Publications by authors named "Zuan Lin"

21 Publications

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Deciphering the potential anti-COVID-19 active ingredients in (Burm. F.) Nees by combination of network pharmacology, molecular docking, and molecular dynamics.

RSC Adv 2021 Nov 11;11(58):36511-36517. Epub 2021 Nov 11.

Department of Pharmacy, Fujian Medical University Union Hospital Fuzhou 350001 China

Currently, coronavirus disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 has posed an enormous threat to public health worldwide. An andrographolide sulfonates preparation, named Xiyanping injection in Chinese, which was prepared from the aqueous extract of (Burm. F.) Nees, showed favorable therapeutic effectiveness on COVID-19, suggesting could contain powerful therapeutic ingredients against COVID-19. In this study, to search for the potential drug candidates for COVID-19 in the herb, 68 potential target proteins and 24 active ingredients from were screened out using TCMSP, STP, Genecards and TTD databases firstly. -Compound-Target network constructed by cytoscape software showed that the protein targets PTGS2, EGFR, MAPK14, had a high network relevance value. GO and KEGG enrichment analysis indicated that the 24 compounds in might exert their therapeutic effects by the biological processes, cellular response to biotic stimulus, response to lipopolysaccharide, response to molecule of bacterial origin, And AGE-RAGE signaling pathway in diabetic complications (hsa04933), Kaposi sarcoma-associated herpesvirus infection (hsa05167), Human cytomegalovirus infection (hsa05163), were predicted as the most significant effect pathways. Andrographidine C (MOL008223) and andrographolide (MOL008232) were found with strong binding affinity to the target active sites of the potential targets by molecular docking. Ultimately, the application of molecular dynamics simulations demonstrated that andrographidine C could bind well to the ACE2 and PIK3CG proteins. This research identified novel molecules against COVID-19 for developing natural medicines from and also provides a possible explanation for the molecular mechanisms of Xiyanping Injection against COVID-19.
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http://dx.doi.org/10.1039/d1ra06487hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9043438PMC
November 2021

A CT-based radiomics model to predict subsequent brain metastasis in patients with ALK-rearranged non-small cell lung cancer undergoing crizotinib treatment.

Thorac Cancer 2022 Apr 18. Epub 2022 Apr 18.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Brain metastasis (BM) comprises the most common reason for crizotinib failure in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). We hypothesize that its occurrence could be predicted by a computed tomography (CT)-based radiomics model, therefore, allowing for selection of enriched patient populations for prevention therapies.

Methods: A total of 75 eligible patients were enrolled from Sun Yat-sen University Cancer Center between June 2014 and September 2019. The primary endpoint was brain metastasis-free survival (BMFS), estimated from the initiation of crizotinib to the date of the occurrence of BM. Patients were randomly divided into two cohorts for model training (n = 51) and validation (n = 24), respectively. A radiomics signature was constructed based on features extracted from chest CT before crizotinib treatment. Clinical model was developed using the Cox proportional hazards model. Log-rank test was performed to describe the difference of BMFS risk.

Results: Patients with low radiomics score had significantly longer BMFS than those with higher, both in the training cohort (p = 0.019) and validation cohort (p = 0.048). The nomogram combining smoking history and the radiomics signature showed good performance for the estimation of BMFS, both in the training (concordance index [C-index], 0.762; 95% confidence interval [CI], 0.663-0.861) and validation cohort (C-index, 0.724; 95% CI, 0.601-0.847).

Conclusion: We have developed a CT-based radiomics model to predict subsequent BM in patients with non-brain metastatic NSCLC undergoing crizotinib treatment. Selection of an enriched patient population at high BM risk will facilitate the design of clinical trials or strategies to prevent BM.
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http://dx.doi.org/10.1111/1759-7714.14386DOI Listing
April 2022

Optimizing the tumor shrinkage threshold for evaluating immunotherapy efficacy for advanced non-small-cell lung cancer.

J Cancer Res Clin Oncol 2022 Mar 18. Epub 2022 Mar 18.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Purpose: The rise of immune checkpoint inhibitors (ICIs) in recent years has coincided with unusual clinical response patterns. Modification of the sum of longest diameters (SLD)-based threshold that reflecting dynamic change of the tumor burden and predicting response to ICIs, may markedly improve current treatment regimens.

Methods: The baseline and post-treatment SLD of target lesion was recorded and the maximum percent change of the SLD from baseline was designated as SLD-change score. The optimal cut-off value was obtained using the X-tile program. The relationship between SLD-change score and survival outcome (PFS, OS) was evaluated.

Results: 10% cut-off value of SLD-change score was found to be most distinctive for PFS. Responders defined according to this cut-off value showed a significant improvement for PFS and OS. Bone metastasis and brain metastasis were also two independent prognostic factors of PFS and OS, respectively.

Conclusions: 10% SLD change score could discriminate for ICIs treatment response, which holds great promise in promoting the development of precise immunotherapeutic strategy.
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http://dx.doi.org/10.1007/s00432-022-03978-3DOI Listing
March 2022

Recent progress (2015-2020) in the investigation of the pharmacological effects and mechanisms of ginsenoside Rb, a main active ingredient in Meyer.

J Ginseng Res 2022 Jan 30;46(1):39-53. Epub 2021 Jul 30.

Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China.

Ginsenoside Rb (Rb), one of the most important ingredients in Meyer, has been confirmed to have favorable activities, including reducing antioxidative stress, inhibiting inflammation, regulating cell autophagy and apoptosis, affecting sugar and lipid metabolism, and regulating various cytokines. This study reviewed the recent progress on the pharmacological effects and mechanisms of Rb against cardiovascular and nervous system diseases, diabetes, and their complications, especially those related to neurodegenerative diseases, myocardial ischemia, hypoxia injury, and traumatic brain injury. This review retrieved articles from PubMed and Web of Science that were published from 2015 to 2020. The molecular targets or pathways of the effects of Rb on these diseases are referring to HMGB1, GLUT4, 11β-HSD1, ERK, Akt, Notch, NF-κB, MAPK, PPAR-γ, TGF-β1/Smad pathway, PI3K/mTOR pathway, Nrf2/HO-1 pathway, Nrf2/ARE pathway, and MAPK/NF-κB pathway. The potential effects of Rb and its possible mechanisms against diseases were further predicted via Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and disease ontology semantic and enrichment (DOSE) analyses with the reported targets. This study provides insights into the therapeutic effects of Rb and its mechanisms against diseases, which is expected to help in promoting the drug development of Rb and its clinical applications.
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http://dx.doi.org/10.1016/j.jgr.2021.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8753521PMC
January 2022

Reducing number of target lesions for RECIST1.1 to predict survivals in patients with advanced non-small-cell lung cancer undergoing anti-PD1/PD-L1 monotherapy.

Lung Cancer 2021 Dec 31;165:10-17. Epub 2021 Dec 31.

State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Objectives: The Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 provides conventional and standardized response assessment for multiple solid tumors. We investigated the smallest number of target lesions that can be measured without compromising response categorization and survival prediction in patients with advanced non-small-cell lung cancer (aNSCLC) undergoing anti-PD-1/PD-L1 monotherapy.

Material And Methods: 125 aNSCLC patients with at least two measurable lesions undergoing PD-1/PD-L1 inhibitor treatment were retrospectively studied. Tumor measurements allowing up to two lesions per organ and five lesions in total were reviewed. Inter-individual agreement and κ values for inter-method concordance on response status were evaluated based on up to five target lesions versus the largest one through four lesions. C-index was calculated to evaluate the prognostic accuracy of response categorization based on the selected number of target lesions for predicting overall survival (OS). Cox regression analysis was conducted for survival analysis.

Results: The highly consistent response assignment (99.2%) could be obtained when measuring the largest two lesions versus up to five lesions. Using the largest two through four lesions produced κ values of 0.986, 1.000 and 1.000 for response assessment, values significantly higher than those obtained when measuring the largest single lesion (κ = 0.850). C-index for overall survival (OS) was similar when assessing the largest one through five lesions, ranging from 0.646 to 0.654. Cox regression analyses showed that radiological response significantly predicted OS, irrespective of the number of target lesions selected.

Conclusions: Reducing the number of target lesions does not affect OS prediction in aNSCLC patients treated with anti-PD-1/PD-L1 therapy. Considering the high intra-individual and inter-method concordance, using the largest two lesions in total is proposed to assess response.
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http://dx.doi.org/10.1016/j.lungcan.2021.12.015DOI Listing
December 2021

Correction to: Hepatotoxicity associated with PD-1 blockade antibodies in cancer patients co-infected with hepatitis B virus.

Cancer Immunol Immunother 2022 May;71(5):1257

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

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http://dx.doi.org/10.1007/s00262-021-03112-1DOI Listing
May 2022

Recent Research Progress (2015-2021) and Perspectives on the Pharmacological Effects and Mechanisms of Tanshinone IIA.

Front Pharmacol 2021 8;12:778847. Epub 2021 Nov 8.

Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University, Fuzhou, China.

Tanshinone IIA (Tan IIA) is an important characteristic component and active ingredient in , and its various aspects of research are constantly being updated to explore its potential application. In this paper, we review the recent progress on pharmacological activities and the therapeutic mechanisms of Tan IIA according to literature during the years 2015-2021. Tan IIA shows multiple pharmacological effects, including anticarcinogenic, cardiovascular, nervous, respiratory, urinary, digestive, and motor systems activities. Tan IIA modulates multi-targets referring to Nrf2, AMPK, GSK-3β, EGFR, CD36, HO-1, NOX4, Beclin-1, TLR4, TNF-α, STAT3, Caspase-3, and bcl-2 proteins and multi-pathways including NF-κB, SIRT1/PGC1α, MAPK, SREBP-2/Pcsk9, Wnt, PI3K/Akt/mTOR pathways, TGF-β/Smad and Hippo/YAP pathways, etc., which directly or indirectly influence disease course. Further, with the reported targets, the potential effects and possible mechanisms of Tan IIA against diseases were predicted by bioinformatic analysis. This paper provides new insights into the therapeutic effects and mechanisms of Tan IIA against diseases.
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http://dx.doi.org/10.3389/fphar.2021.778847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606659PMC
November 2021

Unsatisfied Reporting Quality of Clinical Trials Evaluating Immune Checkpoint Inhibitor Therapy in Cancer.

Front Immunol 2021 5;12:736943. Epub 2021 Oct 5.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, China.

Background: More and more immune-oncology trials have been conducted for treating various cancers, yet it is unclear what the reporting quality of immune-oncology trials is,and characteristics associated with higher reporting quality.

Objective: This study aims to evaluate the reporting quality of immune-oncology trials.

Methods: The PubMed and Cochrane library were searched to identify all English publications of clinical trials assessing immunotherapy for cancer. Reporting quality of immune-oncology trials was evaluated by a quality score with 11 points derived from the Trial Reporting in Immuno-Oncology (TRIO) statement, which contained two parts: an efficacy score of 6 points and toxicity score of 5 point. Linear regression was used to identify characteristics associated with higher scores.

Results: Of the 10,169 studies screened, 298 immune-oncology trial reports were enrolled. The mean quality score, efficacy score, and toxicity score were 6.46, 3.61, and 2.85, respectively. The most common well-reported items were response evaluation criteria (96.0%) and toxicity grade (98.7%), followed by Kaplan-Meier survival analyses (80.5%). Treatment details beyond progression (12.8%) and toxicity onset time and duration (7.7%) were poorly reported. Multivariate regression revealed that higher impact factor (IF) (IF >20 vs. IF <5, < 0.001), specific tumor type ( = 0.018 for lung, = 0.021 for urinary system, vs. pan cancer), and a certain kind of immune checkpoint blocking agent ( < 0.001 for anti-PD-1 or multiagents, vs. anti-CTLA-4) were independent predictors of higher-quality score. Similar independent predictive characteristics were revealed for high-efficacy score. Only IF >20 had a significant high-toxicity score ( < 0.001).

Conclusion: Immune-oncology trial reports presented an unsatisfied quality score, especially in the reporting of treatment details beyond progression and toxicity onset time and duration. High IF journals have better reporting quality. Future improvement of trial reporting was warranted to the benefit-risk assessment of immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.736943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8524036PMC
December 2021

Hepatotoxicity associated with PD-1 blockade antibodies in cancer patients co-infected with hepatitis B virus.

Cancer Immunol Immunother 2022 May 14;71(5):1247-1255. Epub 2021 Oct 14.

Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China.

The use of anti-programmed cell death-1 (PD-1) antibodies in treating malignancies is increasing; however, most registered clinical trials on anti-PD-1 antibodies exclude patients infected with hepatitis B virus (HBV). This retrospective study aimed to assess hepatotoxicity in cancer patients infected with HBV undergoing anti-PD1 antibody therapy and identify the associated risk factors. A total of 301 cancer patients positive for hepatitis B core antibodies (HbcAb) (negative or positive hepatitis B surface antigen [HBsAg]) who received PD-1 inhibitors were enrolled. The primary and secondary endpoints were the incidence rate of hepatotoxicity related to PD-1 inhibitor treatment, and risk factors associated with hepatic toxicity, respectively. Of the enrolled analyzed, 16.9% (n = 51) developed any grade and 4.7% (n = 14) developed grade 3-4 hepatotoxicity, respectively. Higher risk for any-grade hepatotoxicity development was associated with sero-positive HBsAg (OR = 6.30; P = 0.020), existence of liver involvement (OR = 2.10; P = 0.030), and detectable baseline HBV DNA levels (OR = 2.39; P = 0.012). Patients with prophylactic antiviral therapy decreased hazard for the incidence of grade 3-4 hepatotoxicity (OR = 0.10; P = 0.016). Our results suggested chronic (HBsAg-positive)/resolved (HBsAg-negative and HBcAb-positive) HBV-infected cancer patients are at an increased risk of hepatotoxicity following PD-1 inhibitor therapy. Cancer patients should be tested for HBsAg/HBcAb prior to the commencement of immune checkpoint inhibitor therapy. For patients with chronic/resolved HBV infection, ALT/AST and HBV DNA should be closely monitored during the whole immunotherapy period.
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http://dx.doi.org/10.1007/s00262-021-03082-4DOI Listing
May 2022

Association of hepatitis B virus infection status with outcomes of non-small cell lung cancer patients undergoing anti-PD-1/PD-L1 therapy.

Transl Lung Cancer Res 2021 Jul;10(7):3191-3202

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: The aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status.

Methods: Patients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes.

Results: Of the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.4-32.8] and 2.1 months (95% CI: 1.2-3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 2.0 months; P=0.103) and OS (35.0 18.2 months, P=0.119) than did RHB patients.

Conclusions: Anti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used.
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http://dx.doi.org/10.21037/tlcr-21-455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350074PMC
July 2021

Baseline and early changes in circulating Serum Amyloid A (SAA) predict survival outcomes in advanced non-small cell lung cancer patients treated with Anti-PD-1/PD-L1 monotherapy.

Lung Cancer 2021 08 28;158:1-8. Epub 2021 May 28.

State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Background: Systemic inflammation plays an important role in carcinogenesis and is associated with overall survival in patients with different cancer types, including those treated with immune checkpoint blockade (ICB). Serum Amyloid A (SAA) is an acute-phase protein and a marker of persistent inflammation. We hypothesized that circulating SAA may predict outcomes in advanced non-small cell lung (aNSCLC) patients treated with PD-1/PD-L1 ICB.

Materials And Methods: This retrospective study included 91 aNSCLC patients who received anti-PD-(L)1 monotherapy in Sun Yat-sen University Cancer Center (Guangzhou, China) between August 2016 and June 2018. We examined the impact of circulating SAA at baseline and 8 (±2) weeks later on overall survival (OS). X-tile program was used to determine the cut-off values which optimized the significance of the split between Kaplan-Meier survival curves. Kaplan-Meier methodology and Cox regression analyses were conducted for survival analyses.

Results: The optimal cut-off value of baseline SAA for OS stratification was 137.6 mg/L. In univariate analysis, both high level of baseline SAA (hazard ratio [HR], 2.76; 95% confidence interval [CI], 1.47-5.18; P = 0.002) and lack of early SAA descent (HR, 1.51; 95% CI, 1.11-2.06; P = 0.009) were significantly associated with inferior OS. In multivariate analysis, gender, smoking status, performance status, liver metastasis, neutrophil-to-lymphocyte ratio, baseline SAA and early changes in SAA independently predicted OS (all with P < 0.05). A combined baseline SAA ≥ 137.6 mg/L and without early SAA descent identified a small cohort with remarkably worse OS (median, 3.2 months).

Conclusions: Both high baseline and lack of early decline in circulating SAA are significantly associated with inferior outcomes in aNSCLC patients treated with PD-1/PD-L1 ICB. Combined these two SAA indexes provided improved risk stratification. The prognostic value of this simple, readily-available, and cost-effective biomarker warrants larger, prospective validation before definitive recommendation can be made.
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http://dx.doi.org/10.1016/j.lungcan.2021.05.030DOI Listing
August 2021

Pre-Treatment Tumor Growth Rate Predicts Clinical Outcomes of Patients With Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD-1/PD-L1 Therapy.

Front Oncol 2020 19;10:621329. Epub 2021 Jan 19.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Tumor growth rate (TGR; percent size change per month [%/m]) is postulated as an early radio-graphic predictor of response to anti-cancer treatment to overcome limitations of RECIST. We aimed to evaluate the predictive value of pre-treatment TGR (TGR) for outcomes of advanced non-small cell lung cancer (aNSCLC) patients treated with anti-PD-1/PD-L1 monotherapy. We retrospectively screened all aNSCLC patients who received PD-1 axis inhibitors in Sun Yat-Sen University Cancer Center between August 2016 and June 2018. TGR was calculated as the percentage change in tumor size per month (%/m) derived from two computed tomography (CT) scans during a "wash-out" period before the initiation of PD-1 axis inhibition. Final follow-up date was August 28, 2019. The X-tile program was used to identify the cut-off value of TGR based on maximum progression-free survival (PFS) stratification. Patients were divided into two groups per the selected TGR cut-off. The primary outcome was the difference of PFS between the two groups. The Kaplan-Meier methods and Cox regression models were performed for survival analysis. A total of 80 eligible patients were included (54 [67.5%] male; median [range] age, 55 [30-74] years). Median (range) TGR was 21.1 (-33.7-246.0)%/m. The optimal cut-off value of TGR was 25.3%/m. Patients with high TGR had shorter median PFS (1.8 months; 95% CI, 1.6 - 2.1 months) than those with low TGR (2.7 months; 95% CI, 0.5 - 4.9 months) ( = 0.005). Multivariate Cox regression analysis revealed that higher TGR independently predicted inferior PFS (hazard ratio [HR] 1.97; 95% CI, 1.08-3.60; = 0.026). Higher TGR was also significantly associated with less durable clinical benefit rate (34.8% vs. 8.8%, = 0.007). High pre-treatment TGR was a reliable predictor of inferior PFS and clinical benefit in aNSCLC patients undergoing anti-PD-1/PD-L1 monotherapy. The findings highlight the role of TGR as an early biomarker to predict benefit from immunotherapy and could allow tailoring patient's follow-up.
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http://dx.doi.org/10.3389/fonc.2020.621329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863973PMC
January 2021

Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma by Targeting the Epidermal Growth Factor Receptor Combined with Gemcitabine Plus Platinum.

Cancer Manag Res 2020 20;12:10353-10360. Epub 2020 Oct 20.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, People's Republic of China.

Purpose: The purpose of this study was to evaluate the anti-tumor activity and safety of anti-epidermal growth factor receptor (EGFR) monoclonal antibody combined with gemcitabine plus platinum (GP) as a first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC).

Patients And Methods: This retrospective study analyzed RM-NPC patients at Sun Yat-sen University Cancer Center who received anti-EGFR antibody plus GP as a first-line treatment between July 2007 and November 2018. Survival analyses were performed using the Kaplan-Meier method with Log rank test. Cox proportional hazards model was used for the multivariate analysis.

Results: A total of 84 patients were enrolled. The median progression-free survival (PFS) was 10.3 months (95% CI, 6.9-13.6 months), and the median overall survival (OS) was 42.8 months (95% CI, 24.6-60.9 months). The objective response rate and disease control rate were 67.9% and 92.9%, respectively. The multivariate analysis identified a higher baseline EBV DNA level as a risk factor for both PFS (P=0.025) and OS (P=0.013). Additionally, age≥44 years (P =0.003), non-cisplatin (P= 0.009), and poor KPS (≤80) (P =0.034) were other risk factors for OS. The most common adverse events were leukopenia (n=73, 86.9%). The most common grade 3-4 AEs were leukopenia (n=30, 35.7%) and thrombocytopenia (n=22, 26.2%).

Conclusion: Anti-EGFR monoclonal antibody plus GP achieved promising antitumor activity with a tolerable toxicity profile in RM-NPC as a first-line treatment. Randomized clinical trials are warranted to compare the efficacy of GP with or without anti-EGFR antibody in these patients.
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http://dx.doi.org/10.2147/CMAR.S275947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585779PMC
October 2020

Potential mechanism of action of extract injection against cardiovascular diseases revealed by combination of HPLC-Q-TOF-MS, virtual screening and systems pharmacology approach.

RSC Adv 2020 Oct 20;10(63):38497-38504. Epub 2020 Oct 20.

Department of Pharmaceutical Analysis, School of Pharmacy, Fujian Medical University Fuzhou 350122 China

extract injection, a Chinese medicine preparation named as Kudiezi injection (KDZI) in China, has been widely used for the treatment of cardiovascular diseases (CVDs) in recent years. Owing to the component complexity of the preparation, the study on the effect mechanism of the herbal medicine against CVDs is a big challenge. In this research, HPLC-Q-TOF-MS was used to analyze the constituents of the preparation, disclosing that the KDZI mainly consists of 10 ingredients, namely 3-caffeoylquinic acid (KDZI-1), 4-caffeoylquinic acid (KDZI-2), 5-caffeoylquinic acid (KDZI-3), apigenin-7--β-d-glucuronide (KDZI-4), caffeic acid (KDZI-5), chicoric acid (KDZI-6), caftaric acid (KDZI-7), luteolin-7--β-d-gentiobioside (KDZI-8), luteolin-7--β-d-glucopyranoside (KDZI-9) and luteolin-7--β-d-glucuronide (KDZI-10). Afterwards, target fishing and an integrated systems pharmacology approach combined with molecular docking (Sybyl 1.3 and AutoDock Vina) were adopted to predict the potential targets and pathways for the main ingredients in KDZI. As results, 39 protein targets and 9 KEGG pathways, possessing high relevance to the therapeutic effects of the ingredients of KDZI against CVDs, were screened out reasonably. The integrated pharmacology analysis suggested that KDZI could exert its therapeutic effects against CVDs possibly multi-targets including EGFR, MAPK10, and SRC and multi-pathways referring to MAPK, focal adhesion, complement and coagulation cascades, . This research provides insights into understanding the comprehensive therapeutic effect and mechanism of the KDZI on CVDs.
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http://dx.doi.org/10.1039/d0ra07038fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9057262PMC
October 2020

An Integrated Pharmacokinetic Study of an Extract Preparation by Combination of Virtual Screening, Systems Pharmacology, and Multi-Component Pharmacokinetics in Rats.

Front Pharmacol 2020 14;11:1295. Epub 2020 Aug 14.

College of Horticulture, FAFU-UCR Joint Center and Fujian Provincial Key Laboratory of Haixia Applied Plant Systems Biology, Fujian Agriculture and Forestry University, Fuzhou, China.

In this paper, the integrated pharmacokinetics (PK) of an extract preparation (ASEP, named as Ciwujia injection in clinic in China) was explored by combining with multi-component PK in rats, virtual screening, systems pharmacology and molecular docking. Firstly, the ingredients in ASEP with high contents and detectable property in rat plasma were selected. Next, the PK study of the resulted ingredients was performed in rats (1.76 ml/kg and 3.52 ml/kg of 5 times concentrated ASEP, single i.v.). Meanwhile, the drug targets for the ingredients screened out were predicted by using a target fishing online server, PharmMapper (http://www.lilab-ecust.cn/pharmmapper/) with a fit filtration threshold of z'-score >0. Next, the network pharmacology, molecular docking, diseases ontology (DO) analysis, and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed respectively for the predicted targets. Finally, the supporting evidences were obtained to characterize the PK markers and carry out the integrated PK study with "plasma-drug concentration sum" or "plasma-drug AUC weighted" methods. As a result, 6 ingredients, involving 5-caffeoylquinic acid (5-CQA), 3-CQA, 4-CQA, protocatechuic acid, eleutheroside B, and gentiopicroside were selected, and their PK profiles were elucidated. The 6 ingredients were highly related to arteriosclerotic cardiovascular disease and atherosclerosis and could mainly interact with similar targets, e.g., GSK3B, PDPK1, PLAU, etc., or pathways, e.g., Insulin, VEGF, FoxO, etc, providing the basis for integrating plasma drug concentration. Ultimately, the 6 ingredients were considered as PK markers and the whole process of ASEP were characterized. Our study would enhance understanding of the therapeutic effects and mechanisms of ASEP against cardiovascular diseases, and provided useful insights for future integrated PK study on anti-cardiovascular diseases TCM injections.
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http://dx.doi.org/10.3389/fphar.2020.01295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457137PMC
August 2020

A simple fluorescence assay for trypsin through a protamine-induced carbon quantum dot-quenching aggregation platform.

RSC Adv 2020 Jul 28;10(45):26765-26770. Epub 2020 Jul 28.

Department of Pharmaceutical Analysis, School of Pharmacy, The Higher Educational Key Laboratory for Nano Biomedical Technology of Fujian Province, Fujian Medical University Fuzhou 350122 China

The development of a simple detection strategy for trypsin (Try) is urgent, and is ascribed to the diagnostic value of Try in several diseases. Herein, a facile but effective fluorescence strategy for Try was developed based on the protamine (Pro)-induced aggregation of carbon quantum dots (CQDs). The fluorescence of negatively charged CQDs was quenched with Pro due to the assembly of CQDs and Pro (CQDs/Pro) through electrostatic interaction. However, the highly positively charged Pro, which is rich in basic arginine residues, was preferred to be hydrolyzed by Try. Try can induce the deaggregation of CQDs/Pro, thereby enabling the release of CQDs to restore the fluorescence intensity. Thus, the use of CQDs/Pro as a testing platform will be employed as a "turn-on" method for Try. In addition, the fluorescence-resuming response was proportional to Try, ranging from 25 ng mL to 500 ng mL with a limit of detection (LOD) of 8.08 ng mL. This "turn-on" fluorescence assay for Try was label-free, convenient, and relatively free of interference from coexisting substances. Actual applications for Try monitoring and trypsin inhibitor screening also illustrated the considerable prospect of CQDs in the clinical field, combined with the superiority of the simple mixing operation.
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http://dx.doi.org/10.1039/d0ra03970eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9055544PMC
July 2020

Anti-epidermal growth factor receptor monoclonal antibody plus palliative chemotherapy as a first-line treatment for recurrent or metastatic nasopharyngeal carcinoma.

Cancer Med 2020 03 19;9(5):1721-1732. Epub 2020 Jan 19.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Platinum-based chemotherapy is the standard of care as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (RM-NPC); however, the prognosis of patients with RM-NPC remains poor. The aim of this study was to evaluate the role of anti-epidermal growth factor receptor (anti-EGFR) antibody plus chemotherapy for RM-NPC.

Methods: RM-NPC patients who received first-line chemotherapy plus an anti-EGFR antibody were recruited from Sun Yat-Sen University Cancer Center between July 2007 and November 2017. Survival analyses were performed using the Kaplan-Meier method with a log-rank test. A Cox proportional hazards model was used for the multivariate analyses.

Results: A total of 203 patients were enrolled in the present study. The median follow-up time was 34.3 months (interquartile range: 19.7-66.5 months). The median progression-free survival (PFS) was 8.9 months (95% CI: 7.7-10.0 months) and the median overall survival (OS) was 29.1 months (95% CI: 23.5-34.6 months). The 1-, 3-, and 5-year PFS and OS rates were 35.5% and 79.6%, 15.2% and 42.5%, and 11.6% and 23.6%, respectively. The objective response rate (ORR) was 67.5% and the disease control rate (DCR) was 91.1%. The multivariate analysis identified the following prognostic factors for PFS: anti-EGFR agent (P = .010), recurrence/metastasis sequence (P = .016), KPS (P = .017), and combined chemotherapy regimen (P = .015). Independent risk factors for OS included age >43 years (P = .002), Karnofsky performance score ≤80 (P < .001), and higher level of baseline Epstein-Barr virus (EBV) DNA (P = .008). Leukopenia was the most common adverse event (AE) in this cohort (any grade, 84.2%; grades 3-4, 43.4%).

Conclusions: Anti-EGFR antibody plus chemotherapy achieved promising antitumor activity with a tolerable toxicity profile in RM-NPC. Thus, randomized clinical trials are warranted to compare the efficacy of chemotherapy with or without anti-EGFR antibody in these patients.
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http://dx.doi.org/10.1002/cam4.2838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050081PMC
March 2020

Hepatitis B virus reactivation in cancer patients with positive Hepatitis B surface antigen undergoing PD-1 inhibition.

J Immunother Cancer 2019 11 21;7(1):322. Epub 2019 Nov 21.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Background: Hepatitis B virus (HBV) reactivation is a serious complication in patients with cancers and HBV infection undergoing immunosuppressant treatment or chemotherapy. However, the safety of anti-programmed cell death (PD) -1 and anti-programmed cell death-ligand 1 (PD-L1) therapy in these patients is unknown because they were excluded from clinical trials of immunotherapy.

Methods: This retrospective cohort study involved consecutive hepatitis B surface antigen (HBsAg) -positive cancer patients who were referred to Sun Yat-sen University Cancer Center and received an anti-PD-1/PD-L1 antibody between January 1, 2015 and July 31, 2018. The primary end point was the rate of the occurrence of HBV reactivation.

Results: In total, 114 eligible patients were included, among whom 90 (79%) were male, and the median (range) age was 46 (16-76) years. Six patients (5.3%) developed HBV reactivation, occurring at a median of 18 weeks (range, 3-35 weeks) from the commencement of immunotherapy. Among these patients, all of them had undetectable baseline HBV DNA; one had prophylactic antiviral therapy while five did not; four were positive for Hepatitis B e antigen while the other two were negative. At reactivation, the median HBV DNA level was 3.89 × 10 IU/mL (range, 1.80 × 10-6.00 × 10 IU/mL); five had HBV-related hepatitis and one exhibited increasing HBV DNA level without alanine transaminase elevation. No HBV-related fatal events occurred. The lack of antiviral prophylaxis was the only significant risk factor for HBV reactivation (odds ratio, 17.50 [95% CI, 1.95-157.07], P = .004).

Conclusions: HBV reactivation occurs in a subset of HBsAg-positive cancer patients undergoing anti-PD-1 or anti-PD-L1 immunotherapy. Regular monitoring of HBV DNA and antiviral prophylaxis are advised to prevent this potentially fatal complication.
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http://dx.doi.org/10.1186/s40425-019-0808-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873745PMC
November 2019

First-line platinum-based chemotherapy and survival outcomes in locally advanced or metastatic pulmonary lymphoepithelioma-like carcinoma.

Lung Cancer 2019 11 12;137:100-107. Epub 2019 Sep 12.

State Key Laboratory of Oncology in South China, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China. Electronic address:

Objectives: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare subtype of primary lung cancer. Due to the lack of prospective studies, the optimal first-line chemotherapy regimens and survival outcomes remain unclear.

Materials And Methods: This real-world, retrospective study enrolled consecutive patients with unresectable pulmonary LELC. The survival outcomes, prognosis, and comparative efficacy of different chemotherapy regimens were investigated.

Results: In total, 127 patients were included in the analyses. The first-line chemotherapy regimens included gemcitabine plus platinum (GP, n = 19 [15.0%]), taxanes plus platinum (TP, n = 70 [55.1%]) and pemetrexed plus platinum (AP, n = 38 [30.0%]). 25 (19.7%) patients underwent palliative thoracic radiotherapy. 60 (47.2%) patients had detectable baseline Epstein-Barr virus (EBV) DNA. For the entire cohort, objective response was obtained in 41 patients (32.3%). Median progression-free survival (PFS) and overall survival (OS) were 7.7 months (95% CI, 6.6-8.8) and 36.7 months (95% CI, 30.9-42.5), respectively. Among the three chemotherapy regimens, GP achieved the highest response rate (GP, 63.2% vs. TP, 30.0% vs. AP, 21.1%; p = 0.005). Median PFS in the GP group (8.8 months) was also significantly longer than that in the TP group (7.9 months) and AP group (6.4 months) (p = 0.031). In the multivariate model, cycles of first-line chemotherapy (p < 0.001), palliative thoracic radiotherapy (p < 0.001), and chemotherapy regimens (p = 0.031) remained independent prognostic factors for PFS; while cycles of first-line chemotherapy (p = 0.002), baseline EBV DNA (p = 0.033) and palliative thoracic radiotherapy (p = 0.041) were significantly associated with OS.

Conclusion: Gemcitabine-based chemotherapy and palliative thoracic radiotherapy are active in pulmonary LELC. These data provide added evidence for the similarity between pulmonary LELC and nasopharyngeal carcinoma in endemic area. Randomized controlled studies are needed to further define the standard-of-care for patients with advanced pulmonary LELC.
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http://dx.doi.org/10.1016/j.lungcan.2019.09.007DOI Listing
November 2019

First-line treatment for patients with advanced non-small cell lung carcinoma and high PD-L1 expression: pembrolizumab or pembrolizumab plus chemotherapy.

J Immunother Cancer 2019 05 3;7(1):120. Epub 2019 May 3.

State Key Laboratory of Oncology in South China, Guangzhou, China.

Pembrolizumab monotherapy has become the preferred treatment for patients with advanced non-small cell lung carcinoma (NSCLC) and a programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS) of at least 50%. However, little is known about the value of adding chemotherapy to pembrolizumab in this setting. Therefore, we performed an indirect comparison for pembrolizumab plus chemotherapy versus pembrolizumab, using the frequentist methods. The primary outcomes were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Data were retrieved from randomized trials comparing pembrolizumab plus chemotherapy or pembrolizumab monotherapy against chemotherapy. Five trials involving 1289 patients were included. Direct meta-analysis showed that both pembrolizumab plus chemotherapy (ORR: relative risk (RR) 2.16; PFS: hazard ratio (HR) 0.36; OS: HR 0.51) and pembrolizumab alone (ORR: RR 1.33; PFS: HR, 0.65; OS: HR 0.67) improved clinical outcomes compared with chemotherapy. Indirect comparison showed that pembrolizumab plus chemotherapy was superior to pembrolizumab alone, in terms of ORR (RR 1.62, 1.18-2.23) and PFS (HR 0.55, 0.32-0.97). A trend towards improved OS was also observed (HR 0.76, 0.51-1.14). In conclusion, the addition of chemotherapy to pembrolizumab further improves the outcomes of patients with advanced NSCLC and a PD-L1 TPS of at least 50%.
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http://dx.doi.org/10.1186/s40425-019-0600-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500047PMC
May 2019

High molecular weight chitosan derivative polymeric micelles encapsulating superparamagnetic iron oxide for tumor-targeted magnetic resonance imaging.

Int J Nanomedicine 2015 5;10:1155-72. Epub 2015 Feb 5.

State Key Laboratory of Organ Failure Research, Division of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.

Magnetic resonance imaging (MRI) contrast agents based on chitosan derivatives have great potential for diagnosing diseases. However, stable tumor-targeted MRI contrast agents using micelles prepared from high molecular weight chitosan derivatives are seldom reported. In this study, we developed a novel tumor-targeted MRI vehicle via superparamagnetic iron oxide nanoparticles (SPIONs) encapsulated in self-aggregating polymeric folate-conjugated N-palmitoyl chitosan (FAPLCS) micelles. The tumor-targeting ability of FAPLCS/SPIONs was demonstrated in vitro and in vivo. The results of dynamic light scattering experiments showed that the micelles had a relatively narrow size distribution (136.60±3.90 nm) and excellent stability. FAPLCS/SPIONs showed low cytotoxicity and excellent biocompatibility in cellular toxicity tests. Both in vitro and in vivo studies demonstrated that FAPLCS/SPIONs bound specifically to folate receptor-positive HeLa cells, and that FAPLCS/SPIONs accumulated predominantly in established HeLa-derived tumors in mice. The signal intensities of T2-weighted images in established HeLa-derived tumors were reduced dramatically after intravenous micelle administration. Our study indicates that FAPLCS/SPION micelles can potentially serve as safe and effective MRI contrast agents for detecting tumors that overexpress folate receptors.
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http://dx.doi.org/10.2147/IJN.S70022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330038PMC
May 2016
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