Publications by authors named "Jian Hong"

218 Publications

Improved quantification of immune-gold labeling and its use to compare the distribution of cellular factors among sub-chloroplast compartments.

Micron 2021 Mar 18;145:103060. Epub 2021 Mar 18.

Institute of Virology and Biotechnology, Zhejiang Academy of Agricultural Sciences, Hangzhou, 310021, China. Electronic address:

Quantification of immuno-gold labeling can provide valuable information on the quantity and localization of a target within a region of interest (ROI). Background subtraction usually requires preparation of material with a deliberately reduced amount of target component often by gene knockout/knockdown. This paper reports a modified method without the need for gene knockout/knockdown, by using a region outside the ROI as a background and non-immune serum to verify the reliability of the data. An optimized parameter for use in image processing was also developed to improve semi-automatic segmentation of gold particles, by using the standard deviation of pixel intensity together with default parameters (size and intensity) to improve specificity. The modified methods were used to quantify the gold labeling of various components within chloroplasts and their 3 sub-organelle compartments (thylakoid, stroma and starch). Rubisco, actin, myosin, β-tubulin, Endoplasmic reticulum-retention signal HDEL, Sterol methyltransferase 1, and double stranded RNA were all effectively and consistently quantified at the level of the different sub-chloroplast compartments. The approach should be applicable more widely for high resolution labelling of samples in which a background requiring gene knockout/knockdown is not a realistic option.
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http://dx.doi.org/10.1016/j.micron.2021.103060DOI Listing
March 2021

Fruquintinib with gefitinib as first-line therapy in patients carrying EGFR mutations with advanced non-small cell lung cancer: a single-arm, phase II study.

Transl Lung Cancer Res 2021 Feb;10(2):839-854

Hutchison MediPharma, Shanghai, China.

Background: Fruquintinib is an oral vascular endothelial growth factor receptor inhibitor. Previous gefitinib studies with anti-angiogenics show promising efficacy. This phase II trial assessed efficacy and safety of fruquintinib in combination with gefitinib, in patients with advanced non-small cell lung cancer (NSCLC).

Methods: Fifty patients with stage IIIB/IV NSCLC and an epidermal growth factor receptor (EGFR) exon-19 deletion or exon-21 L858R mutation were enrolled between January 2017 and June 2019. Per protocol (version 1.0), patients received 4 mg fruquintinib once daily (qd) Days 1-21 of Cycle 1, using a 3-week-on/1-week-off schedule, plus continuous gefitinib 250 mg qd. If tolerated, patients proceeded to fruquintinib 5 mg qd (fruquintinib 5 mg group, n=26). Following protocol updates, dose escalation of fruquintinib from 4 mg qd to 5 mg qd was not allowed. The primary efficacy endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), disease control rate (DCR), time to response, duration of response and adverse events (AEs).

Results: ORR was 73.5% (95% CI, 58.9-85.1) and DCR was 98.0% (95% CI, 89.2-100.0). Median PFS was 14.7 months for both groups; PFS was highest for patients with exon-19 deletion (16.5 months; 95% CI, 12.9-21.2). Grade ≥3 treatment-emergent AEs occurred in 17 (65.3%; fruquintinib 5 mg,) and 11 patients (45.8%; 4 mg). Serious AEs were recorded for nine patients (fruquintinib 5 mg, six patients; 4 mg, three).

Conclusions: Fruquintinib and gefitinib treatment showed an acceptable safety profile and promising efficacy in patients with NSCLC.
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http://dx.doi.org/10.21037/tlcr-20-1028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947379PMC
February 2021

TANK-Binding Kinase 1 (TBK1) Serves as a Potential Target for Hepatocellular Carcinoma by Enhancing Tumor Immune Infiltration.

Front Immunol 2021 18;12:612139. Epub 2021 Feb 18.

Department of General Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Background: Numerous cancer types present the aberrant TANK-binding kinase 1 (TBK1) expression, which plays an important role in driving inflammation and innate immunity. However, the prognostic role of TBK1 and its relationship with immune cell infiltration in hepatocellular carcinoma (HCC) remain unclear.

Methods: The expression and prognostic value of TBK1 was analyzed by Tumor Immune Estimation Resource (TIMER), Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA), Clinical Proteomic Tumor Analysis Consortium (CPTAC) and further confirmed in the present cohort of patients with HCC. The association between TBK1 and HCC immune infiltrates, and its potential mechanism were investigated analyses of the Tumor Immune Estimation Resource, tumor-immune system interactions database (TISIDB), CIBERSORT, STRING, and Metascape. The effect of TBK1 on immune infiltrates and the therapeutic value of targeting TBK1 were further investigated in a HCC mouse model by treatment with a TBK1 antagonist.

Results: The level of TBK1 expression in HCC was higher than that measured in normal tissues, and associated with poorer overall survival (GEPIA: hazard ratio [HR]=1.80, =0.038; Kaplan-Meier plotter: HR=1.87, <0.001; CPTAC: HR=2.23, =0.007; Our cohort: HR=2.92, =0.002). In addition, high TBK1 expression was found in HCC with advanced TNM stage and identified as an independent poor prognostic factor for overall survival among patients with HCC. In terms of immune infiltration, tumor tissues from HCC patients with high TBK1 expression had a low proportion of CD8 T cells, and TBK1 expression did not show prognostic value in HCC patients with enriched CD8+ T cells. Furthermore, TBK1 expression was positively correlated with the markers of T cell exhaustion and immunosuppressive cells in the HCC microenvironment. Mechanistically, the promotion of HCC immunosuppression by TBK1 was involved in the regulation of inflammatory cytokines. experiments revealed that treatment with a TBK1 antagonist delayed HCC growth by increasing the number of tumor-infiltrating CD8+ T cells.

Conclusions: The up-regulated expression of TBK1 may be useful in predicting poor prognosis of patients with HCC. In addition, TBK1, which promotes the HCC immunosuppressive microenvironment, may be a potential immunotherapeutic target for patients with HCC.
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http://dx.doi.org/10.3389/fimmu.2021.612139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930497PMC
February 2021

Myofibroblast-specific Msi2 knockout inhibits hepatocellular carcinoma progression in a mouse model.

Hepatology 2021 Feb 20. Epub 2021 Feb 20.

Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, China.

Myofibroblasts play a pivotal role in the development and progression of hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of myofibroblast Musashi RNA binding protein 2 (MSI2) in HCC progression. Myofibroblast infiltration and collagen deposition were detected and assessed in the tissues from 117 HCC patients. Transgenic mice (Msi2 ) with floxed Msi2 allele and Col1a1-CreER were constructed to generate a myofibroblast-specific Msi2 knockout model. Mouse HCC cells were orthotopically transplanted into the Msi2 or the control mice (Msi2 ). We found that the deposition of collagen fibers, the main product of myofibroblasts, predicted a poor prognosis for HCC; meanwhile, we detected high MSI2 expression in the peritumoral infiltrated myofibroblasts. Conditional deletion of Msi2 in myofibroblasts significantly inhibited the growth of orthotopically implanted HCC, reduced both intrahepatic and lung metastasis, and prolonged the overall survival of tumor-bearing mice (P = 0.002). In vitro analysis demonstrated that myofibroblasts promoted cell proliferation, invasion, and epithelial-mesenchymal transformation of HCC cells, whereas Msi2 deletion in myofibroblasts reversed these effects. Mechanically, Msi2 knockout decreased myofibroblast-derived IL6 and IL11 secretion by inhibiting the ERK1/2 pathway, and thus attenuated the cancer stem cell promoting effect of myofibroblasts. Interestingly, we found that the simultaneous knockout of Msi2 in myofibroblasts and knockdown of Msi2 in HCC cells could not further attenuate the implanted HCC progression. CONCLUSION: Myofibroblast-specific Msi2 knockout abrogated the tumor-promoting function of myofibroblasts and inhibited HCC progression in mouse models. Targeting myofibroblast MSI2 expression may thus prove to be a therapeutic strategy for HCC treatment in the future.
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http://dx.doi.org/10.1002/hep.31754DOI Listing
February 2021

Protocol for a gallbladder cancer registry study in China: the Chinese Research Group of Gallbladder Cancer (CRGGC) study.

BMJ Open 2021 Feb 16;11(2):e038634. Epub 2021 Feb 16.

Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China

Introduction: Gallbladder cancer (GBC), the sixth most common gastrointestinal tract cancer, poses a significant disease burden in China. However, no national representative data are available on the clinical characteristics, treatment and prognosis of GBC in the Chinese population.

Methods And Analysis: The Chinese Research Group of Gallbladder Cancer (CRGGC) study is a multicentre retrospective registry cohort study. Clinically diagnosed patient with GBC will be identified from 1 January 2008 to December, 2019, by reviewing the electronic medical records from 76 tertiary and secondary hospitals across 28 provinces in China. Patients with pathological and radiological diagnoses of malignancy, including cancer in situ, from the gallbladder and cystic duct are eligible, according to the National Comprehensive Cancer Network 2019 guidelines. Patients will be excluded if GBC is the secondary diagnosis in the discharge summary. The demographic characteristics, medical history, physical examination results, surgery information, pathological data, laboratory examination results and radiology reports will be collected in a standardised case report form. By May 2021, approximately 6000 patient with GBC will be included. The clinical follow-up data will be updated until 5 years after the last admission for GBC of each patient. The study aimed (1) to depict the clinical characteristics, including demographics, pathology, treatment and prognosis of patient with GBC in China; (2) to evaluate the adherence to clinical guidelines of GBC and (3) to improve clinical practice for diagnosing and treating GBC and provide references for policy-makers.

Ethics And Dissemination: The protocol of the CRGGC has been approved by the Committee for Ethics of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine (SHEC-C-2019-085). All results of this study will be published in peer-reviewed journals and presented at relevant conferences.

Trial Registration Number: NCT04140552, Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-038634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888310PMC
February 2021

Comparing the Anti-diabetic Effect of Sleeve Gastrectomy with Transit Bipartition Against Sleeve Gastrectomy and Roux-en-Y Gastric Bypass Using a Diabetic Rodent Model.

Obes Surg 2021 May 28;31(5):2203-2210. Epub 2021 Jan 28.

Department of General Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People's Republic of China.

Purpose: Roux-en-Y gastric bypass (RYGB) has superior long-term diabetes remission outcomes to sleeve gastrectomy (SG). However, in regions with a high prevalence of gastric cancer, RYGB may not be the best option. This study aimed to investigate the anti-diabetic effect of SG with transit bipartition (SG-TB) compared with SG and RYGB.

Materials And Methods: A total of 32 diabetic Sprague-Dawley rat models were assigned to one of four groups: SG (n = 8), RYGB (n = 8), SG-TB (n = 8), and SHAM (n = 8). Body weight, food intake, blood glucose, and hormonal changes (glucagon-like peptide-1 (GLP-1), insulin, and glucagon) were measured to investigate the effect of surgery in all groups. Oral glucose tolerance test and insulin tolerance test were performed before and 8 weeks after surgery.

Results: There were no significant differences in the postoperative changes in body weight and food intake among the SG, RYGB, and SG-TB groups. Postoperatively, the RYGB and SG-TB groups had significantly higher GLP-1 levels and lower insulin levels than the SG group. Further, RYGB and SG-TB had significantly better glucose control improvements than SG. There were no significant differences in GLP-1, insulin, glucagon, and homeostasis model assessment of insulin resistance levels between RYGB and SG-TB. The preoperative and postoperative values of all variables in the SHAM group did not show significant differences.

Conclusion: In this study using a diabetes-induced rodent model, we found that the anti-diabetic effect of SG-TB is superior to that of SG and non-inferior to that of RYGB.
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http://dx.doi.org/10.1007/s11695-021-05256-6DOI Listing
May 2021

Inflammatory microenvironment of fibrotic liver promotes hepatocellular carcinoma growth, metastasis and sorafenib resistance through STAT3 activation.

J Cell Mol Med 2021 Feb 7;25(3):1568-1582. Epub 2021 Jan 7.

Department of Abdominal Surgery, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.

The pro-inflammatory and pro-fibrotic liver microenvironment facilitates hepatocarcinogenesis. However, the effects and mechanisms by which the hepatic fibroinflammatory microenvironment modulates intrahepatic hepatocellular carcinoma (HCC) progression and its response to systematic therapy remain largely unexplored. We established a syngeneic orthotopic HCC mouse model with a series of persistent liver injury induced by CCl gavage, which mimic the dynamic effect of hepatic pathology microenvironment on intrahepatic HCC growth and metastasis. Non-invasive bioluminescence imaging was applied to follow tumour progression over time. The effect of the liver microenvironment modulated by hepatic injury on sorafenib resistance was investigated in vivo and in vitro. We found that the persistent liver injury facilitated HCC growth and metastasis, which was positively correlated with the degree of liver inflammation rather than the extent of liver fibrosis. The inflammatory cytokines in liver tissue were clearly increased after liver injury. The two indicated cytokines, tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6), both promoted intrahepatic HCC progression via STAT3 activation. In addition, the hepatic inflammatory microenvironment contributed to sorafenib resistance through the anti-apoptotic protein mediated by STAT3, and STAT3 inhibitor S3I-201 significantly improved sorafenib efficacy impaired by liver inflammation. Clinically, the increased inflammation of liver tissues was accompanied with the up-regulated STAT3 activation in HCC. Above all, we concluded that the hepatic inflammatory microenvironment promotes intrahepatic HCC growth, metastasis and sorafenib resistance through activation of STAT3.
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http://dx.doi.org/10.1111/jcmm.16256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875922PMC
February 2021

Molecular Characteristics of Jujube Yellow Mottle-Associated Virus Infecting Jujube ( Mill.) Grown at Aksu in Xinjiang of China.

Viruses 2020 12 25;13(1). Epub 2020 Dec 25.

Key Lab of Plant Pathology of Hubei Province, College of Plant Science and Technology, Huazhong Agricultural University, Wuhan 430070, China.

Chinese jujube ( Mill.) is a native fruit crop in China. Leaf mottle and dapple fruit disease is prevalent in cultivated jujube plants grown at Aksu in Xinjiang Uygur Autonomous Region of China. Jujube yellow mottle-associated virus (JYMaV), a tentative member in the genus , was recently identified from mottle-diseased jujube plants grown in Liaoning Province in China, but its incidence and genetic diversity in China is unknown. In this study, the genome sequences of three JYMaV isolates from two jujube cultivars and one jujube variant were determined by high-throughput sequencing (HTS) for small RNA and rRNA-depleted RNA coupled with RT-PCR assays. Comparison of these sequences together with sequences of the viral RNA segments derived by primer set 3C/5H-based RT-PCR revealed that genetic diversity was present in the virus populations and high sequence variation occurred at the non-translational regions of each of the viral genomic segments. Field investigation confirmed the close association of the virus with leaf mottle symptoms of jujube plants. Furthermore, this study revealed that P5 encoded in the viral RNA5 displayed a nuclear localization feature differing from the plasmodesma (PD) subcellular localization of the virus movement protein (P4), and the two proteins could interact with each other in the BiFC assays. Our study provides a snapshot of JYMaV genetic diversity in its natural hosts.
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http://dx.doi.org/10.3390/v13010025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823511PMC
December 2020

Intrahepatic cholangiocarcinoma induced M2-polarized tumor-associated macrophages facilitate tumor growth and invasiveness.

Cancer Cell Int 2020 Dec 7;20(1):586. Epub 2020 Dec 7.

Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, 510630, Guangdong, China.

Background: M2-polarized tumor-associated macrophages (M2-TAMs) have been shown to correlate with the progression of various cancers, including intrahepatic cholangiocarcinoma (ICC). However, the interactions and mechanism between M2 macrophages and ICC are not completely clear. We aimed to clarify whether M2 macrophages promote the malignancy of ICC and its mechanism.

Methods: Two progressive murine models of ICC were used to evaluate the alterations in different macrophage populations and phenotypes. Furthermore, we assessed M2 macrophage infiltration in 48 human ICC and 15 normal liver samples. The protumor functions and the underlying molecular mechanisms of M2 macrophages in ICC were investigated in an in vitro coculture system.

Results: We found that the number of M2 macrophages was significantly higher in ICC tissues than in normal bile ducts in the two murine models. M2 macrophage infiltration was highly increased in peritumoral compared with intratumoral regions and normal liver (p < 0.01). ICC cells induced macrophages to differentiate into the M2-TAM phenotype, and coculture with these M2 macrophages promoted ICC cell proliferation, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, M2-TAM-derived IL-10 promoted the malignant properties of ICC cells through STAT3 signaling. Furthermore, blockade of IL-10/STAT3 signaling partly rescued the effects of M2 macrophages on ICC.

Conclusion: Our results indicated that M2-polarized macrophages induced by ICC promote tumor growth and invasiveness through IL-10/STAT3-induced EMT and might be a potential therapeutic target for ICC.
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http://dx.doi.org/10.1186/s12935-020-01687-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720384PMC
December 2020

Pre-sensitization of Malignant B Cells Through Venetoclax Significantly Improves the Cytotoxic Efficacy of CD19.CAR-T Cells.

Front Immunol 2020 9;11:608167. Epub 2020 Dec 9.

Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg University, Heidelberg, Germany.

Chimeric antigen receptor (CAR) T cell therapy has shown promising responses in patients with refractory or relapsed aggressive B-cell malignancies that are resistant to conventional chemotherapy or stem cell transplantation. A potentially combinatorial therapeutic strategy may be the inhibition of anti-apoptotic Bcl-2 family proteins, overexpressed in most cancer cells. In this study we investigated the combination of 3rd-generation CD19.CAR-T cells and the BH3 mimetics venetoclax, a Bcl-2 inhibitor, or S63845, a Mcl-1 inhibitor, under three different treatment conditions: pre-sensitization of cancer cells with BH3 mimetics followed by CAR-T cell treatment, simultaneous combination therapy, and the administration of BH3 mimetics after CAR-T cell treatment. Our results showed that administration of CAR-T cells and BH3 mimetics had a significant effect on the quantity and quality of CD19.CAR-T cells. The administration of BH3 mimetics prior to CAR-T cell therapy exerted an enhanced cytotoxic efficacy by upregulating the CD19 expression and pro-apoptotic proteins in highly sensitive tumor cells, and thereby improving both CD19.CAR-T cell cytotoxicity and persistence. In simultaneous and post-treatment approaches, however, the quantity of CAR-T cells was adversely affected. Our findings indicate pre-sensitization of highly sensitive tumor cells with BH3 mimetics could enhance the cytotoxic efficacy of CAR-T cell treatment.
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http://dx.doi.org/10.3389/fimmu.2020.608167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756123PMC
December 2020

RCE1 deficiency enhances invasion via the promotion of epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma.

Am J Transl Res 2020 15;12(11):7236-7248. Epub 2020 Nov 15.

Department of Pathophysiology, School of Medicine, Jinan University Guangzhou 510630, Guangdong, China.

Ras converting CAAX endopeptidase 1 (RCE1) is an integral membrane protease involved in cell proliferation, differentiation, and carcinogenesis. RCE1 plays opposite roles in different tumor types; however, the actual biological function of RCE1 in hepatocellular carcinoma (HCC) is unknown. Here, we aim to investigate the prognostic value and molecular function of RCE1 in HCC. We performed immunohistochemistry in 20 normal human liver, 216 HCC, and 216 adjacent non-tumorous tissues and analyzed the expression change and clinical value of RCE1. Additionally, and studies were performed to investigate the role of RCE1 in regulating HCC proliferation, invasion, and metastasis. We found decreased RCE1 expression in HCC tissues. Moreover, the RCE1 expression level was negatively correlated with pathological parameters characteristic of early recurrence ( < 0.044) and the serum alpha-fetoprotein (AFP) level ( < 0.018). Survival analysis indicated that reduced RCE1 expression was a predictor of poor outcomes in patients with HCC. Functional studies showed that the knockdown of RCE1 promoted proliferation, migration, and invasion of HCC cells, while RCE1 overexpression suppressed these effects. studies further confirmed that the stable knockdown of RCE1 resulted in more rapid tumor growth and an increased number of lung metastatic nodules. Mechanistically, we found that RCE1 deficiency induced epithelial-mesenchymal transition (EMT) via activation of the P38 signaling pathway. Collectively, these results indicate that RCE1 deficiency enhances invasion via promoting epithelial-mesenchymal transition. The downregulation of RCE1 in HCC tissues predicts an unsatisfactory prognosis for patients with HCC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724357PMC
November 2020

Development of a dendrimer PAMAM‑based gold biochip for rapid and sensitive detection of endogenous IFN‑γ and anti‑IFN‑γ IgG in patients with hemophagocytic lymphohistiocytosis.

Mol Med Rep 2020 Dec 16;22(6):5369-5377. Epub 2020 Oct 16.

Department of Pathology, Anhui Medical University, Hefei, Anhui 230032, P.R. China.

Hemophagocytic lymphohistiocytosis (HLH) is a rare but severe disease characterized by immune hyperactivation and cytokine storm. Given the high mortality rate of HLH, there is a need for more effective diagnostic tools and treatments. The present study developed a dendrimer‑based protein biochip for rapid, sensitive and simultaneous detection of serum interferon (IFN)‑γ and endogenous anti‑IFN‑γ antibody (Ab) in patients with HLH. A gold biochip was modified with 1, 4‑phenylene diisothiocyanate (PDITC), polyamidoamine (PAMAM) or PDITC‑activated PAMAM. The optimal immobilization concentration for Ab capture and the reaction concentration for detecting Ab on the PDITC‑activated PAMAM‑modified biochip were 6.25 and 3.12 µg/ml, respectively; the limit of detection of IFN‑γ protein was 50 pg/ml. The efficiency of the protein‑probed biochip in detecting IFN‑γ and anti‑IFN‑γ Ab in serum samples from 77 patients with HLH was evaluated; the positive rates for IFN‑γ and anti‑IFN‑γ IgG Ab were 63.6% (49/77) and 61.0% (47/77), respectively. The present results demonstrated that the PDITC‑activated PAMAM‑modified biochip might be a sensitive tool for the specific detection of IFN‑γ and anti‑IFN‑γ Ab in serum, and might have clinical applicability for the diagnosis of HLH.
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http://dx.doi.org/10.3892/mmr.2020.11605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647011PMC
December 2020

Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive NSCLC growth.

Signal Transduct Target Ther 2020 10 9;5(1):214. Epub 2020 Oct 9.

College of Pharmacy, Jinan University, Guangzhou, China.

Epidermal growth factor receptor (EGFR) activation plays a pivotal role in EGFR-driven non-small cell lung cancer (NSCLC) and is considered as a key target of molecular targeted therapy. EGFR tyrosine kinase inhibitors (TKIs) have been canonically used in NSCLC treatment. However, prevalent innate and acquired resistances and EGFR kinase-independent pro-survival properties limit the clinical efficacy of EGFR TKIs. Therefore, the discovery of novel EGFR degraders is a promising approach towards improving therapeutic efficacy and overcoming drug resistance. Here, we identified a 23-hydroxybetulinic acid derivative, namely DPBA, as a novel EGFR small-molecule ligand. It exerted potent in vitro and in vivo anticancer activity in both EGFR wild type and mutant NSCLC by degrading EGFR. Mechanistic studies disclosed that DPBA binds to the EGFR extracellular domain at sites differing from those of EGF and EGFR. DPBA did not induce EGFR dimerization, phosphorylation, and ubiquitination, but it significantly promoted EGFR degradation and repressed downstream survival pathways. Further analyses showed that DPBA induced clathrin-independent EGFR endocytosis mediated by flotillin-dependent lipid rafts and unaffected by EGFR TKIs. Activation of the early and late endosome markers rab5 and rab7 but not the recycling endosome marker rab11 was involved in DPBA-induced EGFR lysosomal degradation. The present study offers a new EGFR ligand for EGFR pharmacological degradation and proposes it as a potential treatment for EGFR-positive NSCLC, particularly NSCLC with innate or acquired EGFR TKI resistance. DPBA can also serve as a chemical probe in the studies on EGFR trafficking and degradation.
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http://dx.doi.org/10.1038/s41392-020-00251-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544691PMC
October 2020

EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3.

Cell Death Dis 2020 10 6;11(10):830. Epub 2020 Oct 6.

Department of Pathophysiology, School of Medicine, Jinan University, 510630, Guangzhou, Guangdong, China.

Elongation factor Tu GTP binding domain containing 2 (EFTUD2), a spliceosomal GTPase, plays a pivotal role in multiple organ development and innate immune. It has been reported that EFTUD2 is a new host factor with activity against HCV infection. However, the role of EFTUD2 in solid tumors, including hepatocellular carcinoma (HCC), remains unexplored. In this study, we investigated the molecular function of EFTUD2 in HCC. Data from The Cancer Genome Atlas (TCGA) indicated an upregulation of EFTUD2 in HCC tissues compared to that in nontumor liver tissues. Immunohistochemical analysis performed on two independent HCC cohorts confirmed the upregulation of EFTUD2 in HCC tissues and further suggested that a high level of EFTUD2 expression predicted shorter overall and recurrence-free survival in HCC patients. Functional studies suggested that siRNA interference with EFTUD2 expression significantly suppressed cell viability, blocked cell cycle progression, facilitated tumor cell apoptosis, and inhibited metastasis, while the enhancement of EFTUD2 expression promoted the proliferation and migration of HCC cells both in vitro and in vivo. Surprisingly, we also found that the stable knockdown of EFTUD2 expression via lentivirus infection was lethal for HCC cells. This finding suggested that EFTUD2 was essential for maintaining the survival of HCC cells. Mechanistically, RNA sequencing and gene set enrichment analysis (GSEA) suggested that the gene sets of epithelial-mesenchymal transition (EMT) and the JAK/STAT3 pathway were enriched in EFTUD2-overexpressing cells. Further verification indicated that EFTUD2-overexpressing cells exhibited an EMT-like phenotype and had enhanced STAT3 activation, while the STAT3 inhibitor S3I-201 partially blocked these pro-malignant effects of EFTUD2 overexpression. In summary, we report EFTUD2 as a novel oncogene that helps to maintain the survival of HCC cells and promotes HCC progression through the activation of STAT3. The high level of expression of EFTUD2 in HCC tissues indicates shorter overall and recurrence-free survival in HCC patients.
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http://dx.doi.org/10.1038/s41419-020-03040-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538941PMC
October 2020

Identification and Characterization of a Pear Chlorotic Leaf Spot-Associated Virus, a Novel Emaravirus Associated with a Severe Disease of Pear Trees in China.

Plant Dis 2020 Nov 30;104(11):2786-2798. Epub 2020 Sep 30.

Jiangxi Academy of Agricultural Sciences, Nanchang, Jiangxi 330200, China.

Pear chlorotic leaf spot (PCLS) is a recently emerged disease of commercially cultivated sandy pear () trees in central and southern China. By integrating high-throughput sequencing and conventional Sanger sequencing of reverse-transcription (RT)-PCR products, a novel emaravirus infecting pear trees was identified and molecularly characterized. The virus was provisionally named pear chlorotic leaf spot-associated virus (PCLSaV). PCLSaV shows the typical molecular features of members of the genus in the family . It has a genome composed of at least five negative-sense RNA segments, with each containing a single open reading frame and two complementary 13-nucleotide stretches at the 5' and 3' termini. PCLSaV shows a close phylogenetic relationship with recognized emaraviruses but forms a separate clade. Moreover, double-membrane-bound bodies were observed in PCLSaV-infected tissues and in extracts of PCLSaV-infected leaves. For the first time, our study revealed the profile distribution of viral RNA reads from the RNA-seq libraries of three samples along the RNA1 to RNA5 of an emaravirus. Field surveys combined with specific RT-PCR assays revealed the presence of PCLSaV in almost all PCLS-diseased pear samples, strongly supporting the association of the virus with the PCLS disease. This study revealed the first emaravirus infecting pear trees and its association with a severe pear chlorotic leaf disease.
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http://dx.doi.org/10.1094/PDIS-01-20-0040-REDOI Listing
November 2020

Safety, Efficacy, and Pharmacokinetics of Almonertinib (HS-10296) in Pretreated Patients With EGFR-Mutated Advanced NSCLC: A Multicenter, Open-label, Phase 1 Trial.

J Thorac Oncol 2020 12 9;15(12):1907-1918. Epub 2020 Sep 9.

Department of Oncology, Shanghai Chest Hospital, Shanghai, People's Republic of China.

Introduction: Almonertinib (HS-10296) is a novel, third-generation EGFR tyrosine kinase inhibitor (EGFR TKI) that targets both EGFR-sensitizing and T790M resistance mutations. This first-in-human trial aimed to evaluate the safety, efficacy, and pharmacokinetics of almonertinib in patients with locally advanced or metastatic EGFR mutation-positive NSCLC that had progressed after pevious EGFR TKI therapy.

Methods: This phase 1, open-label, multicenter clinical trial (NCT0298110) included dose-escalation (55, 110, 220, and 260 mg) and dose-expansion cohorts (55, 110, and 220 mg) with once daily oral administration of almonertinib. In each expansion cohort, tumor biopsies were obtained for the determination of EGFR T790M status. The safety, tolerability, antitumor activity, and pharmacokinetics of almonertinib were evaluated.

Results: A total of 120 patients (26 patients in the dose-escalation cohort and 94 patients in the dose-expansion cohort) were enrolled. The maximum tolerated dose was not defined in the dose-escalation phase; the 260 mg regimen was not further evaluated in the dose-expansion phase owing to safety concerns and saturation of exposure. The most common treatment-related grade greater than or equal to 3 adverse events were increased blood creatine phosphokinase (10%) and increased alanine aminotransferase (3%). Among 94 patients with the EGFR T790M mutation in the dose-expansion cohort, the investigator-assessed objective response rate and disease control rate were 52% (95% confidence interval [CI]: 42-63) and 92% (95% CI: 84-96), respectively. Median progression-free survival was 11.0 months (95% CI: 9.5-not reached) months.

Conclusions: Almonertinib is safe, tolerable and effective for patients with locally advanced or metastatic NSCLC harboring the EGFR T790M mutation who were pretreated with EGFR TKIs.
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http://dx.doi.org/10.1016/j.jtho.2020.09.001DOI Listing
December 2020

Transcriptional regulation of human abraxas brother protein 1 expression by yin yang 1.

Biochem Cell Biol 2020 Aug 26:1-8. Epub 2020 Aug 26.

Department of Experimental Hematology and Biochemistry, Beijing Key Laboratory for Radiobiology, Beijing Institute of Radiation Medicine, Beijing 100850, China.

Abraxas brother protein 1 (ABRO1) is a subunit of the deubiquitinating enzyme BRCC36-containing isopeptidase complex and plays important roles in cellular responses to stress by interacting with its binding partners, such as ubiquitin-specific peptidase 7, p53, activating transcription factor 4, THAP-domain containing 5, and serine hydroxymethyltransferase. However, the transcriptional regulation of remains unexplored. In this study, we identified and characterized the core regulatory elements of the human gene and mapped them to the promoter region. Additionally, 5' rapid amplification of cDNA ends revealed that the transcriptional start site (TSS) was located -13 bp upstream from the start codon. Reporter gene, chromatin immunoprecipitation, and electrophoretic mobility shift assays demonstrated that transcription was regulated through -acting elements located in the region -89 to -59 bp upstream of the TSS and that these elements were targeted by yin yang 1 transcription factor (YY1). Moreover, YY1 overexpression increased human ABRO1 mRNA and protein expression, and small-interfering RNA-mediated downregulation of YY1 attenuated ABRO1 expression. These results suggested that YY1 positively regulated human ABRO1 expression by binding to -acting elements located in the TSS.
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http://dx.doi.org/10.1139/bcb-2019-0279DOI Listing
August 2020

Pyruvate Kinase M2 Tetramerization Protects against Hepatic Stellate Cell Activation and Liver Fibrosis.

Am J Pathol 2020 11 15;190(11):2267-2281. Epub 2020 Aug 15.

Department of Abdominal Surgery, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China; Pathophysiology, School of Medicine, Jinan University, Guangzhou, China. Electronic address:

Liver fibrosis is an increasing health problem worldwide, for which no effective antifibrosis drugs are available. Although the involvement of aerobic glycolysis in hepatic stellate cell (HSC) activation has been reported, the role of pyruvate kinase M2 (PKM2) in liver fibrogenesis still remains unknown. We examined PKM2 expression and location in liver tissues and primary hepatic cells. The in vitro and in vivo effects of a PKM2 antagonist (shikonin) and its allosteric agent (TEPP-46) on liver fibrosis were investigated in HSCs and liver fibrosis mouse model. Chromatin immunoprecipitation sequencing and immunoprecipitation were performed to identify the relevant molecular mechanisms. PKM2 expression was significantly up-regulated in both mouse and human fibrotic livers compared with normal livers, and mainly detected in activated, rather than quiescent, HSCs. PKM2 knockdown markedly inhibited the activation and proliferation of HSCs in vitro. Interestingly, the PKM2 dimer, rather than the tetramer, induced HSC activation. PKM2 tetramerization induced by TEPP-46 effectively inhibited HSC activation, reduced aerobic glycolysis, and decreased MYC and CCND1 expression via regulating histone H3K9 acetylation in activated HSCs. TEPP-46 and shikonin dramatically attenuated liver fibrosis in vivo. Our findings demonstrate a nonmetabolic role of PKM2 in liver fibrosis. PKM2 tetramerization or suppression could prevent HSC activation and protects against liver fibrosis.
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http://dx.doi.org/10.1016/j.ajpath.2020.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786052PMC
November 2020

An optimized approach using cryofixation for high-resolution 3D analysis by FIB-SEM.

J Struct Biol 2020 10 14;212(1):107600. Epub 2020 Aug 14.

Biotechnology and Genetic Germplasm Resources Research Institute, Yunnan Academy of Agricultural Sciences, Key Lab of Southwestern Crop Gene Resources and Germplasm Innovation Ministry of Agriculture and Rural Affairs, Key Lab of Agricultural Biotechnology of Yunnan Province, Kunming 650205, Yunnan, China. Electronic address:

Compared with conventional two-dimensional transmission electron microscopy (TEM), focused ion beam scanning electron microscopy (FIB-SEM) can provide more comprehensive 3D information on cell substructures at the nanometer scale. Biological samples prepared by cryofixation using high-pressure freezing demonstrate optimal preservation of the morphology of cellular structures, as these are arrested instantly in their near-native states. However, samples from cryofixation often show a weak back-scatter electron signal and bad image contrast in FIB-SEM imaging. In addition, it is impossible to do large amounts of heavy metal staining. This is commonly achieved via established osmium impregnation (OTO) en bloc staining protocols. Here, we compared the FIB-SEM image quality of brain tissues prepared using several common freeze-substitution media, and we developed an approach that overcomes these limitations through a combination of osmium tetroxide, uranyl acetate, tannic acid, and potassium permanganate at proper concentrations, respectively. Using this optimized sample preparation protocol for high-pressure freezing and freeze-substitution, perfect smooth membrane morphology, even of the lipid bilayers of the cell membrane, was readily obtained using FIB-SEM. In addition, our protocol is broadly applicable and we demonstrated successful application to brain tissues, plant tissues, Caenorhabditis elegans, Candida albicans, and chlorella. This approach combines the potential of cryofixation for 3D large volume analysis of subcellular structures with the high-resolution capabilities of FIB-SEM.
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http://dx.doi.org/10.1016/j.jsb.2020.107600DOI Listing
October 2020

Mutation profile and prognostic relevance in elderly patients with de novo acute myeloid leukemia treated with decitabine-based chemotherapy.

Int J Lab Hematol 2020 Dec 30;42(6):849-857. Epub 2020 Jul 30.

Department of Hematology, First Affiliated Hospital of Anhui Medical University, Hefei, China.

Introduction: Decitabine-based chemotherapy regimens have shown efficacy in the treatment of elderly patients with acute myeloid leukemia (AML). However, it remains unclear whether any molecular alteration is correlated with the therapeutic effect of such treatment regimens.

Methods: Gene mutations were detected using next-generation sequencing, and their impact on survival was investigated in elderly AML patients receiving decitabine-based chemotherapy.

Results: A higher incidence of gene mutations was identified in elderly AML patients than in the younger cohorts. Elderly patients more frequently carried DNMT3A, IDH2, ASXL1, TET2, RUNX1, CEBPA single mutation (CEBPA ), and TP53 mutations. Survival analysis showed that DNMT3A, FLT3-ITD, and TP53 mutations were associated with inferior overall survival (OS) and event-free survival (EFS) in younger AML patients receiving standard treatment. However, in elderly patients treated with decitabine-based chemotherapy, FLT3-ITD, and ASXL1 mutations, but not DNMT3A and TP53 mutations, were associated with poor OS and EFS. Moreover, contrary to CEBPA double mutation (CEBPA ), CEBPA was identified as an unfavorable prognostic factor.

Conclusion: This study comprehensively analyzed the prognostic implications of gene mutations in elderly AML patients under decitabine-based treatment modality. Identification of genetic biomarkers to predict the subgroup of elderly AML patients who can benefit from decitabine-based regimens might have an immediate clinical utility to optimize the treatment of elderly AML patients.
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http://dx.doi.org/10.1111/ijlh.13299DOI Listing
December 2020

Enolase-phosphatase 1 acts as an oncogenic driver in glioma.

J Cell Physiol 2021 Feb 11;236(2):1184-1194. Epub 2020 Jul 11.

Department of Neurosurgery, Tianjin Huanhu Hospital, Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative diseases, Tianjin Neurosurgical Institute, Tianjin, China.

Enolase-phosphatase 1 (ENOPH1), a newly identified enzyme involved in l-methionine biosynthesis, is associated with anxiety and depression. In this study, ENOPH1 was found to play a crucial role in promoting the proliferation and migration of glioma cells. Among high-grade glioma patients, the overall survival of the group showing high ENOPH1 expression was shorter than that of the group showing low ENOPH1 expression. ENOPH1 knockdown inhibited glioma cell proliferation and migration. In parallel, ENOPH1 knockdown suppressed tumor growth capacity and prolonged survival in an orthotopic glioma model. Mechanistically, we found that ENOPH1 activates the PI3K/AKT/mTOR signaling pathway by regulating THEM4. In conclusion, ENOPH1 is an important mediator that promotes glioma cell proliferation and migration.
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http://dx.doi.org/10.1002/jcp.29926DOI Listing
February 2021

Dexmedetomidine promotes the progression of hepatocellular carcinoma through hepatic stellate cell activation.

Exp Mol Med 2020 07 6;52(7):1062-1074. Epub 2020 Jul 6.

Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, 510315, Guangzhou, China.

Dexmedetomidine (DEX) is an anesthetic that is widely used in the clinic, and it has been reported to exhibit paradoxical effects in the progression of multiple solid tumors. In this study, we sought to explore the mechanism by which DEX regulates hepatocellular carcinoma (HCC) progression underlying liver fibrosis. We determined the effects of DEX on tumor progression in an orthotopic HCC mouse model of fibrotic liver. A coculture system and a subcutaneous xenograft model involving coimplantation of mouse hepatoma cells (H22) and primary activated hepatic stellate cells (aHSCs) were used to study the effects of DEX on HCC progression. We found that in the preclinical mouse model of liver fibrosis, DEX treatment significantly shortened median survival time and promoted tumor growth, intrahepatic metastasis and pulmonary metastasis. The DEX receptor (ADRA2A) was mainly expressed in aHSCs but was barely detected in HCC cells. DEX dramatically reinforced HCC malignant behaviors in the presence of aHSCs in both the coculture system and the coimplantation mouse model, but DEX alone exerted no significant effects on the malignancy of HCC. Mechanistically, DEX induced IL-6 secretion from aHSCs and promoted HCC progression via STAT3 activation. Our findings provide evidence that the clinical application of DEX may cause undesirable side effects in HCC patients with liver fibrosis.
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http://dx.doi.org/10.1038/s12276-020-0461-6DOI Listing
July 2020

Expression of hepatic stellate cell activation-related genes in HBV-, HCV-, and nonalcoholic fatty liver disease-associated fibrosis.

PLoS One 2020 22;15(5):e0233702. Epub 2020 May 22.

Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong, China.

Liver fibrosis is a manifestation of chronic liver injury. It leads to hepatic dysfunction and is a critical element in the pathogenesis of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSC) plays a central role in liver fibrogenesis of different etiologies. To elucidate the molecular mechanism of this phenomenon, it is important to analyze the changes in gene expression that accompany the HSC activation process. In this study, we isolated quiescent and activated HSCs from control mice and mice with CCl4-induced liver fibrosis, respectively, and performed RNA sequencing to compare the differences in gene expression patterns between the two types of HSCs. We also reanalyzed public gene expression data for fibrotic liver tissues isolated from patients with HBV infection, HCV infection, and nonalcoholic fatty liver disease to investigate the gene expression changes during liver fibrosis of these three etiologies. We detected 146 upregulated and 18 downregulated genes in activated HSCs, which were implicated in liver fibrosis as well. Among the overlapping genes, seven transcription factor-encoding genes, ARID5B, GATA6, MITF, PBX1, PLAGL1, SOX4, and SOX9, were upregulated, while one, RXRA, was downregulated. These genes were suggested to play a critical role in HSC activation, and subsequently, in the promotion of liver fibrosis. We undertook the RNA sequencing of quiescent and activated HSCs and analyzed the expression profiles of genes associated with HSC activation in liver fibrotic tissues from different liver diseases, and also aimed to elucidate the changes in gene expression patterns associated with HSC activation and liver fibrosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233702PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244173PMC
August 2020

Variability of EGFR exon 20 insertions in 24 468 Chinese lung cancer patients and their divergent responses to EGFR inhibitors.

Mol Oncol 2020 08 15;14(8):1695-1704. Epub 2020 Jun 15.

Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.

EGFR exon 20 insertions (EGFR e20ins) account for up to 10% of EGFR mutations in lung cancer; however, tumors with EGFR e20ins had poor response rates to EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, afatinib, and osimertinib, and the heterogeneity of EGFR e20ins further complicates the clinical studies. Here, we retrospectively screened next-generation sequencing (NGS) data from 24 468 lung cancer patients, and a total of 85 unique EGFR e20ins variants were identified in 547 cases (2.24%), with p.A767_V769dup (25.1%) and p.S768_D770dup (17.6%) being the most prevalent ones. Comprehensive genomic profiling revealed that TP53 mutations frequently coexisted with p.H773dup (77.8%, P = 0.0558) and p.A767_V769dup (62.8%, P = 0.0325), while RB1 mutations usually co-occurred with p.H773_V774insAH (33.3%, P = 0.0551), implying that different EGFR e20ins variants might require distinct genomic context for tumorigenesis and/or maintenance. Despite that treatment regimens were highly diverse for EGFR e20ins-positive patients, we observed an overall response rate of 14% and a disease control rate (DCR) of 38.4% in 65 patients who received at least one EGFR TKI. The progression-free survival (PFS) differs significantly in six representative EGFR e20ins variants (P = 0.017), and EGFR p.A763_Y764insFQEA was associated with better PFS than other EGFR e20ins when treating with various EGFR TKIs. Some EGFR e20ins variants showed at least partial response to first-generation EGFR TKIs, including p.A767_V769dup, p.S768_D770dup, p.N771_H773dup, p.A763_Y764insFQEA, and p.D770_N771insG. Poziotinib achieved higher DCR for p.S768_D770dup than for p.A767_V769dup, whereas osimertinib showed limited effects for these two insertions when used as the first-line treatment. Overall, our results demonstrated that EGFR e20ins were highly diversified in terms of insertion patterns and co-occurring mutations and these EGFR e20ins variants showed different clinical responses to various EGFR TKIs, suggesting the clinical importance of selecting proper EGFR TKI treatment based on the specific EGFR e20ins type.
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http://dx.doi.org/10.1002/1878-0261.12710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400778PMC
August 2020

Irreversible Kinase Inhibitors Targeting Cysteine Residues and their Applications in Cancer Therapy.

Mini Rev Med Chem 2020 ;20(17):1732-1753

Discovery Chemistry Research, ArromaxPharmatech Co. Ltd. Sangtian Island Innovation Park, No. 1 Huayun Road, Suzhou 215123, China.

Protein kinases are conserved enzymes that catalyse the phosphorylation process in cells. They are recognized as the targets for many diseases. The FDA has approved many kinase inhibitors for the treatment of cancer and confirmed kinases as relevant targets for drug discovery. Major approved drugs are ATP competitive reversible non-covalent inhibitors that achieve selectivity by recognition of specific binding pockets of targeted kinases. In recent years, scientists have paid attention on developing irreversible covalent kinase inhibitors to achieve better selectivity, less toxicity and side effects. Since 2013, seven Irreversible Kinase Inhibitors (IKIs), including; afatinib, ibrutinib, neratinib, dacomitinib, osimertinib, acalabrutinib and zanubrutinib have been approved by the FDA for treatment of severe diseases, like; Metastatic Non-Small Cell Lung Cancer (NSCLC), Mantle Cell Lymphoma (MCL) and HER2-positive breast cancer. These inhibitors target the cysteine residues of kinases. Many IKIs that target cysteine residues are in clinical trials for different diseases and are yet to be approved. We have reviewed the research done and efforts made for finding novel cysteine targeted IKIs as drugs in the recent years.
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http://dx.doi.org/10.2174/1389557520666200513121524DOI Listing
January 2020

The clinical relevance of oliguria in the critically ill patient: analysis of a large observational database.

Crit Care 2020 04 23;24(1):171. Epub 2020 Apr 23.

Departament of Anaesthesiology and Intensive Care, Uniklinikum Jena, Jena, Germany.

Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output < 0.5 ml/kg/h) in acutely ill patients and its association with the need for renal replacement therapy (RRT) and outcome.

Methods: International observational study. All adult (> 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis.

Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient-oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged-oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent-oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103).

Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.
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http://dx.doi.org/10.1186/s13054-020-02858-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181534PMC
April 2020

A non-structural protein encoded by Rice Dwarf Virus targets to the nucleus and chloroplast and inhibits local RNA silencing.

Sci China Life Sci 2020 Nov 15;63(11):1703-1713. Epub 2020 Apr 15.

The State Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, 100871, China.

RNA silencing is a potent antiviral mechanism in plants and animals. As a counter-defense, many viruses studied to date encode one or more viral suppressors of RNA silencing (VSR). In the latter case, how different VSRs encoded by a virus function in silencing remains to be fully understood. We previously showed that the nonstructural protein Pns10 of a Phytoreovirus, Rice dwarf virus (RDV), functions as a VSR. Here we present evidence that another nonstructural protein, Pns11, also functions as a VSR. While Pns10 was localized in the cytoplasm, Pns11 was localized both in the nucleus and chloroplasts. Pns11 has two bipartite nuclear localization signals (NLSs), which were required for nuclear as well as chloroplastic localization. The NLSs were also required for the silencing activities of Pns11. This is the first report that multiple VSRs encoded by a virus are localized in different subcellular compartments, and that a viral protein can be targeted to both the nucleus and chloroplast. These findings may have broad significance in studying the subcellular targeting of VSRs and other viral proteins in viral-host interactions.
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http://dx.doi.org/10.1007/s11427-019-1648-3DOI Listing
November 2020

In vivo efficacy studies of novel quinazoline derivatives as irreversible dual EGFR/HER2 inhibitors, in lung cancer xenografts (NCI-H1975) mice models.

Bioorg Chem 2020 06 24;99:103790. Epub 2020 Mar 24.

Discovery Chemistry Research, Arromax Pharmatech Co. Ltd., Sangtian Island Innovation Park, No. 1 Huayun Road, Suzhou 215123, PR China. Electronic address:

Lung cancer is the most common cancer and leading cause of cancer-related deaths worldwide. The first-generation reversible, ATP-competitive inhibitors gefetinib and elotinib showed good clinical responses in lung adenocarcinoma tumors (NSCLC). But almost all patients developed resistance to these inhibitors over time. Such resistance of EGFR inhibitors was frequently linked to the acquired L858R and T790M point mutations in the kinase domain of EGFR. To overcome these resistance problems, the second and the third generation inhibitors have been discovered. FDA approved afatinib, the second generation irreversible inhibitor and osimitinib, the third generation irreversible EGFR inhibitors for the treatments of NSCLC. We identified new covalent quinazoline inhibitors (E)-N-(4-(3-chloro-4-fluorophenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (6d) and (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-(2-ethoxyethoxy)quinazolin-6-yl)-4-(dimethyl-amino)but-2-enamide (6h) that exhibited potent EGFR kinase inhibitory activities on L858R and T790M mutations. The compound 6 h showed selectivity similar to AZD9291 (osimertinib) in mutated and wild type tumor cell lines. In vitro cell assay 6d and 6h were better than afatinib and osimertinib. In vivo antitumor efficacy studies of these compounds were done in NCI-H1975 mice xenografts.
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http://dx.doi.org/10.1016/j.bioorg.2020.103790DOI Listing
June 2020

Cu/Ni-Catalyzed Cyanomethylation of Alkenes with Acetonitrile for the Synthesis of β,γ-Unsaturated Nitriles.

J Org Chem 2020 May 13;85(9):6143-6150. Epub 2020 Apr 13.

Sixth People's Hospital South Campus, Shanghai Jiao Tong University, No. 6600 Nanfeng Road, Shanghai 201499, China.

We have developed a protocol for the Cu/Ni-catalyzed cyanomethylation of alkenes with acetonitrile for the synthesis of β,γ-unsaturated nitriles. This is the first example of a direct coupling of the alkene sp C-H bond and the acetonitrile sp C-H bond for the preparation of β,γ-unsaturated nitriles. Acetonitrile, an inexpensive and stable solvent, is demonstrated to be a useful cyanomethyl source. The combination of copper and nickel catalysts resulted in a high reaction efficiency.
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http://dx.doi.org/10.1021/acs.joc.0c00141DOI Listing
May 2020