Publications by authors named "Si-Yang Liu"

73 Publications

Highly Sensitive Fluorescence Detection of Global 5-Hydroxymethylcytosine from Nanogram Input with Strongly Emitting Copper Nanotags.

Anal Chem 2021 Oct 12. Epub 2021 Oct 12.

School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.

Quantitative analysis of 5-hydroxymethylcytosine (5hmC) has remarkable clinical significance to early cancer diagnosis; however, it is limited by the requirement in current assays for large amounts of starting material and expensive instruments requring expertise. Herein, we present a highly sensitive fluorescence method, termed hmC-TACN, for global 5hmC quantification from several nanogram inputs based on terminal deoxynucleotide transferase (TdT)-assisted formation of fluorescent copper (Cu) nanotags. In this method, 5hmC is labeled with click tags by T4 phage β-glucosyltransferase (β-GT) and cross-linked with a random DNA primer via click chemistry. TdT initiates the template-free extension along the primer at the modified 5hmC site and then generates a long polythymine (T) tail, which can template the production of strongly emitting Cu nanoparticles (CuNPs). Consequently, an intensely fluorescent tag containing numerous CuNPs can be labeled onto the 5hmC site, providing the sensitive quantification of 5hmC with a limit of detection (LOD) as low as 0.021% of total nucleotides (/ = 3). With only a 5 ng input (∼1000 cells) of genomic DNA, global 5hmC levels were accurately determined in mouse tissues, human cell lines (including normal and cancer cells of breast, lung, and liver), and urines of a bladder cancer patient and healthy control. Moreover, as few as 100 cells can also be distinguished between normal and cancer cells. The hmC-TACN method has great promise of being cost effective and easily mastered, with low-input clinical utility, and even for the microzone analysis of tumor models.
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http://dx.doi.org/10.1021/acs.analchem.1c03266DOI Listing
October 2021

A MOF-Shell-Confined I-Motif-Based pH Probe (MOFC-i) Strategy for Sensitive and Dynamic Imaging of Cell Surface pH.

ACS Appl Mater Interfaces 2021 Sep 20;13(38):45291-45299. Epub 2021 Sep 20.

School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.

Dynamic imaging of cell surface pH is extremely challenging due to the slight changes in pH and the fast diffusion of secreted acid to the extracellular environment. In this work, we construct a novel metal-organic framework (MOF)-shell-confined i-motif-based pH probe (MOFC-i) strategy that enables sensitive and dynamic imaging of cell surface pH. The CY3- and CY5-labeled i-motif, which is hybridized via its short complementary chain with two-base mismatches, is optimized for sensing at physiological pH. After efficiently anchoring the optimized pH probes onto the cell membrane with the aid of cholesterol groups, a biocompatible microporous MOF shell is then formed around the cell by cross-linking ZIF-8 nanoparticles via tannic acid. The microporous MOF shell can confine secreted acid without inhibiting the normal physiological activities of cells; thus, the MOFC-i strategy can be used to monitor dynamic changes in the cell surface pH of living cells. Furthermore, this method can not only clearly distinguish the different metabolic behaviors of cancer cells and normal cells but also reveal drug effects on the cell surface pH or metabolism, providing promising prospects in pH-related diagnostics and drug screening.
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http://dx.doi.org/10.1021/acsami.1c13720DOI Listing
September 2021

Cancer cell identification by facile imaging of intracellular reductive substances with fluorescent nanosensor.

Talanta 2021 Nov 25;234:122650. Epub 2021 Jun 25.

School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, China. Electronic address:

Ascorbic acid (AA) and glutathione (GSH), the most abundant intracellular reductive substances, have been widely used as biomarkers for cancer cells identification. The current methods relying on imaging of AA or GSH alone to identify cancer cells may cause systematic errors, since a mutual conversion relationship exists between AA and GSH. In this work, we propose a fluorescent nanosensor for the simultaneous imaging of intracellular reductive substances including AA and GSH. Biocompatible fluorescent silicon nanoparticles (SiNPs) with rich surface amine and carboxyl groups were synthesized. The fluorescence of the SiNP was initially quenched by chelation of Fe ions, forming SiNP/Fe complex as the fluorescent nanosensor. Upon the redox reaction with reductive substances, the nanosensor showed sensitively fluorescent recovery. Moreover, benefited from the efficient cellular uptake of the SiNP/Fe and the overexpressed intracellular reductive substances in cancer cells, the fluorescent nanosensor was used to accurately identify the human breast carcinoma (MCF-7) cells from normal mammary epithelial (MCF-10A) cells by imaging of intracellular AA and GSH simultaneously. This strategy would be promising in imaging-guided precision cancer diagnosis.
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http://dx.doi.org/10.1016/j.talanta.2021.122650DOI Listing
November 2021

Pearl Necklacelike Strategy Enables Quantification of Global 5-Hydroxymethylcytosine and 5-Formylcytosine by Inductively Coupled Plasma-Atomic Emission Spectrometry.

Anal Chem 2021 06 26;93(22):7787-7791. Epub 2021 May 26.

School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.

5-Hydroxymethylcytosine (5hmC) and 5-formylcytosine (5fC) are key intermediates of active DNA demethylation, for which the global detection methods are still restricted by high cost and long operation time. Here, we demonstrate a pearl necklacelike strategy to accurately quantify global 5hmC and 5fC in genomic DNA. In this method, the metal-organic framework (MOF), [Cu(BTC)] (denoted as HKUST-1, HBTC = 1,3,5-benzenetricarboxylic acid), with a diameter of ∼30 nm that contains ∼15 000 copper ions (Cu) as the "super label" was grown in the carboxylated 5hmC and 5fC loci of genomic DNA via the coordination between Cu and the carboxyl group. After the acid digestion of MOF, the concentration of Cu, which has a quantitative relationship with the 5hmC/5fC content, was measured by inductively coupled plasma-atomic emission spectroscopy (ICP-AES). The metal element enrichment during MOF growth has amplified the signal by 4 orders of magnitude, realizing sensitive and accurate quantification of global 5hmC and 5fC in different tissues with a detection limit of 0.031% and 0.019‰ in DNA, respectively. The bisulfite- and mass spectrometry-free strategy is easily performed in almost all research and medical laboratories and would provide potential capability to quantify other candidate modifications in nucleotides.
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http://dx.doi.org/10.1021/acs.analchem.1c01548DOI Listing
June 2021

Unmet Clinical Demand for Patients With Unresectable Stage III NSCLC Having Actionable Genetic Alterations.

J Thorac Oncol 2021 05;16(5):712-714

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences School of Medicine, South China University of Technology, Guangzhou, People's Republic of China. Electronic address:

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http://dx.doi.org/10.1016/j.jtho.2021.02.020DOI Listing
May 2021

Multiomics analysis reveals a distinct response mechanism in multiple primary lung adenocarcinoma after neoadjuvant immunotherapy.

J Immunother Cancer 2021 04;9(4)

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangzhou, Guangdong, China

Multiple primary lung cancer (MPLC) remains a tough challenge to diagnose and treat. Although neoadjuvant immunotherapy has shown promising results in early stage non-small cell lung cancer, whether such modality can benefit all primary lesions remains unclear. Herein, we performed integrated multiomics analysis in one patient with early stage MPLC with remarkable tumor shrinkage in a solid nodule and no response in two subsolid nodules after treatment with three cycles of neoadjuvant pembrolizumab. Genomic heterogeneity was observed among responding nodules with high levels of infiltrating CD8 and CD68 immune cells. Substantially downregulated human leukocyte antigen (HLA)-related genes and impaired T lymphocyte function were observed in non-responding nodules. A larger proportion of infiltrating tissue resident memory T cells (Trm) along with high T cell receptor repertoire clonality in responding nodules were validated as predictive and prognostic biomarkers in multiple cancer types using external public datasets. These results suggested that neoadjuvant programmed death 1 (PD-1)/programmed death ligand 1 inhibitors alone may not be an optimal therapeutic strategy for MPLC due to disparities in genomic alterations and immune microenvironment among different lesions. Additionally, we postulate that increased infiltration of Trm may be a unique marker of early immune responses to PD-1 blockade.
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http://dx.doi.org/10.1136/jitc-2020-002312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025811PMC
April 2021

Ultrathin 2D Copper(I) 1,2,4-Triazolate Coordination Polymer Nanosheets for Efficient and Selective Gene Silencing and Photodynamic Therapy.

Adv Mater 2021 May 2;33(18):e2100849. Epub 2021 Apr 2.

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, China.

Gene silencing holds promise for cancer therapeutics because of its potential to inhibit genes involved in tumor development. However, gene silencing is still restricted by its limited efficacy and safety. Nanoscale coordination polymers (CPs) emerge as promising nanocarriers for gene delivery, but their responsiveness and potential therapeutic properties have rarely been explored simultaneously. Here, multifunctional ultrathin 2D nanosheets of Cu(I) 1,2,4-triazolate CP with a thickness of 4.5 ± 0.8 nm are synthesized using a bottom-up method. These CP nanosheets can act as both an effective DNAzyme nanocarrier for gene therapy and an intrinsic photosensitizer for hypoxia-tolerant type I photodynamic therapy (PDT), which is ascribed to the Fenton-like reaction. Because of the glutathione (GSH)-responsiveness of the CP nanosheets, DNAzyme-loaded CP nanosheets exhibit excellent cancer-cell-targeting gene silencing of the early growth response factor-1 (EGR-1), with messenger RNA inhibited by 84% in MCF-7 (human breast cancer cells) and only 6% in MCF-10A (normal human mammary epithelial cells). After tail intravenous injection into MCF-7-tumor-bearing mice, the CP nanosheets loaded with chlorin-e6-modified DNAzyme under photoirradiation show a high antitumor efficacy (88.0% tumor regression), demonstrating a promising therapeutic platform with efficient and selective gene silencing and PDT of cancer.
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http://dx.doi.org/10.1002/adma.202100849DOI Listing
May 2021

Fluorescence on-off-on with small and charge-tunable nanoparticles enables highly sensitive intracellular microRNA imaging in living cells.

Talanta 2021 May 15;226:122114. Epub 2021 Jan 15.

School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, China. Electronic address:

Nanomaterial-based on-off-on fluorescence sensing strategies are significant particularly in intracellular nucleic acids imaging assay. There still remains challenge to rationally balance fluorescence quenching efficiency and recovery dynamics. We assume that the performance of on-off-on fluorescence sensing strategy can be fundamentally improved on small zero-dimensional (0D) nanomaterial with precisely modulated surface charge. For a proof-of-concept demonstration, silicon nanoparticle (SiNP) with ~4 nm was synthesized and used as the quencher model, of which the surface charge density was modulated by modification of triphenylphosphonium (TPP). The influence of particle size, surface charge and charge density of the nanomaterials on sensing performance was systematically investigated. The strategy showed a low limit of detection (LOD) as 26 pM for target model miR-494, which is one of the lowest in nanomaterial-based on-off-on sensing platforms. And the LOD is even comparable to amplification-based methods in a greatly shortened assay time (2.5 h). The miR-494 expresses in cancerous and normal living cells of human cervical carcinoma (HeLa), human lung carcinoma (A549), human breast cancer (MCF-7), and normal human mammary epithelial (MCF-10A) cells were imaged and localized with significantly improved sensitivity and specificity. These excellent performances insure it a promising candidate as convenient and non-enzymatic sensing platform for miRNA-associated disease detection and early diagnosis.
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http://dx.doi.org/10.1016/j.talanta.2021.122114DOI Listing
May 2021

Gefitinib Versus Vinorelbine Plus Cisplatin as Adjuvant Treatment for Stage II-IIIA (N1-N2) EGFR-Mutant NSCLC: Final Overall Survival Analysis of CTONG1104 Phase III Trial.

J Clin Oncol 2021 03 17;39(7):713-722. Epub 2020 Dec 17.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, and Guangdong Academy of Medical Sciences, Guangzhou, China.

Purpose: ADJUVANT-CTONG1104 (ClinicalTrials.gov identifier: NCT01405079), a randomized phase III trial, showed that adjuvant gefitinib treatment significantly improved disease-free survival (DFS) versus vinorelbine plus cisplatin (VP) in patients with epidermal growth factor receptor () mutation-positive resected stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC). Here, we report the final overall survival (OS) results.

Methods: From September 2011 to April 2014, 222 patients from 27 sites were randomly assigned 1:1 to adjuvant gefitinib (n = 111) or VP (n = 111). Patients with resected stage II-IIIA (N1-N2) NSCLC and -activating mutation were enrolled, receiving gefitinib for 24 months or VP every 3 weeks for four cycles. The primary end point was DFS (intention-to-treat [ITT] population). Secondary end points included OS, 3-, 5-year (y) DFS rates, and 5-year OS rate. Post hoc analysis was conducted for subsequent therapy data.

Results: Median follow-up was 80.0 months. Median OS (ITT) was 75.5 and 62.8 months with gefitinib and VP, respectively (hazard ratio [HR], 0.92; 95% CI, 0.62 to 1.36; = .674); respective 5-year OS rates were 53.2% and 51.2% ( = .784). Subsequent therapy was administered upon progression in 68.4% and 73.6% of patients receiving gefitinib and VP, respectively. Subsequent targeted therapy contributed most to OS (HR, 0.23; 95% CI, 0.14 to 0.38) compared with no subsequent therapy. Updated 3y DFS rates were 39.6% and 32. 5% with gefitinib and VP ( = .316) and 5y DFS rates were 22. 6% and 23.2% ( = .928), respectively.

Conclusion: Adjuvant therapy with gefitinib in patients with early-stage NSCLC and mutation demonstrated improved DFS over standard of care chemotherapy. Although this DFS advantage did not translate to a significant OS difference, OS with adjuvant gefitinib was one of the longest observed in this patient group compared with historic data.
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http://dx.doi.org/10.1200/JCO.20.01820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078324PMC
March 2021

Tislelizumab: an investigational anti-PD-1 antibody for the treatment of advanced non-small cell lung cancer (NSCLC).

Expert Opin Investig Drugs 2020 Dec 21;29(12):1355-1364. Epub 2020 Oct 21.

Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, School of Medicine, Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, South China University of Technology , Guangzhou, China.

Introduction: Non-small cell lung cancer (NSCLC) accounts for most lung cancers worldwide and has a poor prognosis at later stages; programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have provided promising new treatment approaches for these patients. Tislelizumab, an anti-PD-1 monoclonal antibody, was engineered to minimize binding to FcγR on macrophages to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy. Tislelizumab has demonstrated clinical activity and is approved in China for treatment of previously treated classical Hodgkin lymphoma and previously treated metastatic PD-L1-high urothelial carcinoma.

Areas Covered: This review summarizes the clinical efficacy, safety, and tolerability of tislelizumab in patients with NSCLC and examines the mechanism of action, pharmacokinetic, and pharmacodynamic profiles of tislelizumab.

Expert Opinion: Tislelizumab has higher affinity to PD-1 than pembrolizumab and nivolumab, potentially due to its differential PD‑1 binding orientation. Tislelizumab demonstrated encouraging efficacy results, long duration of response, and a manageable safety profile across multiple clinical trials in advanced NSCLC. Ongoing trials of drug combinations (e.g. tislelizumab plus angiogenesis inhibitors, immune checkpoint inhibitors, or immune agonists) and examining efficacy across the severity of disease will provide opportunities to understand and feature tislelizumab in clinical practice.
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http://dx.doi.org/10.1080/13543784.2020.1833857DOI Listing
December 2020

Specific TP53 subtype as biomarker for immune checkpoint inhibitors in lung adenocarcinoma.

EBioMedicine 2020 Oct 11;60:102990. Epub 2020 Sep 11.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, China. Electronic address:

Background: Although TP53 co-mutation with KRAS/ATM/EGFR/STK11 have been proved to have predictive value for response to immune checkpoint inhibitors (ICIs), not all TP53 mutations are equal in this context. As the main part of TP53 mutant types, Missense and Nonsense alternations in TP53 as independent factors to predict the response to ICIs within Lung Adenocarcinoma (LUAD) patients have not yet been reported.

Methods: An integrated analysis based on multiple-dimensional data types including genomic, transcriptomic, proteomic and clinical data from published lung adenocarcinoma data and local database of LUAD taking immune checkpoint inhibitors. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups. Single-sample GSEA (GSVA) is conducted to calculate the score for enrichment of a set of genes regulating DNA damage repair (DDR) pathway.

Findings: The TP53-missense-mutation group showed increased PD-L1 (CD274) level and enriched IFN-γ signatures compared with the TP53-wild-type subgroup, but no differences were noted in patients with nonsense-mutant vs wild-type p53. Furthermore, a group of suppressor Immune cells like M2 Macrophage and Neutrophils are found enriched in nonsense group. On the other-side, both TP53 missense and nonsense mutations are associated with elevated TMB and neoantigen levels and contribute equally to DNA damage repair deficiency. The distribution regarding to multi-dimensional factors determining the efficacy of ICIs finally transformed into diverse clinical benefits for LUAD. TP53 missense but not -nonsense Mutants are associated with better clinical benefits taking antiPD-1/1L. However, all such TP53 subgroups responds well to nivolumab (antiPD-L1) plus ipilimumab (antiCTLA-4) therapy.

Interpretation: Our study demonstrated that not all TP53 mutations are equal in predicting efficacy in patients with LUAD treated with ICIs. Multi-center data showed that TP53 missense and nonsense mutations were significantly different in terms of associations with PD-L1 expression, IFN-γ signatures and TME composition. Special attention should be paid to potential TP53 mutation heterogeneity when evaluating TP53 status as biomarker for ICIs.

Funding: The study was supported by Key Lab System Project of Guangdong Science and Technology Department - Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (Grant No. 2017B030314120, to Yi-Long WU).
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http://dx.doi.org/10.1016/j.ebiom.2020.102990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494676PMC
October 2020

Clinical characteristics and prognostic value of the mutation in Chinese non-small cell lung cancer patients.

Biomark Res 2020 25;8:22. Epub 2020 Jun 25.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, 106 Zhongshan Er Road, Guangzhou, 510080 China.

Background: The mutation is the second most common genetic variant in Chinese non-small cell lung cancer (NSCLC) patients. At the 2019th World Conference of Lung Cancer, the -specific inhibitor AMG510 showed promising results in the phase I clinical trial. However, the frequency, clinical characteristics, and prognostic significance of the mutation in Chinese NSCLC patients are rarely reported.

Methods: Next-generation sequencing was used to confirm the mutation status in 40,804 NSCLC patients from multiple centers (mCohort). Survival data were collected retrospectively from 1456 patients at one of the centers, the Guangdong Lung Cancer Institute (iCohort).

Results: In the mCohort, 3998 patients (9.8%) were confirmed to harbor a mutation, of whom 1179 (29.5%) had the subtype. In the iCohort, 130 NSCLC patients (8.9%) had a mutation and 42 (32.3%) had the subtype. The subgroup included more male patients (85.2% vs 67.4%,  < 0.0001) and more smokers (76.2% vs 53.4%,  = 0.02) than did the non- subgroup. Both the mutation group and mutation subgroup were associated with a shorter median overall survival (OS) than wildtype tumors (15.1 vs 26.7 months, hazard ratio [HR]  = 1.50,  = 0.002; 18.3 vs 26.7 months, HR  = 1.66,  = 0.007). In Cox regression analysis, smoking (HR = 1.39,  = 0.05) and stage IV disease (HR = 2.72,  < 0.001) remained as independent predictors of shorter OS. Both the mutation (HR = 1.30,  = 0.07) and mutation (HR = 1.47,  = 0.07) reached borderline significance.

Conclusions: In the largest sample used thus for, our study found that approximately 10% of Chinese NSCLC patients had mutations. Of these, nearly 30% harbored the mutation subtype, which was most common in male smokers. The mutation is a biomarker of poor prognosis in Chinese NSCLC patients, which could potentially be improved by -specific inhibitors in the future.(296 words).
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http://dx.doi.org/10.1186/s40364-020-00199-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318746PMC
June 2020

Concomitant genetic alterations having greater impact on the clinical benefit of EGFR-TKIs in EGFR-mutant advanced NSCLC than BIM deletion polymorphism.

Clin Transl Med 2020 Jan;10(1):337-345

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, 510080, China.

Background: In previous studies, the predictive role of BIM deletion polymorphism with respect to responses to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) has been controversial. The potential reasons for these inconsistent findings were unknown.

Methods: Data from CTONG0901 clinical trial and medical records of Guangdong Lung Cancer Institute (GLCI) were retrospectively pooled. A total of 194 and 141 EGFR-mutant non-small cell lung cancer (NSCLC) patients treated with first- and second-generation EGFR-TKIs were examined in the CTONG0901 and GLCI cohorts, respectively. Sixty-eight patients were treated with third-generation EGFR-TKIs in the GLCI cohort. The BIM gene status was examined by next-generation sequencing.

Results: The frequency of BIM deletion polymorphism was 11.3% and 17.0% in CTONG0901 and GLCI cohorts, respectively. For first- and second-generation EGFR-TKIs in CTONG0901 cohort, objective response (ORR) was 54.5% in BIM deletion group versus 56.4% in wild-type BIM group (P = .87); disease control rate (DCR) was 90.9% versus 88.4% (P = 1.00); progression-free survival (PFS) was 10.5 versus 11.2 months (P = .59); and overall survival (OS) was 20.5 versus 20.5 months (P = .73). In GLCI cohort, ORR was 54.2% versus 60.7% (P = .55); DCR was 91.7% versus 96.6% (P = .27); PFS was 10.1 versus 11.6 months (P = .63); and OS was 58.5 versus 45.0 months (P = .93). For third-generation EGFR-TKIs, ORR was 18.2% versus 63.2% (P = .02); DCR was 81.8% versus 96.5%, (P = .12); PFS was 5.8 versus 9.0 months (P = .13); and OS was 30.0 versus 24.8 months (P = .85). Cox regression analysis showed that concomitant genetic alterations could adversely affect the response to EGFR-TKIs, but not BIM deletion.

Conclusions: The presence of BIM deletion showed no relation to an impaired response to first-, second-, and third-generation EGFR-TKIs in NSCLC patients. The factors influencing the response of EGFR-TKIs were concomitant genetic alterations, but not BIM deletion.
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http://dx.doi.org/10.1002/ctm2.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240862PMC
January 2020

Safety of EGFR-TKIs for EGFR mutation-positive non-small cell lung cancer.

Expert Opin Drug Saf 2020 May 28;19(5):589-599. Epub 2020 Apr 28.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, China.

: Lung cancer is the most prevalent malignant tumors worldwide. Over the past decade, the emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has ushered in a new era of lung cancer treatment. Therefore, clinical trials investigating the efficacy and safety of these drugs are important.: This review provides an overview on the safety of three classes of EGFR-TKIs and discusses the adverse events (AEs) and reactions reported in the literature.: EGFR-TKIs significantly improve progression-free survival and overall survival in non-small cell lung cancer (NSCLC) patients with an activating mutation of EGFR. However, EGFR-TKIs also block the EGFR-regulating pathways in the skin and gastrointestinal tract and cause AEs, including diarrhea, liver toxicity, skin disease, stomatitis, interstitial lung disease, and ocular toxicity, which have detrimental effects on quality of life and drug compliance. Clinicians should understand how to prevent and control these adverse reactions, which can often be achieved by dose reduction, discontinuation of treatment, or switching to another drug.
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http://dx.doi.org/10.1080/14740338.2020.1753697DOI Listing
May 2020

Biomarker for personalized immunotherapy.

Transl Lung Cancer Res 2019 Nov;8(Suppl 3):S308-S317

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.

Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) interaction protects cancer cells from immune destruction. Blocking the pathway allows infiltrated T cells to kill tumor cells (TCs), in order to prevent tumor proliferation and distant migration. Immunotherapy with checkpoint blockade (CPB) has emerged as a powerful weapon conquering multiple cancer. However, PD-L1 expression and tumor mutation burden (TMB) are not perfect biomarkers for patients selection to treated with immunotherapy. Increasing evidence showed that other immune-related factored must be payed enough attention and combined biomarkers present promising prospects. Here, we give an overview on available biomarkers in clinic and potential biomarkers for future research.
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http://dx.doi.org/10.21037/tlcr.2019.08.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894992PMC
November 2019

Recursive partitioning analysis of patients with oligometastatic non-small cell lung cancer: a retrospective study.

BMC Cancer 2019 Nov 6;19(1):1051. Epub 2019 Nov 6.

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Key Laboratory of Lung Cancer Translational Medicine, South China University of Technology & Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.

Background: Local consolidative treatment (LCT) is important for oligometastasis, defined as the restricted metastatic capacity of a tumor. This study aimed to determine the effects and prognostic heterogeneity of LCT in oligometastatic non-small cell lung cancer.

Methods: This retrospective study identified 436 eligible patients treated for oligometastatic disease at the Guangdong Provincial People's Hospital during 2009-2016. A Cox regression analysis was used to identify potential predictors of overall survival (OS). After splitting cases randomly into training and testing sets, risk stratification was performed using recursive partitioning analysis with a training dataset. The findings were confirmed using a validation dataset. The effects of LCT in different risk groups were evaluated using the Kaplan-Meier method.

Results: The T stage (p = 0.001), N stage (p = 0.008), number of metastatic sites (p = 0.031), and EGFR status (p = 0.043) were identified as significant predictors of OS. A recursive partitioning analysis was used to establish a prognostic risk model with the following four risk groups: Group I included never smokers with N0 disease (3-year OS: 55.6%, median survival time [MST]: 42.8 months), Group II included never smokers with N+ disease (3-year OS: 32.8%, MST: 26.5 months), Group III included smokers with T0-2 disease (3-year OS: 23.3%, MST: 19.4 months), and Group IV included smokers with T3/4 disease (3-year OS: 12.5%, MST: 11.1 months). Significant differences in OS according to LCT status were observed in all risk groups except Group IV (p = 0.45).

Conclusions: Smokers with T3/4 oligometastatic non-small cell lung cancer may not benefit from LCT.
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http://dx.doi.org/10.1186/s12885-019-6216-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836326PMC
November 2019

Personalized adjuvant treatment: go through the past to the future.

J Thorac Dis 2019 Aug;11(8):E109-E111

Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.

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http://dx.doi.org/10.21037/jtd.2019.08.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753432PMC
August 2019

Visceral pleural invasion in T1 tumors (≤3 cm), particularly T1a, in the eighth tumor-node-metastasis classification system for non-small cell lung cancer: a population-based study.

J Thorac Dis 2019 Jul;11(7):2754-2762

Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital Affiliated with the South China University of Technology and Guangdong Academy of Medical Sciences, Guangdong Key Laboratory of Lung Cancer Translational Medicine, Guangzhou 510080, China.

Background: We aimed to validate the tumor (T) descriptors of visceral pleural invasion (VPI) for T1 tumors (<3 cm) in the 8th edition of the tumor-node-metastasis (TNM) classification system and the prognostic value of VPI for resected T1a tumors.

Methods: The external cohort consisted of 23,501 patients with resected pN0 non-small cell lung cancer (NSCLC) selected from the Surveillance, Epidemiology, and End Results (SEER) database (2010 to 2013). The classification of T1 tumors with VPI was investigated using survival curves. The internal cohort consisted of patients diagnosed with pN0 NSCLC between 2011 and 2013 at Guangdong Lung Cancer Institute. The prognostic value of VPI for T1a tumors (<1 cm) was further assessed in these two cohorts.

Results: The overall survival (OS) and lung cancer-specific survival (LCSS) of the T1-VPI group and groups of each T stage (size only) were compared in the external (SEER) cohort. There were no significant survival differences between the T1-VPI and T2a groups (OS: P=0.706; LCSS: P=0.792) and T1-VPI and T2b groups, although the latter showed a trend toward lower P-values (OS: P=0.117; LCSS: P=0.094). In the internal cohort, a significant difference in OS was observed between patients with T1-VPI and those with T2b (P=0.049). Among patients with T1a tumors and VPI in the SEER database, the prognosis of the non-sub-lobectomy group was superior to that of the sub-lobectomy group, with intrathoracic recurrence as the predominant relapse pattern of T1 tumors with VPI (69.2%).

Conclusions: T1 tumors (<3 cm) with VPI can be staged as T2a in the 8th TNM staging system and surgical resection of T1a tumors is a concern when VPI is present.
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http://dx.doi.org/10.21037/jtd.2019.06.32DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688036PMC
July 2019

Polymerization retardation isothermal amplification (PRIA): a strategy enables sensitively quantify genome-wide 5-methylcytosine oxides rapidly on handy instruments with nanoscale sample input.

Nucleic Acids Res 2019 11;47(19):e119

School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China.

The current methods for quantifying genome-wide 5-methylcytosine (5mC) oxides are still scarce, mostly restricted with two limitations: assay sensitivity is seriously compromised with cost, assay time and sample input; epigenetic information is irreproducible during polymerase chain reaction (PCR) amplification without bisulfite pretreatment. Here, we propose a novel Polymerization Retardation Isothermal Amplification (PRIA) strategy to directly amplify the minute differences between epigenetic bases and others by arranging DNA polymerase to repetitively pass large electron-withdrawing groups tagged 5mC-oxides. We demonstrate that low abundant 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxycytosine (5caC) in genomic DNA can be accurately quantified within 10 h with 100 ng sample input on a laboratory real-time quantitative PCR instrument, and even multiple samples can be analyzed simultaneously in microplates. The global levels of 5hmC and 5fC in mouse and human brain tissues, rat hippocampal neuronal tissue, mouse kidney tissue and mouse embryonic stem cells were quantified and the observations not only confirm the widespread presence of 5hmC and 5fC but also indicate their significant variation in different tissues and cells. The strategy is easily performed in almost all research and medical laboratories, and would provide the potential capability to other candidate modifications in nucleotides.
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http://dx.doi.org/10.1093/nar/gkz704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821303PMC
November 2019

Metastable Dumbbell Probe-Based Hybridization Chain Reaction for Sensitive and Accurate Imaging of Intracellular-Specific MicroRNAs In Situ in Living Cells.

Anal Chem 2019 04 20;91(7):4625-4631. Epub 2019 Mar 20.

School of Chemistry , Sun Yat-Sen University , Guangzhou 510275 , People's Republic of China.

Sensitive and accurate imaging of intracellular-specific microRNAs (miRNAs) in situ in living cells is seriously challenged by the susceptibility of nucleic acid probes and the low dynamics of the hybridization reaction in cellular environments. Herein, we engineer a set of new metastable dumbbell probes (M DPs) to overcome these key limitations by concurrently boosting transfection, antidigestibility, assembly dynamics, and nanostructural uniformity. The M DPs can maintain their stability up to 16 h in living cells and produce uniform and dense DNA nanostructures rapidly (<2 h) and specifically from a hybridization chain reaction (HCR). A sharp signal from the cascade accumulation of fluorescence resonance energy transfer (FRET) further minimizes the effect of system fluctuations. The M DPs-based HCR (M DPHCR) method showed identical performance in the analysis of miR-27a in cell lysate and buffer condition and obtained a limit of detection down to 3.2 pM (corresponding to 160 amol per 50 μL), which is 44-fold lower than on conventional hairpin probes. The M DPHCR method clearly distinguished normal cells from tumor cells and provided more accurate quantitative information on the intracellular-specific miRNAs. The strategy would offer a powerful tool for visualizing and localizing desired nucleic acids in living cells.
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http://dx.doi.org/10.1021/acs.analchem.8b05920DOI Listing
April 2019

Partially Fluorinated Cu(I) Triazolate Frameworks with High Hydrophobicity, Porosity, and Luminescence Sensitivity.

Inorg Chem 2019 Mar 5;58(6):3944-3949. Epub 2019 Mar 5.

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry , Sun Yat-Sen University , Guangzhou 510275 , People's Republic of China.

Solvothermal reactions of 3-methyl-5-trifluoromethyl-1,2,4-triazole (Hfmtz) with Cu(CHCOO) at 120 °C in the presence of Cl generate two partially fluorinated coordination polymers: i.e., [CuCl(fmtz)] (1 or MAF-51) and [CuCl(fmtz)] (2 or MAF-52). Single-crystal X-ray diffraction revealed 1 to have a three-dimensional (3D) nonporous structure with pcu topology consisting of 6-connected Cu(μ-Cl) clusters and 2 to possess a highly porous (void ratio 48%) 3D bnn network consisting of 5-connected Cu(μ-Cl) clusters. Benefiting from the hydrophobic pendant groups, complete coordination of the ligand N atoms, and strong M-N coordination bonds, 1 and 2 possess high water stability (exposed to water for at least 1 year) and hydrophobicity (water contact angles of 141° and 148°, respectively). The N sorption isotherm of activated 2 gave Langmuir/BET surface areas of 1023/848 m g and a pore volume of 0.365 cm g. Moreover, 2 can adsorb large amounts of benzene and methanol but barely adsorb water. Both 1 and 2 show phosphorescence of Cu(I) complexes, but only that of porous 2 is sensitive to O, showing a linear Stern-Volmer response below 1 mbar with an ultrahigh K value of 5234 bar and ultralow limit of detection of 1.9 ppm.
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http://dx.doi.org/10.1021/acs.inorgchem.9b00006DOI Listing
March 2019

Adjuvant TKIs: still an optimal choice.

J Thorac Dis 2018 Dec;10(12):E812-E814

Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou 510080, China.

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http://dx.doi.org/10.21037/jtd.2018.11.67DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344745PMC
December 2018

In Situ Enzyme Immobilization with Oxygen-Sensitive Luminescent Metal-Organic Frameworks to Realize "All-in-One" Multifunctions.

Chemistry 2019 Apr 8;25(21):5463-5471. Epub 2019 Mar 8.

School of Chemistry, Sun Yat-sen University, Guangzhou, 510275, P. R. China.

Metal-organic frameworks (MOFs) for enzyme immobilization have already shown superior tunable and designable characteristics, however, their diverse responsive properties have rarely been exploited. In this work we integrated a responsive MOF into a MOF-enzyme composite with the purpose of designing an "all-in-one" multifunctional composite with catalytic and luminescence functions incorporated into a single particle. As a proof-of-concept, glucose oxidase (GOx) was encapsulated in situ within an oxygen (O )-sensitive, noble-metal-free, luminescent Cu triazolate framework (MAF-2), denoted as [email protected] Owing to the rigid scaffold of MAF-2 and confinement effect, the [email protected] composite showed significantly improved stability (shelf life of 60 days and heat resistance up to 80 °C) as well as good selectivity and recyclability. More importantly, owing to the O sensitivity of MAF-2, the [email protected] composite exhibited a rapid and reversible response towards dissolved O , thereby allowing direct and ratiometric sensing of glucose without the need for chromogenic substrates, cascade enzymatic reactions, or electrode systems. High sensitivity with a detection limit of 1.4 μm glucose was achieved, and the glucose levels in human sera were accurately determined. This strategy has led to a new application for MOFs that can be facilely extended to other MOF-enzyme composites due to the multifunctionality of MOFs.
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http://dx.doi.org/10.1002/chem.201806146DOI Listing
April 2019

High-glucose Induced Mitochondrial Dynamics Disorder of Spinal Cord Neurons in Diabetic Rats and its Effect on Mitochondrial Spatial Distribution.

Spine (Phila Pa 1976) 2019 Jun;44(12):E715-E722

Endocrine Testing Center, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, P. R. China.

Study Design: A randomized, double-blind, controlled trial.

Objective: Few studies have investigated the changes in mitochondrial dynamics in spinal cord neurons. Meanwhile, the distribution of mitochondria in axons remains unclear. In the present study, the investigators attempted to clarify these questions and focused in observing the changes in mitochondrial spatial distribution under a high-glucose environment.

Summary Of Background Data: Mitochondrial dynamics disorder is one of the main mechanisms that lead to nervous system diseases due to its adverse effects on mitochondrial morphology, function, and axon distribution. High-glucose stress can promote the increase in mitochondrial fission of various types of cells.

Methods: The lumbar spinal cord of type 1 diabetic Sprague-Dawley rats at 4 weeks was observed. VSC4.1 cells were cultured and divided into three groups: normal control group, high-glucose intervention group, and high-glucose intervention combined with mitochondrial fission inhibitor Mdivi-1 intervention group. Immunohistochemistry and immunofluorescence methods were used to detect the expression of mitochondrial marker VDAC-1 in the spinal cord. An electron microscope was used to observe the number, structure, and distribution of mitochondria. Western blot was used to detect VDAC-1, fusion protein MFN1, MFN2, and OPA1, and fission protein FIS1 and DRP1. Living cell mitochondrial staining was performed using MitoTracker. Laser confocal microscopy and an Olympus live cell workstation were used to observe the mitochondrial changes.

Results: The mitochondrial dynamics of spinal cord related neurons under an acute high-glucose environment were significantly unbalanced, including a reduction of fusion and increase of fission. Hence, mitochondrial fission has the absolute advantage. The total number of mitochondria in neuronal axons significantly decreased.

Conclusion: Increased mitochondrial fission and abnormal distribution occurred in spinal cord related neurons in a high-glucose environment. Mdivi-1 could significantly improve these disorders of mitochondria in VSC4.1 cells. Mitochondrial division inhibitors had a positive significance on diabetic neuropathy.

Level Of Evidence: N/A.
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http://dx.doi.org/10.1097/BRS.0000000000002952DOI Listing
June 2019

Clinical relevance of PD-L1 expression and CD8+ T cells infiltration in patients with EGFR-mutated and ALK-rearranged lung cancer.

Lung Cancer 2018 11 14;125:86-92. Epub 2018 Sep 14.

School of Medicine, South China University of Technology, Guangzhou, 510006, China; Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou, 510080, China. Electronic address:

Objectives: EGFR-mutated or ALK-rearranged non-small cell lung cancer (NSCLC) often showed unfavorable clinical benefit to checkpoint inhibitors (CPIs). However, few reports exist with integrated analysis, to interpret the underlying mechanism of poor response to PD-1/PD-L1 inhibitors. We have retrospectively analyzed the tumor microenvironment (TME) based on tumor PD-L1 expression and CD8+ T cells infiltration in patients with EGFR mutations and ALK rearrangements, and the prognostic value of TME subtypes on overall survival (OS).

Materials And Methods: Tumor samples from 715 patients with lung cancer were retrospectively collected at Guangdong Lung Cancer Institute. Tumoral PD-L1 expression (N = 715) and CD8+ T cells infiltration (N = 658) was determined by immunohistochemistry (IHC), based on which TME was categorized into four different subtypes: PD-L1+/CD8+, PD-L1-/CD8+, PD-L1+/CD8-, PD-L1-/CD8-. Proportion of four TME subtypes was determined, and overall survival with PD-L1 expression and TME was analyzed.

Results: In patients with EGFR mutations or ALK rearrangements, proportion of PD-L1+/CD8+ tumors was the lowest (5.0%, 17/342), and that of PD-L1-/CD8- tumors was the highest (63.5%, 217/342). In patients with wild-type EGFR and ALK, 14.2% (45/316) tumors were PD-L1+/CD8+ and 50.3% (159/316) tumors were PD-L1-/CD8- (P < 0.001). Median OS of EGFR-mutated or ALK-rearranged lung cancer was 78.6 months in PD-L1 positive group and 93.4 months in PD-L1 negative group (HR 0.47, 95%CI 0.23-0.76, P = 0.005). PD-L1+/CD8+ group exhibited the shortest OS, with 44.3 months, but is likely to respond to CPIs. The PD-L1-/CD8+ group exhibited the longest OS but is unlikely to respond to CPIs.

Conclusion: Patients with EGFR mutations or ALK rearrangements exhibited lower PD-L1 and CD8 co-expression level in TME, which could be responsible for poor response to CPIs. PD-L1 and CD8 co-expression in EGFR-mutated or ALK-rearranged lung cancer is a biomarker for poor prognosis with shorter OS.
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http://dx.doi.org/10.1016/j.lungcan.2018.09.010DOI Listing
November 2018

Strong Programmed Death Ligand 1 Expression Predicts Poor Response and De Novo Resistance to EGFR Tyrosine Kinase Inhibitors Among NSCLC Patients With EGFR Mutation.

J Thorac Oncol 2018 11 26;13(11):1668-1675. Epub 2018 Jul 26.

Southern Medical University, Guangzhou, China; Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China. Electronic address:

Introduction: This study evaluated whether tumor expression of programmed death ligand 1 (PD-L1) could predict the response of EGFR-mutated NSCLC to EGFR tyrosine kinase inhibitor (TKI) therapy.

Methods: We retrospectively evaluated patients who received EGFR-TKIs for advanced NSCLC at the Guangdong Lung Cancer Institute between April 2016 and September 2017 and were not enrolled in clinical studies. The patients' EGFR and PD-L1 statuses were simultaneously evaluated.

Results: Among the 101 eligible patients, strong PD-L1 expression significantly decreased objective response rate, compared with weak or negative PD-L1 expression (35.7% versus 63.2% versus 67.3%, p = 0.002), and shortened progression-free survival (3.8 versus 6.0 versus 9.5 months, p < 0.001), regardless of EGFR mutation type (19del or L858R). Furthermore, positive PD-L1 expression was predominantly observed among patients with de novo resistance rather than acquired resistance to EGFR-TKIs (66.7% versus 30.2%, p = 0.009). Notably, we found a high proportion of PD-L1 and cluster of differentiation 8 (CD8) dual-positive cases among patients with de novo resistance (46.7%, 7 of 15). Finally, one patient with de novo resistance to EGFR-TKIs and PD-L1 and CD8 dual positivity experienced a favorable response to anti-programmed death 1 therapy.

Conclusions: This study revealed the adverse effects of PD-L1 expression on EGFR-TKI efficacy, especially in NSCLC patients with de novo resistance. The findings indicate the reshaping of an inflamed immune phenotype characterized by PD-L1 and CD8 dual positivity and suggest potential therapeutic sensitivity to programmed death 1 blockade.
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http://dx.doi.org/10.1016/j.jtho.2018.07.016DOI Listing
November 2018

Real-Time Sensing of TET2-Mediated DNA Demethylation In Vitro by Metal-Organic Framework-Based Oxygen Sensor for Mechanism Analysis and Stem-Cell Behavior Prediction.

Anal Chem 2018 08 19;90(15):9330-9337. Epub 2018 Jul 19.

School of Chemistry , Sun Yat-sen University , Guangzhou 510275 , P. R. China.

Active DNA demethylation, mediated by O-dependent ten-eleven translocation (TET) enzymes, has essential roles in regulating gene expression. TET kinetics assay is vital for revealing mechanisms of demethylation process. Here, by a metal-organic framework (MOF)-based optical O sensor, we present the first demonstration on real-time TET2 kinetics assay in vitro. A series of luminescent Cu(I) dialkyl-1,2,4-triazolate MOFs were synthesized, which were noble-metal-free and able to intuitively response to dissolved O in a wide range from cellular hypoxia (≤15 μM) to ambient condition (∼257 μM). By further immobilization of the MOFs onto transparent silicon rubber ([email protected]) to construct O film sensors, and real-time monitoring of O consumption on [email protected] over the reaction time, the complete TET2-mediated 5-methylcytosine (5mC) oxidation process were achieved. The method overcomes the limitations of the current off-line methods by considerably shortening the analytical time from 0.5-18 h to 10 min, and remarkably reducing the relative standard deviation from 10%-68% to 0.68%-4.2%. As a result, the Michaelis-Menten constant ( K) values of TET2 for 5mC and O in ascorbic acid-free (AA) condition were precisely evaluated to be 24 ± 1 and 43.8 ± 0.3 μM, respectively. By comparative study on AA-containing (AA) conditions, and further establishing kinetics models, the stem-cell behavior of TETs was successfully predicted, and the effects of key factors (AA, O, Fe) on TETs were revealed, which were fully verified in mouse embryonic stem (mES) cells. The method is promising in wide application in kinetics analysis and cell behavior prediction of other important O-related enzymes.
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http://dx.doi.org/10.1021/acs.analchem.8b01941DOI Listing
August 2018

Serum of sickle cell disease patients contains fetal hemoglobin silencing factors secreted from leukocytes.

J Blood Med 2018 22;9:95-104. Epub 2018 Jun 22.

Department of Anesthesiology and Perioperative Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.

Background: The mechanisms that regulate fetal hemoglobin (HbF) expression in sickle cell disease (SCD) remain elusive. We previously showed that steady-state SCD patients with high HbF levels due to a gene mutation demonstrate strong inverse correlations between HbF levels and leukocyte counts, suggesting that leukocytes play a role in regulating HbF in SCD.

Materials And Methods: To further investigate the role of leukocytes in HbF expression in SCD, we examined the presence of HbF silencing factors in the serum of 82 SCD patients who received hydroxyurea (HU) therapy.

Results: HU-mediated HbF induction was associated with elevated total hemoglobin levels and improved red blood cell parameters, but there was no correlation with reticulocyte or platelet counts. Importantly, we again found that HU-induced HbF levels correlated with reductions in both neutrophils and lymphocytes/monocytes, indicating that these cell lineages may have a role in regulating HU-mediated HbF expression. Our in vitro studies using CD34-derived primary erythroblasts found that patient serum preparations include HbF silencing factors that are distinct from granulocyte-macrophage colony-stimulating factor, and the activity of such factors decreases upon HU therapy.

Conclusion: Together, these results demonstrate the importance of leukocyte numbers in the regulation of HbF levels for SCD patients both in steady state and under HU therapy, and that leukocytes secrete HbF silencing factors that negatively affect HbF expression in erythroid-lineage cells in SCD.
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http://dx.doi.org/10.2147/JBM.S156999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018840PMC
June 2018

Electrochemical Exfoliation of Pillared-Layer Metal-Organic Framework to Boost the Oxygen Evolution Reaction.

Angew Chem Int Ed Engl 2018 04 13;57(17):4632-4636. Epub 2018 Mar 13.

MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, Sun Yat-Sen University, Guangzhou, 510275, China.

Two-dimensional (2D) materials and ultrathin nanosheets are advantageous for elevating the catalysis performance and elucidating the catalysis mechanism of heterogeneous catalysts, but they are mostly restricted to inorganic or organic materials based on covalent bonds. We report an electrochemical/chemical exfoliation strategy for synthesizing metal-organic 2D materials based on coordination bonds. A catechol functionalized ligand is used as the redox active pillar to construct a pillared-layer framework. When the 3D pillared-layer MOF serves as an electrocatalyst for water oxidation (pH 13), the pillar ligands can be oxidized in situ and removed. The remaining ultrathin (2 nm) nanosheets of the metal-organic layers are an efficient catalyst with overpotentials as low as 211 mV at 10 mA cm and a turnover frequency as high as 30 s at an overpotential of 300 mV.
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http://dx.doi.org/10.1002/anie.201801029DOI Listing
April 2018
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