Target immune components to circumvent sorafenib resistance in hepatocellular carcinoma.

[1]  J. Eun,et al.  Cancer‐associated fibroblast‐derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib , 2023, Cancer communications.

[2]  Shudong Wang,et al.  Midkine inhibition enhances anti-PD-1 immunotherapy in sorafenib-treated hepatocellular carcinoma via preventing immunosuppressive MDSCs infiltration , 2023, Cell Death Discovery.

[3]  Rui Xu,et al.  Repolarization of macrophages to improve sorafenib sensitivity for combination cancer therapy. , 2023, Acta biomaterialia.

[4]  Xinning Zhang,et al.  Sorafenib inhibits interferon production by plasmacytoid dendritic cells in hepatocellular carcinoma , 2022, BMC Cancer.

[5]  C. Yen,et al.  Tumor-associated macrophages promote resistance of hepatocellular carcinoma cells against sorafenib by activating CXCR2 signaling , 2022, Journal of Biomedical Science.

[6]  Q. Zhan,et al.  Liver tumour immune microenvironment subtypes and neutrophil heterogeneity , 2022, Nature.

[7]  Yan Zhang,et al.  Using mouse liver cancer models based on somatic genome editing to predict immune checkpoint inhibitor responses. , 2022, Journal of hepatology.

[8]  Hai-Liang Li,et al.  Prospective study of TACE combined with sorafenib vs TACE combined with 125I seed implantation in the treatment of hepatocellular carcinoma with portal vein tumor thrombus and arterioportal fistulas , 2022, Frontiers in Oncology.

[9]  Oliver J. Klein,et al.  Enhancing therapeutic anti-cancer responses by combining immune checkpoint and tyrosine kinase inhibition , 2022, Molecular Cancer.

[10]  Kongming Wu,et al.  Myeloid-derived suppressor cells: an emerging target for anticancer immunotherapy , 2022, Molecular Cancer.

[11]  Haiqing Wang,et al.  Efficacy and safety of transarterial chemoembolization combining sorafenib with or without immune checkpoint inhibitors in previously treated patients with advanced hepatocellular carcinoma: A propensity score matching analysis , 2022, Frontiers in Oncology.

[12]  Lin Zhao,et al.  The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies , 2022, Molecular Cancer.

[13]  Ching-Sheng Hsu,et al.  Therapeutic efficacy of nivolumab plus sorafenib therapy in patients with unresectable hepatocellular carcinoma. , 2022, International immunopharmacology.

[14]  P. Allavena,et al.  Macrophages as tools and targets in cancer therapy , 2022, Nature Reviews Drug Discovery.

[15]  Zhenwei Song,et al.  Sorafenib combined with STAT3 knockdown triggers ER stress-induced HCC apoptosis and cGAS-STING-mediated anti-tumor immunity. , 2022, Cancer letters.

[16]  V. Boussiotis,et al.  The complex role of tumor-infiltrating macrophages , 2022, Nature Immunology.

[17]  H. Reeves,et al.  Sulfatase-2 from Cancer Associated Fibroblasts: An Environmental Target for Hepatocellular Carcinoma? , 2022, Liver Cancer.

[18]  Xiaohe Tian,et al.  Tumor-associated neutrophils and neutrophil-targeted cancer therapies. , 2022, Biochimica et biophysica acta. Reviews on cancer.

[19]  P. Sharma,et al.  Myeloid cell-targeted therapies for solid tumours , 2022, Nature Reviews Immunology.

[20]  Wei Liu,et al.  CAF‐derived exosomes transmitted Gremlin‐1 promotes cancer progression and decreases the sensitivity of hepatoma cells to sorafenib , 2022, Molecular carcinogenesis.

[21]  A. Narang,et al.  CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma , 2022, The Journal of experimental medicine.

[22]  J. Qin,et al.  Efficacy of Sorafenib Combined With Immunotherapy Following Transarterial Chemoembolization for Advanced Hepatocellular Carcinoma: A Propensity Score Analysis , 2022, Frontiers in Oncology.

[23]  Yantong Lu,et al.  Myeloid-derived suppressor cells promote tumor growth and sorafenib resistance by inducing FGF1 upregulation and fibrosis , 2022, Neoplasia.

[24]  P. Saw,et al.  Targeting CAFs to overcome anticancer therapeutic resistance. , 2022, Trends in cancer.

[25]  M. Baretti,et al.  Expanding the immunotherapy roadmap for hepatocellular carcinoma. , 2022, Cancer cell.

[26]  Zhiguang Zhou,et al.  Identification of Sorafenib as a Treatment for Type 1 Diabetes , 2022, Frontiers in Immunology.

[27]  H. Reeves,et al.  Neutrophils as potential therapeutic targets in hepatocellular carcinoma , 2022, Nature Reviews Gastroenterology & Hepatology.

[28]  Y. Chao,et al.  Anti-PD-1 combined sorafenib versus anti-PD-1 alone in the treatment of advanced hepatocellular cell carcinoma: a propensity score-matching study , 2022, BMC cancer.

[29]  Zhiqiang Yu,et al.  CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment , 2022, Bioactive materials.

[30]  OUP accepted manuscript , 2022, Journal of the National Cancer Institute.

[31]  M. Kudo,et al.  Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. , 2021, The Lancet. Oncology.

[32]  J. Bruix,et al.  First-Line Immune Checkpoint Inhibitor-Based Sequential Therapies for Advanced Hepatocellular Carcinoma: Rationale for Future Trials , 2021, Liver Cancer.

[33]  Lu Zheng,et al.  Camrelizumab Plus Sorafenib Versus Sorafenib Monotherapy for Advanced Hepatocellular Carcinoma: A Retrospective Analysis , 2021, Frontiers in Oncology.

[34]  D. Gabrilovich,et al.  Myeloid-Derived Suppressor Cells: A Propitious Road to Clinic. , 2021, Cancer discovery.

[35]  K. Lu,et al.  Induction of IL-6Rα by ATF3 enhances IL-6 mediated sorafenib and regorafenib resistance in hepatocellular carcinoma. , 2021, Cancer letters.

[36]  K. Man,et al.  FSTL1 Secreted by Activated Fibroblasts Promotes Hepatocellular Carcinoma Metastasis and Stemness , 2021, Cancer Research.

[37]  R. Kalluri,et al.  Clinical and therapeutic relevance of cancer-associated fibroblasts , 2021, Nature Reviews Clinical Oncology.

[38]  Jun‐liang Fu,et al.  Intratumoral stem-like CCR4+ regulatory T cells orchestrate the immunosuppressive microenvironment in HCC associated with hepatitis B. , 2021, Journal of hepatology.

[39]  Joseph Mugaanyi,et al.  Therapeutic effectiveness and safety of sintilimab-dominated triple therapy in unresectable hepatocellular carcinoma , 2021, Scientific Reports.

[40]  Y. Morine,et al.  The BAFF/NFκB axis is crucial to interactions between sorafenib‐resistant HCC cells and cancer‐associated fibroblasts , 2021, Cancer science.

[41]  Jiasheng Tu,et al.  Time-Programmed Delivery of Sorafenib and Anti-CD47 Antibody via a Double-Layer-Gel Matrix for Postsurgical Treatment of Breast Cancer , 2021, Nano-micro letters.

[42]  A. Regev,et al.  TIM-3 restrains anti-tumour immunity by regulating inflammasome activation , 2021, Nature.

[43]  H. Hoe,et al.  Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice , 2021, Frontiers in Immunology.

[44]  Jen‐Shin Song,et al.  A highly selective and potent CXCR4 antagonist for hepatocellular carcinoma treatment , 2021, Proceedings of the National Academy of Sciences.

[45]  K. Shirabe,et al.  Conophylline Inhibits Hepatocellular Carcinoma by Inhibiting Activated Cancer-associated Fibroblasts Through Suppression of G Protein–coupled Receptor 68 , 2021, Molecular Cancer Therapeutics.

[46]  P. Allavena,et al.  Tumor-associated myeloid cells: diversity and therapeutic targeting , 2021, Cellular & Molecular Immunology.

[47]  C. Glass,et al.  Monocyte Regulation in Homeostasis and Malignancy. , 2021, Trends in immunology.

[48]  Q. Xue,et al.  GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis , 2020, Cell Death & Disease.

[49]  L. Qin,et al.  IFN-α facilitates the effect of sorafenib via shifting the M2-like polarization of TAM in hepatocellular carcinoma. , 2021, American journal of translational research.

[50]  É. Vivier,et al.  Tumor-Infiltrating Natural Killer Cells. , 2020, Cancer discovery.

[51]  Jefte M. Drijvers,et al.  Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity , 2020, Cell.

[52]  B. Goh,et al.  The pleiotropic role of transcription factor STAT3 in oncogenesis and its targeting through natural products for cancer prevention and therapy , 2020, Medicinal research reviews.

[53]  C. Porta,et al.  An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma , 2020, Cancers.

[54]  Tianqi Wang,et al.  Nanoparticle-Loaded Polarized-Macrophages for Enhanced Tumor Targeting and Cell-Chemotherapy , 2020, Nano-Micro Letters.

[55]  Meng Li,et al.  Cancer-Associated Fibroblasts Provide a Stromal Niche for Liver Cancer Organoids That Confers Trophic Effects and Therapy Resistance , 2020, Cellular and molecular gastroenterology and hepatology.

[56]  Shuhua Wei,et al.  Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects , 2020, Molecular Cancer.

[57]  Hongbing Shen,et al.  Cancer-associated fibroblasts enhance the chemoresistance of CD73+ hepatocellular carcinoma cancer cells via HGF-Met-ERK1/2 pathway. , 2020, Annals of translational medicine.

[58]  M. Merad,et al.  PD-L1 expression by dendritic cells is a key regulator of T-cell immunity in cancer , 2020, Nature Cancer.

[59]  E. D. De Toni,et al.  The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects , 2020, Signal Transduction and Targeted Therapy.

[60]  Zhang Cheng,et al.  New insights on sorafenib resistance in liver cancer with correlation of individualized therapy. , 2020, Biochimica et biophysica acta. Reviews on cancer.

[61]  Yulei N. Wang,et al.  Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. , 2020, The New England journal of medicine.

[62]  Yibin Wang,et al.  Low-Dose Sorafenib Acts as a Mitochondrial Uncoupler and Ameliorates Nonalcoholic Steatohepatitis. , 2020, Cell metabolism.

[63]  Lin Qiu,et al.  Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib , 2020, Journal for ImmunoTherapy of Cancer.

[64]  X. Jia,et al.  CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis , 2020, Molecular Cancer.

[65]  D. Fan,et al.  Sorafenib may enhance antitumour efficacy in hepatocellular carcinoma patients by modulating the proportions and functions of natural killer cells , 2019, Investigational New Drugs.

[66]  M. Kudo,et al.  Randomised, multicentre prospective trial of transarterial chemoembolisation (TACE) plus sorafenib as compared with TACE alone in patients with hepatocellular carcinoma: TACTICS trial , 2019, Gut.

[67]  W. Wen,et al.  Targeting adenosinergic pathway enhances the anti-tumor efficacy of sorafenib in hepatocellular carcinoma , 2019, Hepatology International.

[68]  F. Kiessling,et al.  Sorafenib Induces Pyroptosis in Macrophages and Triggers Natural Killer Cell–Mediated Cytotoxicity Against Hepatocellular Carcinoma , 2019, Hepatology.

[69]  I. Melero,et al.  Dendritic cells in cancer immunology and immunotherapy , 2019, Nature Reviews Immunology.

[70]  L. Xue,et al.  Sorafenib attenuated the function of natural killer cells infiltrated in HCC through inhibiting ERK1/2. , 2019, International immunopharmacology.

[71]  B. Shi,et al.  Combined Antitumor Effects of Sorafenib and GPC3-CAR T Cells in Mouse Models of Hepatocellular Carcinoma. , 2019, Molecular therapy : the journal of the American Society of Gene Therapy.

[72]  L. Jia,et al.  Co-delivery of sorafenib and metapristone encapsulated by CXCR4-targeted PLGA-PEG nanoparticles overcomes hepatocellular carcinoma resistance to sorafenib , 2019, Journal of experimental & clinical cancer research : CR.

[73]  Suihai Wang,et al.  M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma , 2019, British Journal of Cancer.

[74]  Fang,et al.  Fatty acid transporter 2 reprograms neutrophils in cancer Fatty acid transporter 2 reprograms neutrophils in cancer , 2020 .

[75]  Jiajun Xie,et al.  CD24 targeting bi-specific antibody that simultaneously stimulates NKG2D enhances the efficacy of cancer immunotherapy , 2019, Journal of Cancer Research and Clinical Oncology.

[76]  Brian Ruffell,et al.  Macrophages as regulators of tumour immunity and immunotherapy , 2019, Nature Reviews Immunology.

[77]  Bingwei Sun,et al.  Neutrophil Suppresses Tumor Cell Proliferation via Fas /Fas Ligand Pathway Mediated Cell Cycle Arrested , 2018, International journal of biological sciences.

[78]  H. Einsele,et al.  Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose‐ and time‐dependent manner , 2018, Clinical and experimental immunology.

[79]  Chih-Hung Hsu,et al.  Targeting tumor‐infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma , 2018, International journal of cancer.

[80]  Li Xu,et al.  Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma , 2018, Oncoimmunology.

[81]  Yibo Qin,et al.  Dendritic Cells Pulsed with Exosomes in Combination with PD-1 Antibody Increase the Efficacy of Sorafenib in Hepatocellular Carcinoma Model12 , 2018, Translational oncology.

[82]  C. Lai,et al.  Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development , 2018, Theranostics.

[83]  I. Ng,et al.  Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma , 2017, Nature Communications.

[84]  Weidong Zhang,et al.  A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer , 2017, EBioMedicine.

[85]  Daniel M. Corey,et al.  PD-1 expression by tumor-associated macrophages inhibits phagocytosis and tumor immunity , 2017, Nature.

[86]  J. Xu,et al.  Vascular CXCR4 Expression Promotes Vessel Sprouting and Sensitivity to Sorafenib Treatment in Hepatocellular Carcinoma , 2017, Clinical Cancer Research.

[87]  S. Singhal,et al.  Mouse versus Human Neutrophils in Cancer: A Major Knowledge Gap. , 2017, Trends in cancer.

[88]  Shuang Huang,et al.  FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib , 2017, Journal of experimental & clinical cancer research : CR.

[89]  T. Kuijpers,et al.  Neutrophils in cancer , 2016, Immunological reviews.

[90]  K. Straif,et al.  Body Fatness and Cancer--Viewpoint of the IARC Working Group. , 2016, The New England journal of medicine.

[91]  F. Quintana,et al.  Regulation of the T Cell Response by CD39. , 2016, Trends in immunology.

[92]  Ya Cao,et al.  Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. , 2016, Gastroenterology.

[93]  D. Campana,et al.  Expanded and Activated Natural Killer Cells for Immunotherapy of Hepatocellular Carcinoma , 2016, Cancer Immunology Research.

[94]  Fan Wang,et al.  Inhibition of tumor growth and metastasis by photoimmunotherapy targeting tumor-associated macrophage in a sorafenib-resistant tumor model. , 2016, Biomaterials.

[95]  A. Rudensky,et al.  T cell receptor signalling in the control of regulatory T cell differentiation and function , 2016, Nature Reviews Immunology.

[96]  S. Yeh,et al.  Targeting Androgen Receptor (AR)→IL12A Signal Enhances Efficacy of Sorafenib plus NK Cells Immunotherapy to Better Suppress HCC Progression , 2016, Molecular Cancer Therapeutics.

[97]  A. Griffioen,et al.  Role of the tumor stroma in resistance to anti-angiogenic therapy. , 2016, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[98]  N. Hockstein,et al.  CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. , 2016, Immunity.

[99]  N. Ferrara,et al.  The Complex Role of Neutrophils in Tumor Angiogenesis and Metastasis , 2016, Cancer Immunology Research.

[100]  A. Krüger,et al.  The induction of human myeloid derived suppressor cells through hepatic stellate cells is dose-dependently inhibited by the tyrosine kinase inhibitors nilotinib, dasatinib and sorafenib, but not sunitinib , 2016, Cancer Immunology, Immunotherapy.

[101]  J. Llovet,et al.  Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma , 2015, Gut.

[102]  D. Gabrilovich,et al.  Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. , 2015, The Journal of clinical investigation.

[103]  Z. Granot,et al.  MET is required for the recruitment of anti-tumoural neutrophils , 2015, Nature.

[104]  R. Jain,et al.  CXCR4 inhibition in tumor microenvironment facilitates anti‐programmed death receptor‐1 immunotherapy in sorafenib‐treated hepatocellular carcinoma in mice , 2015, Hepatology.

[105]  P. Galle,et al.  Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion. , 2015, Journal of hepatology.

[106]  Z. Tian,et al.  NK cell receptor imbalance and NK cell dysfunction in HBV infection and hepatocellular carcinoma , 2014, Cellular and Molecular Immunology.

[107]  R. Paschke,et al.  Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial , 2014, The Lancet.

[108]  R. Jain,et al.  Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal‐derived factor 1 alpha/C‐X‐C receptor type 4 axis and myeloid differentiation antigen–positive myeloid cell infiltration in mice , 2014, Hepatology.

[109]  C. Strassburg,et al.  Improving immunotherapy of hepatocellular carcinoma (HCC) using dendritic cells (DC) engineered to express IL‐12 in vivo , 2014, Liver international : official journal of the International Association for the Study of the Liver.

[110]  Yun Lu,et al.  SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1α-dependent glycolysis. , 2014, Cancer research.

[111]  P. Carmeliet,et al.  Tumor hypoxia does not drive differentiation of tumor-associated macrophages but rather fine-tunes the M2-like macrophage population. , 2014, Cancer research.

[112]  L. Levy,et al.  Tumor-associated neutrophils (TAN) develop pro-tumorigenic properties during tumor progression , 2013, Cancer Immunology, Immunotherapy.

[113]  M. van Egmond,et al.  Neutrophils as effector cells for antibody-based immunotherapy of cancer. , 2013, Seminars in cancer biology.

[114]  H. Friess,et al.  Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells , 2013, Hepatology.

[115]  Zhao-You Tang,et al.  Antiangiogenic therapy promoted metastasis of hepatocellular carcinoma by suppressing host-derived interleukin-12b in mouse models , 2013, Angiogenesis.

[116]  C. Wu,et al.  Sorafenib Induces Autophagy in Human Myeloid Dendritic Cells and Prolongs Survival of Skin Allografts , 2013, Transplantation.

[117]  Zhao-You Tang,et al.  Suppression of Natural Killer Cells by Sorafenib Contributes to Prometastatic Effects in Hepatocellular Carcinoma , 2013, PloS one.

[118]  C. Wu,et al.  Sorafenib induces autophagy and suppresses activation of human macrophage , 2013, International Immunopharmacology.

[119]  S. Lang,et al.  Neutrophils and granulocytic myeloid-derived suppressor cells: immunophenotyping, cell biology and clinical relevance in human oncology , 2012, Cancer Immunology, Immunotherapy.

[120]  D. Gabrilovich,et al.  Coordinated regulation of myeloid cells by tumours , 2012, Nature Reviews Immunology.

[121]  W. Oyen,et al.  Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients , 2011, International journal of cancer.

[122]  E. Thiel,et al.  Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell carcinoma. , 2011, European journal of cancer.

[123]  Zhao-You Tang,et al.  Depletion of Tumor-Associated Macrophages Enhances the Effect of Sorafenib in Metastatic Liver Cancer Models by Antimetastatic and Antiangiogenic Effects , 2010, Clinical Cancer Research.

[124]  I. Melero,et al.  Influence of bevacizumab, sunitinib and sorafenib as single agents or in combination on the inhibitory effects of VEGF on human dendritic cell differentiation from monocytes , 2009, British Journal of Cancer.

[125]  Yoon-Koo Kang,et al.  Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. , 2009, The Lancet. Oncology.

[126]  Dieter Häussinger,et al.  Sorafenib in advanced hepatocellular carcinoma. , 2008, The New England journal of medicine.

[127]  P. Brossart,et al.  Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses. , 2008, Blood.

[128]  F. Peale,et al.  Bv8 regulates myeloid-cell-dependent tumour angiogenesis , 2007, Nature.

[129]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[130]  D. Auclair,et al.  BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis , 2004, Cancer Research.

[131]  Shigeyoshi Itohara,et al.  Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis , 2000, Nature Cell Biology.

[132]  J. El Benna,et al.  Intracellular pool of vascular endothelial growth factor in human neutrophils. , 1997, Blood.