Publications by authors named "Li-Na He"

30 Publications

  • Page 1 of 1

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 Jun 18;13(11):1558-1569. 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
June 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

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

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

[Chemical constituents from the leaves of Cinnamomum camphora var. linaloolifera and their anti-inflammatory activities].

Zhongguo Zhong Yao Za Zhi 2021 Jul;46(14):3592-3598

Fujian Colleges and Universities Engineering Research Institute of Conservation & Utilization of Natural Bioresources Fuzhou 350000,China.

Thirteen compounds were isolated and purified from the leaves of Cinnamomum camphora by the macroporous resin,silica gel,and Sephadex LH-20 column chromatographies. Those compounds were further identified by IR,UV,MS,and NMR techniques:( 2 S)-1-( 3″,4″-methylenedioxy phenyl)-3-( 2',6'-dimethoxy-4'-hydroxyphenyl)-propan-2-ol( 1),( 2 R,3 R)-5,7-dimethoxy-3',4'-methylenedioxy flavanol( 2),9-hydroxysesamin( 3),sesamin( 4),piperitol( 5),kobusin( 6),(-)-aptosimon( 7),acuminatolide( 8),1β,11-dihydroxy-5-eudesmene( 9),lasiodiplodin( 10),vanillin( 11),p-hydroxybenzaldehyde( 12),and p-hydroxybenzoic acid ethyl ester( 13). Compound 1 was a novel compound,and compounds 2,6,7,9 and 10 were isolated from Cinnamomum plants for the first time. Compounds 4,7 and 10 were found to possess good inhibitory effect on IL-6 production in LPS-induced BV2 cells at a concentration of 20 μmol·L-1 in the in vitro bioassay,with inhibition rates of 51. 26% ± 4. 13%,67. 82% ± 3. 77% and85. 81%±1. 19%,respectively.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20210318.602DOI Listing
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

TERF1 downregulation promotes the migration and invasion of the PC3 prostate cancer cell line as a target of miR‑155.

Mol Med Rep 2020 Dec 21;22(6):5209-5218. Epub 2020 Oct 21.

Department of Urology, Zigong Fourth People's Hospital, Zigong, Sichuan 643000, P.R. China.

Telomeric repeat binding factor 1 (TERF1) has been identified as a tumor suppressor gene in numerous types of human cancer. However, the expression of TERF1 and its mechanism in prostate cancer (PCa) remains unclear. The present study aimed to explore the expression and functions of TERF1 in PCa. The UALCAN database was used to analyze the differential expression of TERF1 between normal prostate tissue and primary PCa tissue. Cell apoptosis was analyzed by Annexin V/propidium iodide staining, and wound healing and Transwell assays were used to detect the cell migration and invasion abilities, respectively. The cell viability was analyzed using an MTT assay. Reverse transcription‑quantitative PCR and western blotting were used to analyze the mRNA and protein expression levels, respectively, of epithelial‑mesenchymal transition (EMT) markers following TERF1 knockdown in the PC3 cell line. A dual luciferase reporter assay was used to verify the association between TERF1 and microRNA (miR)‑155 predicted by bioinformatics analysis. Rescue experiments were performed to determine the role of the miR‑155/TERF1 axis in regulating the cellular behaviors of PCa. The results demonstrated that the expression levels of TERF1 in the primary prostate tumors were significantly downregulated compared with in prostate normal tissue. TERF1 silencing was discovered to significantly promote cell viability, migration and invasion, while suppressing cell apoptosis. The impact of TERF1 on PC3 cells was suggested to occur through the EMT pathway. TERF1 was confirmed to be the direct target of miR‑155. The overexpression of miR‑155 promoted the viability, migration and invasion, while suppressing the apoptosis of the PC3 cell line, while the knockdown of miR‑155 in PC3 cells achieved the opposite trends. In addition, TERF1 overexpression reversed the promotive effects of upregulated miR‑155 expression levels on the migration and apoptosis of PC3 cells. On the contrary, the knockdown of TERF1 reversed the migration and apoptosis abilities of the downregulated miR‑155 expression levels on the cellular behaviors of PC3 cells. In conclusion, TERF1, as a direct target of miR‑155, was discovered to be significantly downregulated in PCa, which was suggested to promote the migration and invasion of PCa via the EMT pathway.
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http://dx.doi.org/10.3892/mmr.2020.11623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646979PMC
December 2020

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

Elevated Prevalence of Abnormal Glucose Metabolism and Other Endocrine Disorders in Patients with β-Thalassemia Major: A Meta-Analysis.

Biomed Res Int 2019 18;2019:6573497. Epub 2019 Apr 18.

Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510150, China.

Background: Endocrinopathies are common in patients with -thalassemia major despite parenteral iron chelation therapy with deferoxamine. Prevalence of abnormal glucose metabolism in previous studies was controversial. The aim of this study was to discuss the prevalence of abnormal glucose metabolism in -thalassemia major based on a meta-analysis.

Methods: PubMed, ScienceDirect, Springerlink, Ovid, Web of Science, MEDLINE, Wanfang database, and Chinese National Knowledge Internet were searched for relevant articles. Two authors selected the articles according to the inclusion criteria and then extracted the data. The prevalence of diabetes mellitus (DM) in -thalassemia major was defined as the primary outcome. The prevalence with the 95% confidence interval (95%CI) was used to evaluate the proportion of abnormal glucose metabolism and other endocrine disorders in patients with -thalassemia major. Subgroup analyses were applied to explore the prevalence in different regions. Sensitivity analysis and publication bias assessment were also conducted.

Results: A total of 44 studies with 16605 cases were included in this analysis. Diabetes mellitus was present in 6.54% (95% CI: 5.30%-7.78%). The fixed subgroup study revealed that the region with the highest prevalence was the Middle East (prevalence= 7.90%, 95% CI: 5.75%-10.05%). The accumulated meta-analysis revealed that the prevalence of DM in -thalassemia major was relatively steady in each year. The prevalence of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and other endocrine disorders in -thalassemia major was 17.21% (95% CI: 8.43%-26.00%), 12.46% (95% CI: 5.98%-18.94%), and 43.92% (95% CI: 37.94%-49.89%), respectively. Sensitivity analysis showed that the pooled results were robust; publication bias assessment revealed that there was no significant evidence that the pooled results were influenced by publication bias.

Conclusion: High prevalence of endocrine disorders involving abnormal glucose metabolism was detected in -thalassemia major. Treatment and prevention measurements may be necessary to prevent growth and endocrine problems.
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http://dx.doi.org/10.1155/2019/6573497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500678PMC
November 2019

Increased CXCL13 and CXCR5 in Anterior Cingulate Cortex Contributes to Neuropathic Pain-Related Conditioned Place Aversion.

Neurosci Bull 2019 Aug 30;35(4):613-623. Epub 2019 Apr 30.

Institute of Pain Medicine, Institute of Special Environmental Medicine, Nantong University, Nantong, 226019, China.

Pain consists of sensory-discriminative and emotional-affective components. The anterior cingulate cortex (ACC) is a critical brain area in mediating the affective pain. However, the molecular mechanisms involved remain largely unknown. Our recent study indicated that C-X-C motif chemokine 13 (CXCL13) and its sole receptor CXCR5 are involved in sensory sensitization in the spinal cord after spinal nerve ligation (SNL). Whether CXCL13/CXCR5 signaling in the ACC contributes to the pathogenesis of pain-related aversion remains unknown. Here, we showed that SNL increased the CXCL13 level and CXCR5 expression in the ACC after SNL. Knockdown of CXCR5 by microinjection of Cxcr5 shRNA into the ACC did not affect SNL-induced mechanical allodynia but effectively alleviated neuropathic pain-related place avoidance behavior. Furthermore, electrophysiological recording from layer II-III neurons in the ACC showed that SNL increased the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), decreased the EPSC paired-pulse ratio, and increased the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor/N-methyl-D-aspartate receptor ratio, indicating enhanced glutamatergic synaptic transmission. Finally, superfusion of CXCL13 onto ACC slices increased the frequency and amplitude of spontaneous EPSCs. Pre-injection of Cxcr5 shRNA into the ACC reduced the increase in glutamatergic synaptic transmission induced by SNL. Collectively, these results suggest that CXCL13/CXCR5 signaling in the ACC is involved in neuropathic pain-related aversion via synaptic potentiation.
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http://dx.doi.org/10.1007/s12264-019-00377-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616612PMC
August 2019

A neuronal molecular switch through cell-cell contact that regulates quiescent neural stem cells.

Sci Adv 2019 02 27;5(2):eaav4416. Epub 2019 Feb 27.

Collaborative Innovation Center for Brain Science, Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

The quiescence of radial neural stem cells (rNSCs) in adult brain is regulated by environmental stimuli. However, little is known about how the neurogenic niche couples the external signal to regulate activation and transition of quiescent rNSCs. Here, we reveal that long-term excitation of hippocampal dentate granule cells (GCs) upon voluntary running leads to activation of adult rNSCs in the subgranular zone and thereby generation of newborn neurons. Unexpectedly, the role of these excited GC neurons in NSCs depends on direct GC-rNSC interaction in the local niche, which is through down-regulated ephrin-B3, a GC membrane-bound ligand, and attenuated transcellular EphB2 kinase-dependent signaling in the adjacent rNSCs. Furthermore, constitutively active EphB2 kinase sustains the quiescence of rNSCs during running. These findings thus elucidate the physiological significance of GC excitability on adult rNSCs under external environments and indicate a key-lock switch regulation via cell-cell contact for functional transition of rNSCs.
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http://dx.doi.org/10.1126/sciadv.aav4416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392779PMC
February 2019

Spinal CXCL9 and CXCL11 are not involved in neuropathic pain despite an upregulation in the spinal cord following spinal nerve injury.

Mol Pain 2018 Jan-Dec;14:1744806918777401. Epub 2018 Apr 30.

1 Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu, China.

Chemokines-mediated neuroinflammation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. Chemokine CXCL9, CXCL10, and CXCL11 have been identified as a same subfamily chemokine which bind to CXC chemokine receptor 3 to exert functions. Our recent work found that CXCL10 is upregulated in spinal astrocytes after spinal nerve ligation (SNL) and acts on chemokine receptor CXCR3 on neurons to contribute to central sensitization and neuropathic pain, but less is known about CXCL9 and CXCL11 in the maintenance of neuropathic pain. Here, we report that CXCL9 and CXCL11, same as CXCL10, were increased in spinal astrocytes after SNL. Surprisingly, inhibition of CXCL9 or CXCL11 by spinal injection of shRNA lentivirus did not attenuate SNL-induced neuropathic pain. In addition, intrathecal injection of CXCL9 and CXCL11 did not produce hyperalgesia or allodynia behaviors, and neither of them induced ERK activation, a marker of central sensitization. Whole-cell patch clamp recording on spinal neurons showed that CXCL9 and CXCL11 enhanced both excitatory synaptic transmission and inhibitory synaptic transmission, whereas CXCL10 only produced an increase in excitatory synaptic transmission. These results suggest that, although the expression of CXCL9 and CXCL11 are increased after SNL, they may not contribute to the maintenance of neuropathic pain.
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http://dx.doi.org/10.1177/1744806918777401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967156PMC
October 2018

MicroRNA-221-3p, a TWIST2 target, promotes cervical cancer metastasis by directly targeting THBS2.

Cell Death Dis 2017 12 14;8(12):3220. Epub 2017 Dec 14.

Department of Obstetrics and Gynecology, Nanfang Hospital/First School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong Province, People's Republic of China.

MicroRNAs have implicated in the relapse and metastasis of cervical cancer, which is the leading cause of cervical cancer-related mortality. However, the underlying molecular mechanisms need further elucidation. Our present study revealed that miR-221-3p is transcriptionally promoted in metastatic cervical cancer tissues compared with non-metastatic cervical cancer tissues. Forced overexpression of miR-221-3p facilitated EMT and promoted cell migration and invasion in vitro and lymphatic metastasis in vivo. Twist homolog 2 (TWIST2) was found to be a key transcription factor binding to the promoter of miR-221-3p. Inhibitors of miR-221-3p drastically reduced the induction of EMT and decreased cell migration and invasion mediated by TWIST2. By combined computational and experimental approaches, THBS2 was recognized to be an important downstream target gene of miR-221-3p. In cervical cancer tissues, especially with lymphatic metastasis, miR-221-3p and TWIST2 were increased and THBS2 was decreased, suggesting that TWIST2 induces miR-221-3p expression and consequently suppresses its direct target THBS2 in lymphatic metastasis CC. Our findings uncover a mechanistic role for miR-221-3p in lymph node metastasis, suggesting that miR-221-3p is upregulated by the transcription factor TWIST2 and downregulates its target THBS2, which may potentially promote lymph node metastasis in cervical cancer.
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http://dx.doi.org/10.1038/s41419-017-0077-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870596PMC
December 2017

Promoted Interaction of C/EBPα with Demethylated Cxcr3 Gene Promoter Contributes to Neuropathic Pain in Mice.

J Neurosci 2017 01;37(3):685-700

Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, and

DNA methylation has been implicated in the pathogenesis of chronic pain. However, the specific genes regulated by DNA methylation under neuropathic pain condition remain largely unknown. Here we investigated how chemokine receptor CXCR3 is regulated by DNA methylation and how it contributes to neuropathic pain induced by spinal nerve ligation (SNL) in mice. SNL increased Cxcr3 mRNA and protein expression in the neurons of the spinal cord. Meanwhile, the CpG (5'-cytosine-phosphate-guanine-3') island in the Cxcr3 gene promoter region was demethylated, and the expression of DNA methyltransferase 3b (DNMT3b) was decreased. SNL also increased the binding of CCAAT (cytidine-cytidine-adenosine-adenosine-thymidine)/enhancer binding protein α (C/EBPα) with Cxcr3 promoter and decreased the binding of DNMT3b with Cxcr3 promoter in the spinal cord. C/EBPα expression was increased in spinal neurons after SNL, and inhibition of C/EBPα by intrathecal small interfering RNA attenuated SNL-induced pain hypersensitivity and reduced Cxcr3 expression. Furthermore, SNL-induced mechanical allodynia and heat hyperalgesia were markedly reduced in Cxcr3 mice. Spinal inhibition of Cxcr3 by shRNA or CXCR3 antagonist also attenuated established neuropathic pain. Moreover, CXCL10, the ligand of CXCR3, was increased in spinal neurons and astrocytes after SNL. Superfusing spinal cord slices with CXCL10 enhanced spontaneous EPSCs and potentiated NMDA-induced and AMPA-induced currents of lamina II neurons. Finally, intrathecal injection of CXCL10 induced CXCR3-dependent pain hypersensitivity in naive mice. Collectively, our results demonstrated that CXCR3, increased by DNA demethylation and the enhanced interaction with C/EBPα, can be activated by CXCL10 to facilitate excitatory synaptic transmission and contribute to the maintenance of neuropathic pain.

Significance Statement: Peripheral nerve injury induces changes of gene expression in the spinal cord that may contribute to the pathogenesis of neuropathic pain. CXCR3 is a chemokine receptor. Whether it is involved in neuropathic pain and how it is regulated after nerve injury remain largely unknown. Our study demonstrates that spinal nerve ligation downregulates the expression of DNMT3b, which may cause demethylation of Cxcr3 gene promoter and facilitate the binding of CCAAT/enhancer binding protein α with Cxcr3 promoter and further increase CXCR3 expression in spinal neurons. The upregulated CXCR3 may contribute to neuropathic pain by facilitating central sensitization. Our study reveals an epigenetic mechanism underlying CXCR3 expression and also suggests that targeting the expression or activation of CXCR3 signaling may offer new therapeutics for neuropathic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.2262-16.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596757PMC
January 2017

Annexin A10 is involved in the development and maintenance of neuropathic pain in mice.

Neurosci Lett 2016 Sep 6;631:1-6. Epub 2016 Aug 6.

Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China. Electronic address:

ANXA10 (annexin A10) is a member of the annexin family, and its biological effects are mediated primarily through the calcium-dependent phospholipid-binding and calcium ion binding. We examined the gene expressions of the L5 spinal cord after spinal nerve ligation (SNL)-induced neuropathic pain in mice by gene chip. The results showed that Anxa10 mRNA was the most upregulated gene in annexin family with 73.7-fold increase. Although previous studies have reported that several annexins are involved in nociceptive pain, the role of Anxa10 in pain remains undefined. We aimed to evaluate the role of ANXA10 in mediating injury-induced heat hyperalgesia and mechanical allodynia. We found that SNL induced persistent upregulation of Anxa10 mRNA and protein in the spinal cord of mice. Moreover, ANXA10 was colocalized with the neuronal marker MAP2 and astrocytic marker glial fibrillary acidic protein (GFAP), but not with microglial marker CD11b. Finally, pretreatment with Anxa10 siRNA partially prevented SNL-induced mechanical allodynia and heat hyperalgesia. Posttreatment with Anxa10 siRNA attenuated SNL-induced neuropathic pain. These findings suggest that ANXA10 might be a novel target in the treatment of neuropathic pain.
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http://dx.doi.org/10.1016/j.neulet.2016.08.009DOI Listing
September 2016

Altered T-UCRs expression profile in the spinal cord of mice with neuropathic pain.

Transl Perioper Pain Med 2016 ;1(3):1-10

Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, Nantong, Jiangsu 226019, China.

Spinal cord plays an important role in the transmission and modulation of nociceptive information. Global changes in gene expression in the spinal cord contribute to the induction and maintenance of neuropathic pain. Transcribed Ultraconserved Regions (T-UCRs), a novel class of long noncoding RNAs, can regulate gene expression at both transcriptional and post-transcriptional levels and are related to many human diseases such as cancer, Alzheimer's disease, and heart diseases. In this study, we screened abnormal T-UCRs expression in the spinal cord under spinal nerve ligation (SNL)-induced neuropathic pain condition. Microarray data showed the alternation of T-UCRs at the transcriptional level in the spinal cord 10 days after SNL. Among 78 altered T-UCRs, 23 T-UCRs were upregulated by more than 1.5-fold and 55 ones downregulated by less than 0.5-fold after SNL. Hierarchical cluster analysis of T-UCRs expression profiles showed the opposite expression pattern between SNL and sham-operated mice. The quantitative real-time reverse transcription polymerase chain reaction analysis further confirmed the expression patterns of uc.305, uc.189, uc.46, and uc.217 after SNL. The gene ontology annotation and signaling pathway analysis for the T-UCRs host genes indicated that differentially expressed T-UCRs were involved in several intracellular activities and signaling pathways, including Ephrin receptor activity, soluble NSF attachment protein receptor (SNARE) interactions in vesicular transport pathway, and WNT signaling pathway. Collectively, the current data suggest the possible role of T-UCR in the pathogenesis of neuropathic pain. T-UCRs may serve as a new kind of target for the treatment of neuropathic pain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971523PMC
January 2016

CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5.

J Clin Invest 2016 Feb 11;126(2):745-61. Epub 2016 Jan 11.

Recent studies have implicated chemokines in microglial activation and pathogenesis of neuropathic pain. C-X-C motif chemokine 13 (CXCL13) is a B lymphocyte chemoattractant that activates CXCR5. Using the spinal nerve ligation (SNL) model of neuropathic pain, we found that CXCL13 was persistently upregulated in spinal cord neurons after SNL, resulting in spinal astrocyte activation via CXCR5 in mice. shRNA-mediated inhibition of CXCL13 in the spinal cord persistently attenuated SNL-induced neuropathic pain. Interestingly, CXCL13 expression was suppressed by miR-186-5p, a microRNA that colocalized with CXCL13 and was downregulated after SNL. Spinal overexpression of miR-186-5p decreased CXCL13 expression, alleviating neuropathic pain. Furthermore, SNL induced CXCR5 expression in spinal astrocytes, and neuropathic pain was abrogated in Cxcr5-/- mice. CXCR5 expression induced by SNL was required for the SNL-induced activation of spinal astrocytes and microglia. Intrathecal injection of CXCL13 was sufficient to induce pain hypersensitivity and astrocyte activation via CXCR5 and ERK. Finally, intrathecal injection of CXCL13-activated astrocytes induced mechanical allodynia in naive mice. Collectively, our findings reveal a neuronal/astrocytic interaction in the spinal cord by which neuronally produced CXCL13 activates astrocytes via CXCR5 to facilitate neuropathic pain. Thus, miR-186-5p and CXCL13/CXCR5-mediated astrocyte signaling may be suitable therapeutic targets for neuropathic pain.
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http://dx.doi.org/10.1172/JCI81950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731172PMC
February 2016

Identification of lncRNA expression profile in the spinal cord of mice following spinal nerve ligation-induced neuropathic pain.

Mol Pain 2015 Jul 17;11:43. Epub 2015 Jul 17.

Pain Research Laboratory, Institute of Nautical Medicine, Jiangsu Key Laboratory of Inflammation and Molecular Drug Target, Nantong University, 9 Seyuan Road, Nantong, 226019, Jiangsu, China.

Background: Neuropathic pain that caused by lesion or dysfunction of the nervous system is associated with gene expression changes in the sensory pathway. Long noncoding RNAs (lncRNAs) have been reported to be able to regulate gene expression. Identifying lncRNA expression patterns in the spinal cord under normal and neuropathic pain conditions is essential for understanding the genetic mechanisms behind the pathogenesis of neuropathic pain.

Results: Spinal nerve ligation (SNL) induced rapid and persistent pain hypersensitivity, characterized by mechanical allodynia and heat hyperalgesia. Meanwhile, astrocytes and microglia were dramatically activated in the ipsilateral spinal cord dorsal horn at 10 days after SNL. Further lncRNA microarray and mRNA microarray analysis showed that the expression profiles of lncRNA and mRNA between SNL and sham-operated mice were greatly changed at 10 days. The 511 differentially expressed (>2 fold) lncRNAs (366 up-regulated, 145 down-regulated) and 493 mRNAs (363 up-regulated, 122 down-regulated) were finally identified. The expression patterns of several lncRNAs and mRNAs were further confirmed by qPCR. Functional analysis of differentially expressed (DE) mRNAs showed that the most significant enriched biological processes of up-regulated genes in SNL include immune response, defense response, and inflammation response, which are important pathogenic mechanisms underlying neuropathic pain. 35 DE lncRNAs have neighboring or overlapping DE mRNAs in genome, which is related to Toll-like receptor signaling, cytokine-cytokine receptor interaction, and peroxisome proliferator-activated receptor signaling pathway.

Conclusion: Our findings uncovered the expression pattern of lncRNAs and mRNAs in the mice spinal cord under neuropathic pain condition. These lncRNAs and mRNAs may represent new therapeutic targets for the treatment of neuropathic pain.
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http://dx.doi.org/10.1186/s12990-015-0047-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504460PMC
July 2015

Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2.

Chem Biol Interact 2015 Jul 16;237:133-40. Epub 2015 Jun 16.

School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.

Myristicin belongs to the methylenedioxyphenyl or allyl-benzene family of compounds, which are found widely in plants of the Umbelliferae family, such as parsley and carrot. Myristicin is also the major active component in the essential oils of mace and nutmeg. However, this compound can cause adverse reactions, particularly when taken inappropriately or in overdoses. One important source of toxicity of natural products arises from their metabolic biotransformations into reactive metabolites. Myristicin contains a methylenedioxyphenyl substructure, and this specific structural feature may allow compounds to cause a mechanism-based inhibition of cytochrome P450 enzymes and produce reactive metabolites. Therefore, the aim of this work was to identify whether the role of myristicin in CYP enzyme inhibition is mechanism-based inhibition and to gain further information regarding the structure of the resulting reactive metabolites. CYP cocktail assays showed that myristicin most significantly inhibits CYP1A2 among five CYP enzymes (CYP1A2, CYP2D6, CYP2E1, CYP3A4 and CYP2C19) from human liver microsomes. The 3.21-fold IC50 shift value of CYP1A2 indicates that myristicin may be a mechanism-based inhibitor of CYP1A2. Next, reduced glutathione was shown to block the inhibition of CYP1A2, indicating that myristicin utilized a mechanism-based inhibition. Phase I metabolism assays identified two metabolites, 5-allyl-1-methoxy-2,3-dihydroxybenzene (M1) and 1'-hydroxymyristicin or 2',3'-epoxy-myristicin (M2). Reduced glutathione capturing assays captured the glutathione-M1 adduct, and the reactive metabolites were identified using UPLC-MS(2) as a quinone and its tautomer. Thus, it was concluded that myristicin is a mechanism-based inhibitor of CYP1A2, and the reactive metabolites are quinone tautomers. Additionally, the cleavage process of the glutathione-M1 adduct was analyzed in further detail. This study provides additional information on the metabolic mechanism of myristicin inhibition and improves risk evaluation for this compound.
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http://dx.doi.org/10.1016/j.cbi.2015.06.018DOI Listing
July 2015

Mechanism-based inhibition of CYPs and RMs-induced hepatoxicity by rutaecarpine.

Xenobiotica 2015 8;45(11):978-89. Epub 2015 Jun 8.

a School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Nankai District , Tianjin , P.R. China and.

1. Rutaecarpine, a quinolone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is one of the main active components used in a variety of clinical applications, including the treatment of hypertension and arrhythmia. However, its hepatotoxicity has also been reported in recent years. 2. Reactive metabolites (RMs) play a vital role in drug-induced liver injury. Rutaecarpine has a secondary amine structure that may be activated to RMs. The aim of the study was to investigate the inhibition of rutaecarpine on CYPs and explore the possible relationship between RMs and potential hepatotoxicity. 3. A cell counting kit-8 cytotoxicity assay indicated that rutaecarpine can decrease the primary rat hepatocyte viability, increase lactate dehydrogenase and reactive oxygen species, reduce JC-1, and cause cell stress and membrane damage. The indexes were significantly restored by adding ABT, an inhibitor of CYPs. A cocktail assay showed that CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 can be inhibited by rutaecarpine in human liver microsomes. The IC50 values of CYP1A2 with and without NADPH were 2.2 and 7.4 μM, respectively, which presented a 3.3 shift. The results from a metabolic assay indicated that three mono-hydroxylated metabolites and two di-hydroxylated metabolites were identified and two GSH conjugates were also trapped. 4. Rutaecarpine can inhibit the activities of CYPs and exhibit a potential mechanism-based inhibition on CYP1A2. RMs may cause herb-drug interactions, providing important information for predicting drug-induced hepatotoxicity.
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http://dx.doi.org/10.3109/00498254.2015.1038742DOI Listing
June 2016

Reactive metabolite activation by CYP2C19-mediated rhein hepatotoxicity.

Xenobiotica 2015 Apr 19;45(4):361-72. Epub 2014 Nov 19.

School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine , Tianjin , PR China and.

1. Rhein, an active ingredient in the root of rhubarb, is used for its beneficial effects in a variety of clinical applications including the treatment of osteoarthritis and diabetic nephropathy. However, its hepatotoxicity has been reported in recent years. Rhein belongs to the conjugate structure which could be activated to reactive metabolites (RMs) inducing side-effects. This study is to explore the relationship between RMs and hepatotoxicity. 2. Based on the early detection of RMs, we have established a series of key technologies to research rhein hepatotoxicity mechanism: IC50 shift experiments and reduced glutathione (GSH) trapping experiment are adopted to identify RMs. The model of low activity of CYP450 enzymes (CYPs) in primary rat hepatocyte is constructed to analyze the relationship between the primary metabolic enzyme and hepatotoxicity of rhein better. 3. The IC50 shift value for CYP2C19 is 1.989, it suggests that CYP2C19 could activate rhein to RM. The structure of RM is epoxide intermediate. Besides, it is found that CYP2C19 is a primary metabolic enzyme for rhein. In the cytotoxicity assay, it is reported that rhein could cause mitochondrial dysfunction. Furthermore, mitochondrial membrane potential (Δψm) and AST levels could be restored by adding inhibitor of CYP2C19 together with rhein, which further shows that CYP2C19 could mediate the hepatotoxicity of rhein. 4. We put forward the possible mechanism that reactive metabolite activation by CYP2C19 mediated rhein hepatotoxicity, it provides important information on predicting in vivo drug-induced liver injury (DILI).
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http://dx.doi.org/10.3109/00498254.2014.984794DOI Listing
April 2015

[Study of integrated state of HPV-16 infection in cervical cancer and precancerous tissues].

Nan Fang Yi Ke Da Xue Xue Bao 2015 Jan;35(1):47-50

Department of Gynecology and Obstetrics, NanFang Hospital, Southern Medical University, Guangdong 510515, China.E-mail:

Objective: To investigate the prevalence of physical state of HPV-16 DNA in cervical cancer and cervical precancerous carcinoma.

Methods: Multiplex PCR was adopted to detect the physical state of HPV in samples from 252 patients with cervical carcinoma, including 48 samples of cervical cancer, 204 cervical intraepithelial neoplasia (CIN ) (125 CIN I, 46 CIN II and 33 CIN III) and 20 normal samples from the subjects with hysteromyoma undergoing hysterectomy, respectively.

Results: Among 48 patients with cervical cancer, 31 (65.6%) were infected with HPV-16. Eighteen among 31 (58.1%) HPV-16 infected patients with cervical cancer were found to have integrated infection of HPV-16. The positive rates of HPV-16 infection in the patients with CIN I, CIN II and CIN III were 19.2%, 34.8% and 42.4%, and the integrated infection rates of HPV-16 were 16.7%, 18.8% and 35.7%, respectively. Compared with patients with different grades of CIN, the integrated rate of HPV-16 infection in those with cervical cancer was significantly elevated.

Conclusion: Among the patients with HPV-16 infection, the integrated state of HPV-16 is positively correlated with the severity of cervical lesions. Combined HPV typing test and detection of integrated viral state contribute to predicting the prognosis of patients with cervical precancerous lesions and increasing the accuracy of screening cervical cancer on the basis of HPV DNA detection.
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January 2015

Inhibition of Dengue virus 2 replication by artificial micrornas targeting the conserved regions.

Nucleic Acid Ther 2013 Aug 7;23(4):244-52. Epub 2013 May 7.

Department of Biotechnology, Beijing Institute of Radiation Medicine, Beijing 100850, China.

Dengue virus (DENV), a mosquito-borne flavivirus, causes serious diseases and threatens public health in tropical and subtropical areas worldwide. RNA interference (RNAi) is a prevailing strategy for antiviral therapy. In this paper, 6 single artificial microRNAs (amiRNAs) targeting the highly conserved regions of the DENV-2 genome were identified and inhibited virus replication efficiently. Then, effective tandem amiRNAs targeting 2 different DENV-2 genome regions were constructed and expressed simultaneously from a single microRNA-like polycistron to avoid virus variation or mutation escape. Finally, the most high-performance tandem amiRNA was embedded in a lenti-viral vector and inhibited DENV-2 virus replication stably and dose-dependently. Overall, these results indicated that RNAi based on multiple amiRNAs targeting viral conserved regions was an effective approach for improvements of nucleic acid inhibitors of DENV and provided a new therapeutic strategy for DENV infection in humans.
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http://dx.doi.org/10.1089/nat.2012.0405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723240PMC
August 2013

A polymorphism of apolipoprotein E (APOE) gene is associated with age at natural menopause in Caucasian females.

Maturitas 2009 Jan 5;62(1):37-41. Epub 2008 Dec 5.

Center of Forensic Sciences, Beijing Institute of Genomics, Beijing 101318, PR China.

Objective: The present study aimed to investigate possible association of the apolipoprotein E (APOE) gene polymorphisms with age at natural menopause (ANM) in Caucasian females.

Design: Four SNPs (including two replacements, SNP3 Cys112Arg and SNP4 Arg158Cys) were genotyped in 253 randomly selected unrelated Caucasian women having experienced natural menopause. The comprehensive statistical analyses focusing on the association of the APOE gene and some environmental factors with ANM were conducted.

Results: Alcohol consumption was a significantly predictor of earlier natural menopause (P<0.05). One SNP (rs769450) was significantly associated with ANM according to both population based and the transmission disequilibrium test (TDT) analyses (P=0.007 and 0.046, respectively). However, no association was observed between APOE varepsilon2, varepsilon3, varepsilon4 and ANM.

Conclusions: Genetic variation in the APOE gene may influence the variation in ANM in Caucasian women.
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http://dx.doi.org/10.1016/j.maturitas.2008.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734973PMC
January 2009

Genome-wide association scan for stature in Chinese: evidence for ethnic specific loci.

Hum Genet 2009 Feb 23;125(1):1-9. Epub 2008 Nov 23.

Laboratory of Molecular and Statistical Genetics and Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, 410081 Changsha, Hunan, People's Republic of China.

In Caucasian, several studies have identified some common variants associated with human stature variation. However, no such study was performed in Chinese, which is the largest population in the world and evidently differs from Caucasian in genetic background. To identify common or ethnic specific genes for stature in Chinese, an initial GWAS and follow-up replication study were performed. Our initial GWAS study found that a group of 13 contiguous SNPs, which span a region of approximately 150 kb containing two neighboring genes, zinc finger protein (ZNP) 510 and ZNP782, achieved strong signals for association with stature, with P values ranging from 9.71 x 10(-5) to 3.11 x 10(-6). After false discovery rate correction for multiple testing, 9 of the 13 SNPs remain significant (FDR q=0.036-0.046). The follow-up replication study in an independent 2,953 unrelated southern Chinese confirmed the association of rs10816533 with stature (P=0.029). All the 13 SNPs were in consistently strong linkage disequilibrium (D'>0.99) and formed a single perfect haplotype block. The minor allele frequencies for the 13 contiguous SNPs have evidently ethnic difference, which range from 0.21 to 0.33 in Chinese but have as low as approximately 0.017 reported in dbSNP database in Caucasian. The present results suggest that the genomic region containing the ZNP510 and ZNP782 genes is an ethnic specific locus associated with stature variation in Chinese.
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http://dx.doi.org/10.1007/s00439-008-0590-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2730511PMC
February 2009

Association study of the oestrogen signalling pathway genes in relation to age at natural menopause.

J Genet 2007 Dec;86(3):269-76

The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.

Genetic factors play a significant role in influencing the variation of age at natural menopause (AANM). Estrogen receptor beta (ESR2), is an important factor in the mechanism of action of estrogen, while the aromatase gene (CYP19) and the 17-alpha-hydroxylase gene (CYP17) are involved in the biosynthesis of estrogen. We tested whether polymorphisms of ESR2, CYP19 and CYP17 genes are associated with AANM in Caucasian females. A total of 52 SNPs (17 for ESR2, 28 for CYP19, and 7 for CYP17) were successfully genotyped for 229 Caucasian women having experienced natural menopause. Comprehensive statistical analyses focusing on the association of these genes with AANM were conducted. The effects of age, height and age at menarche on AANM were adjusted when conducting association analyses. We found that six SNPs (2, 6-7, 9, 13 and 16) within ESR2 were not significantly associated with AANM after Bonferroni correction. However, two blocks of ESR2 were associated with AANM. For CYP19, two SNPs (24 and 27) were nominally associated with AANM. No significant association was observed between CYP17 and AANM. Our results suggest that genetic variation in the ESR2 and CYP19 genes may influence the variation in AANM in Caucasian women.
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http://dx.doi.org/10.1007/s12041-007-0034-7DOI Listing
December 2007
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