Publications by authors named "Jiachen Xu"

23 Publications

  • Page 1 of 1

Weighting tumor-specific TCR repertoires as a classifier to stratify the immunotherapy delivery in non-small cell lung cancers.

Sci Adv 2021 May 19;7(21). Epub 2021 May 19.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Analysis of T cell receptor (TCR) repertoires may contribute to better understanding of the response to immunotherapy. By deep sequencing of the TCR β chain complementarity-determining regions in the paired biopsies and peripheral blood specimens of 31 patients with non-small cell lung cancer (NSCLC) treated with anti-programmed death 1 (PD-1) or PD-ligand 1 (PD-L1) therapy, we developed a previously unidentified index, the TCR-based immunotherapy response index (TIR index), that estimated the degree of overlap of the TCR repertoire between tumor-infiltrating lymphocytes and circulating PD-1CD8T cells (shared TCR clones). This index correlated with response and survival outcomes of anti-PD-(L)1 treatment. All the TCR sequences of neoantigen-stimulated T cells were included in the shared TCR clones, indicating that TCR clones involved in TIR index estimation represented tumor-specific T cells. Therefore, the TIR index is a feasible approach for assessing tumor-specific TCR and stratifying patients with NSCLC for anti-PD-(L)1 therapy.
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http://dx.doi.org/10.1126/sciadv.abd6971DOI Listing
May 2021

PD-L1 and CD47 co-expression predicts survival and enlightens future dual-targeting immunotherapy in non-small cell lung cancer.

Thorac Cancer 2021 Jun 12;12(11):1743-1751. Epub 2021 May 12.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Backgroud: Recent studies have indicated that programmed cell death-ligand 1 (PD-L1) and cluster of differentiation 47 (CD47) play an essential role in tumor immune evasion and may serve as potential targets for combined immunotherapy. The aim of our study was to evaluate the PD-L1/CD47 expression status in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD), and explore its survival impact and relevance with the immune microenvironment.

Methods: The specimens from 190 LUSC and 240 LUAD patients who underwent intent-to-treat surgeries were retrospectively collected for immunohistochemistry assays of PD-L1, CD47, cluster of differentiation 8 (CD8), and cluster of differentiation 68 (CD68).

Results: A total of 96 (22.3%) and 296 (68.8%) cases were positive for PD-L1 and CD47 expression, respectively, and 80 (18.6%) of them demonstrated the co-expression of PD-L1/CD47. The rate of PD-L1/CD47 co-expression was 23.7% in LUSC, significantly higher than the 14.6% in LUAD (p = 0.018). The median overall survival (OS) for all patients was 55.9 months (range 2.0-146.0 months). The univariate analysis showed that patients with positive CD47 expression (LUSC p = 0.003, LUAD p = 0.036) and PD-L1/CD47 co-expression (LUSC p = 0.023, LUAD p = 0.004) exhibited significantly worse prognosis. The multivariate analysis demonstrated that PD-L1/CD47 co-expression was an independent prognostic factor for OS (LUSC hazard ratio [HR] 1.922, 95% CI 1.245-2.969, p = 0.003; LUAD HR 1.549, 95% CI 1.015-2.364, p = 0.043). PD-L1/CD47 co-expression was associated with high CD8-positive T-lymphocyte density in LUSC (p = 0.004) and LUAD (p = 0.043), and with high CD68-positive macrophage density in LUSC (p = 0.026).

Conclusions: PD-L1/CD47 co-expression was an independent prognostic factor for LUSC and LUAD patients and may serve as a potential predictive biomarker for combined dual-targeting immunotherapy.
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http://dx.doi.org/10.1111/1759-7714.13989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169290PMC
June 2021

EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma.

J Immunother Cancer 2020 12;8(2)

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

Background: Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between mutation ( ) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC).

Methods: Multiple cohorts were used to assess the immunotherapeutic predictive performance of , including one discovery cohort (n=79) and two public validation cohort (cohort 1: NSCLC, n=165; cohort 2: pan-cancer, n=1662). The Cancer Genome Atlas cohort was used for prognostic analysis and mechanism exploration.

Results: In the discovery cohort, patients with had superior disease control rate (72.2% vs 36.1%, p=0.01) and progression-free survival (PFS) (HR 0.38; 95% CI 0.21 to 0.68; p<0.001) compared with those with wide-type ( ) in NSCLC. The association between and immunotherapy outcomes in NSCLC was consistently observed in the validation cohorts by multivariable models (cohort 1, PFS HR 0.59; 95% CI 0.37 to 0.96; p=0.03; cohort 2, overall survival (OS) HR 0.63; 95% CI 0.41 to 0.98; p=0.04). Further pooled estimates of the discovery and validation cohorts showed that patients with exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC). Consistently, mechanism analysis revealed that patients with was associated with increased T cell signatures and downregulated signaling compared with patients with in LUAD while not LUSC.

Conclusions: Our results demonstrated that is an independent classifier that could stratify patients with LUAD for ICIs therapy. Further prospective studies are warranted.

Trial Registration Number: NCC2016JZ-03, NCC2018-092.
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http://dx.doi.org/10.1136/jitc-2020-001315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733211PMC
December 2020

Reply to "Does MAFLD really increase the severity of COVID-19?"

Dig Liver Dis 2021 02 4;53(2):168. Epub 2020 Nov 4.

Department of medicine, JingGangshan University, No.28 Xueyuan Road, Qingyuan District, Ji 'an City, Jiangxi province, China.

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http://dx.doi.org/10.1016/j.dld.2020.10.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641532PMC
February 2021

Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma.

J Immunother Cancer 2020 10;8(2)

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

Background: The survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored.

Methods: Cell lines, syngeneic immunocompetent mouse models, and patients' peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized.

Results: Low-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8 T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic.

Conclusions: We first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.
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http://dx.doi.org/10.1136/jitc-2020-000807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594539PMC
October 2020

Influence of adjuvant chemotherapy on survival for patients with stage IB and IIA non-small cell lung cancer.

Thorac Cancer 2021 01 27;12(1):30-39. Epub 2020 Oct 27.

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Background: The role of adjuvant chemotherapy (ACT) for patients with stage IB-IIA non-small cell lung cancer (NSCLC) according to the eighth edition of the AJCC TNM staging system remains controversial.

Methods: Data were collected from patients with NSCLC stage IB-IIA according to the eighth edition of the AJCC TNM staging system who underwent surgical resection from 2008 to 2015. The relationship between ACT and overall survival (OS) or disease-free survival (DFS) was analyzed using the Kaplan-Meier method and Cox proportional hazards model.

Results: The study included 648 patients with completely resected NSCLC stage IB-IIA; 312 underwent ACT after surgical resection and 336 were placed under observation. After propensity score matching, 247 pairs of patients were matched and the five-year OS was 88.08% and 83.12% (P = 0.13) in ACT and non-ACT settings, respectively. Subgroup analyses demonstrated that ACT treatment was correlated with an improved five-year OS in patients with visceral pleural invasion (VPI) in the 3 < tumor ≤ 4 cm subgroup (93.98% and 68.93%, P < 0.01).

Conclusions: ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, further subgroup analysis showed that patients with VPI in the 3 < tumor ≤ 4 cm (T2aN0M0, stage IB) subgroup might benefit more from ACT. Further studies are required to validate the findings and better systemic strategies need to be developed in these patients.

Key Points: SIGNIFICANT FINDINGS OF THE STUDY: For patients with stage IB-IIA NSCLC according to the eighth edition of the AJCC TNM staging system, the effect of ACT remains unclear. ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, it was correlated with better DFS before or after PSM. Patients with VPI in the 3 < tumor ≤ 4 cm subgroup may benefit from ACT.

What This Study Adds: ACT was not significantly associated with improved five-year OS in stage IB-IIA NSCLC patients. However, it was correlated with better DFS before or after PSM. Patients with VPI in the 3 < tumor ≤ 4 cm subgroup may benefit from ACT.
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http://dx.doi.org/10.1111/1759-7714.13685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779205PMC
January 2021

Safety, Antitumor Activity, and Pharmacokinetics of Toripalimab, a Programmed Cell Death 1 Inhibitor, in Patients With Advanced Non-Small Cell Lung Cancer: A Phase 1 Trial.

JAMA Netw Open 2020 10 1;3(10):e2013770. Epub 2020 Oct 1.

Department of Medical Oncology, State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China.

Importance: Programmed cell death 1 (PD-1) antibodies have shown substantial survival benefit in patients with advanced non-small cell lung cancer (NSCLC). Toripalimab is a promising and practicable PD-1 antibody; however, its performance in NSCLC has not been established.

Objectives: To assess the safety, antitumor activity, and pharmacokinetics of toripalimab in patients with advanced NSCLC and to evaluate the utility of JS311, a novel PD ligand 1 (PD-L1) immunohistochemistry (IHC) assay.

Design, Setting, And Participants: This single-arm open-label phase 1 trial enrolled 41 patients with advanced NSCLC that had progressed after at least 3 lines of therapy between September 21, 2017, and June 5, 2018, with a median (interquartile range) follow-up of 14.9 (3.2-22.5) months and included a cohort study comparing JS311 with other PD-L1 IHC assays that included 280 NSCLC specimens collected from January 1, 2016, to May 21, 2018. Data collection was conducted from September 21, 2017, to September 27, 2019, and analysis was conducted from September 27, 2019, to December 30, 2019.

Exposure: Enrolled patients were administered a single dose of toripalimab, under 2 manufacturing processes and scales (200 L and 500 L), for safety and pharmacokinetic analysis within 28 days, followed by subsequent multidose infusions every 2 weeks. PD-L1 expression was determined by IHC with JS311, comparing its results with results from 22C3, 28-8, and SP263 simultaneously.

Main Outcomes And Measures: Progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier curves, and continuous variables compared by t test or Mann-Whitney test. Correlations between PD-L1 IHC antibodies were evaluated by Spearman correlation test.

Results: A total of 41 patients (29 [70.7%] men) with a median (interquartile range) age of 59 (53 to 63) years who experienced disease progression following chemotherapy were included. The most common treatment-related adverse events were rash (6 [14.6%]), increased amylase level (5 [12.2%]), and increased aspartate aminotransferase level (5 [12.2%]). In 35 patients included in the pharmacokinetic analysis, drug exposure and area under curve after 1 dose was similar under both manufacturing processes and scales (mean [SD] for 200-L group: 12 465.28 [4128.17] hour × μg/mL; for 500-L group: 12 331.42 [2472.58] hour × μg/ml). In 28 patients included in the response and survival analysis, the median PFS and OS were 2.8 (95% CI, 2.7 to 4.6) months and 13.8 months (95% CI, 10.0 months to not reached), respectively. Stratified by PD-L1 tumor proportion score of at least 50%, 1% to 49%, and less 1%, median PFS rates were 11.2 months (95% CI, 2.3 months to not evaluable), 2.3 (95% CI, 1.7 to 2.7) months, and 2.8 (95% CI, 2.7 to 4.6) months, respectively. A total of 4 anti-PD-L1 IHC antibodies were compared during PD-L1 staining, using 280 NSCLC specimens. The consistency rates between the 4 antibodies were 80.8% to 89.5% (ρ, 0.619 to 0.790) and 93.3% to 95.5% (ρ, 0.691 to 0.773), with PD-L1 tumor proportion scores of 1% and 50% as cut points, respectively.

Conclusions And Relevance: In this study, toripalimab exhibited encouraging antitumor activity and manageable safety profiles among patients with heavily treated NSCLC. The novel PD-L1 IHC antibody JS311 was highly consistent with previously verified PD-L1 IHC assays.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.13770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536589PMC
October 2020

Metabolic associated fatty liver disease increases the severity of COVID-19: A meta-analysis.

Dig Liver Dis 2021 02 17;53(2):153-157. Epub 2020 Sep 17.

Department of medicine, JingGangshan University, Ji'an,Jiangxi province,China, No.28 Xueyuan Road, Qingyuan District, Ji 'an City, China.

Background: The association between metabolic-associated fatty liver disease (MAFLD) and disease progression in patients with the coronavirus disease 2019 (COVID-19) are unclear.

Aims: To explore the association between MAFLD and the severity of COVID-19 by meta-analysis.

Methods: We conducted a literature search using PubMed, EMBASE, Medline (OVID), and MedRxiv from inception to July 6, 2020. Newcastle-Ottawa Scale (NOS) and Stata 14.0 were used for quality assessment of included studies as well as for performing a pooled analysis.

Results: A total of 6 studies with 1,293 participants were included after screening. Four studies reported the prevalence of MAFLD patients with COVID-19, with a pooled prevalence of 0.31 for MAFLD (95CI 0.28, 0.35, I = 38.8%, P = 0.179). MAFLD increased the risk of COVID-19 disease severity, with a pooled OR of 2.93 (95CI 1.87, 4.60, I = 34.3%, P = 0.166).

Conclusion: In this meta-analysis, we found that a high percentage of patients with COVID-19 had MAFLD. Meanwhile, MAFLD increased the risk of disease progression among patients with COVID-19. Thus, better intensive care and monitoring are needed for MAFLD patients infected by SARS-COV-2.
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http://dx.doi.org/10.1016/j.dld.2020.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498251PMC
February 2021

Integrated molecular characterization reveals potential therapeutic strategies for pulmonary sarcomatoid carcinoma.

Nat Commun 2020 09 28;11(1):4878. Epub 2020 Sep 28.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P.R. China.

Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of lung cancer with poor prognosis. Here, we perform multi-omics analysis of 56 PSC samples, 14 of which are microdissected to analyze intratumoral heterogeneity. We report the mutational landscape of PSC. The epithelial and sarcomatoid components share numerous genomic alterations, indicating a common progenitor. We find that epithelial-mesenchymal transition (EMT) plays important roles in the carcinogenesis of PSC. The pan-cancer analysis reveals high tumor mutation burden and leukocyte fraction of PSC. Integrated molecular classification shows three subgroups with distinct biology, prognosis and potential therapeutic strategies. Actionable mutations are enriched in C1 and C2, patients in C3 have a significantly longer overall survival, and C1 and C2 exhibit T-cell inflamed microenvironments. The three subgroups show molecular similarities to specific subtypes of conventional lung cancer. In conclusion, our study reveals the molecular characteristics and provides entry points for the treatment of PSC.
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http://dx.doi.org/10.1038/s41467-020-18702-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522294PMC
September 2020

Refined Stratification Based on Baseline Concomitant Mutations and Longitudinal Circulating Tumor DNA Monitoring in Advanced EGFR-Mutant Lung Adenocarcinoma Under Gefitinib Treatment.

J Thorac Oncol 2020 12 9;15(12):1857-1870. Epub 2020 Sep 9.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China. Electronic address:

Introduction: The optimal treatment for EGFR-mutant lung adenocarcinoma (LUAD) remains challenging because of intratumor heterogeneity. We aimed to explore a refined stratification model based on the integrated analysis of circulating tumor DNA (ctDNA) tracking.

Methods: ctDNA was prospectively collected at baseline and at every 8 weeks in patients with advanced treatment-naive EGFR-mutant LUAD under gefitinib treatment enrolled in a phase 2 trial and analyzed using next-generation sequencing of a 168-gene panel.

Results: Three subgroups categorized by baseline comutations-EGFR-sensitizing mutations (59, 32.8%), EGFR-sensitizing mutations with tumor suppressor mutations (97, 53.9%), and EGFR-sensitizing mutations with other driver mutations (24, 13.3%)-exhibited distinct progression-free survival (13.2 [11.3-15.2] versus 9.3 [7.6-10.5] versus 4.0 [2.4-9.3] months) and overall survival (32.0 [29.2-41.5] versus 21.7 [19.3-27.0] versus 15.5 [10.5-33.7] months, respectively), providing evidence for initial stratification. A total of 63.7% of the patients achieved week 8 ctDNA clearance, with significant difference noted among the three subgroups (74.5% versus 64.0% versus 29.4%, respectively, p = 0.004, Fisher's exact test). Patients without week 8 ctDNA clearance had worse progression-free survival (clearance versus nonclearance 11.2 [9.9-13.2] versus 7.4 [5.6-9.6] months, p = 0.016, Cox regression], especially in the second subgroup [5.8 (5.6-11.5) months], suggesting the necessity of adaptive stratification during treatment. During follow-up, 56.0% and 20.8% of the patients eventually harbored p.T790M and non-p.T790M mutations, respectively, with a significant difference in non-p.T790M mutations among the three subgroups (7.5% versus 15.7% versus 80.0%, respectively, p < 0.001, Fisher's exact test), giving clues to postline treatment.

Conclusions: The patients with baseline comutations and ctDNA nonclearance at first visit might require combined therapy because of the limited survival benefit of EGFR tyrosine kinase inhibitor monotherapy. We proposed a refined stratification mode for the whole-course management of EGFR-mutant LUAD.
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http://dx.doi.org/10.1016/j.jtho.2020.08.020DOI Listing
December 2020

A novel tumor mutational burden estimation model as a predictive and prognostic biomarker in NSCLC patients.

BMC Med 2020 08 26;18(1):232. Epub 2020 Aug 26.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China.

Background: Tumor mutational burden (TMB) has both prognostic value in resected non-small cell lung cancer (NSCLC) patients and predictive value for immunotherapy response. However, TMB evaluation by whole-exome sequencing (WES) is expensive and time-consuming, hampering its application in clinical practice. In our study, we aimed to construct a mutational burden estimation model, with a small set of genes, that could precisely estimate WES-TMB and, at the same time, has prognostic and predictive value for NSCLC patients.

Methods: TMB estimation model was trained based on genomic data from 1056 NSCLC samples from The Cancer Genome Atlas (TCGA). Validation was performed using three independent cohorts, including Rizvi cohort and our own Asian cohorts, including 89 early-stage and n late-stage Asian NSCLC patients, respectively. TCGA data were obtained on September 3, 2018. The two Asian cohort studies were performed from September 1, 2018, to March 5, 2019. Pearson's correlation coefficient was used to assess the performance of estimated TMB with WES-TMB. The Kaplan-Meier survival analysis was applied to evaluate the association of estimated TMB with disease-free survival (DFS), overall survival (OS), and response to anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) therapy.

Results: The estimation model, consisted of only 23 genes, correlated well with WES-TMB both in the training set of TCGA cohort and validation set of Rizvi cohort and our own Asian cohort. Estimated TMB by the 23-gene panel was significantly associated with DFS and OS in patients with early-stage NSCLC and could serve as a predictive biomarker for anti-PD-1 and anti-PD-L1 treatment response.

Conclusions: The 23-gene panel, instead of WES or the currently used panel-based methods, could be used to assess the WES-TMB with a high relevance. This customized targeted sequencing panel could be easily applied into clinical practice to predict the immunotherapy response and prognosis of NSCLC.
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http://dx.doi.org/10.1186/s12916-020-01694-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448445PMC
August 2020

A new chapter in immune checkpoint inhibitor therapy: starting with advanced lung squamous cell carcinoma.

Transl Lung Cancer Res 2020 Jun;9(3):833-836

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China.

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http://dx.doi.org/10.21037/tlcr-20-570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354157PMC
June 2020

Tangent space spatial filters for interpretable and efficient Riemannian classification.

J Neural Eng 2020 05 1;17(2):026043. Epub 2020 May 1.

Faculty of Computer Science, University of Vienna, Hörlgasse 6, 1090 Vienna, Austria.

Objective: Methods based on Riemannian geometry have proven themselves to be good models for decoding in brain-computer interfacing (BCI). However, these methods suffer from the curse of dimensionality and are not possible to deploy in high-density online BCI systems. In addition, the lack of interpretability of Riemannian methods leaves open the possibility that artifacts drive classification performance, which is problematic in the areas where artifactual control is crucial, e.g. neurofeedback and BCIs in patient populations.

Approach: We rigorously proved the exact equivalence between any linear function on the tangent space and corresponding derived spatial filters. Upon which, we further proposed a set of dimension reduction solutions for Riemannian methods without intensive optimization steps. The proposed pipelines are validated against classic common spatial patterns and tangent space classification using an open-access BCI analysis framework, which contains over seven datasets and 200 subjects in total. At last, the robustness of our framework is verified via visualizing the corresponding spatial patterns.

Main Results: Proposed spatial filtering methods possess competitive, sometimes even slightly better, performances comparing to classic tangent space classification while reducing the time cost up to 97% in the testing stage. Importantly, the performances of proposed spatial filtering methods converge with using only four to six filter components regardless of the number of channels which is also cross validated by the visualized spatial patterns. These results reveal the possibility of underlying neuronal sources within each recording session.

Significance: Our work promotes the theoretical understanding about Riemannian geometry based BCI classification and allows for more efficient classification as well as the removal of artifact sources from classifiers built on Riemannian methods.
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http://dx.doi.org/10.1088/1741-2552/ab839eDOI Listing
May 2020

Allele Frequency-Adjusted Blood-Based Tumor Mutational Burden as a Predictor of Overall Survival for Patients With NSCLC Treated With PD-(L)1 Inhibitors.

J Thorac Oncol 2020 04 12;15(4):556-567. Epub 2019 Dec 12.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, P. R. China.

Introduction: Blood-based tumor mutational burden (bTMB) has been studied to identify patients with NSCLC who would benefit from anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand 1 (anti-PD-L1) therapies. However, it failed to predict overall survival (OS) benefits, which warrants further exploration.

Methods: Three independent cohorts of patients with NSCLC treated with immunotherapy were used in this study. A new bTMB algorithm was first developed in the two independent cohorts (POPLAR, N = 211, and OAK, N = 462) and further validated in the third National Cancer Center (NCC) cohort (N = 64).

Results: bTMB-H (bTMB ≥ cutoff point) was not associated with favorable OS after immunotherapy regardless of the cutoff points in either the POPLAR and OAK or the NCC cohorts (p > 0.05) owing to its correlation with the amount of circulating tumor DNA, which was associated with poor OS. In the POPLAR and OAK cohorts, with allele frequency (AF) adjustment, a high AF bTMB (HAF-bTMB, mutation counts with an AF > 5%) was strongly correlated with the amount of circulating tumor DNA (Pearson r = 0.65), whereas a low AF bTMB (LAF-bTMB, mutation counts with an AF ≤ 5%) was not (Pearson r = 0.09). LAF-bTMB-H was associated with favorable OS (hazard ratio [HR] = 0.70, 95% confidence interval [CI]: 0.52-0.95, p = 0.02), progression-free survival (PFS; HR = 0.62, 95% CI: 0.47-0.80, p < 0.001), and objective response rate (ORR) (p < 0.001) after immunotherapy but not chemotherapy, with a cutoff point of 12 trained in the POPLAR cohort and validated in the OAK cohort. The LAF-bTMB algorithm was further validated in the NCC cohort in which LAF-bTMB-H was associated with OS (HR = 0.20, 95% CI: 0.05-0.84, p = 0.02), PFS (HR = 0.30, 95% CI: 0.13-0.70, p = 0.003), and ORR (p = 0.001).

Conclusions: We developed and validated a new LAF-bTMB algorithm as a feasible predictor of OS, PFS, and ORR after anti-PD-(L)1 therapies in patients with NSCLC, which needs to be prospectively validated.
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http://dx.doi.org/10.1016/j.jtho.2019.12.001DOI Listing
April 2020

PD-L1 and CD47 co-expression in pulmonary sarcomatoid carcinoma: a predictor of poor prognosis and potential targets of future combined immunotherapy.

J Cancer Res Clin Oncol 2019 Dec 14;145(12):3055-3065. Epub 2019 Sep 14.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17, Panjiayuannanli, Chaoyang District, Beijing, 100021, People's Republic of China.

Purpose: Combined immunotherapy with anti-programmed cell death-ligand 1 (PD-L1) and an inhibitor of cluster of differentiation 47 (CD47) have exhibited preliminary anti-tumor effect. Our study attempted to describe the PD-L1/CD47 expression status in pulmonary sarcomatoid carcinoma (PSC), and explore its survival impact and relevance with cytotoxic T lymphocytes and macrophages infiltration.

Methods: 148 patients with PSC who underwent surgeries were retrospectively reviewed. Tissue microarrays were conducted for immunohistochemistry (IHC) of PD-L1, CD47, CD8 and CD68.

Results: 54 (36.5%) and 78 (52.7%) cases were positive for PD-L1 and CD47, respectively, and 36 (24.3%) of them demonstrated PD-L1/CD47 co-expression. There was a significant correlation between PD-L1 and CD47 expression (P = 0.011). The median overall survival (OS) was 22.5 months (range 0.9-102.4 months). The univariate analysis demonstrated a significantly worse OS in cases with CD47 expression (hazard ratio [HR], 1.66; 95% CI, 1.14-2.42, P = 0.008) and PD-L1/CD47 co-expression (HR, 1.75; 95% CI, 1.15-2.67, P = 0.009). The multivariate analysis demonstrated PD-L1/CD47 co-expression (HR, 1.83; 95% CI, 1.17-2.87, P = 0.008), T stage, M stage, completeness of resection and adjuvant therapy were independent prognostic factors for OS. There was a significant relevance between PD-L1 expression and PD-L1/CD47 co-expression with higher densities of CD8-positive T lymphocytes (P = 0.004, 0.012, respectively) and CD68-positive macrophages (P = 0.026, 0.034, respectively).

Conclusion: We demonstrated the PD-L1/CD47 co-expression status in PSC. PD-L1 expression correlated with CD47 expression, and PD-L1/CD47 co-expression correlated with poorer prognosis and may serve as a predictive biomarker for combined dual-targeting immunotherapy in PSC patients.
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http://dx.doi.org/10.1007/s00432-019-03023-wDOI Listing
December 2019

Multiregion Sequencing Reveals the Genetic Heterogeneity and Evolutionary History of Osteosarcoma and Matched Pulmonary Metastases.

Cancer Res 2019 01 2;79(1):7-20. Epub 2018 Nov 2.

State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolutionary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the pathway at both the early and late stages of tumor evolution and in the pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis. SIGNIFICANCE: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1086DOI Listing
January 2019

Controlled feature selection and compressive big data analytics: Applications to biomedical and health studies.

PLoS One 2018 30;13(8):e0202674. Epub 2018 Aug 30.

Statistics Online Computational Resource, Department of Health Behavior and Biological Sciences, University of Michigan, Ann Arbor, Michigan, United States of America.

The theoretical foundations of Big Data Science are not fully developed, yet. This study proposes a new scalable framework for Big Data representation, high-throughput analytics (variable selection and noise reduction), and model-free inference. Specifically, we explore the core principles of distribution-free and model-agnostic methods for scientific inference based on Big Data sets. Compressive Big Data analytics (CBDA) iteratively generates random (sub)samples from a big and complex dataset. This subsampling with replacement is conducted on the feature and case levels and results in samples that are not necessarily consistent or congruent across iterations. The approach relies on an ensemble predictor where established model-based or model-free inference techniques are iteratively applied to preprocessed and harmonized samples. Repeating the subsampling and prediction steps many times, yields derived likelihoods, probabilities, or parameter estimates, which can be used to assess the algorithm reliability and accuracy of findings via bootstrapping methods, or to extract important features via controlled variable selection. CBDA provides a scalable algorithm for addressing some of the challenges associated with handling complex, incongruent, incomplete and multi-source data and analytics challenges. Albeit not fully developed yet, a CBDA mathematical framework will enable the study of the ergodic properties and the asymptotics of the specific statistical inference approaches via CBDA. We implemented the high-throughput CBDA method using pure R as well as via the graphical pipeline environment. To validate the technique, we used several simulated datasets as well as a real neuroimaging-genetics of Alzheimer's disease case-study. The CBDA approach may be customized to provide generic representation of complex multimodal datasets and to provide stable scientific inference for large, incomplete, and multisource datasets.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202674PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116997PMC
February 2019

A study on microwave-assisted fast co-pyrolysis of chlorella and tire in the N and CO atmospheres.

Bioresour Technol 2018 Feb 24;250:821-827. Epub 2017 Nov 24.

School of Electric Power, South China University of Technology, 510640 Guangzhou, China; Guangdong Province Key Laboratory of Efficient and Clean Energy Utilization, 510640 Guangzhou, China.

The microwave-assisted fast co-pyrolysis of chlorella and tire with additive under N and CO atmospheres were investigated. The pyrolysis profiles, yields of three-phase, the chemical composition of liquid and the ultimate analyses of solid residues were gained. With the tire ratio increasing, all the characters had the changes. The finial temperature had a wave change. The yield of liquid decreased and the chemical composition obtained in liquid of oxygenates compounds decreased, while hydrocarbon compounds increased, among which aromatic hydrocarbons had the highest content. The yield of solid increased, the HHV had a wave change and the values of H/C decreased. Under CO atmosphere, the final temperatures were lower with 70% and 100% chlorella ratios, the yield difference of liquid reached the minimal with 70% and 30% chlorella ratios. According to the quantity and quality of liquid and solid, and the former results, 50% percentage of tire was the suitable ratio.
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http://dx.doi.org/10.1016/j.biortech.2017.11.080DOI Listing
February 2018

Safety, anti-tumour activity, and pharmacokinetics of fixed-dose SHR-1210, an anti-PD-1 antibody in advanced solid tumours: a dose-escalation, phase 1 study.

Br J Cancer 2018 08 14;119(5):538-545. Epub 2018 May 14.

Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Background: To assess the safety profile, pharmacokinetics, pharmacodynamics and preliminary antitumour activity of fixed-dose SHR-1210, a novel anti-PD-1 antibody, in advanced solid tumours.

Methods: A total of 36 patients with advanced solid tumours received intravenous SHR-1210 at 60 mg, 200 mg and 400 mg (4-week interval after first dose followed by a 2-week schedule) until disease progression or intolerable toxicity. The concentration of SHR-1210 was detected for pharmacokinetics, and receptor occupancy on circulating T lymphocytes was assessed for pharmacodynamics.

Results: No dose-limiting toxicities were observed. Maximum administered dose was not reached. Most adverse events were grade 1 or 2. Treatment-related severe adverse events were found in two patients. No treatment-related death was reported. Two complete responses (gastric cancer, bladder carcinoma) and seven partial responses were seen. In responders, the median follow-up time was 16.0 months (range 8.3-19.5), and the median duration of response was not reached (range 2.7-17.5+ months). The half-life of SHR-1210 was 2.94 d, 5.61 d and 11.0 d for 3 dose levels, respectively.

Conclusions: Our results demonstrated a promising antitumour activity and a manageable safety profile of SHR-1210, displayed an explicit PK evidence of the feasibility of fixed dose, and established the foundation for further exploration.
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http://dx.doi.org/10.1038/s41416-018-0100-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162236PMC
August 2018

Two young women with severe coronary arterial ostial narrowing: A potential subtype of Takayasu arteritis.

Int J Cardiol 2015 10;189:94-5. Epub 2015 Apr 10.

Department of Cardiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2015.04.070DOI Listing
April 2016

All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity.

J Lipid Res 2015 Mar 20;56(3):537-545. Epub 2015 Jan 20.

School of Pharmacy, Fudan University, China; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY; Molecular and Cellular Cardiology Program, VA New York Harbor Healthcare System, Brooklyn, NY. Electronic address:

Sphingomyelin synthase-related protein (SMSr) synthesizes the sphingomyelin analog ceramide phosphoethanolamine (CPE) in cells. Previous cell studies indicated that SMSr is involved in ceramide homeostasis and is crucial for cell function. To further examine SMSr function in vivo, we generated Smsr KO mice that were fertile and had no obvious phenotypic alterations. Quantitative MS analyses of plasma, liver, and macrophages from the KO mice revealed only marginal changes in CPE and ceramide as well as other sphingolipid levels. Because SMS2 also has CPE synthase activity, we prepared Smsr/Sms2 double KO mice. We found that CPE levels were not significantly changed in macrophages, suggesting that CPE levels are not exclusively dependent on SMSr and SMS2 activities. We then measured CPE levels in Sms1 KO mice and found that Sms1 deficiency also reduced plasma CPE levels. Importantly, we found that expression of Sms1 or Sms2 in SF9 insect cells significantly increased not only SM but also CPE formation, indicating that SMS1 also has CPE synthase activity. Moreover, we measured CPE synthase Km and Vmax for SMS1, SMS2, and SMSr using different NBD ceramides. Our study reveals that all mouse SMS family members (SMSr, SMS1, and SMS2) have CPE synthase activity. However, neither CPE nor SMSr appears to be a critical regulator of ceramide levels in vivo.
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http://dx.doi.org/10.1194/jlr.M054627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340302PMC
March 2015

Research and development of anti-Alzheimer's drugs: an analysis based on technology flows measured by patent citations.

Expert Opin Ther Pat 2014 Jul 5;24(7):791-800. Epub 2014 May 5.

University of Macau, Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine , Macao , China ;

Introduction: Alzheimer's disease (AD) is a serious illness with dramatically increasing incidence. Tremendous worldwide efforts have been exerted to find better ways to treat the disease, delay its onset and prevent it from progressing. In order to discover future anti-AD medicines more rationally, it is crucial to understand the evolving process of existing related technologies from the perspective of technology flow.

Areas Covered: Patent citation has been used broadly as a powerful tool to capture technology flows. This study collects patent data from IMS Health databases on anti-AD drugs, both marketed and in the research and development (R&D) pipeline. In all, 329 US patents from 1978 through 2013 and citations between them are analyzed, in addition to patents related to marketed drugs.

Expert Opinion: To discover effective agents for AD treatment, one promising strategy is to integrate various technology clusters related to anti-AD drugs in terms of the extremely dispersed patent citation network in this area. In this context, governments should pay more attention to encourage basic research, especially to focus on cross-mechanism anti-AD agents. New theories and targets for AD, such as the tau protein hypothesis, are worthy of researcher note. Drugs targeting β-amyloid peptide theory show promise for investors.
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http://dx.doi.org/10.1517/13543776.2014.915943DOI Listing
July 2014

Cross-regional Pharmaceutical Technology Transfer in China: Patterns and Proposed Investment Strategies.

Ther Innov Regul Sci 2014 Mar;48(2):226-235

1 State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China.

The Chinese pharmaceutical market is undergoing dramatic growth, with a huge population, urbanization, a growing number of elderly patients, and increases in the standard of living. As a research-based and high-tech sector, the pharmaceutical industry depends highly upon technological innovation, especially the spatial diffusion of technologies from the perspective of economic geography. In this context, an analysis of technology flowing between regions is of great significance for the investment in a regional market. This article differs from previous studies by focusing on geographic patterns of pharmaceutical technology transfer captured by patent licensing in China, which are further used to analyze investment strategies. The research sample is composed of all pharmaceutical patent licenses filed with the State Intellectual Property Office of China from January 1, 2009, through December 31, 2012. As a result, a geographic network of pharmaceutical technology diffusion in China could be visualized, and province-level regions were ranked and classified into 3 types-input, output, and balance-by various network indicators. Finally, potential investment strategies on different types of regions are recommended for firms abroad, technology holders, contract research organizations, and technology agencies.
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http://dx.doi.org/10.1177/2168479013506003DOI Listing
March 2014