Loma Linda University

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Chien-Shing Chen, MD, PhD
Head, Medicine, Hematology/Oncology Division
School of Medicine
Professor, Medicine
School of Medicine
Professor, Basic Sciences
School of Medicine
Publications    Scholarly Journals--Submitted
  • Tan J, Yang X, Jiang X, Zhou J, Li Z, Lee PL, Aau M, Luo W, Liu SC, Wang J, Ong CT, Hooi SC, Chen CS, Li B, Wei CL5, Liu ET, Robson P, Ruan Y, and Yu Q. Epigenome analysis identifies differentiation regulator HAND1 as a tumor suppressor in colon cancer and is inactivated by both DNA and histone methylations.   Journal of Clinical Investigation, Submitted. ( 9/2009 - 9/2010 )
  Scholarly Journals--Published
  • Rodriguez JP, Murphy MP, Hong S, Madrigal M, March KL, Minev B, Harman RJ, Chen CS, Timmons RB, Marleau AM and Riordan NH.   Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety. International Archives of Medicine 2012, 5:5   doi:10.1186/1755-7682-5-5

    ( 4/2012 )
  • Zhou J, Bi C, Chng W-J*, Cheong LL, Liu S-C, Mahara S, Tay K-G, Zeng Q, Li J, Guo K, Tan CPB, Yu H, Albert D, Chen CS*.  PRL-3, a metastasis associated tyrosine phosphatase, is involved in FLT3-ITD signaling and implicated in anti-AML therapy.  PLoS ONE 2011, 6(5): e19798. doi:10.1371/journal.pone.0019798. [*: Corresponding authors] (I.F. 4.411) (Evaluated by Faculty of 1000 and received FFa 8, Must Read)

    ( 4/2012 )
  • Berenson JR, Yellin O, Kazamel T, Hilger JD,  Chen CS, Cartmell A,  Woliver T, Flam M, Bravin E, Nassir Y,  Vescio R, Swift RA.  A Phase 2 Study of Pegylated Liposomal Doxorubicin, Bortezomib, Dexamethasone, and Lenalidomide for Patients with Relapsed/Refractory Multiple Myeloma.  Accepted for publication in Leukemia, 2012.

    ( 4/2012 )
  • Xie Z, Bi C, Cheong LL, Liu SC, Huang G, Zhou J, Yu Q, Chen CS, Chng WJ. Determinants of sensitivity to DZNep induced apoptosis in multiple myeloma cells. PLoS ONE 2011, 6(6):e21583. (I.F. 4.411)

    ( 4/2012 )
  • Lee ZW, Zhou J, Chen CS, Zhao Y, Tan CH, Li L, Moore PK, Deng LW. The slow-releasing hydrogen sulfide donor, GYY4137, exhibits novel anti-cancer effects in vitro and in vivo. PLoS ONE 2011, 6(6): e21077.

    ( 4/2012 )
  • Xiong L, Darwanto A, Sharma S, Herring J, Hu S, Filippova M, Filippov V, Wang Y, Chen CS, Duerksen-Hughes PJ, Sowers LC and Zhang K. Mass spectrometric studies on epigenetic interaction networks in cell differentiation. Journal of Biological Chemistry.  First Published on February 18, 2011, doi: 10.1074/jbc.M110.204800.

    ( 4/2012 )
  • Ichim TE, Minev B, Braciak T, Luna B, Hunninghake R, Mikirova NA, Jackson JA, Gonzalez MJ, Massari JRM, Alexandrescu DT, Dasanu C, Bogin V, Ancans J, Stevens RB, Markosian B, Koropatnick J, Chen CS and Riordan NH. Intravenous Ascorbic Acid to Prevent and Treat Cancer-Associated Sepsis? Journal of Translational Medicine, 9:25, 2011.


    ( 4/2012 )
  • Kraft AS, Garrett-Mayer E, Wahlquist AE, Golshayan A, Chen CS, Butler W, Bearden J, and Lilly M.  Combination therapy of recurrent prostate cancer with the proteasome inhibitor Bortezomib plus hormone blockade.  Cancer Biology and Therapy. July 15; 12(2), 2011. [Epub ahead of print].


    ( 4/2012 )
  • Raja M. A., Xu S., Tai D.C.S , Sun W., Zhou J., Chen C.S., Rajapakse J.C., So P.T.C., Yu H. Pulse Modulated Second Harmonic Imaging Microscope (PM-SHIM) imaging quantitatively demonstrates marked increase of collagen in tumor after chemotherapy. J Biomed Opt. 2010 Sep-Oct;15(5):056016. (I.F. 2.87)


    ( 4/2012 )
  • Xie Z, Chng WJ, Tay KG, Liu SC,  Zhou J , Chen CS*.Therapeutic potential of antisense oligodeoxynucleotides in downregulating p53 oncogenic mutations in cancers.  Biotechnology Letters, 33:221–228, 2011. [*: Corresponding author]


    ( 4/2012 )
  • Tai Dean CS, Tan N, Xu S, Kang CH, Chia SM, Cheng CL, Wee A, Wei CL, Mythreyi Raja A, Xiao G, Chang S, Rajapakse JC, So Peter TC , Tang HH, Chen CS, Yu H. “Fibro-C-Index: comprehensive, morphology-based quantification of liver fibrosis using second harmonic generation and two-photon microscopy” Journal of Biomedical Optics Vol. 14, 044013, 1-10, Jul 27, 2009.


    ( 4/2012 )
  • Bautista M, Stevens WT, Chen CS, Curtis B, Aster R, Hsueh CT. Hypersensitivity Reaction and Acute Immune-mediated Thrombocytopenia from Oxaliplatin: Report of Two Cases and Review of Literature. Journal of Hematology & Oncology 3:12, 2010. http://www.jhoonline.org/content/3/1/12

    ( 3/2010 - 3/2012 )
  • Zhou J, Bi C, Janakakumara JV, Liu S-C, Tay K-G, Poon L-F, Xie Z, Palaniyandi S, Yu H, Wee-Joo Chng W-J, Glaser K, Albert D, Davidsen S, Chen CS.  Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML.  Blood, 113:4052-4062, 2009. [*: Corresponding author] [Paper highlighted on the cover and Blood editorial: Briesewitz R. Fathoming Flt3. 2009 113: 3889-3890] (I.F. 10.558)

    ( 1/2009 - 12/2010 )
  •  Wong CI, Koh TS, Soo R, Hartono S, Thng CH, McKeegan E, Yong WP, Chen CS, Lee SC, Wong J, Lim R, Sukri N, Lim SE, Ong AB, Steinberg J, Gupta N, Pradhan R, Humerickhouse R, and Goh BC. Phase I and biomarker study of ABT-869, a multiple receptor tyrosine kinase inhibitor, in patients with refractory solid malignancies. Journal of Clinical Oncology 2009 Aug 31, 2009:doi:10.1200/JCO.2008.21.7125.


    ( 1/2009 - 12/2010 )
  • Zhou J, Goh BC, Albert D, Chen CS. ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside. Journal of Hematology & Oncology 2009, 2:33 doi:10.1186/1756-8722-2-33


    ( 9/2009 - 9/2010 )
  • Li Ching Lee, Chien-Shing Chen, Pei Feng Choong, Adrian Fatt-Hoe Low, Huay Cheem Tan, Kian Keong Poh.  Time-dependent Dynamic Mobilization of Circulating Progenitor Cells during Percutaneous Coronary Intervention in Diabetics.  International Journal of Cardiology 2009, doi:10.1016/j.ijcard. 2008.11.198.


    ( 1/2009 - 1/2010 )
  • Zhou J, Pan M, Loh S, Xie Z, Lim Y, Lilly MB, Han JH, Glaser K, Albert D, Davidsen S, Chen CS.  Synergistic antileukemic effects between ABT-869 and chemotherapy involve downregulation of cell cycle regulated genes and c-Mos-mediated MAPK pathway.  Leukemia  2008;22:138-46. Epub 2007 Oct 18 ( 1/2008 - 12/2009 )
  • Zhou J B, Bi C L, Janakakumara J V, Liu S C, Chng W J, . . . Chen C S. (2009). Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood, 113(17), 4052-4062. ( 4/2009 ) Link...
    To further investigate potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R. Gene profiling reveals up-regulation of FLT3LG (FLT3 ligand) and BIRC5 (survivin), but down-regulation of SOCS1, SOCS2, and SOCS3 in MV4-11-R cells. Hypermethylation of these SOCS genes leads to their transcriptional silencing. Survivin is directly regulated by STAT3. Stimulation of the parental MV4-11 cells with FLT3 ligand increases the expression of survivin and phosphorylated protein STAT1, STAT3, STAT5. Targeting survivin by short-hairpin RNA (shRNA) in MV4-11-R cells induces apoptosis and augments ABT-869-mediated cytotoxicity. Overexpression of survivin protects MV4-11 from apoptosis. Sub-toxic dose of indirubin derivative (IDR) E804 resensitizes MV4-11-R to ABT-869 treatment by inhibiting STAT signaling activity and abolishing survivin expression. Combining IDR E804 with ABT-869 shows potent in vivo efficacy in the MV4-11-R xenograft model. Taken together, these results demonstrate that enhanced activation of STAT pathways and overexpression of survivin are important mechanisms of resistance to ABT-869, suggesting that the STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors. (Blood. 2009;113:4052-4062)
  • Xie Z, Choong PF, Poon L-F, Zhou J, Khng J, Janakakumara, JV, Palaniyandi S, Chen CS.  Inhibition of CD44 expression in hepatocellular carcinoma cells enhances apoptosis, chemosensitivity, and reduces tumorigenesis and invasion”  Cancer Chemotherapy and Pharmacology. 2008 Feb 8; [Epub ahead of print]

    ( 1/2008 - 1/2009 )
  • Zhou J, Janakakumara, JV, Bi C, Neo S, Pan M, Poon L-F, Xie Z, Yu H, Yeoh E-J, Lu Y, Glaser K, Albert D, Davidsen S, Chen CS.  In vivo activity of ABT-869, a multi-target kinase inhibitor, against acute myeloid leukemia with wild-type FLT3 receptor, Leuk Res. 32:1091–1100, 2008. ( 1/2008 - 1/2009 )
  • Janakakumara, JV, Xie Z, Zhou J, Khng J, Poon L-F, Palaniyandi S, Glaser KB, Albert DH, Davidsen SK, and Chen CS.  ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft. Journal of Hepatology, Dec;49(6):985-97.2008. [*: Corresponding authors]

    ( 1/2008 - 12/2008 )
  • Koh LP, Chen CS, Tai B-C, Hwang WYK, Tan LK, Ng HY, Linn YC, Koh MBC, Goh YT, Liu TC, Mow MF, Tan B, Ng HJ, Loh SM, Tan KW, Chuah TH, Tan CL, Tan HC.  Impact of Postgrafting Immunosuppressive Regimens on Nonrelapse Mortality and Survival after Nonmyeloablative Allogeneic Haematopoietic Stem Cell Transplant Using the Fludarabine and Low Dose Total Body Irradiation 2 Gy.  Biol Blood Marrow Transplant  13:790-805, 2007.


    ( 9/2007 - 9/2008 )
  • NG, Angela PP, Nin DS, Fong JH, Venkataraman D, Chen CS, and Khan M. Therapeutic targeting of nuclear receptor co-repressor (N-CoR) mis-folding in acute promyelocytic leukemia (APL) cells with genistein.  Molecular Cancer Therapeutic, Aug;6(8):2240-8, 2007. ( 1/2007 - 1/2008 )
  • Choong L-Y, Lim S, Marie Loh C-S, Xiaohui M, Chen Y, Toy W, Pan M, Chen, CS, Poonepalli A, Hande PM, Tan P-H, Salto-Tellez M, Wong C-Y, Shah N, Druker BJ and Lim YP.  Progressive loss of epidermal growth factor receptor in a subpopulation of breast cancers: implications in target-directed therapeutics. Mol Cancer Ther. 2007 Nov; 6(11):2828-42. Epub 2007 Nov 7. ( 1/2007 - 1/2008 )
  • Nash RA, McSweeney PA, Crofford LJ, Abidi M, Chen CS, Godwin D, Gooley TA, Holmberg L, Henstorf G, LeMaistre CF, Mayes MD, McDonagh KT, McLaughlin B, Molitor JA, Nelson JL, Shulman H, Storb R, Viganego F, Wener M, Seibold JR, Sullivan KM, Furst DE. High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation for Severe Systemic Sclerosis: U.S. Multi-center Pilot Study.  Blood 15;110(4):1388-96, 2007. ( 1/2007 - 1/2008 )
  • Shen J, Tai YC, Zhou J, Wong CHS, Cheang PTS, Wong WSF, Khan M, Han JH, Chen CS. Synergistic anti-leukemia effect of genistein and chemotherapy in mouse xenograft model and potential mechanism through MAPK signaling.  Exp Hematology, (35)1: 75-83, 2007.

    ( 1/2007 - 12/2007 )
  • Zhang DH, Tai YC, Wong CHS, Koay SC, Chen CS.  Deciphering the molecular response of leukemia HL-60 cells to genistein treatment by proteomics approach. Leukemia Research, 31(1): 75-82, 2007.

    ( 1/2007 - 12/2007 )
  • Zemskova M, Wechter W, Bashkirova S, Chen CS, Reiter R, Lilly MB.  Gene expression profiling in R-flurbiprofen-treated prostate cancer: R-Flurbiprofen regulates prostate stem cell antigen through activation of AKT kinase. Biochemical Pharmacology, 72(10),1257-1267, 2006. ( 1/2006 - 1/2007 )
  • NG, Angela PP, Howe FJ, Dawn NS, Hirpara JL, Asou N,  Chen CS, Pervaiz S and Khan M. Cleavage of Mis-folded N-CoR in APL Cell by a Glycoprotein Endopeptidase Confers Resistance to UPR-induced Apoptosis. Cancer Research, 66(20): 9903-12, 2006. ( 1/2006 - 12/2006 )
  • Lilenbaum RC, Chen CS, Chidiac T, Schwarzenberger PO, Thant M, Versola M, Lane SR. Phase II randomized trial of vinorelbine and gemcitabine versus carboplatin and paclitaxel in advanced non-small-cell lung cancer.  Ann Oncol. Jan;16(1):97-101, 2005. ( 1/2005 - 1/2006 )
  • Nash RA, Dansey R, Storek J, Georges GE, Bowen JD, Holmberg LA, Kraft GH, Mayes MD, McDonagh KT, Chen CS, DiPersio J, LeMaistre CF, Pavletic S, Sullivan KM, Sunderhaus J, Furst DE, McSweeney PA.  Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disorder After High-Dose Immunosuppressive Therapy And Autologous CD34-Selected Hematopoietic Stem Cell Transplantation For Severe Autoimmune Diseases. Biol Blood Marrow Transplant, 9:583-91, 2003. ( 1/2003 - 1/2004 )
  • Chen CS, Seidel K, Boeckh M, Clark J, Madtes D, Wagner J, witherspoon R, Anasetti C, Appelbaum FR, Bensinger W, Deeg HJ, Sanders JE, Storb R, Wade J, Siadak M, Flowers MED and Sullivan KM.  Incidence and risk factors for developing pneumonia late after autologous and allogeneic hematopoietic stem cell transplantation. Blood Marrow Transplant  32, 515-522, 2003. ( 1/2003 - 1/2004 )
  • McSweeney PA, Nash RA, Sullivan KM, Storek J, Crofford LJ, Dansey R, Mayes MD, McDonagh KT, Nelson JL, Gooley TA, Holmberg LA, Chen CS, Wener MH, Ryan K, Sunderhaus J, Russell K, Rambharose J, Storb R, Furst DE.  High-dose Immunosuppressive Therapy for Severe Systemic Sclerosis - Initial Outcomes. Blood  1;100(5):1602-10, 2002. ( 1/2002 - 1/2004 )
  • Sweetser DA, Chen CS, Flowers DA, Galipeau PC, Barrett MT, Heerema NA, Bernstein ID, and Reid BJ. Loss of heterozygosity (LOH) in childhood de novo acute myelogenous leukemia. Blood98:1188-1194, 2001. ( 1/2001 - 1/2003 )
  • Chen CS, Seidel K, Armitage JO, Fay JW, Appelbaum FR, Horowitz MM,     Shpall EJ, Weiden PL, Antman KS, Champlin RE, Kersey JH, and Sullivan KM.  “ Safeguarding the administration of high-dose chemotherapy: A national practice survey by the American Society for Blood and Marrow Transplantation.” Biol. Blood Marrow Transplant. 3:331-340, 1997. ( 1/1997 - 1/1999 )
  • Chen CS, Bejcek BE, Kersey JH. “A Mapping study of 13 genes on human chromosome bands 4q11-q25.” Cytogenet. cell Genet. 69:260-265, 1995. ( 1/1995 - 1/1996 )
  • Sorensen PHB, Chen CS, Smith, FO, Arthur DC, Domer PH, Bernstein ID, Korsmeyer SJ,  Hammond GD, Kersey JH. “ Molecular rearrangements of the MLL gene are present in most cases of infant Acute Myeloid Leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes.” J. Clin. Invest. 93:429-437, 1994. ( 1/1994 - 1/1996 )
  • Chen CS, Hilden JM, Frestedt J, Domer P, Moore R, Korsmeyer SJ, Kersey JH. “ The chromosome 4q21 gene (AF-4/FEL) is widely expressed in normal tissues and shows breakpoint diversity in t(4;11)(q21;q23) acute leukemia.” Blood 82:1080-1085, 1993. ( 1/1993 - 1/1995 )
  • Domer PH, Fakharzadeh SS, Chen CS, Jockel J, Johansen L, Silverman GA, Kersey JH, Korsmeyer SJ. “The acute mixed lineage leukemia associated t(4;11)(q21;q23) produces an MLL-AF-4 fusion transcript.” Proc NatlAcadSci USA 90:7884-7888, 1993. ( 1/1993 - 1/1995 )
  • Chen CS, Sorensen PHB, Domer PH, Reaman GH, Korsmeyer SJ, Heerema NA, Hammond GD, Kersey JH. “ Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome.” Blood 81:2386-2393, 1993. ( 1/1993 - 1/1995 )
  • Hilden JM, Chen CS, Moore R, Frestedt J, Kersey JH. “ Heterogeneity in MLL/AF-4 fusion messenger RNA detected by the polymerase chain reaction in t(4;11) acute leukemia.” Cancer Research 53: 3853-6, 1993. ( 1/1993 - 1/1994 )
  • Chen CS, Medberry PS, Arthur DC, and Kersey JH. “ Breakpoint clustering in t(4;11)(q21;q23) acute leukemia.”  Blood 78:2498-2504, 1991. ( 1/1991 - 1/1993 )
  • Berenson James, Yellin Ori, Shamasunder Hesaraghatta, Chen Chien-Shing, Charu Veena, . . . Vescio Robert. (2015). A phase 3 trial of armodafinil for the treatment of cancer-related fatigue for patients with multiple myeloma. Supportive Care in Cancer, 23(6), 1503-1512. ( 0/2015 - Present ) Link...
    Purpose: Fatigue is a common problem among multiple myeloma (MM) patients. Armodafinil is a drug known to promote wakefulness, which is related to modafinil, a compound that improves fatigue in some cancer patients treated with chemotherapeutic agents. We investigated whether armodafinil could reduce cancer-related fatigue in MM patients. Methods: This double-blind, placebo-controlled phase 3 trial evaluated the efficacy of armodafinil in MM patients with evidence of moderate fatigue. Patients were randomized to one of two arms: treatment-only, with armodafinil given at 150 mg/daily for 56 days, or placebo-first, with placebo given on days 1-28, followed by armodafinil administered at 150 mg daily on days 29-56. Fatigue was measured on days 1 (pre-dose: baseline), 15, 28, 43, and 56 using seven separate assessments, including four patient-reported outcomes of fatigue and related quality of life measures, as well as three objective measures of cognitive function. Results: Overall toxicities were similar between treatment groups. No significant differences were observed between the placebo-first and the treatment-only arms after 28 days. Treatment with armodafinil for 28 additional days did not produce responses. Both placebo-first and treatment-only patients showed similar significant improvements in three patient-reported measures and one objective task at day 28 compared to baseline. Placebo-first patients improved on eight additional measures (one patient-reported measure, six subscales, and one objective task), suggesting a strong placebo effect in this patient population. Conclusions: Evaluation and treatment of cancer-related fatigue continues to be challenging; a clear definition of this symptom and better assessment tools are needed. [ABSTRACT FROM AUTHOR] Copyright of Supportive Care in Cancer is the property of Springer Science & Business Media B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
  • Shouse Geoffrey P, de Necochea-Campion Rosalia, Mirshahidi Saied, Liu Xuan, & Chen Chien-Shing. (2014). Novel AML-Associated Loss of Function Mutations in the B55 Alpha Subunit of PP2A Are Associated with Increased Phosphorylation and Activation of AKT and Enhanced Sensitivity to AKT Inhibitor Induced Cell Growth Arrest. Blood, 124(21), . ( 12/2014 - Present )
  • Craig Michael, Hanna Wahid T, Cabanillas Fernando, Chen Chien-Shing, Esseltine Dixie-Lee, Neuwirth Rachel, & O'Connor Owen A. (2014). Phase II study of bortezomib in combination with rituximab, cyclophosphamide and prednisone with or without doxorubicin followed by rituximab maintenance in patients with relapsed or refractory follicular lymphoma. British Journal of Haematology, 166(6), 920-928. ( 9/2014 - Present ) Link...
    This non-comparative phase II study (ClinicalTrials.gov: NCT00715208) evaluated bortezomib in place of vincristine in established rituximab-chemotherapy regimens in relapsed/refractory follicular (FL) or marginal zone lymphoma (MZL). Patients were allocated (physician/patient preference) to receive six 21-d cycles of: bortezomib 1.6 mg/m(2) (days 1, 8), rituximab 375 mg/m(2) (day 1), cyclophosphamide 1000 mg/m(2) (day 1) and prednisone 100 mg (days 1-5; VR-CP; 47 FL, 1 MZL patients); or bortezomib, rituximab, prednisone per VR-CP, cyclophosphamide 750 mg/m(2) and doxorubicin 50 mg/m(2) (day 1; VR-CAP; 4 FL, 2 MZL, 1 chronic lymphocytic leukaemia patients). With VR-CP, the response rate was 77%, with a 27% complete response rate. After a median follow-up of 10.9 months, 40% of patients had relapsed/progressed or died. Median duration of response and progression-free survival was 21.9 and 14.9 months, respectively. Common drug-related grade >= 3 adverse events were neutropenia (25%), thrombocytopenia (6%) and lymphopenia (6%). Thirteen (27%) patients reported peripheral neuropathy (one grade 3). With VR-CAP, one FL patient achieved complete response and three FL and two MZL patients achieved partial responses. Three patients reported drug-related grade 1/2 peripheral neuropathy. Weekly bortezomib and rituximab represents an active, feasible treatment platform in FL. VR-CP was active and well tolerated in patients with relapsed/refractory FL.
  • Tang H, Mirshahidi S, Senthil M, Kazanjian K, Chen C S, & Zhang K. (2014). Down-regulation of LXR/RXR activation and negative acute phase response pathways in colon adenocarcinoma revealed by proteomics and bioinformatics analysis. Cancer Biomark, 14(5), 313-24. ( 0/2014 - Present ) Link...
    BACKGROUND AND OBJECTIVE: Deficiency of vitamin D could be a major cause of colon cancer as suggested as early as 1980 by Drs. Cedric and Frank Garland of the University of California and has recently been underscored by a large European case control study. Whether vitamin D deficiency is because of inadequate intake (food and sunshine) or because of vitamin D metabolism disorder in the patient body is unknown. A proteomics approach to identify protein pathways associated with vitamin D transportation and metabolism pathways will help us understand better the pathology of the colon cancer. METHODS: Lysates of colon adenocarcinoma tissues and their matched healthy tissues, from seven colon cancer patients, have been evaluated by quantitative proteomics and bioinformatics analysis to determine protein expression profiles. Unsupervised hierarchical clustering and principle component analysis (PCA) were utilized for protein expression profiling and biomarker identification, while the reporter ion ratios from tandem-mass-tagging (TMT) labeled peptides were used for quantification. Ingenuity Pathway Analysis (IPA) was used to analyze protein pathways. RESULTS AND CONCLUSION: Proteomics analyses demonstrated that the proteins involved in vitamin D/E binding, heme/iron binding and transportation, and lipid/steroid transportation/metabolic systems were down-regulated in colon cancer and the same set of proteins were down-regulated in the LXR/RXR activation and acute-phase response pathways, revealing a plausible mechanistic connection between vitamin D deficiency, iron homeostasis, and colon cancer.
  • Twardowski P W, Beumer J H, Chen C S, Kraft A S, Chatta G S, . . . Lilly M B. (2013). A phase II trial of dasatinib in patients with metastatic castration-resistant prostate cancer treated previously with chemotherapy. Anti-Cancer Drugs, 24(7), 743-753. ( 8/2013 - Present ) Link...
    There is a need for efficacious therapies for metastatic castration-resistant prostate cancer (mCRPC) after disease progression on docetaxel. The SRC tyrosine kinase and its related family members may be important drivers of prostate cancer and can be inhibited by dasatinib. mCRPC patients, after one previous chemotherapy, started dasatinib at 70 mg twice daily, amended to 100 mg daily. The primary endpoint was the disease control (DC) rate, defined as complete response (CR), partial response (PR), or stable disease (SD) in prostate specific antigen (PSA), RECIST, bone scan, and FACT-P score. Up to 41 patients were to be accrued (two-stage design, 21+20) to rule out a null-hypothesized effect of 5 versus 20% (=0.05, =0.1). Secondary endpoints included progression-free survival, toxicity, and pharmacokinetic and pharmacodynamic correlatives. Of 38 patients, 27 were evaluable for response or toxicity. The median duration of therapy was 55 days (6-284). Five patients showed DC after 8 weeks of therapy (18.5% DC, 95% CI: 6.3-38.1%). One PR (3.7% response rate, 95% CI: 0.1-19.0%) was observed in a patient treated for 284 days. Twelve patients (43%) discontinued treatment for toxicity. Dasatinib induced a decrease in phytohemagglutinin-stimulated CSF2, CD40L, GZMB, and IL-2 mRNAs in blood cells, indicating target engagement. Decreases in plasma IL-6 and bone alkaline phosphatase, and in urinary N-telopeptide, were associated with DC. Dasatinib has definite but limited activity in advanced mCRPC, and was poorly tolerated. The observation of a patient with prolonged, objective, clinically significant benefit warrants molecular profiling to select the appropriate patient population. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
  • Hsu Heng-Wei, Gridley Daila S, Kim Paul D, Shaoyan Hu, de Necochea-Campion Rosalia, . . . Mirshahid Saied. (2013). Linifanib (ABT-869) enhances radiosensitivity of head and neck squamous cell carcinoma cells. Oral Oncology, 49(6), 591-597. ( 0/2013 - Present ) Link...
    Objectives: Novel targeted therapeutic strategies to overcome radio-resistance of cancer cells tradition-ally treated with radiation may improve patient survival with the added benefit of reduced systemic tox-icity. Herein, we tested the feasibility of Linifanib (ABT-869), a multi-receptor tyrosine kinase inhibitor of members of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) recep-tor families, on radio-sensitization of Head and Neck Squamous Cell Carcinoma (HNSCC). Materials and methods: UMSCC-22A and UMSCC-22B cells were treated with Linifanib and y-radiation response was determined. Cell viability, cytotoxicity, apoptosis induction and cell cycle distribution were examined by MTT assay, colony formation assay and flow cytometry. In addition, expression of STAT3 and downstream signaling proteins were assessed using western immunoblotting. Results: Treatment with Linifanib resulted in cell growth inhibition, G2/M cell cycle arrest, induction of cell death via apoptosis, reduced phosphorylation of STAT3, which has been linked to radio-resistance, lower expression of cyclin Dl, survivin and increased PARP cleavage. In addition, Linifanib overcame the radio-resistance of the cell lines and significantly enhanced radiation-induced cytotoxicity (p < 0.05). Conclusion: These data suggest the possibility of combining targeted therapeutic such as Linifanib with radiation to enhance inhibition of cell growth and apoptosis in HNSCC cells. Thus, it may provide a novel therapeutic strategy and improve efficacy of radiation against HNSCC in the future. [ABSTRACT FROM AUTHOR] Copyright of Oral Oncology is the property of Pergamon Press - An Imprint of Elsevier Science and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
  • Berenson J R, Yellin O, Kazamel T, Hilger J D, Chen C S, . . . Swift R A. (2012). A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma. Leukemia, 26(7), 1675-1680. ( 7/2012 - Present ) Link...
    Our previous studies have shown that lowering the dose of pegylated liposomal doxorubicin (PLD) and bortezomib in combination with intravenous dexamethasone on a longer 4-week cycle maintained efficacy and improved tolerability in both previously untreated and relapsed/refractory (R/R) multiple myeloma (MM) patients. Lenalidomide has shown efficacy in combination with bortezomib and dexamethasone but this combination has been poorly tolerated. We conducted this phase 2 study (clinicaltrials.gov identifier: NCT01160484) to evaluate whether a longer 4-week schedule using modified doses and schedules of IV dexamethasone (40 mg), bortezomib (1.0 mg/m(2)) and PLD (4.0 mg/m(2)) administered on days 1, 4, 8, and 11 with lenalidomide 10 mg daily on days 1-14 (DVD-R) would be effective and tolerated for patients with R/R MM. A total of 40 heavily pretreated patients were enrolled and 84.6% showed clinical benefit (complete response, 20.5%; very good partial response, 10.3%; partial response, 17.9%; minimal response, 35.9%) to the combination regimen. An additional 10.3% showed stable disease and 5.1% progressed while on study. The regimen was well tolerated, with a low incidence of adverse events such as fatigue (40%), thrombocytopenia (35%), neutropenia (35%), anemia (30%), peripheral neuropathy (25%) and pneumonia (15%). Thus, the DVD-R regimen is well tolerated and produces high response rates for patients with R/R MM.
  • Marleau A M, Chen C S, Joyce J A, & Tullis R H. (2012). Exosome removal as a therapeutic adjuvant in cancer. Journal of Translational Medicine, 10, . ( 6/2012 - Present ) Link...
    Exosome secretion is a notable feature of malignancy owing to the roles of these nanoparticles in cancer growth, immune suppression, tumor angiogenesis and therapeutic resistance. Exosomes are 30-100 nm membrane vesicles released by many cells types during normal physiological processes. Tumors aberrantly secrete large quantities of exosomes that transport oncoproteins and immune suppressive molecules to support tumor growth and metastasis. The role of exosomes in intercellular signaling is exemplified by human epidermal growth factor receptor type 2 (HER2) over-expressing breast cancer, where exosomes with the HER2 oncoprotein stimulate tumor growth and interfere with the activity of the therapeutic antibody Herceptin (R). Since numerous observations from experimental model systems point toward an important clinical impact of exosomes in cancer, several pharmacological strategies have been proposed for targeting their malignant activities. We also propose a novel device strategy involving extracorporeal hemofiltration of exosomes from the entire circulatory system using an affinity plasmapheresis platform known as the Aethlon ADAPT (TM) (adaptive dialysis-like affinity platform technology) system, which would overcome the risks of toxicity and drug interactions posed by pharmacological approaches. This technology allows affinity agents, including exosome-binding lectins and antibodies, to be immobilized in the outer-capillary space of plasma filtration membranes that integrate into existing kidney dialysis systems. Device therapies that evolve from this platform allow rapid extracorporeal capture and selective retention of target particles < 200 nm from the entire circulatory system. This strategy is supported by clinical experience in hepatitis C virus-infected patients using an ADAPT (TM) device, the Hemopurifier (R), to reduce the systemic load of virions having similar sizes and glycosylated surfaces as cancer exosomes. This review discusses the possible therapeutic approaches for targeting immune suppressive exosomes in cancer patients, and the anticipated significance of these strategies for reversing immune dysfunction and improving responses to standard of care treatments.
  • Marleau A M, McDonald G, Koropatnick J, Chen C S, & Koos D. (2012). Reduction of Tumorigenicity by Placental Extracts. Anticancer Research, 32(4), 1153-1161. ( 4/2012 - Present )
    The influence of adult stem cells on tumor growth is paradoxical. On one hand, angiogenic factors secreted by stem cells are known to be essential for tumor vascularization. On the other hand, stem cell-derived factors can reportedly induce tumor differentiation or direct death of tumor cells. Both the placenta and umbilical cord are rich sources of stem cells with immune modulatory and tissue-healing properties; however, the effects of placental components on cancer cells have not been fully defined. Here we demonstrate that extracts of placental lysates reduce the malignancy of a variety of human tumor cell lines in a species-unrestricted manner. Using a standard model of leukemia cell differentiation, we demonstrated that addition of placental extracts to tumor cells, or co-culture of tumor cells with the CD34(+) cells from umbilical cord blood, induced tumor cell differentiation. Inhibition of tumor growth and metastasis in vivo was also observed following administration of placental extracts. These data support the concept of non-toxic biological therapy of cancer using stem cell derivatives, possibly through the induction of tumor cell differentiation.
  • de Necochea-Campion R, Ghochikyan A, Josephs S F, Zacharias S, Woods E, . . . Carrier E. (2011). Expression of the Epigenetic factor BORIS (CTCFL) in the Human Genome. Journal of Translational Medicine, 9, . ( 12/2011 - Present ) Link...
    BORIS, or CTCFL, the so called Brother of the Regulator of Imprinted Sites because of the extensive homology in the central DNA binding region of the protein to the related regulator, CTCF, is expressed in early gametogenesis and in multiple cancers but not in differentiated somatic cells. Thus it is a member of the cancer testes antigen group (CTAs). Since BORIS and CTCF target common DNA binding sites, these proteins function on two levels, the first level is their regulation via the methylation context of the DNA target site and the second level is their distinct and different epigenetic associations due to differences in the non-homologous termini of the proteins. The regulation on both of these levels is extensive and complex and the sphere of influence of each of these proteins is associated with vastly different cellular signaling processes. On the level of gene expression, BORIS has three known promoters and multiple spliced mRNAs which adds another level of complexity to this intriguing regulator. BORIS expression is observed in the majority of cancer tissues and cell lines analyzed up to today. The expression profile and essential role of BORIS in cancer make this molecule very attractive target for cancer immunotherapy. This review summarizes what is known about BORIS regarding its expression, structure, and function and then presents some theoretical considerations with respect to its genome wide influence and its potential for use as a vaccine for cancer immunotherapy.
  • Berenson J R, Yellin O, Chen C S, Patel R, Bessudo A, . . . Swift R A. (2011). A modified regimen of pegylated liposomal doxorubicin, bortezomib and dexamethasone (DVD) is effective and well tolerated for previously untreated multiple myeloma patients. British Journal of Haematology, 155(5), 580-587. ( 12/2011 - Present ) Link...
    The combination of pegylated liposomal doxorubicin (PLD), bortezomib and dexamethasone has shown efficacy in the treatment of multiple myeloma (MM) patients. Our earlier retrospective study suggested that modification of the doses, schedules and route of administration of these drugs appears to reduce toxicity without compromising anti-MM activity. As a result, we evaluated this modified drug combination in the frontline setting in a prospective multicentre phase II trial. Thirty-five previously untreated MM patients were enrolled. Dexamethasone IV 40 mg, bortezomib 1 mg/m(2) and PLD 5 mg/m(2) were administered on days 1, 4, 8 and 11 of a 4-week cycle. Patients were treated to their maximum response plus two additional cycles. The treatment regimen was discontinued after a maximum of eight cycles. Our modified schedule and dosing regimen achieved a high overall response rate of 86%, while showing a marked decrease in the incidence and severity of peripheral neuropathy, palmar-plantar erythrodysesthesia and myelo-suppression compared to the standard dosing on a 3-week cycle using these drugs. This modified regimen of dexamethasone, bortezomib and PLD shows improved tolerability and safety while maintaining a high response rate when compared to standard treatment with these agents in the frontline setting.
  • Kraft A S, Garrett-Mayer E, Wahlquist A E, Golshayan A, Chen C S, . . . Lilly M. (2011). Combination therapy of recurrent prostate cancer with the proteasome inhibitor bortezomib plus hormone blockade. Cancer Biology & Therapy, 12(2), 119-124. ( 7/2011 - Present ) Link...
    A single arm phase II trial of single-agent bortezomib (BZM) alone or combined with hormone blockade was conducted in patients with early PSA recurrence after definitive local therapy. The primary endpoint of this study was to determine the time to PSA relapse after BZM therapy alone or when BZM was combined with hormone blockade. The secondary endpoint was to determine the safety of combination therapy. Part A of the treatment schedule consisted of three cycles of BZM 1.3 mg/m(2) IV given on days 1, 4, 8 and 11. If patients progressed on Part A, they were entered on Part B which consisted of a single dose of LH-RH antagonist, daily oral antiandrogen, and weekly BZM 1.3 mg/m(2) for 3 out of 4 weeks for a total of 3 months. BZM treatment significantly decreased the slope of the log PSA (p = 0.024) demonstrating that this agent alone was capable of slowing the rise of the PSA. Of eight patients treated with BZM alone five had stable disease, two progressed and one went off study secondary to toxicity. The major toxicity was neurotoxicity requiring discontinuation of therapy in three patients and treatment interruption in nine patients. Of those receiving Parts A and B or B only, there were 11 of 15 CRs with the average time to progression of 5.5 months. BZM treatment can change the slope of PSA rise and can be combined with hormone deprivation therapy without significant additional side effects; these agents are associated with a median time to CR of 42 days.
  • Lee Z W, Zhou J B, Chen C S, Zhao Y J, Tan C H, . . . Deng L W. (2011). The Slow-Releasing Hydrogen Sulfide Donor, GYY4137, Exhibits Novel Anti-Cancer Effects In Vitro and In Vivo. Plos One, 6(6), . ( 6/2011 - Present ) Link...
    The slow-releasing hydrogen sulfide (H2S) donor, GYY4137, caused concentration-dependent killing of seven different human cancer cell lines (HeLa, HCT-116, Hep G2, HL-60, MCF-7, MV4-11 and U2OS) but did not affect survival of normal human lung fibroblasts (IMR90, WI-38) as determined by trypan blue exclusion. Sodium hydrosulfide (NaHS) was less potent and not active in all cell lines. A structural analogue of GYY4137 (ZYJ1122) lacking sulfur and thence not able to release H2S was inactive. Similar results were obtained using a clonogenic assay. Incubation of GYY4137 (400 mu M) in culture medium led to the generation of low (< 20 mM) concentrations of H2S sustained over 7 days. In contrast, incubation of NaHS (400 mu M) in the same way led to much higher (up to 400 mu M) concentrations of H2S which persisted for only 1 hour. Mechanistic studies revealed that GYY4137 (400 mu M) incubated for 5 days with MCF-7 but not IMR90 cells caused the generation of cleaved PARP and cleaved caspase 9, indicative of a pro-apoptotic effect. GYY4137 (but not ZYJ1122) also caused partial G(2)/M arrest of these cells. Mice xenograft studies using HL-60 and MV4-11 cells showed that GYY4137 (100-300 mg/kg/day for 14 days) significantly reduced tumor growth. We conclude that GYY4137 exhibits anti-cancer activity by releasing H2S over a period of days. We also propose that a combination of apoptosis and cell cycle arrest contributes to this effect and that H2S donors should be investigated further as potential anti-cancer agents.
  • Xie Z G, Bi C L, Cheong L L, Liu S C, Huang G F, . . . Chng W J. (2011). Determinants of Sensitivity to DZNep Induced Apoptosis in Multiple Myeloma Cells. Plos One, 6(6), . ( 6/2011 - Present ) Link...
    The 3-Deazaneplanocin A (DZNep), one of S-adenosylhomocysteine (AdoHcy) hydrolase inhibitors, has shown antitumor activities in a broad range of solid tumors and acute myeloid leukemia. Here, we examined its effects on multiple myeloma (MM) cells and found that, at 500 nM, it potently inhibited growth and induced apoptosis in 2 of 8 MM cell lines. RNA from un-treated and DZNep treated cells was profiled by Affymetrix HG-U133 Plus 2.0 microarray and genes with a significant change in gene expression were determined by significance analysis of microarray (SAM) testing. ALOX5 was the most down-regulated gene (5.8-fold) in sensitive cells and was expressed at low level in resistant cells. The results were corroborated by quantitative RT-PCR. Western-blot analysis indicated ALOX5 was highly expressed only in sensitive cell line H929 and greatly decreased upon DZNep treatment. Ectopic expression of ALOX5 reduced sensitivity to DZNep in H929 cells. Furthermore, down- regulation of ALOX5 by RNA interference could also induce apoptosis in H929. Gene expression analysis on MM patient dataset indicated ALOX5 expression was significantly higher in MM patients compared to normal plasma cells. We also found that Bcl-2 was overexpressed in DZNep insensitive cells, and cotreatment with DZNep and ABT-737, a Bcl-2 family inhibitor, synergistically inhibited growth and induced apoptosis of DZNep insensitive MM cells. Taken together, this study shows one of mechanisms of the DZNep efficacy on MM correlates with its ability to down- regulate the ALOX5 levels. In addition, DZNep insensitivity might be associated with overexpression of Bcl-2, and the combination of ABT-737 and DZNep could synergistically induced apoptosis. These results suggest that DZNep may be exploited therapeutically for a subset of MM.
  • Zhou J B, Bi C L, Chng W J, Cheong L L, Liu S C, . . . Chen C S. (2011). PRL-3, a Metastasis Associated Tyrosine Phosphatase, Is Involved in FLT3-ITD Signaling and Implicated in Anti-AML Therapy. Plos One, 6(5), . ( 5/2011 - Present ) Link...
    Combination with other small molecule drugs represents a promising strategy to improve therapeutic efficacy of FLT3 inhibitors in the clinic. We demonstrated that combining ABT-869, a FLT3 inhibitor, with SAHA, a HDAC inhibitor, led to synergistic killing of the AML cells with FLT3 mutations and suppression of colony formation. We identified a core gene signature that is uniquely induced by the combination treatment in 2 different leukemia cell lines. Among these, we showed that downregulation of PTP4A3 (PRL-3) played a role in this synergism. PRL-3 is downstream of FLT3 signaling and ectopic expression of PRL-3 conferred therapeutic resistance through upregulation of STAT (signal transducers and activators of transcription) pathway activity and anti-apoptotic Mcl-1 protein. PRL-3 interacts with HDAC4 and SAHA downregulates PRL-3 via a proteasome dependent pathway. In addition, PRL-3 protein was identified in 47% of AML cases, but was absent in myeloid cells in normal bone marrows. Our results suggest such combination therapies may significantly improve the therapeutic efficacy of FLT3 inhibitors. PRL-3 plays a potential pathological role in AML and it might be a useful therapeutic target in AML, and warrant clinical investigation.
  • Ichim T E, Minev B, Braciak T, Luna B, Hunninghake R, . . . Riordan N H. (2011). Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?. Journal of Translational Medicine, 9, . ( 3/2011 - Present ) Link...
    The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.
  • Cheng O, Ostrowski R P, Wu B, Liu W, Chen C, & Zhang J H. (2011). Cyclooxygenase-2 mediates hyperbaric oxygen preconditioning in the rat model of transient global cerebral ischemia. Stroke, 42(2), 484-90. ( 2/2011 - Present ) Link...
    BACKGROUND AND PURPOSE: Hyperbaric oxygen (HBO) preconditioning (PC) allows brain protection against transient global ischemia. In the present study, we hypothesize that the mechanism of HBO-PC involves the induction of cyclooxygenase-2 (COX-2) in cerebral tissues before ischemia, which leads to a suppression of COX-2 and its downstream targets after global ischemic insult. METHODS: One hundred twenty-nine male Sprague Dawley rats (body weight 280-300 grams) were allocated to the naive control group and the sham operation group, and 3 groups of animals were subjected to 15-minute 4-vessel occlusion: untreated, preconditioned with HBO 2.5 atmospheres absolutes for 1 hour daily for 5 days, preconditioned as mentioned and administered with COX-2 inhibitor NS-398 (1 mg/kg body weight intraperitoneal) before each preconditioning session, and normal rats preconditioned with HBO without ischemia. The mortality, the incidence of seizures, and T-maze scores were recorded. The quantitative cell count in Nissl stain and TUNEL was conducted on day 7 after ischemia. The brain expression of COX-2 was analyzed with Western blotting and immunofluorescence staining. RESULTS: HBO-PC increased the number of surviving neurons in the Cornu Ammonis area 1, which was associated with the reduced COX-2 expression in the hippocampus and in the cerebral cortex at 1 and 3 days after ischemia. HBO-PC improved functional performance and tended to decrease mortality and the frequency of seizures. These beneficial effects of HBO-PC were abolished by the COX-2 selective inhibitor NS-398. CONCLUSIONS: HBO-PC reduced COX-2 expression and provided brain protection after global ischemia. Administration of COX-2 inhibitor with HBO before ischemia abolished preconditioning effect, thereby implicating COX-2 as a mediator of HBO-PC in the ischemic brain.
  • Cheng O M, Ostrowski R P, Wu B H, Liu W W, Chen C H, & Zhang J H. (2011). Cyclooxygenase-2 Mediates Hyperbaric Oxygen Preconditioning in the Rat Model of Transient Global Cerebral Ischemia. Stroke, 42(2), 484-490. ( 2/2011 - Present ) Link...
    Background and Purpose-Hyperbaric oxygen (HBO) preconditioning (PC) allows brain protection against transient global ischemia. In the present study, we hypothesize that the mechanism of HBO-PC involves the induction of cyclooxygenase-2 (COX-2) in cerebral tissues before ischemia, which leads to a suppression of COX-2 and its downstream targets after global ischemic insult. Methods-One hundred twenty-nine male Sprague Dawley rats (body weight 280-300 grams) were allocated to the naive control group and the sham operation group, and 3 groups of animals were subjected to 15-minute 4-vessel occlusion: untreated, preconditioned with HBO 2.5 atmospheres absolutes for 1 hour daily for 5 days, preconditioned as mentioned and administered with COX-2 inhibitor NS-398 (1 mg/kg body weight intraperitoneal) before each preconditioning session, and normal rats preconditioned with HBO without ischemia. The mortality, the incidence of seizures, and T-maze scores were recorded. The quantitative cell count in Nissl stain and TUNEL was conducted on day 7 after ischemia. The brain expression of COX-2 was analyzed with Western blotting and immunofluorescence staining. Results-HBO-PC increased the number of surviving neurons in the Cornu Ammonis area 1, which was associated with the reduced COX-2 expression in the hippocampus and in the cerebral cortex at 1 and 3 days after ischemia. HBO-PC improved functional performance and tended to decrease mortality and the frequency of seizures. These beneficial effects of HBO-PC were abolished by the COX-2 selective inhibitor NS-398. Conclusions-HBO-PC reduced COX-2 expression and provided brain protection after global ischemia. Administration of COX-2 inhibitor with HBO before ischemia abolished preconditioning effect, thereby implicating COX-2 as a mediator of HBO-PC in the ischemic brain. (Stroke. 2011; 42: 484-490.)
  • Xie Z G, Chng W J, Tay K G, Liu S C, Zhou J B, & Chen C S. (2011). Therapeutic potential of antisense oligodeoxynucleotides in downregulating p53 oncogenic mutations in cancers. Biotechnology Letters, 33(2), 221-228. ( 2/2011 - Present ) Link...
    Mutation of the p53 gene is the most common genetic alteration in human cancers. Our study proposes to rationally design a p53 antisense oligonucleotide (ASO) repository, which contains a series of ASOs containing single nucleotide differences to discriminate between each mutant and wild type (WT) p53. The Sfold software was used to predict target-accessibility and we designed an initial series of antisense oligonucleotides (ASO) that target the p53 mutants A161T, R175H and R249S. Western-blot analysis indicated that ASOs strongly inhibited the expression of p53 mutants in a panel of human tumor cell lines (SNU-449, SK-BR-3 and PLC/PRF/5) while having little effect on the expression of WT p53 (HepG2 cells). In three cancer lines harboring each of the p53 mutations, mutant-specific ASO treatment led to a dose-dependent inhibition of cell growth, cell viability, colony formation and invasion, and expression of mutant p53-dependent survival proteins. Our preliminary results indicate that a single nucleotide difference in ASOs can discriminate between mutant and WT p53. These observations support the hypothesis that a p53 ASO repository can be a potentially valuable tool to knock down oncogenic mutant p53 and warrant the testing of a p53 ASO repository in in vivo settings.
  • Hu S Y, Gu W Y, Chen Z X, Wang X L, Cen J N, . . . Chen C S. (2010). THE SIGNIFICANCE OF DETECTING WT1 EXPRESSION IN CHILDHOOD ACUTE LEUKEMIAS. Pediatric Hematology and Oncology, 27(8), 581-591. ( 11/2010 - Present ) Link...
    WT1 (Wilms' tumor gene 1) overexpression is implicated in the prognosis of acute leukemia. The purpose of this study was to investigate WT1 expression and its clinical implication in childhood acute leukemia (AL) in Chinese population. Bone marrow specimen from 200 children at different stages of acute leukemia and from 21 children without leukemia were studied. The WT1 expression at diagnostic marrow specimen in both acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) was higher than control group, whereas WT1 expression in AML was higher than in ALL, and WT1 expression level in relapse in ALL increased more significantly than in AML. The WT1 expression level showed positive correlation with the hypodiploidy and BCR-ABL fusion gene in acute leukemia. A rapidly decrease of WT1 expression level predicted a good response to the induction therapy and low expression of WT1 correlates with remission status. This study suggested that WT1 expression levels in acute leukemia can potentially be a marker for evaluating therapeutic efficacy, correlating with monitoring minimal residue disease, and predicting hematological relapse in children acute leukemia.
  • Raja A M, Xu S Y, Sun W X, Zhou J B, Tai D C S, . . . Yu H. (2010). Pulse-modulated second harmonic imaging microscope quantitatively demonstrates marked increase of collagen in tumor after chemotherapy. Journal of Biomedical Optics, 15(5), . ( 9/2010 - Present ) Link...
    Pulse-modulated second harmonic imaging microscopes (PM-SHIMs) exhibit improved signal-to-noise ratio (SNR) over conventional SHIMs on sensitive imaging and quantification of weak collagen signals inside tissues. We quantify the spatial distribution of sparse collagen inside a xenograft model of human acute myeloid leukemia (AML) tumor specimens treated with a new drug against receptor tyrosine kinase (ABT-869), and observe a significant increase in collagen area percentage, collagen fiber length, fiber width, and fiber number after chemotherapy. This finding reveals new insights into tumor responses to chemotherapy and suggests caution in developing new drugs and therapeutic regimens against cancers. (C) 2010 Society of Photo-Optical Instrumentation Engineers. [DOI: 10.1117/1.3497565]
  • Lee L C, Chen C S, Choong P F, Low A, Tan H C, & Poh K K. (2010). Time-dependent dynamic mobilization of circulating progenitor cells during percutaneous coronary intervention in diabetics. International Journal of Cardiology, 142(2), 199-201. ( 7/2010 - Present ) Link...
  • Bautista M A, Stevens W T, Chen C S, Curtis B R, Aster R H, & Hsueh C T. (2010). Hypersensitivity reaction and acute immune-mediated thrombocytopenia from oxaliplatin: two case reports and a review of the literature. Journal of Hematology & Oncology, 3, . ( 3/2010 - Present ) Link...
    Background: Oxaliplatin is a platinum compound used in the treatment of gastrointestinal malignancies, including colorectal cancer. The incidence of hypersensitivity reaction in patients receiving oxaliplatin is approximately 15%, with severe reaction (grade 3 and 4) occurring in 2% of patients. Case presentation: We report two patients with metastatic colorectal cancer who developed de novo hypersensitivity reaction and acute thrombocytopenia after oxaliplatin infusion. Both patients had oxaliplatin treatment several years before and exhibited hypersensitivity on the third dose of oxaliplatin in recent treatment. Oxaliplatin was discontinued when clinical reaction was identified. Both patients were confirmed to have strong oxaliplatin-induced IgG platelet-reactive antibodies. Both patients' thrombocytopenia resolved within two weeks after discontinuation of oxaliplatin. One patient had disease stabilization lasting for three months without chemotherapy. Both patients subsequently received other chemotherapeutic agents without evidence of hypersensitivity reaction or immune-mediated thrombocytopenia. Conclusion: We recommend vigilant monitoring of complete blood count and signs and symptoms of bleeding after the occurrence of oxaliplatin-induced hypersensitivity to avoid serious complications of immune-mediated thrombocytopenia.
  • Hsu V J, Agarwal M R, Chen C S, & Rossi C. (2010). IgA Orbital Plasmacytoma in Multiple Myeloma. Ophthalmic Plastic and Reconstructive Surgery, 26(2), 126-127. ( 3/2010 - Present ) Link...
    The authors report a case of orbital plasmacytoma in a 48-year-old man with known multiple myeloma. He presented with proptosis, diplopia, and decreased vision of the left eye for several weeks. He had been previously treated for IgA lambda multiple myeloma with chemotherapy, radiation, and autologous stem cell transplant. After a left orbitotomy, flow cytometry revealed a tumor rich in plasma cells expressing CD138 with equivocal lambda light chain expression. The patient underwent orbital radiation, with improvement of vision and disc edema OS. The patient is currently undergoing salvage chemotherapy for relapse of multiple myeloma. This is the third reported case of IgA myeloma involving the orbit.
  • Zhou J B, Goh B C, Albert D H, & Chen C S. (2009). ABT-869, a promising multi-targeted tyrosine kinase inhibitor: from bench to bedside. Journal of Hematology & Oncology, 2, . ( 7/2009 - Present ) Link...
    Tyrosine Kinase Inhibitors (TKI) have significantly changed the landscape of current cancer therapy. Understanding of mechanisms of aberrant TK signaling and strategies to inhibit TKs in cancer, further promote the development of novel agents. ABT-869, a novel ATP-competitive receptor tyrosine kinase inhibitor is a potent inhibitor of members of the vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) receptor families. ABT-869 showed potent antiproliferative and apoptotic properties in vitro and in animal cancer xenograft models using tumor cell lines that were "addicted" to signaling of kinases targeted by ABT-869. When given together with chemotherapy or mTOR inhibitors, ABT-869 showed at least additive therapeutic effects. The phase I trial for ABT-869 was recently completed and it demonstrated respectable efficacy in solid tumors including lung and hepatocellular carcinoma with manageable side effects. Tumor cavitation and reduction of contrast enhancement after ABT-869 treatment supported the antiangiogenic activity. The correlative laboratory studies conducted with the trial also highlight potential biomarkers for future patient selection and treatment outcome. Parallel to the clinical development, in vitro studies on ABT-869 resistance phenotype identified novel resistance mechanism that may be applicable to other TKIs. The future therapeutic roles of ABT-869 are currently been tested in phase II trials.
  • Mirshahidi S, Hsu H W, & Chen C S. (2012). Effects of a multi-targeted receptor tyrosine kinase inhibitor on radiosentization of head and neck squamous cell carcinoma. Journal of Immunology, 188, . ( 5/2012 - Present )
  • Hu S Y, Mirshahidi S, Bi C L, Chng W J, Hsu H W, . . . Chen C S. (2011). C3aR1 Contributed to Acute Myeloid Leukemia Acquired Resistance to ABT-737 and Involved In the Process of AML. Blood, 118(21), 623-623. ( 11/2011 - Present )
  • Craig M, Hanna W T, Cabanillas F, Chen C S, Parasuraman S, Neuwirth R, & O'Connor O A. (2010). Bortezomib In Combination with Rituximab, Cyclophosphamide, and Prednisone with or without Doxorubicin Followed by Rituximab Maintenance In Patients with Relapsed or Refractory Follicular Lymphoma: Results of a Phase 2 Study. Blood, 116(21), 1153-1154. ( 11/2010 - Present )
  • Zhang J H, Chen W, Ostrowski R, Chen C, & Tang J. (2009). HIF-1 RESPONSES AFTER STROKE. Journal of Neurochemistry, 110, 155-155. ( 9/2009 - Present )
  • Turner J S, Chen C S, Butler W, Bearden J, Garrett-Mayer E, Onicescu G, & Kraft A S. (2009). Bortezomib therapy for prostate specific antigen (PSA)-only relapse after definitive local therapy. Journal of Clinical Oncology, 27(15), . ( 5/2009 - Present )