Publications by authors named "Sha Fu"

53 Publications

Clinical Significance of a CD3/CD8-Based Immunoscore in Neuroblastoma Patients Using Digital Pathology.

Front Immunol 2022 10;13:878457. Epub 2022 May 10.

Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, National Children's Medical Center for South Central Region, Guangzhou, China.

Background: Infiltrating immune cells have been reported as prognostic markers in many cancer types. We aimed to evaluate the prognostic role of tumor-infiltrating lymphocytes, namely CD3+ T cells, CD8+ cytotoxic T cells and memory T cells (CD45RO+), in neuroblastoma.

Patients And Methods: Immunohistochemistry was used to determine the expression of CD3, CD8 and CD45RO in the tumor samples of 244 neuroblastoma patients. We then used digital pathology to calculate the densities of these markers and derived an immunoscore based on such densities.

Results: Densities of CD3+ and CD8+ T cells in tumor were positively associated with the overall survival (OS) and event-free survival (EFS), whereas density of CD45RO+ T cells in tumor was negatively associated with OS but not EFS. An immunoscore with low density of CD3 and CD8 (CD3-CD8-) was indictive of a greater risk of death (hazard ratio 6.39, 95% confidence interval 3.09-13.20) and any event (i.e., relapse at any site, progressive disease, second malignancy, or death) (hazard ratio 4.65, 95% confidence interval 2.73-7.93). Multivariable analysis revealed that the CD3-CD8- immunoscore was an independent prognostic indicator for OS, even after adjusting for other known prognostic indicators.

Conclusions: The new immunoscore based on digital pathology evaluated densities of tumor-infiltrating CD3+ and CD8+ T cells contributes to the prediction of prognosis in neuroblastoma patients.
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http://dx.doi.org/10.3389/fimmu.2022.878457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9128405PMC
May 2022

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

Contingency response decision of network public opinion emergencies based on intuitionistic fuzzy entropy and preference information of decision makers.

Sci Rep 2022 02 28;12(1):3246. Epub 2022 Feb 28.

School of Information Technology and Management, Hunan University of Finance and Economics, No.139, Section 2, Fenglin Road, Yuelu District, Changsha, 410205, China.

A multi-attribute group decision-making (MAGDM) method based on intuitionistic fuzzy preference information is proposed for the multi-attribute intuitionistic fuzzy group decision-making problem where the decision-makers weight and attribute weight are completely unknown and the decision-maker has preference information for the scheme. Firstly, an intuitionistic fuzzy interval judgment matrix is established to describe the original data of the key decision indicators for multiple network public opinion emergencies that erupt simultaneously. Secondly, the attribute weights are determined based on the improved intuitionistic fuzzy entropy construction method, and the expert weights are determined by using objective decision information, taking into account the intuitionistic fuzzy entropy of decision matrix. MAGDM can not only synthesize experts' professional experience in different aspects, but also avoid experts' decision-making errors caused by insufficient domain knowledge. It is necessary to continuously adjust the expert weight based on decision-making information to make the comprehensive decision-making information more accurate. Thirdly, a scheme preference model and an attribute weight optimization model are established to determine the ranking method of intuitionistic fuzzy interval values. Then, a modified distance measure of intuitionistic fuzzy sets (IFSs) is introduced to make the evaluation result more accurate and reasonable when it comes to solving the deviation between the evaluation value and ideal solution of each scheme. Finally, the effectiveness and practicability of the proposed decision-making method are verified by an example of emergency crisis severity, It assists decision makers in selecting and implementing the optimal emergency response plan in a timely and efficient manner, which improves the emergency treatment efficiency of network public opinion crisis, helps emergency departments to better deal with the network public opinion crisis, improves the ability of public opinion guidance and control, and provides a new method and idea for multi-attribute intuitionistic fuzzy group decision-making problem.
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http://dx.doi.org/10.1038/s41598-022-07183-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8885920PMC
February 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

PD-1/PD-L1 inhibitor plus chemotherapy versus bevacizumab plus chemotherapy in first-line treatment for non-squamous non-small-cell lung cancer.

J Immunother Cancer 2021 11;9(11)

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

Anti-PD-1)/programmed cell death-ligand 1 (PD-L1) antibody plus platinum-based chemotherapy (PBC) has replaced PBC as first-line treatment for patients with non-squamous (sq) non-small cell lung cancer (NSCLC) lacking targetable driver mutations. However, few studies have directly compared immune checkpoint inhibitor (ICI) plus chemotherapy with bevacizumab plus chemotherapy (beva +chemo) in this setting. Herein, we conducted an indirect comparison for anti-PD-1/PD-L1 antibody plus chemotherapy (ICI +chemo) versus beva +chemo in non-sq NSCLC using the frequentist methods. The main outcomes analyzed include progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). Data were subtracted from randomized trials comparing ICI +chemo or beva +chemo against PBC. Fourteen trials involving 6165 patients were included. Direct meta-analyses showed that both ICI +chemo (PFS: HR 0.58, OS: HR 0.73, ORR: relative risk (RR) 1.66) and beva +chemo (PFS: HR 0.74, OS: HR 0.89, ORR: RR 1.62) improved clinical outcomes compared with PBC. Indirect comparison showed that ICI +chemo reduced the risk of disease progression (HR 0.78, 95% CI 0.60 to 1.00) and death (HR 0.82, 95% CI 0.71 to 0.94) compared with beva +chemo. The PFS benefits with ICI +chemo over beva +chemo were non-significant in those with negative PD-L1 expression and non-smokers. In conclusion, ICI +chemo is superior to beva +chemo in first-line treatment for non-sq NSCLC.
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http://dx.doi.org/10.1136/jitc-2021-003431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576478PMC
November 2021

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

Effects of Sacubitril-Valsartan in Heart Failure With Preserved Ejection Fraction in Patients Undergoing Peritoneal Dialysis.

Front Med (Lausanne) 2021 21;8:657067. Epub 2021 Jun 21.

Department of Nephrology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.

The effect of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF) remains unclear, and data on ARNI treatment in peritoneal dialysis (PD) patients are lacking. The present study was designed to assess the efficacy and safety of sacubitril-valsartan in patients with HFpEF undergoing peritoneal dialysis. End-stage kidney disease (ESKD) patients undergoing PD for 3 months with New York Heart Association (NYHA) class II-IV heart failure, ejection fraction of 50% or higher, and elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) were assigned to receive sacubitril-valsartan. Patients were followed up regularly after medication treatment. The alterations in clinical and biochemical parameters before and after taking sacubitril-valsartan (generally 50-100 mg b.i.d) were investigated, and safety was also assessed. Twenty-one patients were recruited in this study. Compared with baseline levels, NT-proBNP levels [9769.0 (3093.5-21941.0) vs. 3034.0 (1493.2-6503.0), = 0.002], and heart rate [80.0 (74.5-90.5) vs. 75.0 (70.3-87.0), = 0.031] were markedly decreased after treatment with sacubitril-valsartan. Signs and symptoms of heart failure (21/21 vs. 15/21, = 0.021) were obviously alleviated, NYHA classification and E/e' ratio showed a notable trend of improvement after 3-12 months of follow-up. None of the patients showed adverse drug reactions. The present data suggested that sacubitril-valsartan treatment in patients with HFpEF undergoing PD was effective and safe.
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http://dx.doi.org/10.3389/fmed.2021.657067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255468PMC
June 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

Pittsburgh Sleep Quality Index score predicts all-cause mortality in Chinese dialysis patients.

Int Urol Nephrol 2021 Nov 31;53(11):2369-2376. Epub 2021 Mar 31.

Department of Nephrology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 Yanjiang West Road, Yuexiu District, Guangzhou, Guangdong, People's Republic of China.

Background: The relationship between Pittsburgh Sleep Quality Index (PSQI) score and survival of dialysis patients has not been well studied. The aim of this study was to explore the association between PSQI score and all-cause mortality in dialysis patients.

Methods: Fifty-one hemodialysis and 58 peritoneal dialysis patients were enrolled in this study. PSQI score > 5 and ≤ 5 indicated "poor sleepers" and "good sleepers", respectively. The primary outcome was all-cause mortality. Kaplan-Meier survival curve and Cox proportional hazards regression analysis were performed.

Results: The median PSQI score was 7.0 (4.0-10.0). Sixty-seven (61.5%) patients had poor sleep quality (SQ). Compared with good sleepers, poor sleepers had significantly lower levels of hemoglobin [74.0 (61.0, 85.0) vs. 78.0 (68.0, 97.0), P = 0.03] and serum bicarbonate (18.0 ± 4.5 vs. 20.0 ± 3.7, P = 0.022). The follow-up time was 69.1 ± 29.9 months. By multivariate Cox proportional hazards analysis, PSQI total score was the independent risk factor of all-cause mortality [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.05-1.36, P = 0.007]. Restricted cubic spline (RCS) analysis showed that 7 was the cutoff value at which the effect of PSQI score on mortality changed. Patients with a PSQI score > 7 had a 2.96-fold increased risk of all-cause mortality (HR 2.96, 95% CI 1.15-7.61, P = 0.025).

Conclusions: PSQI score can be used as a predictor of all-cause mortality in dialysis patients, and those with PSQI > 7 were associated with increased odds of mortality.
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http://dx.doi.org/10.1007/s11255-021-02842-6DOI Listing
November 2021

Systematic review and subgroup analysis of the incidence of acute kidney injury (AKI) in patients with COVID-19.

BMC Nephrol 2021 02 5;22(1):52. Epub 2021 Feb 5.

Department of Nephrology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.

Background: Acute kidney injury (AKI) occurs among patients with coronavirus disease-19 (COVID-19) and has also been indicated to be associated with in-hospital mortality. Remdesivir has been authorized for the treatment of COVID-19. We conducted a systematic review to evaluate the incidence of AKI in hospitalized COVID-19 patients. The incidence of AKI in different subgroups was also investigated.

Methods: A thorough search was performed to find relevant studies in PubMed, Web of Science, medRxiv and EMBASE from 1 Jan 2020 until 1 June 2020. The systematic review was performed using the meta package in R (4.0.1).

Results: A total of 16,199 COVID-19 patients were included in our systematic review. The pooled estimated incidence of AKI in all hospitalized COVID-19 patients was 10.0% (95% CI: 7.0-12.0%). The pooled estimated proportion of COVID-19 patients who needed continuous renal replacement therapy (CRRT) was 4% (95% CI: 3-6%). According to our subgroup analysis, the incidence of AKI could be associated with age, disease severity and ethnicity. The incidence of AKI in hospitalized COVID-19 patients being treated with remdesivir was 7% (95% CI: 3-13%) in a total of 5 studies.

Conclusion: We found that AKI was not rare in hospitalized COVID-19 patients. The incidence of AKI could be associated with age, disease severity and ethnicity. Remdesivir probably did not induce AKI in COVID-19 patients. Our systematic review provides evidence that AKI might be closely associated with SARS-CoV-2 infection, which should be investigated in future studies.
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http://dx.doi.org/10.1186/s12882-021-02244-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863041PMC
February 2021

Transforming Growth Factor-induced Protein Promotes NF-κB-mediated Angiogenesis during Postnatal Lung Development.

Am J Respir Cell Mol Biol 2021 03;64(3):318-330

Department of Pediatrics, Center for Excellence in Pulmonary Biology, and.

Pulmonary angiogenesis is a key driver of alveolarization. Our prior studies showed that NF-κB promotes pulmonary angiogenesis during early alveolarization. However, the mechanisms regulating temporal-specific NF-κB activation in the pulmonary vasculature are unknown. To identify mechanisms that activate proangiogenic NF-κB signaling in the developing pulmonary vasculature, proteomic analysis of the lung secretome was performed using two-dimensional difference gel electrophoresis. NF-κB activation and angiogenic function was assessed in primary pulmonary endothelial cells (PECs) and TGFBI (transforming growth factor-β-induced protein)-regulated genes identified using RNA sequencing. Alveolarization and pulmonary angiogenesis was assessed in wild-type and null mice exposed to normoxia or hyperoxia. Lung TGFBI expression was determined in premature lambs supported by invasive and noninvasive respiratory support. Secreted factors from the early alveolar, but not the late alveolar or adult lung, promoted proliferation and migration in quiescent, adult PECs. Proteomic analysis identified TGFBI as one protein highly expressed by the early alveolar lung that promoted PEC migration by activating NF-κB via αvβ3 integrins. RNA sequencing identified as a TGFBI-regulated gene that enhances nitric oxide production in PECs. Loss of TGFBI in mice exaggerated the impaired pulmonary angiogenesis induced by chronic hyperoxia, and TGFBI expression was disrupted in premature lambs with impaired alveolarization. Our studies identify TGFBI as a developmentally regulated protein that promotes NF-κB-mediated angiogenesis during early alveolarization by enhancing nitric oxide production. We speculate that dysregulation of TGFBI expression may contribute to diseases marked by impaired alveolar and vascular growth.
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http://dx.doi.org/10.1165/rcmb.2020-0153OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909333PMC
March 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

miR-20a-5p is enriched in hypoxia-derived tubular exosomes and protects against acute tubular injury.

Clin Sci (Lond) 2020 08;134(16):2223-2234

Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.

Exosomes have been shown to effectively regulate the biological functions of target cells. Here, we investigated the protective effect and mechanism of hypoxia-induced renal tubular epithelial cells (TECs)-derived exosomes on acute tubular injury. We found that in vitro hypoxia-induced tubular exosomes (Hy-EXOs) were protective in acute tubular injury by promoting TECs proliferation and improving mitochondrial functions. By using exosome miRNA sequencing, we identified miR-20a-5p was abundant and was a key mechanism for the protective effect of Hy-EXOs on tubular injury as up-regulation of miR-20a-5p enhanced but down-regulation of miR-20a-5p inhibited the protective effect of Hy-EXOs on tubular injury under hypoxia conditions. Further study in a mouse model of ischemia-reperfusion-induced acute kidney injury (IRI-AKI) also confirmed this notion as pre-treating mice with the miR-20a-5p agomir 48 h prior to AKI induction was capable of inhibiting IRI-AKI by lowering serum levels of creatinine and urea nitrogen, and attenuating the severity of tubular necrosis, F4/80(+) macrophages infiltration and vascular rarefaction. Mechanistically, the protective effect of miR-20a-5p on acute kidney injury (AKI) was associated with inhibition of TECs mitochondrial injury and apoptosis in vitro and in vivo. In conclusion, miR-20a-5p is enriched in hypoxia-derived tubular exosomes and protects against acute tubular injury. Results from the present study also reveal that miR-20a-5p may represent as a novel therapy for AKI.
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http://dx.doi.org/10.1042/CS20200288DOI Listing
August 2020

[Effect of Baixiao moxibustion at meridian sinew nodal points on upper limb motor function in children with spastic hemiplegic cerebral palsy].

Zhen Ci Yan Jiu 2020 Jun;45(6):480-3

Third Department of Rehabilitation, Hunan Children's Hospital, Changsha 410007, China.

Objective: To investigate the effect of Baixiao moxibustion at meridian sinew nodal points combined with routine rehabilitation on upper limb motor function in children with spastic hemiplegic cerebral palsy.

Methods: A total of 50 children with spastic hemiplegic cerebral palsy were divided into control group and treatment group using a random number table, with 25 children in each group. The children in the control group were given routine rehabilitation training of the ipsilateral upper and lower limbs, and those in the treatment group were given Baixiao moxibustion at the meridian sinew nodal points of the ipsilateral upper limb in addition to the treatment in the control group, once a day and five times a week. Each course of treatment was 4 consecutive weeks, and both groups were treated for 3 courses. Before treatment and at weeks 4 and 12 of treatment, modified Ashworth score was used to evaluate muscle tension of the ipsilateral upper limb, and 88-item version of the Gross Motor Function Measure (GMFM-88) and Carroll upper extremities functional test (UEFT) were used to assess the motor function of the ipsilateral upper limb.

Results: At weeks 4 and 12 of treatment, both groups had a significant reduction in modified Ashworth score (<0.05) and significant increases in GMFM-88 and UEFT scores (<0.05). Both groups had significant changes in modified Ashworth score, GMFM-88 score, and UEFT score from week 4 to week 12 of treatment (<0.05). Compared with the control group at week 12 of treatment, the treatment group had a significant reduction in modified Ashworth score (<0.05) and significant increases in GMFM-88 and UEFT scores (<0.05).

Conclusion: Baixiao moxibustion at meridian sinew nodal points can significantly improve the muscle tension and motor function of the ipsilateral upper limb in children with spastic hemiplegic cerebral palsy, and the improvement becomes more apparent as the treatment lasts longer.
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http://dx.doi.org/10.13702/j.1000-0607.190585DOI Listing
June 2020

Systemic inflammation modulates the ability of serum ferritin to predict all-cause and cardiovascular mortality in peritoneal dialysis patients.

BMC Nephrol 2020 06 23;21(1):237. Epub 2020 Jun 23.

Department of Nephrology, SunYat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510080, China.

Background: This study aimed to ascertain whether the correlation of high serum ferritin with mortality is affected by systemic inflammation and to investigate the optimal serum ferritin level for predicting death when inflammation is considered in peritoneal dialysis (PD) patients.

Methods: We classified 221 patients into four groups according to serum ferritin concentration (100 μg/L) and high-sensitivity CRP (hs-CRP) level (3 mg/L), and followed them regularly from the date of catheterization to Dec 31, 2016, at Sun Yat-Sen Memorial Hospital, China. Clinical and biochemical data were collected at baseline, and clinical outcomes such as all-cause and cardiovascular mortality were assessed.

Results: During a median follow-up of 35 months (3 ~ 109 months), 50 (22.6%) deaths occurred. Cardiovascular disease (46.0%) was the most common cause of death, followed by infection (10.0%). The Kaplan-Meier survival analysis and log-rank test revealed significantly worse survival accumulation among PD patients with higher serum ferritin (≥100 μg/L) under elevated hsCRP levels (> 3 mg/L) (P = 0.022). A multivariate Cox regression analysis revealed that an increased serum ferritin level was independently associated with a higher risk of all-cause and cardiovascular mortality in PD patients (HR = 3.114, P = 0.021; and HR = 9.382, P = 0.032) with hsCRP above 3 mg/L after adjusting for relevant confounding factors.

Conclusion: Higher serum ferritin levels were associated with an increased risk of all-cause and cardiovascular mortality in patients undergoing PD only in the presence of elevated hsCRP levels. The correlation of serum ferritin with poor outcome should take into consideration systemic inflammation.
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http://dx.doi.org/10.1186/s12882-020-01892-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310354PMC
June 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

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

HBx regulates transcription factor PAX8 stabilization to promote the progression of hepatocellular carcinoma.

Oncogene 2019 10 7;38(40):6696-6710. Epub 2019 Aug 7.

Department of Infectious Diseases, Xiangya Hospital, Central South University, Changsha, China.

Transcription factor PAX8 expression is upregulated in several types of cancers. However, little is known about the function of PAX8 in the progression of hepatoma and its regulatory mechanisms. Here, we show that PAX8 silencing inhibits the proliferation and clonogenicity of hepatoma cells and its growth in vivo. The HBV X protein (HBx) does not directly interacts, but stabilizes PAX8 by inhibiting proteasome-dependent ubiquitination and degradation. Furthermore, the E3 ubiquitin ligase complex component Skp2 through its LRR domain directly interacts with the Prd domain of PAX8 and targets PAX8 by recognizing its lysine 275 for ubiquitination and degradation in hepatoma cells. In addition, HBx directly interacts and is colocalized with Skp2 to inhibit its recognition and subsequent ubiquitination and degradation of PAX8 in hepatoma cells. Moreover, HBx upregulates the expression and phosphorylation of Aurora A, a serine-threonine kinase, which interacts with and phosphorylates PAX8 at S209 and T277, compromising the Skp2-recognized PAX8 ubiquitination and destabilization. Thus, HBx stabilizes PAX8 protein by inhibiting the Skp2 targeted PAX8 ubiquitination and enhancing the Aurora A-mediated its phosphorylation, contributing to the progression of hepatoma. Our findings suggest that PAX8 may a new target for design of therapies and uncover new insights into the pathogenesis of hepatoma.
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http://dx.doi.org/10.1038/s41388-019-0907-2DOI Listing
October 2019

Aggressive Surgical Resection of Enormous Cervical Metastasis from Nasopharyngeal Carcinoma.

Acta Stomatol Croat 2019 Jun;53(2):168-173

Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou 510120, China.

While nasopharyngeal carcinoma (NPC) commonly presents lymphoid metastases, the enormous cervical metastasis causing dysphagia and limitation of neck motion is not a familiar symptom for most of NPC cases. We report a 23-year-old male with undifferentiated carcinoma of the nasopharynx, stage III (T3N2M0), who had undergone aggressive surgical resection of bilateral huge cervical mass first followed by concurrent chemo-radiotherapy with cisplatin-based regimens. The postoperative clinical course was uneventful and follow-up, 2 years later, revealed no recurrence of primary lesion and neck metastases. We recommend that aggressive surgical resection may be considered when NPC patients significantly suffer clinical symptoms from a huge cervical metastasis.
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http://dx.doi.org/10.15644/asc53/2/9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604566PMC
June 2019

The genomic landscape of Epstein-Barr virus-associated pulmonary lymphoepithelioma-like carcinoma.

Nat Commun 2019 07 16;10(1):3108. Epub 2019 Jul 16.

Department of Medical Oncology, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare and distinct subtype of primary lung cancer characterized by Epstein-Barr virus (EBV) infection. Herein, we reported the mutational landscape of pulmonary LELC using whole-exome sequencing, targeted deep sequencing and single-nucleotide polymorphism arrays. We identify a low degree of somatic mutation but widespread existence of copy number variations. We reveal predominant signature 2 mutations and frequent loss of type I interferon genes that are involved in the host-virus counteraction. Integrated analysis shows enrichment of genetic lesions affecting several critical pathways, including NF-κB, JAK/STAT, and cell cycle. Notably, multi-dimensional comparison unveils that pulmonary LELC resemble NPC but are clearly different from other lung cancers, natural killer/T-cell lymphoma or EBV-related gastric cancer in terms of genetic features. In all, our study illustrates a distinct genomic landscape of pulmonary LELC and provides a road map to facilitate genome-guided personalized treatment.
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http://dx.doi.org/10.1038/s41467-019-10902-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635366PMC
July 2019

Corticosteroids combined with doublet or single-agent immunosuppressive therapy for active proliferative lupus nephritis.

Clin Rheumatol 2019 Sep 12;38(9):2519-2528. Epub 2019 May 12.

Department of Nephrology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China.

Objectives: We performed a meta-analysis to assess whether corticosteroids (C) plus (+) doublet immunosuppressive therapy (IT) is superior to the classical combination of C with single-agent IT in active proliferative lupus nephritis (LN).

Method: Randomized trials evaluating the benefits and risks of C+doublet versus single-agent IT in active proliferative LN were obtained by searching PubMed, EMBASE, and Cochrane Central Register. The primary outcome was overall response rate (ORR). The secondary outcomes were the change from baseline in Systemic Lupus Erythematosus Disease Activity Index (SLE-DAI) score, negative conversion ratio of anti-double-stranded DNA (anti-dsDNA), and adverse events. The PROSPERO registry number is CRD42017068491.

Results: Eleven trials with 1855 patients were included. Compared with C+single-agent IT, C+doublet IT had a significantly higher ORR (relative risk [RR], 1.22; 95% confidence interval [CI], 1.09 to 1.35; P < 0.01). In a subgroup analysis, C+doublet IT without biologics had a significantly higher ORR than C+single-agent IT (RR, 1.30; 95% CI, 1.13 to 1.50; P < 0.01), while C+doublet IT including biologics improved ORR only for refractory severe LN (RR, 1.46; 95% CI, 1.09 to 1.96; P = 0.012). A larger change from baseline in SLE-DAI scores (standardized mean difference, - 0.49; 95% CI, - 0.68 to - 0.30; P < 0.01) and a higher negative conversion ratio of anti-dsDNA (RR, 1.34; 95% CI, 1.06 to 1.69; P = 0.014) were observed with C+doublet IT than with C+single-agent IT. The rates of adverse events were similar between the two regimens.

Conclusions: Compared with single-agent IT, the combination of C and doublet IT without biologics improved clinical outcomes in active proliferative LN. Key Points • Compared with corticosteroids + single-agent immunosuppressive therapy, corticosteroids + doublet immunosuppressive therapy without biologics had a significantly higher overall response rate in active proliferative lupus nephritis. • Compared with corticosteroids + single-agent immunosuppressive therapy, corticosteroids + doublet immunosuppressive therapy including biologics improved overall response rate only for refractory severe lupus nephritis. • A larger change from baseline in SLE-DAI scores and a higher negative conversion ratio of anti-dsDNA were observed with corticosteroids + doublet immunosuppressive therapy than with corticosteroids + single-agent immunosuppressive therapy.
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http://dx.doi.org/10.1007/s10067-019-04596-0DOI Listing
September 2019

Immune-checkpoint inhibitor plus chemotherapy versus conventional chemotherapy for first-line treatment in advanced non-small cell lung carcinoma: a systematic review and meta-analysis.

J Immunother Cancer 2018 12 22;6(1):155. Epub 2018 Dec 22.

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

Background: Immune-checkpoint inhibitors plus chemotherapy are emerging as effective first-line treatment in advanced non-small-cell lung carcinoma (NSCLC), but little is known about the magnitude of benefits and potential clinical predictors.

Methods: We performed a meta-analysis of randomized trials that compared PD-1/PD-L1 inhibitor plus chemotherapy with chemotherapy in first line of treatment for advanced NSCLC. The outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and treatment-related adverse events (AEs). A fixed-effect or random-effects model was adopted depending on between-study heterogeneity.

Results: Six trials involving 3144 patients were included. PD-1/PD-L1 inhibitor plus chemotherapy was significantly associated with improvement of PFS (hazards ratio [HR], 0.62; 95% CI 0.57-0.67; P < .001), OS (HR, 0.68; 95% CI 0.53-0.87; P = .002) and ORR (relative ratio [RR], 1.56; 95% CI 1.29-1.89; P < .001), irrespective of PD-L1 expression level. The significant predictor(s) for treatment benefit with combination therapy versus chemotherapy alone were PD-L1 expression level for PFS (P < .001); types of checkpoint inhibitor for ORR (P < .001); histology (P = .025), age (P = .038), gender (P < .001), and types of checkpoint inhibitor (P < .001) for OS. In safety analyses, PD-1/PD-L1 inhibitor plus chemotherapy had significantly higher incidence of adverse events (AEs) of grade 3 or higher (RR, 1.14; P = .007), AEs leading to treatment discontinuation (RR, 1.29; P = .022), serious AEs (RR 1.70; P = .006), immune mediated AEs of any grade (RR, 2.37; P < .001), and immune mediated AEs of grade 3 or higher (RR, 3.71; P < .001).

Conclusions: PD-1/PD-L1 inhibitor plus chemotherapy, compared with chemotherapy, is associated with significantly improved PFS, ORR, and OS in first-line therapy in NSCLC, at the expense of increased treatment-related AEs.
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http://dx.doi.org/10.1186/s40425-018-0477-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6303974PMC
December 2018

Novel ANO5 mutation c.1067G>T (p.C356F) identified by whole genome sequencing in a big family with atypical gnathodiaphyseal dysplasia.

Head Neck 2019 01 15;41(1):230-238. Epub 2018 Dec 15.

Department of Oral and Maxillofacial Surgery, Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University, Guangzhou, China.

Background: Gnathodiaphyseal dysplasia (GDD) is a rare skeletal disorder that has not been well studied.

Methods: Sanger sequencing, whole-genome sequencing (WGS), and bioinformatics and structural modeling analyses were performed.

Results: A family with patients with fibro-osseous lesions of the jawbones were initially diagnosed with cherubism. Sequencing of SH3BP2, which is the causal gene of cherubism, revealed no pathogenic mutation. Through WGS, we identified a novel mutation c.1067G>T (p.C356F) in ANO5, and bioinformatics analyses and structural modeling showed that the mutation was deleterious. Because ANO5 is the gene responsible for GDD, we reappraised the clinical data of the patients, and the diagnosis was corrected to atypical GDD. A review of the literature showed that 67% of GDD cases confirmed by molecular testing were initially misdiagnosed.

Conclusions: The novel mutation c.1067G>T (p.C356F) in ANO5 is responsible for the atypical GDD observed in our patients. GDD should be included in the differential diagnosis for patients with fibro-osseous lesions.
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http://dx.doi.org/10.1002/hed.25516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8779835PMC
January 2019

Protamine-gold nanoclusters as peroxidase mimics and the selective enhancement of their activity by mercury ions for highly sensitive colorimetric assay of Hg(II).

Anal Bioanal Chem 2018 Nov 13;410(28):7385-7394. Epub 2018 Sep 13.

College of Public Health, University of South China, West Changsheng Road 28#, Hengyang, 421001, Hunan, China.

We certify that protamine-gold nanoclusters (PRT-AuNCs) synthesized by one-pot method exhibit peroxidase-like activity. The catalytic activity of PRT-AuNCs followed typical Michaelis-Menten kinetics and exhibited higher affinity to 3,3',5,5'-tetramethylbenzidine (TMB) as the substrate compared to that of natural horseradish peroxidase. Meanwhile, we found that Hg(II) could dramatically and selectively enhance the peroxidase-like activity of PRT-AuNCs, and the enhanced mechanism by Hg(II) was demonstrated to be generation of the cationic Au species and the partly oxidized Au species (Au) by Hg-Au/Au interaction. Based on this finding, quantitative determinations of Hg(II) via visual observation and absorption spectra were achieved. The proposed strategy displays high selectivity that arises from the strong aurophilic interaction of mercury towards gold. Moreover, the developed method is highly sensitive with a wide linear range and low detection limit of 1.16 nM. This strategy is not only helpful to develop effective nanomaterials-based artificial enzyme mimics but also irradiative to discover new applications of artificial mimic enzymes in bio-detection, medical diagnostics, and biotechnology. Graphical abstract Protamine-gold nanoclusters (PRT-AuNCs) synthesized by one-pot method exhibit peroxidase-like activity. Hg(II) can stimulate the peroxidase-like activity of PRT-AuNCs selectively, enhancing their ability to catalyze the chromogenic reaction of TMB by HO.
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http://dx.doi.org/10.1007/s00216-018-1344-8DOI Listing
November 2018

The baseline levels and risk factors for high-sensitive C-reactive protein in Chinese healthy population.

Immun Ageing 2018 8;15:21. Epub 2018 Sep 8.

3Department of Medicine and Therapeutics, Li KaShing Institute of Health Sciences, the Chinese University of Hong Kong, Hong Kong, SAR China.

Background: Recent studies show that C-reactive protein (CRP) is not only a biomarker but also a pathogenic mediator contributing to the development of inflammation and ageing-related diseases. However, serum levels of CRP in the healthy ageing population remained unclear, which was investigated in the present study.

Methods: Serum levels of high sensitive C-reactive protein (hs-CRP), glucose (Glu), triglyceride (TG), cholesterol (CHOL), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), superoxide dismutase (SOD), serum creatinine (SCr), serum uric acid (SUA) were measured in 6060healthy subjects (3672 male and 2388 female, mean age:45.9 years) who received routine physical examination at Sun Yat-sen Memorial Hospital, Guangzhou, China.

Results: In total of 6060 healthy people, serum levels of hs-CRP were significantly increased with ageing ( < 0.05), particularly in those with age over 45-year-old (1.31[0.69-2.75] vs 1.05[0.53-2.16]mg/L,  < 0.001). Interestingly, levels of serum hs-CRP were significantly higher in male than female population (1.24[0.65-2.57] vs 1.07[0.53-2.29]mg/L,  < 0.001). Correlation analysis also revealed that serum levels of hs-CRP positively correlated with age and SUA, but inversely correlated with serum levels of HDL-c and SOD (all  < 0.05).

Conclusions: Baseline levels of serum hs-CRP are increased with ageing and are significantly higher in male than female healthy population. In addition, elevated serum levels of hs-CRP are also associated with increased SUA but decreased HDL-c and SOD. Thus, serum levels of hs-CRP may be an indicator associated with ageing in healthy Chinese population.
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http://dx.doi.org/10.1186/s12979-018-0126-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128988PMC
September 2018

TGF-β-Induced CD8CD103 Regulatory T Cells Show Potent Therapeutic Effect on Chronic Graft-versus-Host Disease Lupus by Suppressing B Cells.

Front Immunol 2018 30;9:35. Epub 2018 Jan 30.

Department of Clinical Immunology, The Third Affiliate Hospital of Sun Yat-sen University, Guangzhou, China.

Lupus nephritis is one of most severe complications of systemic erythematosus lupus and current approaches are not curative for lupus nephritis. Although CD4Foxp3 regulatory T cells (Treg) are crucial for prevention of autoimmunity, the therapeutic effect of these cells on lupus nephritis is not satisfactory. We previously reported that CD8CD103 Treg induced with TGF-β1 and IL-2 (CD8CD103 iTreg), regardless of Foxp3 expression, displayed potent immunosuppressive effect on Th cell response and had therapeutic effect on Th cell-mediated colitis. Here, we tested whether CD8CD103 iTreg can ameliorate lupus nephritis and determined potential molecular mechanisms. Adoptive transfer of CD8CD103 iTreg but not control cells to chronic graft-versus-host disease with a typical lupus syndrome showed decreased levels of autoantibodies and proteinuria, reduced renal pathological lesions, lowered renal deposition of IgG/C3, and improved survival. CD8CD103 iTreg cells suppressed not only T helper cells but also B cell responses directly that may involve in both TGF-β and IL-10 signals. Using RNA-seq, we demonstrated CD8CD103 iTreg have its own unique expression profiles of transcription factors. Thus, current study has identified and extended the target cells of CD8CD103 iTreg and provided a possible application of this new iTreg subset on lupus nephritis and other autoimmune diseases.
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http://dx.doi.org/10.3389/fimmu.2018.00035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797539PMC
February 2019

Crosstalk between hepatitis B virus X and high-mobility group box 1 facilitates autophagy in hepatocytes.

Mol Oncol 2018 03 24;12(3):322-338. Epub 2018 Jan 24.

Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China.

Hepatitis B virus (HBV) X (HBx) protein is a pivotal regulator of HBV-triggered autophagy. However, the role of HBx-induced epigenetic changes in autophagy remains largely unknown. The cytoplasmic (Cyt) high-mobility group box 1 (HMGB1) has been identified as a positive regulator of autophagy, and its Cyt translocation is closely associated with its acetylation status. Here, we evaluated the function of HMGB1 in HBx-mediated autophagy and its association with histone deacetylase (HDAC). Using cell lines with enforced expression of HBx, we demonstrated that HBx upregulated the expression of HMGB1 and promoted its Cyt translocation by acetylation to facilitate autophagy. We further identified the underlying mechanism by which decreased nuclear HDAC activity and expression levels contribute to the HBx-promoted hyperacetylation and subsequent translocation of HMGB1. We also identified the HDAC1 isoform as a critical factor in regulating this phenomenon. In addition, HBx bound to HMGB1 in the cytoplasm, which triggered autophagy in hepatocytes. Pharmacological inhibition of HMGB1 Cyt translocation with ethyl pyruvate prevented HBx-induced autophagy. These results demonstrate a novel function of acetylated HMGB1 in HBx-mediated autophagy in hepatocytes.
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http://dx.doi.org/10.1002/1878-0261.12165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830655PMC
March 2018

Smad7 protects against acute kidney injury by rescuing tubular epithelial cells from the G1 cell cycle arrest.

Clin Sci (Lond) 2017 Aug 13;131(15):1955-1969. Epub 2017 Jul 13.

Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, China

Smad7 plays a protective role in chronic kidney disease; however, its role in acute kidney injury (AKI) remains unexplored. Here, we report that Smad7 protects against AKI by rescuing the G1 cell cycle arrest of tubular epithelial cells (TECs) in ischemia/reperfusion-induced AKI in mice in which Smad7 gene is disrupted or restored locally into the kidney. In Smad7 gene knockout (KO) mice, more severe renal impairment including higher levels of serum creatinine and massive tubular necrosis was developed at 48 h after AKI. In contrast, restored renal Smad7 gene locally into the kidney of Smad7 KO mice protected against AKI by promoting TEC proliferation identified by PCNA+ and BrdU+ cells. Mechanistic studies revealed that worsen AKI in Smad7 KO mice was associated with a marked activation of TGF-β/Smad3-p21/p27 signaling and a loss of CDK2/cyclin E activities, thereby impairing TEC regeneration at the G1 cell cycle arrest. In contrast, restored Smad7 locally into the kidneys of Smad7 KO mice protected TECs from the G1 cell cycle arrest and promoted TEC G1/S transition via a CDK2/cyclin E-dependent mechanism. In conclusion, Smad7 plays a protective role in AKI. Blockade of TGF-β/Smad3-p21/p27-induced G1 cell cycle arrest may be a key mechanism by which Smad7 treatment inhibits AKI. Thus, Smad7 may be a novel therapeutic agent for AKI.
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http://dx.doi.org/10.1042/CS20170127DOI Listing
August 2017
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