Publications by authors named "Zhuqing Liu"

48 Publications

The upregulation of PYCR2 is associated with aggressive colon cancer progression and a poor prognosis.

Biochem Biophys Res Commun 2021 Oct 28;572:20-26. Epub 2021 Jul 28.

Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Tongji University Cancer Center, Shanghai, China. Electronic address:

PYCR2 has previously been shown to be related to a range of malignancies including hepatocellular carcinoma and melanoma, but its mechanistic functions and prognostic relevance in colon cancer patients remain to be defined. Herein, we used the Oncomine, Human Protein Atlas, The Cancer Genome Atlas (TCGA), and UALCAN databases to explore the expression of this gene in different human cancer, after which the relationship between PYCR2 expression and patient clinicopathologic characteristics was evaluated. We utilized an in vitro approach to evaluate the association between PYCR2 expression and colon cancer cell proliferation, migration, invasion, and tumor microsphere formation. The cell apoptosis was analyzed by flow cytometry. Gene set enrichment analysis (GSEA) approaches were additionally used to probe signaling pathways related to PYCR2. These analyses confirmed that PYCR2 was upregulated in several cancer types including colon cancer, with such upregulation correlating with a poor patient prognosis and with malignant clinicopathological characteristics. PYCR2 expression was identified as an independent predictor of colon cancer patients' survival, and in vitro analyses suggested that knocking down this gene was sufficient to disrupt the proliferative, migratory, invasive, and microsphere formation activities of colon cancer cells. Moreover, shPYCR2 transfection induced colon cancer cell apoptosis. GSEA suggested that high PYCR2 expression correlates with the differential enrichment of the Wnt β-catenin signaling, MYC targets, RNA polymerase, and Notch signaling pathways. Overall, these data indicate that PYCR2 is an important mediator of tumor progression and metastasis, and suggest that it may be a valuable prognostic indicator for colon cancer patient evaluation.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.084DOI Listing
October 2021

Targeting STAT3 Abrogates Tim-3 Upregulation of Adaptive Resistance to PD-1 Blockade on Regulatory T Cells of Melanoma.

Front Immunol 2021 15;12:654749. Epub 2021 Apr 15.

Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Background: Less than 20% of melanoma patients respond to programmed cell death-1 (PD-1) blockade immunotherapies. Thus, it is crucial to understand the dynamic changes in the tumor microenvironment (TME) after PD-1 blockade, for developing immunotherapy efficacy.

Methods: A genomic analysis was conducted by The Cancer Genome Atlas (TCGA) datasets and web platform TIMER2.0 datasets. Pathway enrichment analysis was performed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Peripheral blood mononuclear cells (PBMCs), regulatory T (Treg) cells, and B16-F10 melanoma mice were used as models. The cellular and molecular characteristics and mechanisms of Treg cells in melanoma were assessed by performing gene expression studies, immunohistochemistry, RNA sequencing, and flow cytometry.

Results: Here, we evaluate the countenance of T cell immunoglobulin and mucin-domain containing-3 (Tim-3), and various immunosuppressive factors within tumor-infiltrated Treg cells after treatment with anti-PD-1 or the indicator transduction and activator of transcription 3 (STAT3) inhibitors. Increased expression of Tim-3 is markedly observed within the tissues of the PD-1 blockade resistance of melanoma patients. Targeting STAT3 significantly boosts the response of resistant-PD-1 therapy within the melanoma mouse model. Mechanistically, the manifestation of STAT3 decreases the expression of Tim-3 and various cytokines in the purified Treg cells from individual PBMCs and the murine melanoma model, limiting the immunosuppression of Treg cells.

Conclusions: Our findings indicate that Tim-3 expression on Treg cells within the TME is STAT3-dependent, providing support to STAT3 as a target and enhancing the immunotherapy for patients suffering from melanoma.
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http://dx.doi.org/10.3389/fimmu.2021.654749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082190PMC
April 2021

Serum from patients with hypertension promotes endothelial dysfunction to induce trophoblast invasion through the miR‑27b‑3p/ATPase plasma membrane Ca transporting 1 axis.

Mol Med Rep 2021 05 24;23(5). Epub 2021 Mar 24.

Department of Obstetrics, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, P.R. China.

Pregnancy‑induced hypertension is often accompanied by preeclampsia. The present study investigated whether microRNA (miR)‑27b‑3p affected the occurrence of preeclampsia by regulating the function of endothelial cells. Expressions levels of miR‑27b‑3p and ATPase plasma membrane Ca transporting 1 (ATP2B1) were determined using reverse‑transcription quantitative PCR. miR‑27b‑3p targeting ATP2B1 was predicted using bioinformatics and further confirmed by dual‑luciferase reporter assays. Cell Counting Kit‑8, Transwell and Matrigel tube formation assays were performed to detect the effects of miR‑27b‑3p on proliferation, migration and tube formation of human umbilical vein endothelial cells (HUVECs), respectively. Moreover, HTR8/SVneos cells were co‑cultured with HUVECs to detect the invasion of trophoblast cells, and the expression levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)‑2 and MMP‑9 of HUVECs and HTR8/SVneos were detected by western blotting. Expression levels of miR‑27b‑3p were upregulated in the serum of patients with hypertension and preeclampsia, which could target and regulate the expression of ATP2B1. The expression levels of miR‑27b‑3p were increased and those of ATP2B1 were reduced in HUVECs from hypertensive serums. Moreover, miR‑27b‑3p mimics reduced the expression level of ATP2B1, and miR‑27b‑3p inhibitor reversed the effect of hypertensive serum on ATP2B1 expression. Furthermore, patients with hypertension showed increased endothelial dysfunction, reduced trophoblastic invasion and the expressions of VEGF, MMP‑2 and MMP‑9, and miR‑27b‑3p mimics and silencing of ATP2B1 produced similar results to HUVECs. The miR‑27b‑3p inhibitor reversed the effect of hypertensive serum, and silencing of ATP2B1 inhibited the improvement of miR‑27b‑3p inhibitor to HUVECs and HTR‑8/SVneo cells in proliferation, migration and tube formation. The current findings suggested that miR‑27b‑3p promoted proliferation, migration and tube formation of HUVECs and enhanced invasion of trophoblast cells, via regulation of ATP2B1. Thus, miR‑27b‑3p could be considered as a molecular risk factor in the pathogenesis and development of preeclampsia.
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http://dx.doi.org/10.3892/mmr.2021.11958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7974411PMC
May 2021

TBAI/KSO-Promoted [4 + 2] Annulation of Ketene ,-Acetals and -Tosylhydrazones toward Pyridazines.

Org Lett 2021 03 10;23(5):1606-1610. Epub 2021 Feb 10.

State Key Laboratory of Biobased Material and Green Papermaking, Qilu University of Technology, Shandong Academy of Sciences, Jinan 250353, P. R. China.

A TBAI/KSO-promoted [4 + 2] annulation of ketene -acetals, and -tosylhydrazones was efficiently developed, enabling straightforward access to a variety of trisubstituted pyridazines in reasonable to good yields. The synthetic methodology features a broad substrate scope and a good functional group tolerance. Control experiments demonstrated the indispensability of the alkylthio functionality in the enaminone substrates.
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http://dx.doi.org/10.1021/acs.orglett.1c00026DOI Listing
March 2021

Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody.

Clin Cancer Res 2021 Apr 29;27(8):2168-2178. Epub 2021 Jan 29.

START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.

Purpose: T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor.

Patients And Methods: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis.

Results: No dose-limiting toxicities were observed in the monotherapy ( = 30) or combination ( = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%-70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non-small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [ = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders ( = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts ( = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients.

Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4405DOI Listing
April 2021

Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors.

Clin Cancer Res 2021 May 13;27(10):2773-2781. Epub 2021 Jan 13.

National Cancer Center Hospital East, Chiba, Japan.

Purpose: Investigate the safety and efficacy of LY3415244, a TIM-3/PD-L1 bispecific antibody that blocks TIM-3 and PD-L1 in patients with advanced solid tumors.

Patients And Methods: A phase I, multicenter, open-label study was conducted in patients with advanced solid tumors. Patients were dosed every 2 weeks intravenously with flat doses of LY3415244 escalating from 3 to 70 mg. The primary endpoints were safety, tolerability, and identification of the recommended phase II dose.

Results: Between November 2018 and October 2019, 12 patients were enrolled into four cohorts and received at least one dose of LY3415244. Two patients (16.7%) developed clinically significant anaphylactic infusion-related reactions and all patients developed treatment-emergent antidrug antibodies (TE-ADA). ADA titers were sometimes very high and negatively impacted soluble TIM-3 target engagement in most patients. ADA epitope specificity was against both TIM-3 and PD-L1 arms of the bispecific antibody; most TE-ADAs initially targeted the TIM-3 arm after the first dose. Preexisting ADAs against LY3415244 were also detected in normal (unexposed) human serum samples. One patient with PD-1 refractory non-small cell lung cancer had a near partial response (-29.6%).

Conclusions: This TIM-3 and PD-L1 bispecific format was associated with unexpected immunogenicity targeting both arms of the bispecific antibody, resulting in early study termination. Epitope specificity analysis revealed an initial response toward the TIM-3 arm and presence of preexisting ADAs to the bispecific molecule in the general population. This experience emphasizes the importance of thorough analyses for preexisting ADAs as part of immunogenicity risk assessment of novel antibodies..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3716DOI Listing
May 2021

Taohong Siwu Decoction Ameliorates Ischemic Stroke Injury Via Suppressing Pyroptosis.

Front Pharmacol 2020 8;11:590453. Epub 2020 Dec 8.

Anhui University of Chinese Medicine, Hefei, China.

Taohong Siwu decoction (THSWD) is one of the classic prescriptions for promoting blood circulation and removing blood stasis, and it has a good therapeutic effect on ischemic stroke. We sought to explore the therapeutic effects of THSWD on pyroptosis in rats with middle cerebral artery occlusion-reperfusion (MCAO/R). MCAO/R model of rats were established by suture-occluded method. MCAO/R rats were randomly divided into five groups, which were model group, nimodipine group, THSWD high, medium and low dose group (18, 9, and 4.5 g/kg, respectively), rats of sham group without thread embolus. All rats were treated by intragastric administration for 7 days. We detected the level of inflammatory factors. NLRP3 and Caspase-1 were detected by immunofluorescence. Western blot was used to detect NLRP3, Caspase-1, ASC, and GSDMD in penumbra. Also, the expression of TXNIP, HMGB1, toll-like receptors (TLR4), NF-κB, and MAPK were detected. THSWD treatment improved the behavioral function and brain pathological damage. These results showed that the levels of TNF-α, TGF-β, IL-2, IL-6, IL-1β, and IL-18 were significantly reduced in THSWD treatment groups. THSWD could significantly decrease the expression levels of NLRP3, Caspase-1, Caspase-1 p10, ASC, TXNIP, GSDMD, HMGB1, TLR4/NFκB, p38 MAPK, and JNK in penumbra. Our results showed that THSWD could reduce the activation level of NLRP3 inflammatory corpuscle, down-regulate GSDMD, and inhibit pyroptosis in MCAO/R rats. These may be affected by inhibiting HMGB1/TLR4/NFκB, MAPK signaling pathways.
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http://dx.doi.org/10.3389/fphar.2020.590453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793954PMC
December 2020

Composition, physicochemical properties, and anti-fatigue activity of water-soluble okra (Abelmoschus esculentus) stem pectins.

Int J Biol Macromol 2020 Dec 26;165(Pt B):2630-2639. Epub 2020 Oct 26.

College of Food Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China.

Okra, Abelmoschus esculentus (L.) Moench, an annual herbaceous plant, is widely distributed in tropical and subtropical regions. Water-soluble pectic hydrocolloids from okra stems (HOS) were extracted and purified using polydivinylbenzene HP-20 resins. The sugar composition of the purified HOS with an weight-average molecular weight of 178.4 ± 2.1 kDa and a polydispersity index of 1.02 ± 0.02 contained galacturonic acid (34%), galactose (31%), rhamnose (21%), arabinose (4.2%), glucuronic acid (2.5%), xylose (1.2%), and other monosaccharides (6.1%) by weight. Its favorable rheological behaviors were evident on relatively higher concentrations (20, 25, and 30 mg/mL) and moderately lower pH levels (3 and 5) of HOS. The anti-fatigue experiments in vivo demonstrated that a high dose of HOS (450 mg/kg feed) prolonged the exhaustive swimming time of mice, significantly induced an increase in blood glucose and glycogen, and decreased lactic acid and serum urea nitrogen levels. HOS digestion in vivo was fairly conducive to the improvement of energy storage capacity and renal function for physically induced fatigue, compared with the conventional herbal supplement Panax quinquefolium. Accordingly, HOS exhibits potential for reutilization of okra stem waste.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.10.167DOI Listing
December 2020

Correlation of tumor-infiltrating immune cells of melanoma with overall survival by immunogenomic analysis.

Cancer Med 2020 11 15;9(22):8444-8456. Epub 2020 Sep 15.

Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

Aims: Different types of tumor-infiltrating immune cells not only augment but also dampen antitumor immunity in the microenvironment of melanoma. Therefore, it is critical to provide an overview of tumor-infiltrating immune cells in melanoma and explore a novel strategy for immunotherapies.

Methods: We analyzed the immune states of different stages in melanoma patients by the immune, stromal, and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) scores. Immune cell types were identified by the estimating relative subsets of RNA transcripts (CIBERSORTx) algorithm in 471 melanoma and 324 healthy tissues. Moreover, we performed a gene set variation analysis (GSVA) to determine the differentially regulated pathways in the tumor microenvironment.

Results: In melanoma cohorts, we found that ESTIMATE and immune scores were involved in survival or tumor clinical stage. Among the 22 immune cells, CD8 T cells, M2 macrophages, and regulatory T cells (Tregs) showed significant differences using the CIBERSORTx algorithm. Furthermore, GSVA identified the immune cell-related pathways; the primary immunodeficiency pathway, intestinal immune network for IgA, and TGF-β pathways were identified as participants of the crosstalk in CD8 T cells, Tregs, and M2 macrophages in the melanoma microenvironment.

Conclusion: These results reveal the cellular and molecular characteristics of immune cells in melanoma, providing a method for selecting targets of immunotherapies and promoting the efficacy of therapies for the treatment of melanoma.
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http://dx.doi.org/10.1002/cam4.3466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666744PMC
November 2020

Key candidate genes of STAT1 and CXCL10 in melanoma identified by integrated bioinformatical analysis.

IUBMB Life 2019 10 19;71(10):1634-1644. Epub 2019 Jun 19.

Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.

The underlying mechanisms and gene signatures of melanoma are unknown. In this study, three expression profile data sets (GSE65568, GSE100050, GSE114445) were integrated to identify candidate genes explaining the pathways and functions of melanoma. Expression data sets including 24 melanoma tumours and 13 normal skin samples were merged and analysed in detail. The three GSE profiles shared 431 differentially expressed genes (DEGs), including 227 upregulated genes, 200 downregulated genes and 4 differentially regulated genes. Moreover, the functions and signalling pathways of the shared DEGs with significant p-values were identified. The two most significant modules were filtered from the DEGs protein-protein interaction (PPI) network, which consisted of 284 nodes. We also plotted the prognostic value of hub genes from an online database. In summary, using integrated bioinformatic analysis, we have identified candidate DEGs and pathways in melanoma that could improve our understanding of the causes and underlying molecular events of melanoma, and these candidate genes and pathways could be therapeutic targets for melanoma.
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http://dx.doi.org/10.1002/iub.2103DOI Listing
October 2019

Benzofuran-isatin-imine hybrids tethered via different length alkyl linkers: Design, synthesis and in vitro evaluation of anti-tubercular and anti-bacterial activities as well as cytotoxicity.

Eur J Med Chem 2019 Mar 22;165:323-331. Epub 2019 Jan 22.

Academy of Advanced Interdisciplinary Studies, Qilu University of Technology (Shandong Academy of Sciences), Jinan, PR China; School of Chemistry and Pharmaceutical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, PR China. Electronic address:

Herein we report the design and synthesis of twenty-two novel benzofuran-isatin-imine hybrids 7a-v tethered through propylene, butylene, pentylene and hexylene, and for the evaluation of their in vitro anti-tubercular and anti-bacterial activities as well as cytotoxicity. All benzofuran-isatin-imine hybrids exhibited considerable in vitro anti-TB (MIC: <0.016-0.218 μg/mL and 0.062-14.15 μg/mL against drug-sensitive and MDR MTB, respectively) and anti-bacterial (MIC: 0.25-64 μg/mL and 0.06-16 μg/mL against Gram-positive and Gram-negative strains, respectively) activities. All of them also showed acceptable cytotoxicity towards VERO (CC: 8-128 μg/mL). The most active hybrid 7j (MIC: <0.016, 0.062 and 0.16 μg/mL, respectively) was >4.8 and ≥ 48 folds more potent than the first line anti-TB agents RIF and INH against both drug-sensitive MTB HRv and MDR-TB isolates, respectively. Moreover, hybrid 7j also demonstrated promising anti-bacterial activities with MIC values of ≤1 μg/mL against the majority of the tested Gram-negative and Gram-positive pathogens, which was comparable to vancomycin (MIC: 0.5-4 μg/mL) and CPFX (MIC: 0.125-8 μg/mL) against Gram-positive bacteria, but slightly less potent than CPFX (MIC: ≤0.03-0.5 μg/mL) against Gram-negative bacteria. The results indicated that benzofuran-isatin-imine hybrids could act as candidates for the development of anti-TB and anti-bacterial agents.
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http://dx.doi.org/10.1016/j.ejmech.2019.01.042DOI Listing
March 2019

Modeling the impact of preplanned dose titration on delayed response.

J Biopharm Stat 2019 25;29(2):287-305. Epub 2018 Oct 25.

a Global Statistical Sciences , Eli Lilly and Company , Indiana , USA.

Dose titration becomes more and more common in improving drug tolerability as well as determining individualized treatment doses, thereby maximizing the benefit to patients. Dose titration starting from a lower dose and gradually increasing to a higher dose enables improved tolerability in patients as the human body may gradually adapt to adverse gastrointestinal effects. Current statistical analyses mostly focus on the outcome at the end-of-study follow-up without considering the longitudinal impact of dose titration on the outcome. Better understanding of the dynamic effect of dose titration over time is important in early-phase clinical development as it could allow to model the longitudinal trend and predict the longer term outcome more accurately. We propose a parametric model with two empirical methods of modeling the error terms for a continuous outcome with dose titrations. Simulations show that both approaches of modeling the error terms work well. We applied this method to analyze data from a few clinical studies and achieved satisfactory results.
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http://dx.doi.org/10.1080/10543406.2018.1535499DOI Listing
June 2020

Palladium-Catalyzed C-S Bond Cleavage with Allenoates: Synthesis of Tetrasubstituted 2-Alkenylfuran Derivatives.

Org Lett 2018 10 26;20(19):6007-6011. Epub 2018 Sep 26.

Dalian Institute of Chemical Physics , Chinese Academy of Sciences , 457 Zhongshan Road , Dalian 116023 , China.

Palladium-catalyzed C-S cleavage of tetrasubstituted internal alkene α-oxo ketene dithioacetals was realized with allenoates as the coupling partners, efficiently affording tetrasubstituted 2-alkenylfuran derivatives with excellent regioselectivity under mild conditions. Allenoates acted as C1 synthons in the desulfurative [4 + 1] annulation.
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http://dx.doi.org/10.1021/acs.orglett.8b02253DOI Listing
October 2018

Novel Effector Phenotype of Tim-3 Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients.

Clin Cancer Res 2018 09 30;24(18):4529-4538. Epub 2018 Apr 30.

Department of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Regulatory T (Treg) cells are important suppressive cells among tumor-infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3 Tregs remains unclear. CD4CTLA-4CD25 Treg cells were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3 and Tim-3 TIL Tregs were tested by o suppression assays and multi-color flow cytometry. Gene-expression profiling and NanoString analysis of Tim-3 TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3 Treg. Despite high PD-1 expression, Tim-3 TIL Treg displayed a greater capacity to inhibit naïve T-cell proliferation than Tim-3 Treg. Tim-3 Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39, and IFN-γ receptor. Exogenous IFN-γ treatment could partially reverse the suppressive function of Tim-3 TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs. Tim-3 Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T-cell proliferation despite high PD-1 expression. IFN-γ induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3 Treg suppression. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-1350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6139056PMC
September 2018

Synthesis of Vibegron Enabled by a Ketoreductase Rationally Designed for High pH Dynamic Kinetic Reduction.

Angew Chem Int Ed Engl 2018 06 3;57(23):6863-6867. Epub 2018 May 3.

Codexis, Inc., 200 Penobscot Drive, Redwood City, CA, 94063, USA.

Described here is an efficient stereoselective synthesis of vibegron enabled by an enzymatic dynamic kinetic reduction that proceeds in a high-pH environment. To overcome enzyme performance limitations under these conditions, a ketoreductase was evolved by a computationally and structurally aided strategy to increase cofactor stability through tighter binding.
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http://dx.doi.org/10.1002/anie.201802791DOI Listing
June 2018

Amide Bond Formation Assisted by Vicinal Alkylthio Migration in Enaminones: Metal- and CO-Free Synthesis of α,β-Unsaturated Amides.

J Org Chem 2018 05 30;83(10):5731-5750. Epub 2018 Apr 30.

Dalian Institute of Chemical Physics , Chinese Academy of Sciences , 457 Zhongshan Road , Dalian 116023 , People's Republic of China.

Amide bond formation is one of the most important transformations in organic synthesis, drug development, and materials science. Efficient construction of amides has been among the most challenging tasks for organic chemists. Herein, we report a concise methodology for amide bond (-CONH-) formation assisted by vicinal group migration in alkylthio-functionalized enaminones (α-oxo ketene N, S-acetals) under mild conditions. Simple treatment of such enaminones with PhI(OAc) at ambient temperature in air afforded diverse multiply functionalized α,β-unsaturated amides including β-cyclopropylated acrylamides, in which a wide array of functional groups such as aryl, (hetero)aryl, alkenyl, and alkyl can be conveniently introduced to a ketene moiety. The reaction mechanism was investigated by exploring the origins of the amide oxygen and carbon atoms as well as isolation and structural characterization of the reaction intermediates. The amide bond formation reactions could also be efficiently performed under solventless mechanical milling conditions.
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http://dx.doi.org/10.1021/acs.joc.8b00775DOI Listing
May 2018

A direct determination of AFBs in vinegar by aptamer-based surface plasmon resonance biosensor.

Toxicon 2018 May 19;146:24-30. Epub 2018 Mar 19.

Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, China. Electronic address:

Aflatoxin (AFB) is one of the most toxic fungal metabolites produced by Aspergillus flavus, which may contaminate food and agricultural products. Herein, an aptamer-based surface plasmon resonance (SPR) biosensor was developed to detect AFBs. The chosen aptamer showed comparable interaction with the two AFBs, namely aflatoxin B1 (AFB1) and aflatoxin B2 (AFB2). Such phenomenon was rarely reported, and might lead to a simultaneous detection of both AFBs. In this study, AFB1 was used to systematically establish the detection method. In the SPR system, streptavidin proteins were immobilized on the surface of a CM5 sensor chip as a cross-linker and biotin-aptamers were captured through streptavidin-biotin interaction. After optimization, the assay showed a dynamic range between 0.09 and 200 ng mL (linear range from 1.5 to 50 ng mL and a LOD of 0.19 ng mL) of AFB1 in buffer. As expected, the aptasensor showed high specificity towards AFB1 and AFB2, but hardly bound to other toxins with similar structures, including ochratoxin A (OTA), ochratoxin B (OTB), Zeralenone (ZEA) and T-2 toxin (T-2). Determination of AFB1 in vinegar was further performed using the SPR biosensor. Recoveries of AFB1 from spiked samples ranged from 96.3 to 117.8%. The developed SPR assay is a simple, fast and sensitive approach for the detection of residual AFBs in agricultural products and foodstuffs like vinegar.
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http://dx.doi.org/10.1016/j.toxicon.2018.03.006DOI Listing
May 2018

A mixed-effects, spatially varying coefficients model with application to multi-resolution functional magnetic resonance imaging data.

Stat Methods Med Res 2019 04 15;28(4):1203-1215. Epub 2018 Jan 15.

5 Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Spatial resolution plays an important role in functional magnetic resonance imaging studies as the signal-to-noise ratio increases linearly with voxel volume. In scientific studies, where functional magnetic resonance imaging is widely used, the standard spatial resolution typically used is relatively low which ensures a relatively high signal-to-noise ratio. However, for pre-surgical functional magnetic resonance imaging analysis, where spatial accuracy is paramount, high-resolution functional magnetic resonance imaging may play an important role with its greater spatial resolution. High spatial resolution comes at the cost of a smaller signal-to-noise ratio. This begs the question as to whether we can leverage the higher signal-to-noise ratio of a standard functional magnetic resonance imaging study with the greater spatial accuracy of a high-resolution functional magnetic resonance imaging study in a pre-operative patient. To answer this question, we propose to regress the statistic image from a high resolution scan onto the statistic image obtained from a standard resolution scan using a mixed-effects model with spatially varying coefficients. We evaluate our model via simulation studies and we compare its performance with a recently proposed model that operates at a single spatial resolution. We apply and compare the two models on data from a patient awaiting tumor resection. Both simulation study results and the real data analysis demonstrate that our newly proposed model indeed leverages the larger signal-to-noise ratio of the standard spatial resolution scan while maintaining the advantages of the high spatial resolution scan.
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http://dx.doi.org/10.1177/0962280217752378DOI Listing
April 2019

SHP2 negatively regulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in prostate cancer cells.

Oncotarget 2017 Aug 21;8(32):53518-53530. Epub 2017 Jun 21.

Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai 200072, China.

Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitous protein tyrosine phosphatase that activates the signal transduction pathways of several growth factors and cytokines. In our study, SHP2 expression was very high in prostate cancer (PCa) cell lines, and the expression of phospho-signal transducer and activator of transcription 1 (p-STAT1) and STAT1 was very low. SHP2 knockdown upregulated the expression of p-STAT1 and downregulated phospho-extracellular signal regulated kinase (p-ERK). SHP2 depletion also increased the expression of human leukocyte antigen (HLA)-ABC and programmed death ligand 1 (PD-L1). When tumor cells were pretreated with Janus kinase 2 (JAK2) inhibitor, SHP2 depletion failed to induce HLA-ABC and PD-L1 expression. Furthermore, treating tumor cells with the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor PD0325901 did not upregulate HLA-ABC and PD-L1. SHP2 depletion was associated with increased T-cell activation (CD25 MFI of CD8) by coculture of allogeneic healthy donor peripheral blood monocytes (PBMC) with SHP2 siRNA pretreated PCa cell lines. These results show that SHP2 targeting upregulates HLA-ABC and PD-L1 expression via STAT1 phosphorylation in PCa cells and SHP2 depletion could increase T-cell activation.
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http://dx.doi.org/10.18632/oncotarget.18591DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581127PMC
August 2017

Copper-promoted direct C-H alkoxylation of S,S-functionalized internal olefins with alcohols.

Org Biomol Chem 2017 Jul;15(26):5535-5540

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, Liaoning 116023, People's Republic of China.

Copper-promoted direct C-H alkoxylation of S,S-functionalized internal olefins, that is, α-oxo ketene dithioacetals, was efficiently achieved with alcohols as the alkoxylating agents, (diacetoxyiodo)benzene (PhI(OAc)) as the oxidant, and benzoquinone (BQ) as the co-oxidant. The alkoxylated olefins were thus constructed and applied for the synthesis of alkoxylated N-heterocycles. The polarization of the olefinic carbon-carbon double bond by the electron-donating dialkylthio and electron-withdrawing α-oxo functionalities plays a crucial role in making such C-H alkoxylation reactions to occur under mild conditions. Mechanistic studies implicate a single-electron-transfer (SET) reaction pathway involved in the overall catalytic cycle.
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http://dx.doi.org/10.1039/c7ob01234aDOI Listing
July 2017

Copper-Catalyzed Formal Carbene Migratory Insertion into Internal Olefinic C═C Bonds with N-Tosylhydrazones To Access Iminofuran and 2(3H)-Furanone Derivatives.

Org Lett 2017 07 14;19(13):3660-3663. Epub 2017 Jun 14.

Dalian Institute of Chemical Physics, Chinese Academy of Sciences , 457 Zhongshan Road, Dalian 116023, China.

Efficient copper-catalyzed formal carbene migratory insertion into the olefinic C═C bonds of internal olefins, that is, α-oxo ketene N,S-acetals, has been achieved by means of N-tosylhydrazones of ketones as the carbene precursors. Iminofuran derivatives were obtained and further transformed to the corresponding 2(3H)-furanones and 4-oxobutanoates (γ-ketoesters), respectively, under mild conditions. In a similar fashion, α-thioxo ketene N,S-acetals reacted with N-tosylhydrazones of ketones to afford iminothiophenes. It is suggested that formal carbene migratory insertion into the olefinic C═C bond is involved in the overall catalytic cycle, demonstrating a new type of carbene insertion reaction for five-membered heterocycle construction.
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http://dx.doi.org/10.1021/acs.orglett.7b01668DOI Listing
July 2017

A novel antimicrobial peptide against dental-caries-associated bacteria.

Anaerobe 2017 Oct 29;47:165-172. Epub 2017 May 29.

Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing 100029, PR China. Electronic address:

Dental caries, a highly prevalent oral disease, is primarily caused by pathogenic bacteria infection, and most of them are anaerobic. Herein, we investigated the activity of a designed antimicrobial peptide ZXR-2, and found it showed broad-spectrum activity against a variety of Gram-positive and Gram-negative oral bacteria, particularly the caries-related taxa Streptococcus mutans. Time-course killing assays indicated that ZXR-2 killed most bacterial cells within 5 min at 4 × MIC. The mechanism of ZXR-2 involved disruption of cell membranes, as observed by scanning electron microscopy. Moreover, ZXR-2 inhibited the formation of S. mutans biofilm, but showed limited hemolytic effect. Based on its potent antimicrobial activity, rapid killing, and inhibition of S. mutans biofilm formation, ZXR-2 represents a potential therapeutic for the prevention and treatment of dental caries.
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http://dx.doi.org/10.1016/j.anaerobe.2017.05.016DOI Listing
October 2017

Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189.

Org Lett 2017 05 18;19(9):2218-2221. Epub 2017 Apr 18.

Department of Process Chemistry, Merck & Co., Inc. , P.O. Box 2000, Rahway, New Jersey 07065, United States.

A general and efficient method for the synthesis of pronucleotide (ProTide) 5'-phosphoramidate monoesters is reported. This method consists of a highly stereoselective 5'-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing 3'-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated.
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http://dx.doi.org/10.1021/acs.orglett.7b00469DOI Listing
May 2017

[Effect and its molecular mechanisms of curcumin on pulmonary artery smooth muscle cells in rat model with chronic obstructive pulmonary disease].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2016 May;45(5):469-476

Acupuncture Clinical Traumatology Institute, Anhui University of Chinese Medicine, Hefei 230031, China.

To investigate the effects and the underlying molecular mechanisms of curcumin on pulmonary artery smooth muscle cells in rat model with chronic obstructive pulmonary disease (COPD). A total of 75 male Wistar rats were randomly divided into control group (group CN), model group (group M), low-dose curcumin group (group CL), medium-dose curcumin group (group CM) and high-dose curcumin group (group CH). HE staining was used to observe the morphology of pulmonary artery. Proliferating cell nuclear antigen (PCNA), apoptosis-related protein Bcl-2 and Bax were detected by immunohistochemical staining. TUNEL kit was used to analyze the effects of curcumin on apoptosis of smooth muscle cells, and the protein expressions of SOCS-3/JAK2/STAT pathway in lung tissues were determined by western blot. Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVMI) in group M were significantly higher than those in group CN, group CH and group CM (all <0.05). HE staining and TUNEL kit test showed that the number of pulmonary artery smooth muscle cells had a significant increase in group M, while the pulmonary artery tube became thin, and the smooth muscle cells shrinked in group CM and group CH. Immunohistochemistry showed that PCNA and Bcl-2 in group M were significantly higher than those in group CN (all <0.05), while Bax expression was significantly lower than that in group CN (<0.05). PCNA in group CM and group CH were significantly lower than that in group M (all <0.05), while Bax expression was significantly higher than that in group M (<0.05). Western blot showed that SOCS-3 protein was significantly decreased in group M, while the p-JAK2, p-STAT1, p-STAT3 were significantly increased (all <0.05). Compared with group M, SOCS-3 protein in group CM and group CH were significantly increased (all <0.05), while the p-JAK2, p-STAT3 were significantly reduced (all <0.05). Curcumin could promote the apoptosis of smooth muscle cells in rats with COPD, and improve the mean pulmonary artery pressure and RVMI through stimulating SOCS-3/JAK2/STAT signaling pathway.
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May 2016

Isoleucine/leucine residues at "a" and "d" positions of a heptad repeat sequence are crucial for the cytolytic activity of a short anticancer lytic peptide.

Amino Acids 2017 01 24;49(1):193-202. Epub 2016 Oct 24.

Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China.

Many lytic peptides contain a heptad sequence with leucine or isoleucine residues at "a" and "d" positions. However, their roles in the peptide-induced cytolytic process remain unclear. We have recently reported an anticancer lytic peptide ZXR-2 (FKIGGFIKKLWRSLLA), which contains a shortened zipper-like sequence with Ile/Leu at "a" and "d" positions. To understand the roles of these Ile/Leu residues, a series of analogs were constructed by sequentially replacing the Ile or Leu residue with alanine (Ala). Significant reduction of the cytolytic activity was observed when the Ile (3rd and 7th) and Leu (10th and 14th) residues at the "a" and "d" positions were substituted, while the replacement of the separate Leu (15th) residue had less effect. Based on the quenching of the intrinsic fluorescence of the peptides and their induced surface pressure changes of lipid monolayer, it was conjectured that the peptide ZXR-2 might insert into cell membranes from the C-terminal and to a depth of the W position. Accordingly, I, I, and L residues which mainly exposed in aqueous solution were more responsible for the peptide self-association on cell membranes, while L, together with L, might help peptide insert and anchor to cell membranes. These results are significant to elucidate the crucial roles of such Ile/Leu residues at "a" and "d" positions in peptide-peptide and peptide-membrane interactions to exert the membrane disruption activity of lytic peptides. With further understanding about the structure-activity relationship of lytic peptides, it would be helpful for designing novel anticancer lytic peptides.
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http://dx.doi.org/10.1007/s00726-016-2350-9DOI Listing
January 2017

Pre-Surgical fMRI Data Analysis Using a Spatially Adaptive Conditionally Autoregressive Model.

Bayesian Anal 2016 Jun 26;11(2):599-625. Epub 2015 Aug 26.

Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109;

Spatial smoothing is an essential step in the analysis of functional magnetic resonance imaging (fMRI) data. One standard smoothing method is to convolve the image data with a three-dimensional Gaussian kernel that applies a fixed amount of smoothing to the entire image. In pre-surgical brain image analysis where spatial accuracy is paramount, this method, however, is not reasonable as it can blur the boundaries between activated and deactivated regions of the brain. Moreover, while in a standard fMRI analysis strict false positive control is desired, for pre-surgical planning false negatives are of greater concern. To this end, we propose a novel spatially adaptive conditionally autoregressive model with variances in the full conditional of the means that are proportional to error variances, allowing the degree of smoothing to vary across the brain. Additionally, we present a new loss function that allows for the asymmetric treatment of false positives and false negatives. We compare our proposed model with two existing spatially adaptive conditionally autoregressive models. Simulation studies show that our model outperforms these other models; as a real model application, we apply the proposed model to the pre-surgical fMRI data of two patients to assess peri- and intra-tumoral brain activity.
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http://dx.doi.org/10.1214/15-BA972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814103PMC
June 2016

C-Alkylation of Ketones and Related Compounds by Alcohols: Transition-Metal-Catalyzed Dehydrogenation.

Angew Chem Int Ed Engl 2016 Jan 7;55(3):862-75. Epub 2015 Dec 7.

Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), 457 Zhongshan Road, Dalian, Liaoning, 116023, China.

Transition-metal-catalyzed C-alkylation of ketones and secondary alcohols, with alcohols, avoids use of organometallic or environmentally unfriendly alkylating agents by means of borrowing hydrogen (BH) or hydrogen autotransfer (HA) activation of the alcohol substrates. Water is formed as the only by-product, thus making the BH process atom-economical and environmentally benign. Diverse homogeneous and heterogeneous transition-metal catalysts, ketones, and alcohols can be used for this transformation, thus rendering the BH process promising for replacing those procedures that use traditional alkylating agents. This Minireview summarizes the advances during the last five years in transition-metal-catalyzed BH α-alkylation of ketones, and β-alkylation of secondary alcohols with alcohols. A discussion on the application of the BH strategy for C-C bond formation is included.
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http://dx.doi.org/10.1002/anie.201507521DOI Listing
January 2016

Palladium-Catalyzed Oxidative Cross-Coupling of α-Cyanoketene Dithioacetals with Olefins.

Chemistry 2015 Sep 19;21(40):14085-94. Epub 2015 Aug 19.

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023 (P. R. China).

Efficient palladium-catalyzed cross-coupling reactions of the internal olefins α-cyanoketene dithioacetals with a variety of olefins were achieved in dioxane/HOAc/DMSO (9:3:1 v/v/v) under air atmosphere or by means of AgOAc as the terminal oxidant. Electron-deficient terminal olefins reacted to form the linear diene derivatives with air as the oxidant. Styrenes underwent the cross-coupling to give both the linear and branched dienes when using AgOAc as the oxidant. Unactivated cyclic and linear internal olefin substrates both reacted in the presence of a catalytic amount of benzoquinone in air to produce skipped dienes. The typical products were structurally confirmed by X-ray crystallography.
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http://dx.doi.org/10.1002/chem.201502280DOI Listing
September 2015

Cloning, expression, purification and application of a novel chitinase from a thermophilic marine bacterium Paenibacillus barengoltzii.

Food Chem 2016 Feb 23;192:1041-8. Epub 2015 Jul 23.

College of Food Science and Nutritional Engineering, The Research and Innovation Center of Food Nutrition and Human Health (Beijing), China Agricultural University, Beijing 100083, China. Electronic address:

A novel chitinase gene (PbChi70) from a marine bacterium Paenicibacillus barengoltzii was cloned and functionally expressed in Escherichia coli. The recombinant enzyme (PbChi70) was purified to homogeneity with a recovery yield of 51.9%. The molecular mass of purified enzyme was estimated to be 70.0 kDa by SDS-PAGE. PbChi70 displayed maximal activity at pH 5.5 and 55 °C, respectively. It exhibited strict substrate specificity for colloidal chitin, glycol chitin, powdery chitin, and N-acetyl chitooligosaccharides with degrees of polymerization above three. The enzyme exhibited an endo-type cleavage pattern and hydrolyzed colloidal chitin to yield mainly (GlcNAc)2. Furthermore, colloidal chitin was hydrolyzed by PbChi70 to produce 21.6 mg mL(-1) (GlcNAc)2 with the highest conversion yield of 89.5% (w/w). (GlcNAc)2 was further separated by an active charcoal column with a purity of 99% and a final yield of 61%. The unique enzymatic properties of the chitinase may make it a good candidate for (GlcNAc)2 production.
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http://dx.doi.org/10.1016/j.foodchem.2015.07.092DOI Listing
February 2016

The traditional Chinese medicinal formula BDL301 suppresses tumor growth by inhibiting STAT3 pathway and inducing apoptosis in colorectal cancer cells.

DNA Cell Biol 2015 Mar 21;34(3):178-88. Epub 2015 Jan 21.

1 Department of Medical Oncology, Shanghai Tenth People's Hospital, Tongji University , School of Medicine, Shanghai, China .

The traditional Chinese medicinal formula BDL301 has been used to inhibit inflammation for hundreds of years. The development of colorectal cancer and chronic inflammation are closely related. In this study, we investigated whether BDL301 could inhibit tumor growth. We found that angiogenesis and tumor growth were both inhibited in vivo. In addition, apoptosis was induced and the signal transducer and activator of transcription-3 (STAT3) pathway were suppressed in the colorectal cancer cells in vitro and in vivo by BDL301. This study demonstrates that BDL301 exerted significant anticancer activity by inhibiting the STAT3 pathways and inducing apoptosis in colorectal cancer cells.
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http://dx.doi.org/10.1089/dna.2014.2532DOI Listing
March 2015
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