Publications by authors named "Lichun Ma"

28 Publications

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Single-cell atlas of tumor cell evolution in response to therapy in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

J Hepatol 2021 Jun 30. Epub 2021 Jun 30.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892. Electronic address:

Background & Aims: Intratumor molecular heterogeneity is a key feature of tumorigenesis and is linked to treatment failure and patient prognosis. Here, we aimed to determine what drives tumor cell evolution by performing single-cell transcriptomic analysis.

Methods: We analyzed 46 hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) biopsies from 37 patients enrolled for interventional studies at the NIH Clinical Center, with 16 biopsies collected before and after treatment from 7 patients. We developed a novel machine learning-based consensus clustering approach to track cellular states of 57,000 malignant and non-malignant cells including tumor cell transcriptome-based functional clonality analysis. We determined tumor cell relationships using RNA velocity and reverse graph embedding. We also studied longitudinal samples from 4 patients to determine tumor cellular state and its evolution. We validated our findings in bulk transcriptomic data from 488 patients with HCC and 277 patients with iCCA.

Results: Using transcriptomic clusters as a surrogate for functional clonality, we observed an increase in tumor cell state heterogeneity which was tightly linked to patient prognosis. Furthermore, increased functional clonality was accompanied by a polarized immune cell landscape which included an increase in pre-exhausted T-cells. We found that SPP1 expression was tightly associated with tumor cell evolution and microenvironmental reprogramming. Finally, we developed a user-friendly online interface as a knowledge base for a single-cell atlas of liver cancer.

Conclusions: Our study offers insight into the collective behavior of tumor cell communities in liver cancer as well as potential drivers of tumor evolution in response to therapy.

Lay Summary: Intratumor molecular heterogeneity is a key feature of tumorigenesis, and is linked to treatment failure and patient prognosis. In this study, we present a single-cell atlas of liver tumors from patients treated with immunotherapy and describe intratumoral cell states and their hierarchical relationship. We suggest osteopontin, encoded by the gene SPP1, as a candidate regulator of tumor evolution in response to treatment.
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http://dx.doi.org/10.1016/j.jhep.2021.06.028DOI Listing
June 2021

Toward a Liver Cell Atlas: Understanding Liver Biology in Health and Disease at Single-Cell Resolution.

Semin Liver Dis 2021 Jun 15. Epub 2021 Jun 15.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

Single-cell technologies are revolutionizing our understanding of cellular heterogeneity and functional diversity in health and disease. Here, we review the current knowledge and advances in liver biology using single-cell approaches. We focus on the landscape of the composition and the function of cells in a healthy liver in the context of its spatial organization. We also highlight the alterations of the molecular landscape in chronic liver disease and liver cancer, which includes the identification of disease-related cell types, altered cellular functions, dynamic cell-cell interactions, the plasticity of malignant cells, the collective behavior of a cell community, and microenvironmental reprogramming. We anticipate that the uncovered liver cell atlas will help deciphering the molecular and cellular mechanisms driving a healthy liver into a disease state. It also offers insight into the detection of new therapeutic targets and paves the way for effective disease interventions.
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http://dx.doi.org/10.1055/s-0041-1729970DOI Listing
June 2021

Hypoxia is a key regulator in liver cancer progression.

J Hepatol 2021 Jun 19. Epub 2021 Jun 19.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, USA.

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http://dx.doi.org/10.1016/j.jhep.2021.05.032DOI Listing
June 2021

Activity and Safety of Tegafur, Gimeracil, and Oteracil Potassium for Nasopharyngeal Carcinoma: A Systematic Review and Meta-Analysis.

J Oncol 2021 23;2021:6690275. Epub 2021 Mar 23.

Department of Preventive Medicine, School of Public Health, Guangzhou Medical University, Guangzhou 511436, China.

In clinical practice, tegafur, gimeracil, and oteracil potassium (S-1) therapy is commonly administered to treat nasopharyngeal carcinoma (NPC). However, its efficacy and safety remain controversial in both randomized controlled trials (RCTs) and non-RCTs. We aimed to evaluate the efficacy and safety of S-1 treatment for NPC. We searched PubMed, Ovid, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, Wanfang Database, and VIP databases for RCTs of chemotherapy with or without S-1 for NPC, from 2001 to 2020. A meta-analysis was performed using RevMan5.3 and Stata15. Randomized controlled trials published in journals were included irrespective of blinding and language used. Patients were diagnosed with NPC through a clinicopathological examination; patients of all cancer stages and ages were included. Overall, 25 trials and 1858 patients were included. There were significant differences in the complete remission (OR = 2.42, 95% CI (1.88-3.10), < 0.05) and overall response rate (OR = 2.68, 95% CI (2.08-3.45), < 0.05) between the S-1 and non-S-1 groups. However, there was no significant difference in partial remission (OR = 1.10, 95% CI (0.87-1.39), =0.42) and seven adverse reactions (leukopenia, thrombocytopenia, nausea and vomiting, diarrhea, dermatitis, oral mucositis, and anemia) between the S-1 and non-S-1 groups. Additionally, statistical analyses with six subgroups were performed. S-1 was found to be a satisfactory chemotherapeutic agent combined with radiotherapy, intravenous chemotherapy, or chemoradiotherapy for NPC. As an oral medicine, the adverse reactions of S-1, especially gastrointestinal reactions, can be tolerated by patients, thereby optimizing their quality of life. S-1 may be a better choice for the treatment of NPC. This trial is registered with CRD42019122041.
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http://dx.doi.org/10.1155/2021/6690275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009729PMC
March 2021

Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma.

Nat Commun 2021 03 5;12(1):1455. Epub 2021 Mar 5.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.

T-cell exhaustion denotes a hypofunctional state of T lymphocytes commonly found in cancer, but how tumor cells drive T-cell exhaustion remains elusive. Here, we find T-cell exhaustion linked to overall survival in 675 hepatocellular carcinoma (HCC) patients with diverse ethnicities and etiologies. Integrative omics analyses uncover oncogenic reprograming of HCC methionine recycling with elevated 5-methylthioadenosine (MTA) and S-adenosylmethionine (SAM) to be tightly linked to T-cell exhaustion. SAM and MTA induce T-cell dysfunction in vitro. Moreover, CRISPR-Cas9-mediated deletion of MAT2A, a key SAM producing enzyme, results in an inhibition of T-cell dysfunction and HCC growth in mice. Thus, reprogramming of tumor methionine metabolism may be a viable therapeutic strategy to improve HCC immunity.
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http://dx.doi.org/10.1038/s41467-021-21804-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935900PMC
March 2021

Investigation of Carbon Nanotube Grafted Graphene Oxide Hybrid Aerogel for Polystyrene Composites with Reinforced Mechanical Performance.

Polymers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Institute of Polymer Materials, School of Material Science and Engineering, Qingdao University, No. 308 Ningxia Road, Qingdao 266071, China.

The rational design of carbon nanomaterials-reinforced polymer matrix composites based on the excellent properties of three-dimensional porous materials still remains a significant challenge. Herein, a novel approach is developed for preparing large-scale 3D carbon nanotubes (CNTs) and graphene oxide (GO) aerogel (GO-CNTA) by direct grafting of CNTs onto GO. Following this, styrene was backfilled into the prepared aerogel and polymerized in situ to form GO-CNTA/polystyrene (PS) nanocomposites. The results of X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy indicate the successful establishment of CNTs and GO-CNT and the excellent mechanical properties of the 3D frameworks using GO-CNT aerogel. The nanocomposite fabricated with around 1.0 wt% GO-CNT aerogel displayed excellent thermal conductivity of 0.127 W/m∙K and its mechanical properties were significantly enhanced compared with pristine PS, with its tensile, flexural, and compressive strengths increased by 9.01%, 46.8%, and 59.8%, respectively. This facile preparation method provides a new route for facilitating their large-scale production.
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http://dx.doi.org/10.3390/polym13050735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956833PMC
February 2021

Dynamic variations in salinity and potassium grade of a potassium-rich brine deposit in Lop Nor basin, China.

Sci Rep 2021 Feb 8;11(1):3351. Epub 2021 Feb 8.

SDIC Xinjiang Lop Nor Potash Co., Ltd., Hami, 839000, China.

The Quaternary Lop Nor playa is the largest production base of potassium sulfate in the world. It has a mining history of more than 10 years, and its share in the Chinese potassium sulfate market is about 50% to-date. In this basin, the high-salinity potassium-rich brines are mainly contained in Middle Pleistocene-Holocene glauberite strata. Based on the monitoring of the underground brine table and geochemical analysis, this study reveals variations in the underground brine table and potassium-bearing grade before and after large-scale mining in the Lop Nor potash deposit. The results showed that the underground brine table and potassium sulfate grade decreased by varying degrees over sub-mineral areas after large-scale mining. The underground brine table declined by 8.5 m, on average, in the Luobei depression, by 6.4 m in the Tenglong platform and by 1.9 m in the Xinqing platform. However, the potassium-bearing grade showed the different trend. The Tenglong platform had the largest decline with average decreases in layers W, W and W of 18.2%, 13.0% and 24.8%, respectively. In the Xinqing platform, the average decrease in layersW and W were 17.4% and 16.0% respectively. The Luobei depression decreases were relatively small (W, W and W decreased 4.3%, 4.2% and 3.1%, respectively). This research provides a theoretical basis for the rational development and sustainable use of the potassium-rich brines in the Lop Nor basin.
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http://dx.doi.org/10.1038/s41598-021-82958-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870849PMC
February 2021

Gut Microbiome Directs Hepatocytes to Recruit MDSCs and Promote Cholangiocarcinoma.

Cancer Discov 2021 May 15;11(5):1248-1267. Epub 2020 Dec 15.

Cancer and Inflammation Program, Center for Cancer Research, NCI, NIH, Bethesda, Maryland.

Gut dysbiosis is commonly observed in patients with cirrhosis and chronic gastrointestinal disorders; however, its effect on antitumor immunity in the liver is largely unknown. Here we studied how the gut microbiome affects antitumor immunity in cholangiocarcinoma. Primary sclerosing cholangitis (PSC) or colitis, two known risk factors for cholangiocarcinoma which promote tumor development in mice, caused an accumulation of CXCR2 polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). A decrease in gut barrier function observed in mice with PSC and colitis allowed gut-derived bacteria and lipopolysaccharide to appear in the liver and induced CXCL1 expression in hepatocytes through a TLR4-dependent mechanism and an accumulation of CXCR2 PMN-MDSCs. In contrast, neomycin treatment blocked CXCL1 expression and PMN-MDSC accumulation and inhibited tumor growth even in the absence of liver disease or colitis. Our study demonstrates that the gut microbiome controls hepatocytes to form an immunosuppressive environment by increasing PMN-MDSCs to promote liver cancer. SIGNIFICANCE: MDSCs have been shown to be induced by tumors and suppress antitumor immunity. Here we show that the gut microbiome can control accumulation of MDSCs in the liver in the context of a benign liver disease or colitis...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102309PMC
May 2021

Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis.

J Hepatol 2021 Mar 30;74(3):700-715. Epub 2020 Nov 30.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, USA. Electronic address:

Over the last decade, precision medicine and immunotherapeutic approaches have become increasingly popular in oncology. Early clinical trials reported promising results, but response rates in phase III clinical trials have been suboptimal. Knowledge gained from subsequent translational studies indicates the importance of targeting the tumour microenvironment to overcome resistance to immunotherapy. In this era of precision medicine, it is crucial to consider inter- as well as intratumoural heterogeneity. Single-cell analysis is a cutting-edge technology that enables us to better define the tumour cell community and to identify potential targets for immunotherapy or combination treatments. This review focuses on single-cell analysis in the context of immunotherapy in liver cancer, including the rationale behind studying hepatocellular carcinoma biology at a single-cell level. Single-cell technologies have the potential to revolutionise our understanding of resistance mechanisms and to guide drug discovery efforts, leading to further advances in personalised medicine.
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http://dx.doi.org/10.1016/j.jhep.2020.11.036DOI Listing
March 2021

Endovascular treatment of cerebrovascular stenosis with stent for patients with ischemic cerebrovascular disease.

Medicine (Baltimore) 2020 Nov;99(47):e23313

Department of cardiovascular surgery, General Hospital of Western Theater Command, Chengdu, Sichuan, China.

This study aimed to investigate the therapeutic effect of cerebrovascular stent implantation in southwest Chinese patients with ischemic cerebrovascular disease and underlying risk factors for stent restenosis.We made a retrospectively analysis of occurring risk, cerebrovascular lesion, stent implantation, complication treatment, and prognosis of 54 patients with ischemic cerebrovascular disease in our department.A total of 85 stents were implanted into 54 patients, involving 44 of the internal carotid artery system, 34 of the vertebral-basal artery system and 7 of the subclavian artery system. All patients with stenosis were reduced by >70%, with all stenosis complete reduction in 5 (9%) patients and reduction of over 90% in 25 (46%) patients. A total of 50 patients were followed up for 28.5 (21-35) months. The stents in 42 patients exhibited satisfactory shape and location while restenosis occurred in 8 patients. Univariate analysis revealed that hyperlipidemia, hyperuricemia, surgery duration, and total length of hospital stay are significantly correlated with stent restenosis, and hyperlipidemia and hyperuricemia were proven to be independent risk factors for restenosis using logistic regression analysis.Cerebrovascular stent implantation and balloon inflation surgery can assist in abating angiostenosis and improving blood supplement effectively in patients with ischemic cerebrovascular disease. Besides, an overall evaluation, strict care, and regular check-up in perioperative period may reduce the occurrence of complications. Finally, several clinical parameters may need to be highly focused on in surgery for better prognosis.
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http://dx.doi.org/10.1097/MD.0000000000023313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7676544PMC
November 2020

Effects of different "rigid-flexible" structures of carbon fibers surface on the interfacial microstructure and mechanical properties of carbon fiber/epoxy resin composites.

J Colloid Interface Sci 2021 Feb 15;583:13-23. Epub 2020 Sep 15.

Institute of Polymer Materials, School of Material Science and Engineering, Qingdao University, Qingdao 266071, China. Electronic address:

In order to comprehend the influence of different "rigid-flexible" structures on the interface strength of carbon fiber(CF)/epoxy composites, CNTs was firstly chemically grafted on CFs surface, and then polyamide (PA) was grafted onto CF-CNTs surface through varying anionic polymerization time of caprolactam [CF-CNTs-PA (n = 6 h, 12 h, 24 h)]. X-ray photoelectron spectroscopy (XPS) and Raman spectroscopy indicated the successful establishment of CNTs and PA. TGA demonstrated the different grafting amounts of CF-CNTs-PA (n = 6 h, 12 h and 24 h). SEM images revealed a compactness and uniform coverage of the CNTs/PA, with increasing polymerization time, the CF and CNTs surface was covered by a thick layer of PA. The surface energy increased and then decreased. The optimal interfacial shear strength (IFSS) and interlaminar shear strength (ILSS) of the CF/epoxy composites with a polymerization time of 12 h (CF-CNTs-PA) was 86.7 and 85.4 MPa, which was 77.6% and 45.7% higher than that of untreated CF/epoxy composite. As the polymerization time grew, the impact toughness and tensile strength of CF/epoxy composites enhanced and conductivity of CF/epoxy composite reduced. In addition, the mechanisms of reinforcement and toughening were also illuminated. This work would provide a certain theoretical basis for the preparation and applications of high-performance CF composites with different structures.
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http://dx.doi.org/10.1016/j.jcis.2020.09.005DOI Listing
February 2021

Serological Responses to Human Virome Define Clinical Outcomes of Italian Patients Infected with SARS-CoV-2.

medRxiv 2020 Sep 7. Epub 2020 Sep 7.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the pandemic respiratory infectious disease COVID-19. However, clinical manifestations and outcomes differ significantly among COVID-19 patients, ranging from asymptomatic to extremely severe, and it remains unclear what drives these disparities. Here, we studied 159 hospitalized Italian patients with pneumonia from the NIAID-NCI COVID-19 Consortium using a phage-display method to characterize circulating antibodies binding to 93,904 viral peptides encoded by 1,276 strains of human viruses. SARS-CoV-2 infection was associated with a marked increase in individual's immune memory antibody repertoires linked to trajectories of disease severity from the longitudinal analysis also including anti-spike protein antibodies. By applying a machine-learning-based strategy, we developed a viral exposure signature predictive of COVID-19-related disease severity linked to patient survival. These results provide a basis for understanding the roles of memory B-cell repertoires in COVID-19-related symptoms as well as a predictive tool for monitoring its clinical severity.
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http://dx.doi.org/10.1101/2020.09.04.20187088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480049PMC
September 2020

Intratumoral γδ T-Cell Infiltrates, Chemokine (C-C Motif) Ligand 4/Chemokine (C-C Motif) Ligand 5 Protein Expression and Survival in Patients With Hepatocellular Carcinoma.

Hepatology 2021 Mar;73(3):1045-1060

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD.

Background And Aims: Hepatocellular carcinoma (HCC) is an aggressive malignancy which is often associated with a complex tumor microenvironment attributable to etiology-induced cellular inflammation. γδ T cells are known to detect and react to chronic inflammation, which is linked to cancer development, progression, and metastasis. Our recent genomic study revealed an increased infiltration of several immune cell types, including γδ T cells, in tumor microenvironments of a Thai HCC subtype associated with a good prognosis.

Approach And Results: Here, we quantified the amount of γδ T cells using a γδ T-cell-specific gene signature in 247 Chinese HCC patients. We also validated the γδ T-cell signature in American HCC patients. Additionally, such an association was only found in tumor transcriptomic data, but not in adjacent nontumor transcriptomic data, suggesting a selective enrichment of γδ T cells in the tumor microenvironment. Moreover, the γδ T-cell signature was positively correlated with the expression of natural killer cell receptor genes, such as NKG2D and cytolytic T-cell genes granzymes and perforin, suggesting a stronger T-cell-mediated cytotoxic activity. Furthermore, we found that the γδ T-cell-specific gene expression is positively correlated with the expression of chemokine (C-C motif) ligand 4 (CCL4)/chemokine (C-C motif) ligand 5 (CCL5) and C-C chemokine receptor type 1 (CCR1)/C-C chemokine receptor type 5 (CCR5), the receptors for γδ T cells. We validated these results using immunohistochemical analysis of formalin-fixed, paraffin-embedded tumor biopsies from 182 HCC patients. Moreover, we found evidence of CCL4/CCL5-mediated recruitment of γδ T cells both in vitro and in a murine orthotopic Hepa1-6 HCC model.

Conclusions: We propose that CCL4/CCL5 may interact with their receptor, CCR1/CCR5, which may facilitate the recruitment of γδ T cells from peripheral blood or peritumor regions to the tumor regions. Consequently, an increasing infiltration of γδ T cells in tumors may enhance antitumor immunity and improve patients' prognosis.
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http://dx.doi.org/10.1002/hep.31412DOI Listing
March 2021

PKM2 inhibition may reverse therapeutic resistance to transarterial chemoembolization in hepatocellular carcinoma.

J Exp Clin Cancer Res 2020 Jun 3;39(1):99. Epub 2020 Jun 3.

Laboratory of Human Carcinogenesis and Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, MSC 4258, Building 37, Room 3044A, Bethesda, MD, 20892, USA.

Background: Therapeutic options for patients with hepatocellular carcinoma (HCC) are limited. Transarterial chemoembolization (TACE) is an interventional procedure used to deliver chemotherapy and embolizing agents directly to the tumor and is the procedure of choice for patients with intermediate stage HCC. While effective, more than 40% of patients do not respond to therapy, highlighting the need to investigate possible mechanisms of resistance. We sought to evaluate mechanisms of TACE resistance and evaluate a potential therapeutic target to overcome this resistance.

Methods: Using a prognostic gene signature which predicts TACE response (TACE Navigator) in a cohort of HCC patients who received TACE, patients were classified as responders and non-responders. Transcriptomic and gene pathway analysis were used to identify potential drivers of TACE resistance. Knockdown of the gene encoding rate limiting enzyme PKM2 using shRNA in HCC cell lines, as well as pharmacologic inhibition of PKM2 with shikonin using an in vitro TACE model measured response to chemotherapy under hypoxia. Finally, we replicated the TACE model with shikonin using patient derived cell line organoids (PDC). Functional studies were performed in vitro using immunoblotting, quantitative polymerase chain reaction, glycolysis and hypoxia assays.

Results: In patient non-responders, we identified enrichment of the glycolysis pathway, specifically of the gene encoding the rate-limiting enzyme PKM2. We identified four HCC cell lines which recapitulated a TACE responder-like and non-responder-like phenotype. PKM2 knockdown in HCC cell lines demonstrated a less proliferative and aggressive phenotype as well as improved drug sensitivity to both doxorubicin and cisplatin. In vitro TACE model demonstrated that TACE non-responder-like cells overcame therapeutic resistance and rendered them susceptible to therapy through PKM2 knockdown. Lastly, we obtained similar results using a pharmacologic PKM2 inhibitor, shikonin in both cell lines, and PDC organoids.

Conclusion: Elevated PKM2 is associated with treatment resistance and abbreviated survival in patients receiving TACE. Elevated PKM2 in vitro is associated with increased utilization of the glycolysis pathway, resulting in oxygen independent cell metabolism. Through PKM2 knockdown as well as with pharmacologic inhibition with shikonin, non-responder cells can be reprogrammed to act as responders and could improve TACE efficacy in patients.
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http://dx.doi.org/10.1186/s13046-020-01605-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268641PMC
June 2020

Mussel-Inspired Co-Deposition of Polydopamine/Silica Nanoparticles onto Carbon Fiber for Improved Interfacial Strength and Hydrothermal Aging Resistance of Composites.

Polymers (Basel) 2020 Mar 23;12(3). Epub 2020 Mar 23.

School of Chemistry and Materials Science, Ludong University, Yantai 264025, China.

A novel and effective strategy was first proposed for the codeposition of a mussel-inspired nanohybrid coating with excellent wettability onto the surface of carbon fibers (CFs) by simultaneous polymerization of bioinspired dopamine (DA) and hydrolysis of commercial tetraethoxysilane (TEOS) in an eco-friendly one-pot process. Mussel-inspired nanohybrids could be adhered onto the surface of CFs firmly. The novel modification could afford sufficient polar groups and significantly improve fiber surface roughness and energy without decreasing fiber intrinsic strength, which were advantageous to promote interfacial compatibility and wettability between CFs and matrix resin. As a result, the interfacial shear strength of composites increased to 48.21 ± 1.45 MPa compared to that of untreated composites 29.47 ± 0.88 MPa. Meanwhile, the nanohybrid coating increased significantly composites' hydrothermal aging resistance. The efficient strategy shows a promising and green platform of surface functionalization of CFs for preparing advanced polymer composites arising from broadly mechanical-demanding and energy-saving usages.
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http://dx.doi.org/10.3390/polym12030712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182870PMC
March 2020

Hydroxyl-Terminated Triazine Derivatives Grafted Graphene Oxide for Epoxy Composites: Enhancement of Interfacial and Mechanical Properties.

Polymers (Basel) 2019 Nov 12;11(11). Epub 2019 Nov 12.

Institute of Polymer Materials, Qingdao University, Qingdao 266071, China.

An effective approach to the fabrication of progressive epoxy nanocomposites by the incorporation of hydroxyl-terminated dendrimers functionalized graphene oxide (GO-TCT-Tris) is reported. The relationship between surface grafting, chemical construction, morphology, dispersion, and interfacial interaction as well as the corresponding mechanical properties of the composites were studied in detail. It was shown that hydroxyl-terminated triazine derivatives have been resoundingly bonded onto the GO surface through covalent bonding, which effectively improved the dispersion and compatibility of GO sheets in epoxy resin. The tensile and flexural tests manifested that the GO-TCT-Tris/epoxy composites exhibited greater tensile/flexural strength and modulus than either the pure epoxy or the GO/epoxy composites. For GO-TCT-Tris (0.10 wt%)/epoxy composite, the tensile strength and elastic modulus increased from 63 ± 4 to 89 ± 6 MPa (41.27%) and from 2.8 ± 0.1 to 3.6 ± 0.2 GPa (28.57%), and the flexural strength and modulus increased from 106 ± 5 to 158 ± 6 MPa (49.06%) and from 3.0 ± 0.1 to 3.5 ± 0.2 GPa (16.67%), respectively, compared to the pure epoxy matrix. Moreover, the fractographic analysis also illustrated the ameliorative interfacial interaction between GO-TCT-Tris and epoxy matrix.
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http://dx.doi.org/10.3390/polym11111866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918404PMC
November 2019

Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer.

Cancer Cell 2019 10 3;36(4):418-430.e6. Epub 2019 Oct 3.

Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA; Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Cellular diversity in tumors is a key factor for therapeutic failures and lethal outcomes of solid malignancies. Here, we determined the single-cell transcriptomic landscape of liver cancer biospecimens from 19 patients. We found varying degrees of heterogeneity in malignant cells within and between tumors and diverse landscapes of tumor microenvironment (TME). Strikingly, tumors with higher transcriptomic diversity were associated with patient's worse overall survival. We found a link between hypoxia-dependent vascular endothelial growth factor expression in tumor diversity and TME polarization. Moreover, T cells from higher heterogeneous tumors showed lower cytolytic activities. Consistent results were found using bulk genomic and transcriptomic profiles of 765 liver tumors. Our results offer insight into the diverse ecosystem of liver cancer and its impact on patient prognosis.
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http://dx.doi.org/10.1016/j.ccell.2019.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801104PMC
October 2019

Boolean network modeling of β-cell apoptosis and insulin resistance in type 2 diabetes mellitus.

BMC Syst Biol 2019 04 5;13(Suppl 2):36. Epub 2019 Apr 5.

School of Information Science and Technology, ShanghaiTech University, Shanghai, China.

Background: Major alteration in lifestyle of human population has promoted Type 2 diabetes mellitus (T2DM) to the level of an epidemic. This metabolic disorder is characterized by insulin resistance and pancreatic β-cell dysfunction and apoptosis, triggered by endoplasmic reticulum (ER) stress, oxidative stress and cytokines. Computational modeling is necessary to consolidate information from various sources in order to obtain a comprehensive understanding of the pathogenesis of T2DM and to investigate possible interventions by performing in silico simulations.

Results: In this paper, we propose a Boolean network model integrating the insulin resistance pathway with pancreatic β-cell apoptosis pathway which are responsible for T2DM. The model has five input signals, i.e. ER stress, oxidative stress, tumor necrosis factor α (TNF α), Fas ligand (FasL), and interleukin-6 (IL-6). We performed dynamical simulations using random order asynchronous update and with different combinations of the input signals. From the results, we observed that the proposed model made predictions that closely resemble the expression levels of genes in T2DM as reported in the literature.

Conclusion: The proposed model can make predictions about expression levels of genes in T2DM that are in concordance with literature. Although experimental validation of the model is beyond the scope of this study, the model can be useful for understanding the aetiology of T2DM and discovery of therapeutic intervention for this prevalent complex disease. The files of our model and results are available at https://github.com/JieZheng-ShanghaiTech/boolean-t2dm .
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http://dx.doi.org/10.1186/s12918-019-0692-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449890PMC
April 2019

Single-cell gene expression analysis reveals β-cell dysfunction and deficit mechanisms in type 2 diabetes.

Authors:
Lichun Ma Jie Zheng

BMC Bioinformatics 2018 Dec 31;19(Suppl 19):515. Epub 2018 Dec 31.

School of Information Science and Technology, ShanghaiTech University, Shanghai, 201210, China.

Background: Type 2 diabetes (T2D) is one of the most common chronic diseases. Studies on T2D are mainly built upon bulk-cell data analysis, which measures the average gene expression levels for a population of cells and cannot capture the inter-cell heterogeneity. The single-cell RNA-sequencing technology can provide additional information about the molecular mechanisms of T2D at single-cell level.

Results: In this work, we analyze three datasets of single-cell transcriptomes to reveal β-cell dysfunction and deficit mechanisms in T2D. Focused on the expression levels of key genes, we conduct discrimination of healthy and T2D β-cells using five machine learning classifiers, and extracted major influential factors by calculating correlation coefficients and mutual information. Our analysis shows that T2D β-cells are normal in insulin gene expression in the scenario of low cellular stress (especially oxidative stress), but appear dysfunctional under the circumstances of high cellular stress. Remarkably, oxidative stress plays an important role in affecting the expression of insulin gene. In addition, by analyzing the genes related to apoptosis, we found that the TNFR1-, BAX-, CAPN1- and CAPN2-dependent pathways may be crucial for β-cell apoptosis in T2D. Finally, personalized analysis indicates cell heterogeneity and individual-specific insulin gene expression.

Conclusions: Oxidative stress is an important influential factor on insulin gene expression in T2D. Based on the uncovered mechanism of β-cell dysfunction and deficit, targeting key genes in the apoptosis pathway along with alleviating oxidative stress could be a potential treatment strategy for T2D.
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http://dx.doi.org/10.1186/s12859-018-2519-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6311914PMC
December 2018

Preparation and Magnetic Properties of Nd/FM (FM=Fe, Co, Ni)/PA66 Three-Layer Coaxial Nanocables.

Nanoscale Res Lett 2018 Oct 19;13(1):326. Epub 2018 Oct 19.

Institute of Polymer Materials, School of Materials Science and Engineering, Qingdao University, No. 308 Ningxia Road, Qingdao, 266071, People's Republic of China.

A new preparation method of three-layer coaxial nanocables has been developed in this work. Nd/FM (FM=Fe, Co, Ni)/PA66 three-layer coaxial nanocables were assembled successfully from outer to inner layer by layer. PA66 nanotubes which served as the outer shell were prepared by polymer solution wetting AAO template. Ferromagnetic metals and Nd were deposited into pre-prepared PA66 nanotubes to be served as the middle layer and inner core, respectively. The results show that the structure has effects on the magnetic properties, and the nanocable preparation allows each layer, length, and thickness of the nanocables to be tuned.
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http://dx.doi.org/10.1186/s11671-018-2742-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6195504PMC
October 2018

A polynomial based model for cell fate prediction in human diseases.

Authors:
Lichun Ma Jie Zheng

BMC Syst Biol 2017 12 21;11(Suppl 7):126. Epub 2017 Dec 21.

Biomedical Informatics Lab, School of Computer Science and Engineering, Nanyang Technological University, Singapore, 639798, Singapore.

Background: Cell fate regulation directly affects tissue homeostasis and human health. Research on cell fate decision sheds light on key regulators, facilitates understanding the mechanisms, and suggests novel strategies to treat human diseases that are related to abnormal cell development.

Results: In this study, we proposed a polynomial based model to predict cell fate. This model was derived from Taylor series. As a case study, gene expression data of pancreatic cells were adopted to test and verify the model. As numerous features (genes) are available, we employed two kinds of feature selection methods, i.e. correlation based and apoptosis pathway based. Then polynomials of different degrees were used to refine the cell fate prediction function. 10-fold cross-validation was carried out to evaluate the performance of our model. In addition, we analyzed the stability of the resultant cell fate prediction model by evaluating the ranges of the parameters, as well as assessing the variances of the predicted values at randomly selected points. Results show that, within both the two considered gene selection methods, the prediction accuracies of polynomials of different degrees show little differences. Interestingly, the linear polynomial (degree 1 polynomial) is more stable than others. When comparing the linear polynomials based on the two gene selection methods, it shows that although the accuracy of the linear polynomial that uses correlation analysis outcomes is a little higher (achieves 86.62%), the one within genes of the apoptosis pathway is much more stable.

Conclusions: Considering both the prediction accuracy and the stability of polynomial models of different degrees, the linear model is a preferred choice for cell fate prediction with gene expression data of pancreatic cells. The presented cell fate prediction model can be extended to other cells, which may be important for basic research as well as clinical study of cell development related diseases.
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http://dx.doi.org/10.1186/s12918-017-0502-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770079PMC
December 2017

Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations.

Sci Rep 2017 07 26;7(1):6595. Epub 2017 Jul 26.

Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.

Metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutations responds very well to first and second generation tyrosine-kinase inhibitors (TKI) including gefitinib, erlotinib and afatinib. Unfortunately, drug resistance will eventually develop and about half of the cases are secondary to the emergence of acquired T790M somatic mutation. In this work, we prospectively recruited 68 patients with metastatic EGFR-mutated NSCLC who have developed progressive disease after first-line TKI with or without subsequent TKI and/or other systemic therapy. Liquid biopsy after progression to their last line of systemic therapy were taken for detection of acquired T790M mutation. By performing attribute ranking we found that several attributes, including the initial EGFR mutational type, had a high correlation with the presence of acquired T790M mutation. We also conducted computational studies and discovered that the EGFR mutation delE746_A750 had a lower stability around the residue T790 than delS752_I759 and L858R, which was consistent with our clinical observation that patients with delE746_A750 were more likely to acquire T790M mutation than those with delS752_I759 or L858R. Our results provided new insight to future direction of research on investigating the mechanisms of acquired T790M mutation, which is essential to the development of novel mutation-specific TKIs.
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http://dx.doi.org/10.1038/s41598-017-06632-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529360PMC
July 2017

Identifying EGFR mutation-induced drug resistance based on alpha shape model analysis of the dynamics.

Proteome Sci 2016 8;14(1):12. Epub 2016 Sep 8.

Department of Electronic Engineering, City University of Hong Kong, 83 Tat Chee Avenue, Kowloon, Hong Kong.

Background: Epidermal growth factor receptor (EGFR) mutation-induced drug resistance is a difficult problem in lung cancer treatment. Studying the molecular mechanisms of drug resistance can help to develop corresponding treatment strategies and benefit new drug design.

Methods: In this study, Rosetta was employed to model the EGFR mutant structures. Then Amber was carried out to conduct molecular dynamics (MD) simulation. Afterwards, we used Computational Geometry Algorithms Library (CGAL) to compute the alpha shape model of the mutants.

Results: We analyzed the EGFR mutation-induced drug resistance based on the motion trajectories obtained from MD simulation. We computed alpha shape model of all the trajectory frames for each mutation type. Solid angle was used to characterize the curvature of the atoms at the drug binding site. We measured the knob level of the drug binding pocket of each mutant from two ways and analyzed its relationship with the drug response level. Results show that 90 % of the mutants can be grouped correctly by setting a certain knob level threshold.

Conclusions: There is a strong correlation between the geometric properties of the drug binding pocket of the EGFR mutants and the corresponding drug responses, which can be used to predict the response of a new EGFR mutant to a drug molecule.
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http://dx.doi.org/10.1186/s12953-016-0102-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5015241PMC
September 2016

An Eigen-Binding Site Based Method for the Analysis of Anti-EGFR Drug Resistance in Lung Cancer Treatment.

IEEE/ACM Trans Comput Biol Bioinform 2017 Sep-Oct;14(5):1187-1194. Epub 2016 May 12.

We explore the drug resistance mechanism in non-small cell lung cancer treatment by characterizing the drug-binding site of a protein mutant based on local surface and energy features. These features are transformed to an eigen-binding site space and used for drug resistance level prediction and analysis.
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http://dx.doi.org/10.1109/TCBB.2016.2568184DOI Listing
May 2018

Selectivity profile of afatinib for EGFR-mutated non-small-cell lung cancer.

Mol Biosyst 2016 04;12(5):1552-63

Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.

EGFR-mutated non-small-cell lung cancer (NSCLC) has long been a research focus in lung cancer studies. Besides reversible tyrosine kinase inhibitors (TKIs), new-generation irreversible inhibitors, such as afatinib, embark on playing an important role in NSCLC treatment. To achieve an optimal application of these inhibitors, the correlation between the EGFR mutation status and the potency of such an inhibitor should be decoded. In this study, the correlation was profiled for afatinib, based on a cohort of patients with the EGFR-mutated NSCLC. Relying on extracted DNAs from the paraffin-embedded tumor samples, EGFR mutations were detected by direct sequencing. Progression-free survival (PFS) and the response level were recorded as study endpoints. These PFS and response values were analyzed and correlated to different mutation types, implying a higher potency of afatinib to classic activation mutations (L858R and deletion 19) and a lower one to T790M-related mutations. To further bridge the mutation status with afatinib-related response or PFS, we conducted a computational study to estimate the binding affinity in a mutant-afatinib system, based on molecular structural modeling and dynamics simulations. The derived binding affinities were well in accordance with the clinical response or PFS values. At last, these computational binding affinities were successfully mapped to the patient response or PFS according to linear models. Consequently, a detailed mutation-response or mutation-PFS profile was drafted for afatinib, implying the selective nature of afatinib to various EGFR mutants and further encouraging the design of specialized therapies or innovative drugs.
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http://dx.doi.org/10.1039/c6mb00038jDOI Listing
April 2016

Contribution of EGFR and ErbB-3 Heterodimerization to the EGFR Mutation-Induced Gefitinib- and Erlotinib-Resistance in Non-Small-Cell Lung Carcinoma Treatments.

PLoS One 2015 20;10(5):e0128360. Epub 2015 May 20.

Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong.

EGFR mutation-induced drug resistance has become a major threat to the treatment of non-small-cell lung carcinoma. Essentially, the resistance mechanism involves modifications of the intracellular signaling pathways. In our work, we separately investigated the EGFR and ErbB-3 heterodimerization, regarded as the origin of intracellular signaling pathways. On one hand, we combined the molecular interaction in EGFR heterodimerization with that between the EGFR tyrosine kinase and its inhibitor. For 168 clinical subjects, we characterized their corresponding EGFR mutations using molecular interactions, with three potential dimerization partners (ErbB-2, IGF-1R and c-Met) of EGFR and two of its small molecule inhibitors (gefitinib and erlotinib). Based on molecular dynamics simulations and structural analysis, we modeled these mutant-partner or mutant-inhibitor interactions using binding free energy and its components. As a consequence, the mutant-partner interactions are amplified for mutants L858R and L858R_T790M, compared to the wild type EGFR. Mutant delL747_P753insS represents the largest difference between the mutant-IGF-1R interaction and the mutant-inhibitor interaction, which explains the shorter progression-free survival of an inhibitor to this mutant type. Besides, feature sets including different energy components were constructed, and efficient regression trees were applied to map these features to the progression-free survival of an inhibitor. On the other hand, we comparably examined the interactions between ErbB-3 and its partners (EGFR mutants, IGF-1R, ErbB-2 and c-Met). Compared to others, c-Met shows a remarkably-strong binding with ErbB-3, implying its significant role in regulating ErbB-3 signaling. Moreover, EGFR mutants corresponding to poor clinical outcomes, such as L858R_T790M, possess lower binding affinities with ErbB-3 than c-Met does. This may promote the communication between ErbB-3 and c-Met in these cancer cells. The analysis verified the important contribution of IGF-1R or c-Met in the drug resistance mechanism developed in lung cancer treatments, which may bring many benefits to specialized therapy design and innovative drug discovery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128360PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439022PMC
April 2016

EGFR Mutant Structural Database: computationally predicted 3D structures and the corresponding binding free energies with gefitinib and erlotinib.

BMC Bioinformatics 2015 Mar 14;16:85. Epub 2015 Mar 14.

Li Ka Sing Faculty of Medicne, University of Hong Kong, Pokfulam, Hong Kong.

Background: Epidermal growth factor receptor (EGFR) mutation-induced drug resistance has caused great difficulties in the treatment of non-small-cell lung cancer (NSCLC). However, structural information is available for just a few EGFR mutants. In this study, we created an EGFR Mutant Structural Database (freely available at http://bcc.ee.cityu.edu.hk/data/EGFR.html ), including the 3D EGFR mutant structures and their corresponding binding free energies with two commonly used inhibitors (gefitinib and erlotinib).

Results: We collected the information of 942 NSCLC patients belonging to 112 mutation types. These mutation types are divided into five groups (insertion, deletion, duplication, modification and substitution), and substitution accounts for 61.61% of the mutation types and 54.14% of all the patients. Among all the 942 patients, 388 cases experienced a mutation at residue site 858 with leucine replaced by arginine (L858R), making it the most common mutation type. Moreover, 36 (32.14%) mutation types occur at exon 19, and 419 (44.48%) patients carried a mutation at exon 21. In this study, we predicted the EGFR mutant structures using Rosetta with the collected mutation types. In addition, Amber was employed to refine the structures followed by calculating the binding free energies of mutant-drug complexes.

Conclusions: The EGFR Mutant Structural Database provides resources of 3D structures and the binding affinity with inhibitors, which can be used by other researchers to study NSCLC further and by medical doctors as reference for NSCLC treatment.
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http://dx.doi.org/10.1186/s12859-015-0522-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364680PMC
March 2015

Decoding the EGFR mutation-induced drug resistance in lung cancer treatment by local surface geometric properties.

Comput Biol Med 2015 Aug 28;63:293-300. Epub 2014 Jun 28.

Department of Electronic Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.

Epidermal growth factor receptor (EGFR) mutation-induced drug resistance leads to a limited efficacy of tyrosine kinase inhibitors during lung cancer treatments. In this study, we explore the correlations between the local surface geometric properties of EGFR mutants and the progression-free survival (PFS). The geometric properties include local surface changes (four types) of the EGFR mutants compared with the wild-type EGFR, and the convex degrees of these local surfaces. Our analysis results show that the Spearman׳s rank correlation coefficients between the PFS and three types of local surface properties are all greater than 0.6 with small P-values, implying a high significance. Moreover, the number of atoms with solid angles in the ranges of [0.71, 1], [0.61, 1] or [0.5, 1], indicating the convex degree of a local EGFR surface, also shows a strong correlation with the PFS. Overall, these characteristics can be efficiently applied to the prediction of drug resistance in lung cancer treatments, and easily extended to other cancer treatments.
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http://dx.doi.org/10.1016/j.compbiomed.2014.06.016DOI Listing
August 2015
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