Pediatrics

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Summary of Activity

We are developing genetically modified T-cells to express a chimeric antigen receptor (CAR) redirected to tumor antigens. Cancer immunotherapy using CAR T cells has been applied in the treatment of acute lymphoblastic leukemia and malignant lymphoma. We are developing a new CAR-T cells to treat acute myeloid leukemia or pediatric solid tumors.
We are also working on a new cancer gene therapy using a biodegradable liposome (nanocapsule). We aim to deliver genes of interest into the target cancer cells using the nanocapule to improve safety and reduce the costs of gene therapy.

Research Subject

• ・Cancer immunotherapy with CAR-T cells
• ・Cancer gene therapy with biodegradable liposome (nanocapsule)

Outlook for Research

We strive to improve medical care for children and all future generations by understanding the mechanisms of disease, developing potential treatments, and gathering evidence from daily clinical practice.
Your research discoveries may generate a cure for some disease!

Major Publications

1. Matsuda K, Shimada A, Yoshida N, Ogawa A, Watanabe A, Yajima S, Iizuka S, Koike K, Yanai F, Kawasaki K, Yanagimachi M, Kikuchi A, Ohtsuka Y, Hidaka E, Yamauchi K, Tanaka M, Yanagisawa R, Nakazawa Y, Shiohara M, Manabe A, Kojima S, Koike K. Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood, 109:5477-80, 2007.

2. Ueda I, Kurokawa Y, Koike K, Ito S, Sakata A, Matsumora T, Fukushima T,Morimoto A, Ishii E, Imashuku S.
Late-onset cases of familial hemophagocytic lymphohistiocytosis withmissense perforin gene mutations. Am J Hematol. in press.
3.Matsuda K, Nakazawa Y, Sakashita K, Shiohara M, Yamauchi K, Koike K. Acquirement of loss of the wild-type NRAS locus with aggressive disease progression in a patient with juvenile myelomonocytic leukemia and a heterozygous NRAS mutation. Haematologica, in press.

3. Merlo D, Mollinari C, Inaba Y, Cardinale A, Rinaldi AM, D'Antuono M, D'Arcangelo G, Tancredi V, Ragsdale D, Avoli M : Reduced GABA(B) receptor subunit expression and paired-pulse depression in a genetic model of absence seizures. Neurobiol Dis 25 : 631-41, 2007

4. Yasui K, Kobayashi N, Yamazaki T, Agematsu K, Matsuzaki S, Nakata S, Baba A.
Differential Effects of Short-Acting beta(2)-Agonists on Human Granulocyte Functions.
Int Arch Allergy Immunol. 2006 Jan;139(1):1-8. Epub 2005 Nov 2.

5. Shiohara M, Shiozawa R, Kurata K, Matsuura H, Yasuda T, Koike k.
Effect of parathyroid hormone administration in a patient with severe hypoparathyroidism caused by gain-of-function mutation of calcium-sensing receptor.
Endocrine J. 2006, 53: 797-802.

6. Fukuyma T, Yokouchi K, Fukushima N, Kawagishi K, Kakegawa A, Moriizumi T.
Differential effects of hypoglossal and facial nerve injuries on survival and growth of rats at different developmental stages.
Int J Dev Neurosci. 2006 Aug;24(5):307-17.Epub 2006 Jun 27.

7. Matsuura H, Shiohara M, Yamano M, Kurata K, Arai F, Koike K.
Novel compound heterozygous mutation of the MC2R gene in a patient with familial glucocorticoid deficiency.
J PediatrEndocrinol Metab. 2006, 19: 167-1170.

8. Hiroma T, Baba A, Tamaru M, Nakamura T.
Liquid incubator with perfluorochemicals for extremely premature infants.
Biol Neonate. 2006;90(3):162-7.Epub 2006 Apr 3.

9. Kobayashi N, Yasui K, Nagumo H, Agematsu K, Koike K.
Successful treatment with methotrexate of a child with atlantoaxial subluxxation from enthesitis-related arthritis.
Clin Exp Rheumatol. 2006 Mar-Apr;24(2):211-2.

10. Saito S, Yasui K, Hosoda W, Ogawa M, Kobayashi N, Sakashita K, Koike K.
CD30+ anaplastic large cell lymphoma complicated by pyoderma gangrenosum with increased levels of serum cytokines.
Eur J Haematol. 2006 Sep;77(3):251-4.

11. Ogawa M, Sakashita K, Zhao XY, Hayakawa A, Kubota T, Koike K.
Analysis of histone modification around the CpG island region of the p15
gene in acute myeloblastic leukemia. Leukemia Res. 2006 (in press)

12. Nakazawa Y, Saito S, Hasegawa Y, Yanagisawa Y, Sakashita K, Kamijo T,
Miyazaki T, Sato S, Ikeda H, Ikebuchi K, Koike K.
A possible role for the production of multiple HLA antibodies in fatal
platelet transfusion refractoriness after peripheral blood stem cell
transplantation from the mother in a patient with relapsed leukemia.
Transfusion. 2006 (in press)

13. Matsuda K, Matsuzaki S, Miki J, Hidaka E, Yanagisawa R, Nakazawa Y,
Sakashita K, Kamijo T, Asami K, Sano K, Koike K.
Chromosomal change during 6-mercaptopurine (6-MP) therapy in juvenile
myelomonocytic leukemia: the growth of a 6-MP-refractory clone that
already exists at onset. Leukemia, 20: 485-490, 2006.

14. Yabe H, Inoue H, Matsumoto M, Hamanoue S, Koike T, Ishiguro H, Koike H,
Suzuki K, Kato S, Kojima S, Tsuchida M, Mori T, Adachi S, Tsuji K, Koike K,
Morimoto A, Sako M, Yabe M.
Allogeneic haematopoietic cell transplantation from alternative
donors with a conditioning regimen of low-dose irradiation, fludarabine and
cyclophosphamide in Fanconi anaemia. Br J Haematol. 134(2):208-12, 2006.

15. Ishii E, Oda M, Kinugawa N, Oda T, Takimoto T, Suzuki N, Kosaka Y, Ohara A, Ogawa A, Ishii M, Sakata N, Okamura T, Koike K, Kojima S, Horibe K, Mizutani S.
Features and outcome of neonatal leukemia in Japan: experience of the Japan infant leukemia study group.
Pediatr Blood Cancer. 2006 Sep;47(3):268-72.

16. Kakegawa A, Yokouchi K, Fukushima N, Fukuyama T, Moriizumi T.
Motor neurons essential for normal sciatic function in neonatally nerve-injured rats.
Neuroreport. 2006 Jul 31;17(11):1149-52

17. Fujita K, Yokouchi K, Fukuyama T, Fukusima N, Kawagishi K, Moriizumi T.
Effects of hypoglossal and facial nerve injuries on milk-suckling.
Int J Dev Neurosci. 2006 Feb;24(1):29-34. Epub 2005 Dec 27.

18. Inaba Y, Biagini G, Avoli M : The H current blocker ZD7288 decreases epileptiform hyperexcitability in the rat neocortex by depressing synaptic transmission. Neuropharmacology 51(3) : 681-91, 2006

19. Inaba Y, de Guzman P, Avoli M : NMDA receptor-mediated transmission contributes to network 'hyperexcitability' in the rat insular cortex. Eur J Neurosci 23 : 1071-6, 2006

20. D'Antuono M, Inaba Y, Biagini G, D'Arcangelo G, Tancredi V, Avoli M : Synaptic hyperexcitability of deep layer neocortical cells in a genetic model of absence seizures. Genes Brain Behav 5 : 73-84, 2006

21. de Guzman P, Inaba Y, Biagini G, Baldelli E, Mollinari C, Merlo D, Avoli M : Subiculum network excitability is increased in a rodent model of temporal lobe epilepsy. Hippocampus 16(10) : 843-60, 2006

22. Inaba Y, Avoli M : Volume-conducted epileptiform events between adjacent necortical slices in an interface tissue chamber. J Neurosci Methods 151(2) : 287-90, 2006

23. Yasui K, Kobayashi N, Yamazaki T, Agematsu K, Matsuzaki S, Ito S, Nakata S, Baba A, Koike K.
Superoxide dismutase (SOD) as a potential inhibitory mediator of inflammation via neutrophil apoptosis.
Free Radic Res. 2005 Jul;39(7):755-62.

24. Yasui K, Kobayashi N, Yamazaki T, Agematsu K.
Thalidomide as an immunotherapeutic agent: the effects on neutrophil-mediated inflammation.
Curr Pharm Des. 2005;11(3):395-401. Review.

25. Yasui K, Kobayashi N, Yamazaki T, Koike K, Fukushima K, Taniuchi S, Kobayashi Y.
Neutrophilic inflammation in childhood bronchial asthma.
Thorax. 2005 Aug;60(8):704-5.

26. Yasui K, Baba A, Iwasaki Y, Kubo T, Aoyama K, Mori T, Yamazaki T, Kobayashi N, Ishiguro A.
Neutrophil-mediated inflammation in respiratory syncytial viral bronchiolitis.
Pediatr Int. 2005 Apr;47(2):190-5.

27. Shiohara M, Koike K. Related Articles, Links
Regulation of mast cell development.
Chem Immunol Allergy. 2005;87:1-21. Review.

28. Matsuzaki S, Matsuda K, Miki J, Nakazawa Y, Sakashita K, Kamijo T, Hidaka E, Koike K.
Development of two cytogenetically abnormal clones from multipotential hematopoietic stem cells in a patient with juvenile myelomonocytic leukemia.
Leuk Res. 2005 Sep;29(9):1069-72.

29. Matsuzaki S, Shinozaki K, Kobayashi N, Agematsu K.
Polarization of Th1/Th2 in human CD4 T cells separated by CD62L: analysis by transcription factors.
Allergy. 2005 Jun;60(6):780-7.

30. Yamazaki T, Nagumo H, Hayashi T, Sugane K, Agematsu K.
CD72-mediated suppression of human naive B cell differentiation by down-regulating X-box binding protein 1.
Eur J Immunol. 2005 Aug;35(8):2325-34.

31. Shi Y, Yamazaki T, Okubo Y, Uehara Y, Sugane K, Agematsu K.
Regulation of aged humoral immune defense against pneumococcal bacteria by IgM memory B cell.
J Immunol. 2005 Sep 1;175(5):3262-7.

32. Sekiguchi Y, Yasui K, Yamazaki T, Agematsu K, Kobayashi N, Koike K.
Effective combination therapy using interferon-gamma and interleukin-2 for disseminated Mycobacterium avium complex infection in a pediatric patient with AIDS.
Clin Infect Dis. 2005 Dec 1;41(11):e104-6. Epub 2005 Oct 21.

33. Zhao XY, Sakashita K, Kamijo T, Hidaka E, Sugane K, Kubota T, Koike K.
Granulocyte-macrophage colony-stimulating factor induces de novo methylation of the p15 CpG island in hematopoietic cells.
Cytokine. 2005 Aug 7;31(3):203-12.

34. Matsuda M, Yamada T, Gono T, Shimojima Y, Ishii W, Fushimi T, Sakashita K, Koike K, Ikeda S.
Serum levels of free light chain before and after chemotherapy in primary systemic AL amyloidosis.
Intern Med. 2005 May;44(5):428-33.

35. Hasegawa D, Manabe A, Kubota T, Kawasaki H, Hirose I, Ohtsuka Y, Tsuruta T, Ebihara Y, Goto Y, Zhao XY, Sakashita K, Koike K, Isomura M, Kojima S, Hoshika A, Tsuji K, Nakahata T.
Methylation status of the p15 and p16 genes in paediatric myelodysplastic syndrome and juvenile myelomonocytic leukaemia.
Br J Haematol. 2005 Mar;128(6):805-12.

36. Ishii E, Ueda I, Shirakawa R, Yamamoto K, Horiuchi H, Ohga S, Furuno K, Morimoto A, Imayoshi M, Ogata Y, Zaitsu M, Sako M, Koike K, Sakata A, Takada H, Hara T, Imashuku S, Sasazuki T, Yasukawa M. Related Articles, Links
Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions.
Blood. 2005 May 1;105(9):3442-8. Epub 2005 Jan 4.

37. Masuya M, Moussa O, Abe T, Deguchi T, Higuchi T, Ebihara Y, Spyropoulos DD, Watson DK, Ogawa M.
Dysregulation of granulocyte, erythrocyte, and NK cell lineages in Fli-1 gene-targeted mice.
Blood. 2005 Jan 1;105(1):95-102. Epub 2004 Sep 14.

38. Uchida C, Miwa S, Kitagawa K, Hattori T, Isobe T, Otani S, Oda T, Sugimura H, Kamijo T, Ookawa K, Yasuda H, Kitagawa M. Related Articles, Links
Enhanced Mdm2 activity inhibits pRB function via ubiquitin-dependent degradation.
EMBO J. 2005 Jan 12;24(1):160-9. Epub 2004 Dec 2.

39. Igarashi S, Manabe A, Ohara A, Kumagai M, Saito T, Okimoto Y, Kamijo T, Isoyama K, Kajiwara M, Sotomatsu M, Sugita K, Sugita K, Maeda M, Yabe H, Kinoshita A, Kaneko T, Hayashi Y, Ikuta K, Hanada R, Tsuchida M. Related Articles, Links
No advantage of dexamethasone over prednisolone for the outcome of standard- and intermediate-risk childhood acute lymphoblastic leukemia in the Tokyo Children's Cancer Study Group L95-14 protocol.
J Clin Oncol. 2005 Sep 20;23(27):6489-98.

40. Shimojima Y, Matsuda M, Ishii W, Koyama J, Yamamoto K, Shimodaira S, Sakashita K, Koike K, Ikeda S.
High-dose melphalan followed by autologous stem cell support in primary systemic AL amyloidosis with multiple organ involvement.
Intern Med. 2005 May;44(5):484-9.

41. Kano T, Inaba Y, Avoli M : Periodic oscillatory activity in parahippocampal slices maintained in vitro. Neuroscience 130(4) : 1041-53, 2005.