of TIL (tumor-infiltrating lymphocyte) CD8+T cells, and caused a decreasing trend in the number of TIL Tregs and exhausted T cells in mice xenografts. Thus, the tumor immune microenvironment was significantly improved. Meanwhile, triple therapy (AZD6738 plus radiotherapy plus anti-PD-L1) also induced a better immunophenotype than radioimmunotherapy in mice spleens. As a consequence, triple therapy displayed greater benefit in antitumor efficacy and mice survival than radioimmunotherapy. Mechanism study revealed that the synergistic antitumor effect of AZD6738 with radioimmunotherapy relied on the activation of cyclic GMP–AMP synthase /stimulator of interferon genes (cGAS/STING) signaling pathway. Furthermore, triple therapy led to stronger immunologic memory and lasting antitumor immunity than radioimmunotherapy, thus preventing tumor recurrence in mouse models.ConclusionsOur findings indicate that AZD6738 might be a potential synergistic treatment for radioimmunotherapy to control the proliferation of HCC cells, prolong survival, and prevent tumor recurrence in patients with HCC by improving the immune microenvironment.
- Published
- 2020
31. Evaluation of Differences in MS/MS Spectra from Two Differentgeneration Q-TOF Instruments: Implications for Metabolomic Database Use
- Author
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Hua-Yi Qi, Xiao-Ying Xu, Yan Jiang, Dong-Mei Fang, Zhi-Jun Wu, Ze-Qin Guo, and Zhen-Hua Wang
- Subjects
Metabolomics ,Chromatography ,Ms ms spectra ,Chemistry ,Biophysics ,Pharmaceutical Science ,Molecular Medicine ,Biochemistry - Published
- 2015
32. Fragmentation of Moxifloxacin and Its Analogs by Electrospray Ionization Time-of-Flight Mass Spectrometry
- Author
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Ze-Qin Guo, Zhi-Jun Wu, Jian-Hua Wang, and Dong-Mei Fang
- Subjects
Chemistry ,Electrospray ionization ,Biochemistry (medical) ,Clinical Biochemistry ,Analytical chemistry ,Protonation ,Tandem mass spectrometry ,Biochemistry ,Analytical Chemistry ,Ion ,Deuterium ,Fragmentation (mass spectrometry) ,Moxifloxacin ,Electrochemistry ,medicine ,Time-of-flight mass spectrometry ,Spectroscopy ,medicine.drug - Abstract
The fragmentation of patterns of moxifloxacin, 2-N-methylated moxifloxacin (analog 1), and 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (analog 2) were investigated by electrospray ionization quadrupole time-of-flight tandem mass spectrometry in the positive-ion mode. Many unusual ions were detected in the tandem mass spectra of moxifloxacin. Although the structures of moxifloxacin and analog 1 were similar, the relative abundances of products varied greatly. Comparison of the relative abundances of the product ions that lost CO2 or H2O and complementary product ions resulting from sequential four-membered hydrogen rearrangement showed that the differences were related to the protonation sites. The loss of HF, probably though the formation of an ion/neutral complex, is of scientific interest. The identities of the major product ions were confirmed by deuterium-labeling experiments that demonstrated an unusual loss of a deuterium atom. The major differences in fragmentation patterns were compared to previous reports in the literature.
- Published
- 2014
33. Analysis of a caffeic acid derivative by ESI-MS/MS: unexpected product ions formed by ‘internal residue loss’
- Author
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Yan Jiang, Ze-Qin Guo, Guolin Zhang, Zhi-Jun Wu, Dong-Mei Fang, and Hua-Yi Qi
- Subjects
Residue (chemistry) ,chemistry.chemical_compound ,chemistry ,Stereochemistry ,Electrospray ionization ,Caffeic acid ,Tandem mass spectrometry ,Medicinal chemistry ,Spectroscopy ,Ion - Published
- 2014
34. [M−H]+ ions in 3-alkyl substituted indoles detected by electrospray mass spectrometry
- Author
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Zhi-Jun Wu, Guolin Zhang, Jian-Hua Wang, Ze-Qin Guo, and Dong-Mei Fang
- Subjects
Indole test ,chemistry.chemical_classification ,Steric effects ,Electrospray ,Chemistry ,Hydride ,Analytical chemistry ,Condensed Matter Physics ,Mass spectrometry ,Medicinal chemistry ,Ion ,Electronic effect ,Physical and Theoretical Chemistry ,Instrumentation ,Spectroscopy ,Alkyl - Abstract
A series of six C-3 alkyl-substituted indole derivatives were investigated using electrospray, ionization quadrupole time-of-flight mass spectrometry (ESI-QTOF-MS). Anomalous [M-H](+) ions, were detected. Three possible pathways forming [M-H](+) were proposed. MS/MS spectra and radical, trapping experiment support direct loss of hydride anion. Notably, the positions losing the hydride, anion were different for these compounds, and were tentatively confirmed by D-labeled and MS/MS, spectra. Both steric hindrance and electronic effect might contribute the difference. (c) 2014 Elsevier B.V. All rights reserved.
- Published
- 2014
35. Analysis of calcium adduct molecules of paeoniflorin and albiflorin using electrospray ionization quadrupole time-of-flight mass spectrometry
- Author
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Zhi-Jun Wu, Dong-Mei Fang, Ze-Qin Guo, and Guolin Zhang
- Subjects
Electrospray ionization ,Analytical chemistry ,Condensed Matter Physics ,Paeoniflorin ,Mass spectrometry ,Medicinal chemistry ,Ion ,Adduct ,chemistry.chemical_compound ,chemistry ,Molecule ,Qualitative inorganic analysis ,Physical and Theoretical Chemistry ,Instrumentation ,Spectroscopy ,Benzoic acid - Abstract
Paeoniflorin and albiflorin were investigated by electrospray quadrupole time-of-flight mass spectrometry (ESI-QTOF-MS) in positive-ion mode, when ultrapure water was selected as solvent. In full-scan mode, the ions [M+H2O+Ca](2+), [M+2H(2)O+Ca](2+), [2M+Ca](2+), [3M+Ca](2+), and [4M+Ca](2+) as the primary ions were detected. Low-energy collision-induced experiments for the precursor[M+H2O+Ca](2+) and [2M+Ca](2+) ions provided many interesting productions. Most product ions are formed by combinations of a paeoniflorin (or albiflorin) molecule, benzoic acid anion, aglycone moiety, glucosyl group, H2O, or Ca2+ ion. Strong noncovalent bond formed by Ca2+ and O atom of neutral molecules and proper coordination number might contribute to producing these complex ions. A labeling experiment involving HID exchange of paeoniflorin indicates the H2O molecule did not come from solvent. Although the fragmentation patterns of the isomers of paeoniflorin and albiflorin are similar, they can be completely distinguished by the MS/MS spectra of either [M+H2O+Ca](2+) or [2M+Ca](2+). (C) 2013 Elsevier B.V. All rights reserved.
- Published
- 2013
36. Recent (2000-2015) developments in the analysis of minor unknown natural products based on characteristic fragment information using LC-MS
- Author
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Tian, Cai, Ze-Qin, Guo, Xiao-Ying, Xu, and Zhi-Jun, Wu
- Abstract
Liquid chromatography-Mass Spectrometry (LC-MS) has been widely used in natural product analysis. Global detection and identification of nontargeted components are desirable in natural product research, for example, in quality control of Chinese herbal medicine. Nontargeted components analysis continues to expand to exciting life science application domains such as metabonomics. With this background, the present review summarizes recent developments in the analysis of minor unknown natural products using LC-MS and mainly focuses on the determination of the molecular formulae, selection of precursor ions, and characteristic fragmentation patterns of the known compounds. This review consists of three parts. Firstly, the methods used to determine unique molecular formula of unknown compounds such as accurate mass measurements, MS
- Published
- 2015
37. Analysis of a caffeic acid derivative by ESI-MS/MS: unexpected product ions formed by 'internal residue loss'
- Author
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Ze-Qin, Guo, Hua-Yi, Qi, Yan, Jiang, Dong-Mei, Fang, Guo-Lin, Zhang, and Zhi-Jun, Wu
- Subjects
Ions ,Spectrometry, Mass, Electrospray Ionization ,Caffeic Acids ,Tandem Mass Spectrometry - Published
- 2014
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