Publications by authors named "Yanqiu Zhao"

65 Publications

Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing.

J Thorac Oncol 2021 Feb 13. Epub 2021 Feb 13.

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

Introduction: By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC.

Methods: In a multicenter phase 2 trial, patients with ALK-positive NSCLC who progressed on crizotinib were treated with ensartinib. Blood samples for ctDNA analysis were collected at baseline, cycle 3 day 1, and progression disease (PD) and analyzed with a 212-gene panel.

Results: A total of 440 samples were collected from 168 patients. Baseline TP53 mutations (20.2%) significantly correlated with inferior progression-free survival (4.2 mo versus 11.7 mo, p < 0.0001). Patients with TP53 mutations had higher mutation load than those without TP53 mutations at baseline (13.79 ± 3.72 versus 4.67 ± 0.39, p < 0.001). Although there was no significant difference in mutation load between these groups at cycle 3 day 1 (5.89 ± 2.25 versus 3.72 ± 0.62, p = 0.425), patients with mutated TP53 developed more mutations at PD (7.07 ± 1.25 versus 3.20 ± 0.33, p = 0.003). Frequency and abundance of secondary ALK mutations G1269A, G1202R, and E1210K increased markedly at PD than baseline. In patients without secondary ALK mutations, we identified ALK-independent resistance mechanisms including bypass signaling activation, downstream effector protein reactivation, epithelial-mesenchymal transformation, and epigenetic dysregulation.

Conclusions: Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib.
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http://dx.doi.org/10.1016/j.jtho.2021.01.1615DOI Listing
February 2021

Growth inhibition and suppression of the mTOR and Wnt/β-catenin pathways in T-acute lymphoblastic leukemia by rapamycin and MYCN depletion.

Hematol Oncol 2020 Dec 10. Epub 2020 Dec 10.

Department of Hematology, The First Affiliated Hospital, Harbin Medical University, Harbin, China.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy. Understanding of the molecular pathogenesis may lead to novel therapeutic targets. Rapamycin, the mammalian target of rapamycin (mTOR) inhibitor, showed inhibitory effects on T-ALL cells. In this study, we showed that rapamycin significantly reduced MYCN mRNA and protein in a concentration-dependent manner in T-ALL cells. Selective knockdown of MYCN by small interfering RNA had similar effects to rapamycin to inhibit T-ALL proliferation and colony formation and to induce G1-phase cell-cycle arrest and apoptosis. The inhibitory effects of rapamycin and MYCN depletion were also found in a Molt-4 xenograft model. Rapamycin and MYCN inhibition suppressed both Wnt/β-catenin and mTOR signaling pathways. The results suggest the effects of rapamycin on adult T-ALL is likely mediated by downregulation of MYCN. The findings suggest MYCN a potential target for the treatment of adult T-ALL. Additionally, dual targeting of mTOR and Wnt/β-catenin pathways may represent a novel strategy in the treatment of adult T-ALL.
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http://dx.doi.org/10.1002/hon.2831DOI Listing
December 2020

Case Report: PD-1 Inhibitor Is Active in Lung Adenocarcinoma With B Cell Deficiency.

Front Immunol 2020 6;11:563622. Epub 2020 Nov 6.

Department of Immunotherapy, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China.

Introduction: In murine cancer models, B cells are unnecessary for efficacy of PD-1 inhibitor. However, we do not know whether this applies to clinical settings, especially in patients with non-small-cell lung carcinoma (NSCLC).

Case Presentation: We report on the case of an advanced lung adenocarcinoma patient without oncogenic driver mutations whose disease progressed on second-line bevacizumab-containing chemotherapy regimens. These previous treatments resulted in profound thrombocytopenia and increased number of B cells; both effects were hard to alleviate. The patient was diagnosed with marginal zone B-cell lymphoma by flow cytometry immunophenotyping. After five cycles of rituximab in combination with lenalidomide treatment, the percentage of B cells rapidly declined to undetectable levels and the lymphoma regressed completely. However, because masses in the lung gradually increased, this patient was subsequently treated with a PD-1 inhibitor. The patient's condition stabilized, and the mass shrank to reach partial response, with progression free survival exceeding 15 months and no serious adverse events.

Conclusion: The present case proves the efficacy of PD-1 inhibitor in metastatic lung adenocarcinoma in the absence of B cells. Immune checkpoint inhibitions are thus a choice for patients with B cell deficiencies, such as X-linked agammaglobulinemia, immunoglobulin deficiencies, and common variable immunodeficiency, diseases that have historically been excluded from clinical trials for oncologic drugs.
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http://dx.doi.org/10.3389/fimmu.2020.563622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681247PMC
November 2020

Ratiometric Detection of DNA and Protein in Serum by a Universal Tripyridinyl Ru Complex-Encapsulated SiO@Polydopamine Fluorescence Nanoplatform.

Anal Chem 2020 12 25;92(24):15908-15915. Epub 2020 Nov 25.

Zhangdayu School of Chemistry, Dalian University of Technology, Dalian 116023, PR China.

Fluorescence ratiometric biosensors are valuable tools for the accurate and sensitive prediction and diagnosis of diseases. However, seldom have fluorescence ratiometric biosensors for protein and DNA been reported because of the shortage of suitable nanoscale scaffolds. Herein, a tripyridinyl Ru complex-encapsulated SiO@polydopamine (Ru-SiO@PDA) nanocomposite was designed as a universal platform for fluorescence ratiometric detection of DNA and protein in serum samples. The Ru-SiO@PDA nanocomposites have a narrow size distribution, exhibit good biosafety, and are convenient for the postmodification of biorecognition elements. Under irradiation, they can emit a stable and strong luminescence at 650 nm and simultaneously quench the fluorescence emitted from the fluorophores getting close to them. Once the capture probes such as single-stranded DNA and aptamer are assembled, the fluorophores labeled on them are then brought close to their PDA shell and quenched. However, the biorecognition behaviors change the probe's configuration and take the fluorophore far away from the PDA shell. Correspondingly, the fluorescence recovers and its ratio to the constant fluorescence reference is linear to the targets' concentration. Using a D-catalyst and thrombin as model analytes, the Ru-SiO@PDA-based nanoplatform shows high sensitivity and good accuracy in the serum sample analysis. Regarding these attractive properties, the Ru-SiO@PDA nanoplatform provides a new avenue for the accurate and sensitive fluorescence assay of a wide range of targets in complex systems.
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http://dx.doi.org/10.1021/acs.analchem.0c03306DOI Listing
December 2020

Characterization of poplar growth-regulating factors and analysis of their function in leaf size control.

BMC Plant Biol 2020 Nov 5;20(1):509. Epub 2020 Nov 5.

State Key Laboratory of Tree Genetics and Breeding, Key Laboratory of Tree Breeding and Cultivation of the National Forestry and Grassland Administration, Research Institute of Forestry, Chinese Academy of Forestry, Beijing, 100091, China.

Background: Growth-regulating factors (GRFs) are plant-specific transcription factors that control organ size. Nineteen GRF genes were identified in the Populus trichocarpa genome and one was reported to control leaf size mainly by regulating cell expansion. In this study, we further characterize the roles of the other poplar GRFs in leaf size control in a similar manner.

Results: The 19 poplar GRF genes were clustered into six groups according to their phylogenetic relationship with Arabidopsis GRFs. Bioinformatic analysis, degradome, and transient transcription assays showed that 18 poplar GRFs were regulated by miR396, with GRF12b the only exception. The functions of PagGRF6b (Pag, Populus alba × P. glandulosa), PagGRF7a, PagGRF12a, and PagGRF12b, representing three different groups, were investigated. The results show that PagGRF6b may have no function on leaf size control, while PagGRF7a functions as a negative regulator of leaf size by regulating cell expansion. By contrast, PagGRF12a and PagGRF12b may function as positive regulators of leaf size control by regulating both cell proliferation and expansion, primarily cell proliferation.

Conclusions: The diversity of poplar GRFs in leaf size control may facilitate the specific, coordinated regulation of poplar leaf development through fine adjustment of cell proliferation and expansion.
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http://dx.doi.org/10.1186/s12870-020-02699-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643314PMC
November 2020

is a distinct prognostic biomarker that worsens the tumor immune microenvironment in lung adenocarcinoma.

Aging (Albany NY) 2020 10 22;12(20):20308-20331. Epub 2020 Oct 22.

Department of Internal Medicine, The Affiliated Tumor Hospital of Zhengzhou University, Zhengzhou, China.

The tumor immune microenvironment (TIME) is an important determinant of cancer prognosis and treatment efficacy. To identify immune-related prognostic biomarkers of lung adenocarcinoma, we used the ESTIMATE algorithm to calculate the immune and stromal scores of 517 lung adenocarcinoma patients from The Cancer Genome Atlas (TCGA). We detected 985 differentially expressed genes (DEGs) between patients with high and low immune and stromal scores, and we analyzed their functions and protein-protein interactions. was upregulated in lung adenocarcinoma patients with low immune and stromal scores, and was associated with a poor prognosis. The TISIDB and TIMER databases indicated that expression correlated negatively with immune infiltration. We then explored genes that were co-expressed with in TCGA, and investigated DEGs based on expression in GSE43580 and GSE7670. The 429 common DEGs from these analyses were functionally analyzed. We also performed a Gene Set Enrichment Analysis using TCGA data, and predicted substrates of TRIM28 using UbiBrowser. The results indicated that TRIM28 may negatively regulate the TIME by increasing the SUMOylation of IRF5 and IRF8. Correlation analyses and validations in two lung adenocarcinoma cell lines (PC9 and H1299) confirmed these findings. Thus, TRIM28 may worsen the TIME and prognosis of lung adenocarcinoma.
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http://dx.doi.org/10.18632/aging.103804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655206PMC
October 2020

Glypican-1-targeted and gemcitabine-loaded liposomes enhance tumor-suppressing effect on pancreatic cancer.

Aging (Albany NY) 2020 Oct 9;12(19):19585-19596. Epub 2020 Oct 9.

Department of Oncology, Affiliated Cancer Hospital of Zhengzhou University / Henan Cancer Hospital, Zhengzhou, China.

Liposomes (LPs) as promising drug delivery systems are widely applied in cancer therapy. This study aimed to investigate the effect of glypican-1 (GPC1)-targeted and gemcitabine (GEM)-loaded LP [GPC1-LP (GEM)] on cell proliferation and apoptosis in PANC-1s, as well as on orthotopic pancreatic cancer (PDAC) mice. The GPC1-LP (GEM) and LP (GEM) was prepared, and then the size distribution of GPC1-LP (GEM) was analyzed by dynamic light scattering (DLS). drug release assay of GPC1-LP (GEM) and LP (GEM) was performed, and the expression of GPC1 in PANC1 cells was detected as well. Next, the effects of free GEM, LP (GEM) and GPC1-LP (GEM) on cell viability, clone number, and apoptosis, as well as the expression of proteins associated with apoptosis were measured in 239T and PANC-1 cells. Furthermore, the body weight and tumor size of orthotopic PDAC mice were evaluated following the treatment of free GEM, LP (GEM) or GPC1-LP (GEM). LP (GEM) and GPC1-LP (GEM) were successfully prepared with a successful GEM release within 24 h. In addition, GPC1 was positively expressed in PANC-1 cells but not 293T cells. These findings provided more insights into the anti-tumor potential for the biomedical application of GPC1-LP (GEM) in PDAC.
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http://dx.doi.org/10.18632/aging.103918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732280PMC
October 2020

SUFU mediates EMT and Wnt/β-catenin signaling pathway activation promoted by miRNA-324-5p in human gastric cancer.

Cell Cycle 2020 Oct 5;19(20):2720-2733. Epub 2020 Oct 5.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University School of Medicine , Shenzhen, Guangdong, China.

The poor prognosis of late gastric carcinomas (GC) underscores the necessity to identify novel biomarkers for earlier diagnosis and effective therapeutic targets. MiRNA-324-5p has been shown to be over-expressed in GC, however the biological function of miRNA-324-5p implicated in gastric cancer and its downstream targets were not well understood. Wnt/β-catenin signaling pathway is aberrantly regulated in GC. We sought to explore if miRNA-324-5p promotes oncogenesis through modulating Wnt signaling and EMT. MiRNA-324-5p is highly expressed in GC based on qRT-PCR and TCGA data. In addition, in vitro cell proliferation, cell migration assays and in vivo animal exenograft were executed to show that miRNA-324-5p is an oncogenic miRNA in GC. MiRNA-324-5p activates Wnt signaling and induces EMT in GC. Further, SUFU was identified as a target of miRNA-324-5p confirmed by western blotting and luciferase assays. Spearson analysis and TCGA data indicate that the expression of SUFU is negatively associated with the expression of miRNA-324-5p. Rescue experiments were performed to determine if SUFU mediates the Wnt activation, EMT and oncogenic function of miRNA-324-5p. MiRNA-324-5p inhibitors plus SUFU siRNAs rescue partially the inhibitory effect on Wnt signaling and EMT caused by miRNA-324-5p inhibitors. Finally, the suppression of cell proliferation, migration, and colony formation ability induced by miRNA-324-5p inhibitors is alleviated by addition of SUFU siRNAs. In summary, miRNA-324-5p is overexpressed and exerts cell growth and migration-promoting effects through activating Wnt signaling and EMT by targeting SUFU in GC. It represents a potential miRNA with an oncogenic role in human gastric cancer.
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http://dx.doi.org/10.1080/15384101.2020.1826632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644164PMC
October 2020

Bone marrow mesenchymal stem cells-derived exosomal microRNA-193a reduces cisplatin resistance of non-small cell lung cancer cells via targeting LRRC1.

Cell Death Dis 2020 09 25;11(9):801. Epub 2020 Sep 25.

Department of Internal Medicine, The Affiliated Tumor Hospital of Zhengzhou University, He'nan Cancer Hospital, Zhengzhou, He'nan Province, 450008, China.

Exosomes are small endogenous membrane vesicles that can mediate cell communication by transferring genetic materials. Based on that, exosomes have always been discussed as a cargo carrier for microRNA (miRNA) transportation. Accumulating data have reported the inhibitory effects of microRNA-193a (miR-193a) on non-small cell lung cancer (NSCLC) cell progression. However, the mechanisms of miR-193a delivery to cancer cells and miR-193a in exosomes have not been explored clearly in NSCLC. Given that, this work aims to decode exosomal miR-193a in cisplatin (DDP) resistance of NSCLC cells. A549 and H1299 cell lines were screened out and their parent cells and drug-resistant cells were co-cultured with human bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-Exo) that had been transfected with miR-193a mimic or si-LRRC1 to detect the colony formation, migration, apoptosis, invasion and proliferation of NSCLC cells. In vivo experiment was conducted to verify the in vitro results. BMSC-Exo with upregulated miR-193a and downregulated LRRC1 suppressed colony formation, invasion, proliferation and migration as well as advanced apoptosis of NSCLC parent cells and drug-resistant cells. BMSC-Exo combined with upregulated miR-193a reduced tumor volume and weight in mice with NSCLC. Functional studies report that BMSC-Exo shuffle miR-193a to suppress the colony formation, invasion, migration, and proliferation as well as advance apoptosis of NSCLC DDP-resistant cells via downregulating LRRC1.
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http://dx.doi.org/10.1038/s41419-020-02962-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519084PMC
September 2020

Efficacy of Plinabulin vs Pegfilgrastim for Prevention of Chemotherapy-Induced Neutropenia in Adults With Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.

JAMA Oncol 2020 Sep 24. Epub 2020 Sep 24.

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

Importance: Plinabulin is a novel, non-granulocyte colony-stimulating factor (GCSF) small molecule with both anticancer and neutropenia-prevention effects.

Objective: To assess the efficacy and safety of plinabulin compared with pegfilgrastim for the prevention of chemotherapy-induced neutropenia following docetaxel chemotherapy in patients with non-small lung cancer.

Design, Setting, And Participants: This was a randomized, open-label, phase 2 clinical trial of 4 treatment arms that was conducted in 19 cancer treatment centers in the United States, China, Russia, and Ukraine. Participants were adult patients with non-small cell lung cancer whose cancer had progressed after platinum-based chemotherapy. Data were collected from April 2017 through March 2018 and analyzed from August 2019 through February 2020.

Interventions: All patients received docetaxel 75 mg/m2 on day 1 and were randomly assigned to 1 of 3 doses of plinabulin (5, 10, or 20 mg/m2) on day 1 or to pegfilgrastim 6 mg on day 2. Patients were treated every 21 days for 4 chemotherapy cycles.

Main Outcomes And Measures: The primary end point was the determination of the recommended phase 3 dose of plinabulin based on the days of severe neutropenia during chemotherapy cycle 1. Daily complete blood cell counts and absolute neutrophil counts were drawn during times of anticipated neutropenia during cycle 1.

Results: Of the 55 patients randomized and evaluated, the mean (SD) age was 61.3 (10.2) years, and 38 (69.1%) were men. With each escalation of the plinabulin dose, the incidence of any grade of neutropenia decreased. There were no significant differences in mean (SD) days of severe neutropenia among those treated with pegfilgrastim (0.15 [0.38] days) when dosed at day 2 vs plinabulin 20 mg/m2 (0.36 [0.93] days; P = .76) when dosed at day 1, and no safety signals were detected.

Conclusions And Relevance: Single dose-per-cycle plinabulin has a similar neutropenia protection benefit as pegfilgrastim. Plinabulin 40 mg fixed dose, which is pharmacologically equivalent to 20 mg/m2, will be compared with pegfilgrastim 6 mg in the phase 3 portion of this trial. Noninferior days of severe neutropenia will be the primary end point, and bone pain reduction, thrombocytopenia reduction, and quality of life maintenance will be secondary end points.

Trial Registration: ClinicalTrials.gov Identifier: NCT03102606.
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http://dx.doi.org/10.1001/jamaoncol.2020.4429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516815PMC
September 2020

Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11).

J Thorac Oncol 2020 10 8;15(10):1636-1646. Epub 2020 Aug 8.

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

Introduction: Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539).

Methods: A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee.

Results: As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p < 0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group.

Conclusions: In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.
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http://dx.doi.org/10.1016/j.jtho.2020.07.014DOI Listing
October 2020

Exosomes Derived from Hypoxic Colorectal Cancer Cells Transfer miR-410-3p to Regulate Tumor Progression.

J Cancer 2020 25;11(16):4724-4735. Epub 2020 May 25.

Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.

Hypoxia is a common characteristic of solid tumors and is associated with cancer progression and poor outcomes. However, the roles and specific mechanisms of exosomes and hypoxia during cancer progression still remain unclear. Herein, we found that exosomes secreted from hypoxic colorectal cancer (CRC) cells promoted the proliferation, migration, invasion, and metastasis of normoxic CRC cells, and these hypoxic exosomes exerted their biological effects depending on miR-410-3p. We discovered that miR-410-3p was highly enriched in hypoxic CRC-derived exosomes in a HIF1α or HIF2α-dependent manner, and miR-410-3p levels positively associated with poor prognosis of CRC. Moreover, decreased PTEN levels caused by hypoxic CRC cells-derived exosomal miR-410-3p increased activation of PI3K/Akt as well as tumor progression. Conversely, inhibition of miR-410-3p or PI3K/Akt signaling pathway effectively decreased hypoxic CRC cells-derived exosomes-mediated tumor progression. In conclusion, our findings indicate that the hypoxic microenvironment in CRC may promote tumor cells to release miR-410-3p-rich exosomes that are transferred to normoxic cells to enhance tumor progression, revealing a new investigation into the therapeutic targets of exosome for CRC treatment.
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http://dx.doi.org/10.7150/jca.33232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330706PMC
May 2020

Oxygen defects engineered CdS/BiO direct Z-Scheme heterojunction for highly sensitive photoelectrochemical assay of Hg.

Talanta 2020 Sep 29;217:121090. Epub 2020 Apr 29.

School of Chemical Engineering, Dalian University of Technology, Dalian, 116023, PR, China. Electronic address:

This work demonstrates that the photoelectrochemical response of the CdS/BiO direct Z-scheme heterojunction, synthesized by in situ deposition of CdS nanocrystals on the defect engineered BiO, can be modulated by oxygen defect concentration. The appropriate oxygen defects not only increase the visible light absorption, provide active reaction sites to enhance PEC activity, but also promote the separation of carriers. The formation of CdS/BiO direct Z-scheme heterojunction further improves these properties by extending the visible light absorption and promoting separation and transport of carriers, but avoids the usage of noble metal nanoparticles as electron transfer mediators, thus has a low cost and easy fabrication technology. The CdS/BiO direct Z-scheme junction shows significantly improved photocurrent response as compared with those containing less oxygen defects, and is applied as a photoelectrochemical assay platform for Hg. The specific interaction between Hg and the S in CdS significantly quenches the photocurrent response of the CdS/BiO due to the formation of HgS. The photocurrent decrease is linear to the concentration of Hg in the range from 10 to 10 g/mL, with the limit of detection of 3.2 pg/mL. High accuracy and good reproducibility are realized in the real sample analysis of urine, river water, and sea water. The integration of oxygen defect engineering and direct Z-scheme electron transport principle provides a new avenue for fabricating high performance photoelectrochemical materials, which can be further combined with bio-recognition strategy for the ultrasensitive detection of biological molecules.
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http://dx.doi.org/10.1016/j.talanta.2020.121090DOI Listing
September 2020

Study on the correlation among dysbacteriosis, imbalance of cytokine and the formation of intrauterine adhesion.

Ann Transl Med 2020 Feb;8(4):52

Department of Gynecology, Third Xiangya Hospital of Central South University, Changsha 410013, China.

Background: Intrauterine adhesion (IUA) is one of the most important causes of female infertility, while iatrogenic endometrial injury is the main, but not the entire, cause of IUA. The microorganisms of the female reproductive tract play an important role in its health and disease. The imbalance of immune regulation caused by the imbalance of reproductive tract dysbacteriosis may be an important link in the formation mechanism of uterine cavity adhesion.

Methods: We prospectively enrolled 30 patients diagnosed with IUA and 30 women with a history of intrauterine surgery, but without IUA, as control subjects. All participants were diagnosed with hysteroscopy while two swabs-one being leucorrhea drawn from the middle of the vagina and the other being cervical mucus drawn from the cervical canal-were taken. The bacterial load and community were identified by 16S rDNA quantitative polymerase chain reaction and pyrosequencing. Immunocytokines in serum were quantitatively detected by human T-helper cytokine kit. The correlation between Th cytokines and microorganisms in IUA and non-IUA groups was analyzed.

Results: Compared with non-IUA participants at the phylum level, patients with IUA had a significantly higher percentage of firmicutes in most samples, while the diversity of bacteria was significantly decreased. Some species that were members of vaginal and cervical canal bacterial phyla, including Euryarchaeota, Acidobacteria, Chlamydiae, Chlorobi, Planctomycetes and TM6 (Dependentiae), almost disappeared. The quantity in serum of IUA patients of classical proinflammatory cytokines IL-6 and TNF-γ, released from immune cells, also known as profibrotic cytokines, were significantly higher than that of the non-IUA women in our study (P<0.05).

Conclusions: IUA is characterized by an increased bacterial burden, decreased diversity of bacterial communities in the vagina/cervical canal, and increased immune cytokines of pro-fibrosis, which may predict new and more effective therapeutic schemes for the treatment of IUA.
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http://dx.doi.org/10.21037/atm.2019.11.124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049045PMC
February 2020

miRNA-192 and -215 activate Wnt/β-catenin signaling pathway in gastric cancer via APC.

J Cell Physiol 2020 09 24;235(9):6218-6229. Epub 2020 Feb 24.

Department of Pathology, Guangdong Key Laboratory for Genome Stability & Disease Prevention, The Shenzhen University School of Medicine, Shenzhen, Guangdong, China.

Although great progress has been made in surgical techniques, traditional radiotherapy, and chemotherapy, gastric cancer (GC) is still the most common malignant tumor and has a high mortality, which highlights the importance of novel diagnostic markers. Emerging studies suggest that different microRNAs (miRNAs) are involved in tumorigenesis of GC. In this study, we found that miRNA-192 and -215 are significantly upregulated in GC and promote cell proliferation and migration. Adenomatous polyposis coli (APC), a well-known negative regulator in Wnt signaling, has been proved to be a target of miRNA-192 and -215. Inhibition of miRNA-192 or -215 reduced the Topflash activities and repressed the expression of Wnt signaling pathway proteins, while APC small interfering RNAs reversed the inhibitory effects, suggesting that miRNA-192 and -215 activate Wnt signaling via APC. In addition, APC mediates the cell proliferation and migration regulated by miRNA-192 and -215. Furthermore, APC is downregulated in GC tissues and negatively correlated with the expression of miRNA-192 and -215. In summary, miRNA-192 and -215 target APC and function as oncogenic miRNAs by activating Wnt signaling in GC, revealing to be potential therapeutic targets.
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http://dx.doi.org/10.1002/jcp.29550DOI Listing
September 2020

Long noncoding RNA TMPO-AS1 promotes lung adenocarcinoma progression and is negatively regulated by miR-383-5p.

Biomed Pharmacother 2020 May 13;125:109989. Epub 2020 Feb 13.

Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China. Electronic address:

Long noncoding RNAs (lncRNAs) play critical roles in the pathogenesis of various diseases, including a variety of tumors. Nevertheless, its functional roles and underlying molecular basis for their dysregulation in lung adenocarcinoma (LUAD) are largely unknown. Herein, in our study, we identified that lncRNA TMPO-AS1 is significantly upregulated in LUAD tissues and cell lines. Knockdown of TMPO-AS1 remarkably suppressed LUAD cell growth, induced apoptosis as well as G1/S arrest, and inhibited LUAD cell invasion, whereas overexpression of TMPO-AS1 exerts the opposite effects. Next, we implemented online database analysis tools to find that mir-383-5p could target TMPO-AS1, and our data showed that TMPO-AS1 was negatively correlated with mir-383-5p in LUAD specimens. We found that inhibiting miR-383-5p expression led to a marked upregulation of TMPO-AS1 level, while overexpression of miR-383-5p markedly suppressed TMPO-AS1's expression and function, suggesting that TMPO-AS1 is negatively regulated by miR-383-5p. In addition, we confirmed that miR-383-5p directly targeted TMPO-AS1 by binding to microRNA binding sites in the TMPO-AS1 sequence with a luciferase reporter and RIP assays. Besides, the inhibition of TMPO-AS1 significantly suppressed the tumorigenesis ability of LUAD cells in vivo. Together, these results demonstrate that TMPO-AS1 could be considered as a potential therapeutic target for LUAD patients.
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http://dx.doi.org/10.1016/j.biopha.2020.109989DOI Listing
May 2020

Biosimilar candidate IBI305 plus paclitaxel/carboplatin for the treatment of non-squamous non-small cell lung cancer.

Transl Lung Cancer Res 2019 Dec;8(6):989-999

Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510000, China.

Background: Bevacizumab is a monoclonal antibody (mAb) against vascular endothelial growth factor (VEGF) and used for treatments of various cancers. Due to the high costs of bevacizumab treatments, a biosimilar provides an affordable alternative therapy for cancer patients.

Methods: In this randomized, double-blind, multicenter, phase 3 study, locally advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) patients with wild-type epidermal growth factor receptor were enrolled and randomized (1:1) into IBI305 or bevacizumab groups. Patients received 6 cycles of paclitaxel/carboplatin plus IBI305 or bevacizumab 15 mg/kg intravenously followed by IBI305 or bevacizumab 7.5 mg/kg maintenance until disease progression, unacceptable toxicity or death. The primary endpoint was confirmed objective response rate (ORR) by an independent radiological review committee (IRRC) and secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), overall survival (OS) and safety.

Results: A total of 450 NSCLC patients were enrolled (224 in IBI305 group and 226 in bevacizumab group). ORRs were 44.3% for IBI305 and 46.4% for bevacizumab, and the ORR ratio was 0.95 (90% CI: 0.803 to 1.135), within the predefined equivalence margin of 0.75 to 1.33. No significant difference in PFS (7.64 7.77 m, P=0.9987) was observed between the 2 groups. Serious adverse events (AEs) occurred in 33.5% (75/224) of patients in the IBI305 group and 37.6% (85/226) in the bevacizumab group. AEs ≥ grade 3 were similar in the IBI305 and bevacizumab groups [84.4% (189/224) 89.8% (203/226), P=0.085].

Conclusions: IBI305 is similar to bevacizumab in terms of efficacy and safety.

Trial Registration: Clinicaltrials.org Identifier: NCT02954172. Registered on 3 November 2016. Https://clinicaltrials.gov/.
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http://dx.doi.org/10.21037/tlcr.2019.12.23DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976344PMC
December 2019

CRISPR/Cas9-mediated precise genome modification by a long ssDNA template in zebrafish.

BMC Genomics 2020 Jan 21;21(1):67. Epub 2020 Jan 21.

Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China.

Background: Gene targeting by homology-directed repair (HDR) can precisely edit the genome and is a versatile tool for biomedical research. However, the efficiency of HDR-based modification is still low in many model organisms including zebrafish. Recently, long single-stranded DNA (lssDNA) molecules have been developed as efficient alternative donor templates to mediate HDR for the generation of conditional mouse alleles. Here we report a method, zLOST (zebrafish long single-stranded DNA template), which utilises HDR with a long single-stranded DNA template to produce more efficient and precise mutations in zebrafish.

Results: The efficiency of knock-ins was assessed by phenotypic rescue at the tyrosinase (tyr) locus and confirmed by sequencing. zLOST was found to be a successful optimised rescue strategy: using zLOST containing a tyr repair site, we restored pigmentation in at least one melanocyte in close to 98% of albino tyr embryos, although more than half of the larvae had only a small number of pigmented cells. Sequence analysis showed that there was precise HDR dependent repair of the tyr locus in these rescued pigmented embryos. Furthermore, quantification of zLOST knock-in efficiency at the rps14, nop56 and th loci by next generation sequencing demonstrated that zLOST showed a clear improvement. We utilised the HDR efficiency of zLOST to precisely model specific human disease mutations in zebrafish with ease. Finally, we determined that this method can achieve a germline transmission rate of up to 31.8%.

Conclusions: In summary, these results show that zLOST is a useful method of zebrafish genome editing, particularly for generating desired mutations by targeted DNA knock-in through HDR.
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http://dx.doi.org/10.1186/s12864-020-6493-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974980PMC
January 2020

Osimertinib for Patients With Leptomeningeal Metastases Associated With EGFR T790M-Positive Advanced NSCLC: The AURA Leptomeningeal Metastases Analysis.

J Thorac Oncol 2020 04 27;15(4):637-648. Epub 2019 Dec 27.

Department of Clinical Oncology, State Key Laboratory in Translational Oncology, Chinese University of Hong Kong, Hong Kong, People's Republic of China.

Introduction: Osimertinib has shown promising activity in patients with leptomeningeal metastases (LMs) of EGFR-positive NSCLC at 160 mg once daily (qd) (BLOOM; NCT02228369). We report LM activity with osimertinib (80 mg qd) in a retrospective analysis of studies across the AURA program (AURA extension, AURA2, AURA17, and AURA3).

Methods: Patients with EGFR T790M-positive advanced NSCLC and progression after previous EGFR-tyrosine kinase inhibitor therapy received osimertinib (80 mg qd). Patients with central nervous system (CNS) metastases (including LMs) were eligible if the lesions were neurologically asymptomatic and stable. Patients with evidence of LMs at the study entry were retrospectively included for the analysis; brain scans were assessed for radiologic LM response by neuroradiologically blinded, independent central review per the modified Response Assessment in Neuro-Oncology LM criteria. LM objective response rate, duration of response, progression-free survival, and overall survival were assessed. A longitudinal analysis was performed to investigate the relationship between changes from the baseline in non-CNS tumor sizes and LM responses at each visit of patients in AURA LM and BLOOM studies.

Results: For the 22 patients included in the analysis, LM objective response rate was 55% (95% confidence interval [CI]: 32-76). Median LM duration of response was not reached (95% CI: 2.8-not calculable [NC]). Median LM progression-free survival and overall survival were 11.1 months (95% CI: 4.6-NC) and 18.8 months (95% CI: 6.3-NC), respectively. The longitudinal analysis revealed similar non-CNS and LM responses between the patients in AURA LM and BLOOM programs.

Conclusions: Patients with EGFR T790M-positive NSCLC and radiologically detected LM obtained clinical benefit from osimertinib (80 mg qd).
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http://dx.doi.org/10.1016/j.jtho.2019.12.113DOI Listing
April 2020

LncRNA TDRG1 promotes the metastasis of NSCLC cell through regulating miR-873-5p/ZEB1 axis.

J Cell Biochem 2019 Nov 19. Epub 2019 Nov 19.

Department of Respiratory, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Long noncoding RNAs (lncRNAs) are dysregulated in various malignancies and involved in the growth and aggressive phenotypes of cancer cells. Previous studies indicate that lncRNA testis development related 1 (TDRG1) plays critical roles in the development of several malignancies. Nevertheless, the molecular mechanism underlying TDRG1 contributes to non-small cell lung cancer (NSCLC) remains elusive. Here, we demonstrate that TDRG1 is significantly overregulated in NSCLC tissues and cell lines. Knockdown of TDRG1 inhibits the proliferation and metastatic-related traits of NSCLC cell in vitro whereas overexpression of TDRG1 causes opposite results. In addition, TDRG1 silencing inhibits the growth and metastatic ability of NSCLC cell in vivo as demonstrated by xenograft tumor model and lung metastasis model. The binding capacity of TDRG1 with miR-873-5p is demonstrated by bioinformatics prediction tool and luciferase reporter gene assay. Additional, the rescue experiments indicate that TDRG1 interacts with miR-873-5p and its expression is positively associated with the target of miR-873-5p, zinc finger e-box binding homeobox 1 (ZEB1). Altogether, lncRNA TDRG1 facilitates the progression of NSCLC via interacting with miR-873-5p and positively regulates the expression of ZEB1.
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http://dx.doi.org/10.1002/jcb.29559DOI Listing
November 2019

Efficacy, safety, and biomarker analysis of ensartinib in crizotinib-resistant, ALK-positive non-small-cell lung cancer: a multicentre, phase 2 trial.

Lancet Respir Med 2020 01 15;8(1):45-53. Epub 2019 Oct 15.

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

Background: Ensartinib is a potent new-generation ALK inhibitor with high activity against a broad range of known crizotinib-resistant ALK mutations and CNS metastases. We aimed to assess the efficacy and safety of ensartinib in ALK-positive patients with non-small-cell lung cancer (NSCLC), in whom crizotinib therapy was unsuccessful. The associations between ensartinib efficacy and crizotinib-resistant mutations were also explored.

Methods: We did a single-arm, open-label, phase 2 study at 27 centres in China. Patients were aged 18 years or older, had stage IIIb or stage IV ALK-positive NSCLC that had progressed while they were on crizotinib therapy, an Eastern Cooperative Oncology Group performance status of 2 or less, had measurable disease, and had received fewer than three previous treatments. Patients with CNS metastases were included if these metastases were asymptomatic and did not require steroid therapy. All patients received 225 mg ensartinib orally once daily on a continuous dosing schedule. The primary outcome was the proportion of patients with an objective response according to the Response Evaluation Criteria in Solid Tumors (version 1.1), as assessed by an independent review committee in all patients who received at least one dose of ensartinib with no major violations of the inclusion criteria (ie, the full analysis set). Safety was assessed in all enrolled patients who received at least one dose of ensartinib. This trial was registered with ClinicalTrials.gov, NCT03215693.

Findings: Between Sept 28, 2017, and April 11, 2018, 160 patients were enrolled and had at least one dose of ensartinib (safety analysis set). Four patients had inclusion violations and were excluded from the efficacy analysis, which thus included 156 patients (full analysis set). 97 (62%) patients in the full analysis set had brain metastases. 76 (52% [95% CI 43-60]) of 147 patients in the full analysis set, with responses that could be assessed by the independent review committee, had an objective response. 28 (70% [53-83]) of 40 patients with measurable brain metastases as assessed by the independent review committee had an intracranial objective response. 145 (91%) of 160 patients had at least one treatment-related adverse event, which were mostly grade 1 or 2. The most common treatment-related adverse events were rash (89 [56%]), increased alanine aminotransferase concentrations (74 [46%]), and increased aspartate aminotransferase concentrations (65 [41%]).

Interpretation: Ensartinib has activity and is well tolerated in patients with crizotinib-refractory, ALK-positive NSCLC, including those with brain metastases. The role of ensartinib in patients in whom other second-generation ALK inhibitors have been unsuccessful warrants further studies.

Funding: Betta Pharmaceuticals.
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http://dx.doi.org/10.1016/S2213-2600(19)30252-8DOI Listing
January 2020

KNAT2/6b, a class I KNOX gene, impedes xylem differentiation by regulating NAC domain transcription factors in poplar.

New Phytol 2020 02 5;225(4):1531-1544. Epub 2019 Aug 5.

State Key Laboratory of Tree Genetics and Breeding, Research Institute of Forestry, Chinese Academy of Forestry, Beijing, 100091, China.

Wood formation is the terminal differentiation of xylem mother cells derived from cambial initials, and negative regulators play important roles in xylem differentiation. The molecular mechanism of the negative regulator of xylem differentiation PagKNAT2/6b was investigated. PagKNAT2/6b is an ortholog of Arabidopsis KNAT2 and KNAT6 that is highly expressed in phloem and xylem. Compared to nontransgenic control plants, transgenic poplar plants overexpressing PagKNAT2/6b present with altered vascular patterns, characterized by decreased secondary xylem with thin cell walls containing less cellulose, xylose and lignin. RNA sequencing analyses revealed that differentially expressed genes are enriched in xylem differentiation and secondary wall synthesis functions. Expression of NAM/ATAF/CUC (NAC) domain genes including PagSND1-A1, PagSND1-A2, PagSND1-B2 and PagVND6-C1 is downregulated by PagKNAT2/6b, while PagXND1a is directly upregulated. Accordingly, the dominant repression form of PagKNAT2/6b leads to increased xylem width per stem diameter through downregulation of PagXND1a. PagKNAT2/6b can inhibit cell differentiation and secondary wall deposition during wood formation in poplar by modulating the expression of NAC domain transcription factors. Direct activation of PagXND1a by PagKNAT2/6b is a key node in the negative regulatory network of xylem differentiation by KNOXs.
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http://dx.doi.org/10.1111/nph.16036DOI Listing
February 2020

Assessment of the presence and anti-tumor potential of tumor-infiltrating lymphocytes in patients with acute myeloid leukemia.

Cancer Manag Res 2019 12;11:3187-3196. Epub 2019 Apr 12.

Department of Hematology, The First Affiliated Clinical Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, People's Republic of China.

Assessing the possibility of finding tumor-infiltrating lymphocytes (TIL) in bone marrow of acute myeloid leukemia (AML) patients and evaluating the anti-tumor activity of these TIL against autologous AML cells. TIL were immunomagnetically isolated by using anti-CD3 from bone marrow samples of 20 patients at the presentation of AML or four weeks upon completion of chemotherapy. TIL were ex vivo expanded for two weeks and immunophenotyped. Functionality in terms of cytokine secretion and cytotoxicity was assessed by γ-interferon quantitation and Elispot assay, respectively. TIL were detected in bone marrow samples of 50% (10/20) of the patient cohort. They were noted to highly express CD137 and PD-1 and display a significantly higher anti-tumor reactivity compared to that of autologous peripheral blood lymphocytes. TIL could be expanded in co-cultures with irradiated feeder cells supplemented with interleukin (IL)-7 and IL-15. Data suggested the presence of reactive γ-interferon-secreting TIL in AML patients. They are expandable and possess anti-tumor activity, which might have a great potential in the development of adoptive cellular therapy for AML.
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http://dx.doi.org/10.2147/CMAR.S199817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489577PMC
April 2019

Unique profiles of targetable genomic alterations and prognosis in young Chinese patients with lung adenocarcinoma.

Pathol Res Pract 2019 Jun 1;215(6):152407. Epub 2019 Apr 1.

Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. Electronic address:

Objective: Lung adenocarcinoma in young patients is a rare entity, and the targetable genomic alterations (GAs) are poorly studied. In other cancers, it has been demonstrated that young age defines unique disease biology. Here, the association of young age with GAs and prognosis is studied in a large cohort of Chinese patients.

Methods: We retrospectively screened 1000 consecutive patients, and identified 181 patients aged 40 years or younger. GAs were identified by next-generation sequencing (NGS) assay. The clinical and genetic characteristics were analyzed.

Results: Among younger group, 167(92.3%) patients were diagnosed with advanced-stage adenocarcinoma, 98(54.1%) were female, 27(14.9%) were smokers, and the median age was 35 years. Targetable GAs which were significantly more common in the younger population (P <  0.001), were associated with young age (P < 0.05). The frequency of ALK translocations, EGFR and KRAS mutations was 37.6%, 34.3% and 6.1%, respectively. Younger patients had a higher prevalence of rare GAs including HER2, ROS1 and MET (P < 0.05). Prognosis for younger patients was similar (median OS of patients with GAs, 23.91 vs 23.67 months, P >  0.05) or better than that for older population (median OS of patients without GAs, 44.28 vs 41.88 months, P <  0.05) according to GAs. Therapy modality was an independent prognostic factor (P <  0.05), and 83% of death rate decreased if given preferred therapy.

Conclusion: Younger patients with lung adenocarcinoma had unique prevalence of targetable GAs. Comprehensive genotyping including NGS is recommended for personalized therapy and prognosis evaluation in this population.
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http://dx.doi.org/10.1016/j.prp.2019.03.035DOI Listing
June 2019

Population pharmacokinetics and individualized lobaplatin regimen for the treatment of Chinese small cell lung cancer in the elderly.

Medicine (Baltimore) 2019 Jan;98(3):e14136

Clinical Research Centre of Shanghai University of Traditional Chinese Medicine, Shanghai, China.

Background: Lobaplatin (LBP) is a third-generation platinum compound.

Material And Methods: This prospective study was performed in 7 institutions in 2014-2016. Elderly small cell lung cancer (SCLC) patients (≥65 years old) were divided into 2 groups to receive LBP regimens according to endogenous creatinine clearance rate (Ccr). LBP was administered at 30 and 20 mg/m in groups A (Ccr ≥ 80 ml/min) and B (60 ml/min ≤ Ccr < 80 ml/min), respectively. The primary endpoint was plasma LBP concentrations. Secondary endpoints were safety and efficacy parameters, including progression-free survival (PFS) and overall survival (OS).

Results: One-hundred patients were enrolled. Median PFS and OS in groups A and B were 155 vs170 days and 306 vs 272 days, respectively. The rates of grade III/IV AEs in groups A and B were 60.8% (n = 31) and 51.0% (n = 25), respectively. In population pharmacokinetics, the area under the curve (AUC) value for group B was 39% lower than that of group A. With LBP administration based on body surface area (BSA), AUC differences between individuals were small.

Conclusion: With Ccr ≥ 60 ml/min, BSA based administration is necessary. Meanwhile, LBP-based regimens are reliable in treating elderly patients with SCLC.
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http://dx.doi.org/10.1097/MD.0000000000014136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370119PMC
January 2019

Inhibition of miR‑194 suppresses the Wnt/β‑catenin signalling pathway in gastric cancer.

Oncol Rep 2018 Dec 8;40(6):3323-3334. Epub 2018 Oct 8.

Guangdong Key Laboratory for Genome Stability & Disease Prevention, Department of Pathology, The Shenzhen University School of Medicine, Shenzhen, Guangdong 518060, P.R. China.

A mounting body of evidence has revealed that microRNAs (miRs) serve pivotal roles in various developmental processes, and in tumourigenesis, by binding to target genes and subsequently regulating gene expression. Continued activation of the Wnt/β‑catenin signalling is positively associated with human malignancy. In addition, miR‑194 dysregulation has been implicated in gastric cancer (GC); however, the molecular mechanisms underlying the effects of miR‑194 on GC carcinogenesis remain to be elucidated. The present study demonstrated that miR‑194 was upregulated in GC tissues and SUFU negative regulator of Ηedgehog signaling (SUFU) was downregulated in GC cell lines. Subsequently, inhibition of miR‑194 attenuated nuclear accumulation of β‑catenin, which consequently blocked Wnt/β‑catenin signalling. In addition, the cytoplasmic translocation of β‑catenin induced by miR‑194 inhibition was mediated by SUFU. Furthermore, genes associated with the Wnt/β‑catenin signalling pathway were revealed to be downregulated following inhibition of the Wnt signalling pathway by miR‑194 suppression. Finally, the results indicated that cell apoptosis was markedly increased in response to miR‑194 inhibition, strongly suggesting the carcinogenic effects of miR‑194 in GC. Taken together, these findings demonstrated that miR‑194 may promote gastric carcinogenesis through activation of the Wnt/β‑catenin signalling pathway, making it a potential therapeutic target for GC.
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http://dx.doi.org/10.3892/or.2018.6773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196585PMC
December 2018

Over-expression of S100B protein as a serum marker of brain metastasis in non-small cell lung cancer and its prognostic value.

Pathol Res Pract 2019 Mar 12;215(3):427-432. Epub 2018 Nov 12.

Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China. Electronic address:

Validated serum biomarkers for patients suffering from non-small cell lung cancer (NSCLC) brain metastasis are urgently needed for early diagnosis, treatment monitoring, and prognostic classification in daily clinical practice. Serum S100B was reported to be a marker of leaky blood-brain barrier (BBB), which was often caused by brain tumors. This study aimed to investigate the role of S100B in NSCLC brain metastasis. The results showed that serum S100B correlated significantly with NSCLC brain metastasis (P < 0.001). When evaluated by the ROC curve, at the cutoff point 13.83 pg/ml, the sensitivity and specificity were 94% and 93%, respectively (AUC= 0.938, P < 0.001). High level of serum S100B was significantly correlated with a higher number of brain metastases and significantly worse prognosis (P <  0.05). In addition, S100B was an independent prognostic factor (P <  0.001). In conclusion, serum S100B was a sensitive and specific marker for early detection of brain metastasis in NSCLC and could be used as a surveillance tool for prognosis evaluation.
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http://dx.doi.org/10.1016/j.prp.2018.11.011DOI Listing
March 2019

Phosphonate-Substituted Ruthenium(II) Bipyridyl Derivative as a Photoelectrochemical Probe for Sensitive and Selective Detection of Mercury(II) in Biofluids.

Anal Chem 2018 12 30;90(24):14423-14432. Epub 2018 Nov 30.

School of Chemistry , Dalian University of Technology , Dalian 116023 , People's Republic of China.

A ruthenium(II) bipyridyl derivative photoelectrochemical probe, Ru-1, is synthesized and coupled with TiO nanoparticles (Ru-1/TiO) for the specific recognition and highly sensitive photoelectrochemical (PEC) detection of Hg in a series of biofluids. The probe is designed with a chromophore, a thiocyanate recognition unit, a π-conjugated photoelectron-transfer pathway, and a phosphonate anchor. TiO nanoparticles with strong affinity to phosphonate and suitable conduction band energy are used as intermediate layers to increase the Ru-1 adsorption amount and amplify the photocurrent response. Under irradiation, the Ru-1/TiO/fluorine-doped tin oxide (FTO), with strong visible light-harvesting capacity, aqueous stability, and efficient photoelectron transfer, shows a high and stable photocurrent response. In the presence of Hg, however, the specific Hg and NCS coordination changes the photophysical properties of Ru-1, imposing the probe with a wider band gap, a weaker absorbance, and a poorer photoelectron and hole separation efficiency, thus resulting in a significant photocurrent decrease. On the basis of the Hg-induced photocurrent change, the Ru-1/TiO/FTO shows good selectivity and high sensitivity toward the PEC detection of Hg, with wide linear ranges from 10 to 10 and 10 to 10 g/mL, and a low limit of detection of 0.63 pg/mL. The PEC probe is recyclable and accurate for selective detection of Hg in urine, serum, and cell extracts. The whole analysis can be completed within 15 min. These good analytical performances indicate that the PEC method might have great potential for the onsite detection of small molecules in biosystems.
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http://dx.doi.org/10.1021/acs.analchem.8b03985DOI Listing
December 2018

Growth-regulating factor 15 is required for leaf size control in Populus.

Tree Physiol 2019 03;39(3):381-390

State Key Laboratory of Tree Genetics and Breeding, Research Institute of Forestry, Chinese Academy of Forestry, Beijing, China.

Growth-regulating factors (GRFs) are involved in various developmental events, particularly leaf development. However, the functions of GRFs in woody plants remain elusive. In this study, functional characterization of GRF15 in Populus was performed. Most GRFs are preferentially expressed in young leaves. As GRF15 was expressed at the highest level and with highest ratio in Populus species with large leaves, this gene was investigated through transgenic analyses. Promotor-β-glucuronidase analysis revealed expression of GRF15 at the leaf expansion zone. Additionally, GRF15 was found to be localized in the nucleus and regulated by miR396. Leaf size and palisade cell size were significantly increased and decreased in GRF15-overexpressing and dominant repression lines, respectively. Consistently, expression of EXPA11a, a homolog of cell-expansion marker EXPA11 in Arabidopsis, was strongly upregulated and downregulated in the GRF15-overexpressing and dominant repression lines, respectively, which was further manifested by activation of EXPA11a by GRF15 in transactivation assays. Therefore, GRF15 is required for leaf size control and primarily modulates cell expansion during leaf development in Populus.
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http://dx.doi.org/10.1093/treephys/tpy107DOI Listing
March 2019

Development of a risk grading system to identify patients with acute promyelocytic leukemia at high risk of early death.

Cancer Manag Res 2018 17;10:3619-3627. Epub 2018 Sep 17.

Department of Central Laboratory, The First Affiliated Hospital, Harbin Medical University, Harbin, People's Republic of China,

Background: Early death (ED) rate in acute promyelocytic leukemia (APL) remains high. Some studies have identified prognostic factors capable of predicting ED, whereas no risk rating system for ED has been reported in the literature. In this study, a risk classification system was built to identify subgroup at high risk of ED among patients with APL.

Methods: Totally, 364 consecutive APL patients who received arsenic trioxide as induction therapy were included. Ten baseline clinical characteristics were selected for analysis, and they were de novo/relapse, age, sex, white blood cell count, platelet count, serum fibrinogen, creatinine, uric acid, aspartate aminotransferase, and albumin. Using a training cohort (N=275), a multivariable logistic regression model was constructed, which was internally validated by the bootstrap method and externally validated using an independent cohort (N=89). Based on the model, a risk classification system was designed. Then, all patients were regrouped into de novo (N=285) and relapse (N=79) cohorts and the model and risk classification system were applied to both cohorts.

Results: The constructed model included 8 variables without platelet count and sex. The model had excellent discriminatory ability (optimism-corrected area under the receiver operator characteristic curve=0.816±0.028 in the training cohort and area under the receiver operator characteristic curve=0.798 in the independent cohort) and fit well for both the training and independent data sets (Hosmer-Lemeshow test, =0.718 and 0.25, respectively). The optimism-corrected calibration slope was 0.817±0.12. The risk classification system could identify a subgroup comprising ~25% of patients at high risk of ED in both the training and independent cohorts (OR=0.140, <0.001 and OR=0.224, =0.027, respectively). The risk classification system could effectively identify patient subgroups at high risk of ED in not only de novo but also relapse cohorts (OR=0.233, <0.001 and OR=0.105, =0.001, respectively).

Conclusion: All the results highlight the high practical value of the risk classification system.
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http://dx.doi.org/10.2147/CMAR.S167686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149832PMC
September 2018