Medicine (Gastroenterology, Nephrology and Hematology)

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Summary of Activity

We have worked on the basic and clinical research of Gastroenterology, Hepatology, Pancreatology, Hematology and Nephrology.

Gastroenterology, Hepatology, and Pancreatology
There are several projects in each field. We have published many papers especially on viral hepatitis, autoimmune liver diseases, Helicobacter pilori,cancers of liver, pancreas, and stomach, and IgG4 related diseases.

Hematology
We have worked on the pathologic phenomena of various disorders of granular lymphocytes. We have shown the relationships of chemokine system and aggressive NK cell leukemia (ANKL) or T-cell large granular lymphocyte leukemia. Currently, we focused on the molecular aspects of proliferative mechanism of ANKL.
Another our recent concern  is  to  characterize Celiac disease and its complications among non Caucasian populations. After reporting the first Japanese case of Celiac disease complicated with diffuse large B cell lymphoma, epidemiological research of Celiac disease is underway.

Nephrology
One of the pillars of the research in our department is to clarify the factors which develop chronic kidney disease (CKD). To investigate the progressive mechanism in CKD, we use cultured mesangial cells and several animal models. Also, we investigate the laboratory and histological findings in CKD patients.

Research Projects

The specific current research interests are as follows:
Gastroenterology, Hepatology, and Pancreatology
*Clinical research of hepatitis C virus, especially treatment with interferon and ribavirin.
*HBV core-related antigen.
*Radio-frequency ablation of hepatocellular carcinoma
*Genetic analysis of autoimmune liver diseases.
*Establishment of suitable management for various type of gastrointestinal malignant lymphoma such as MALT lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, and T-cell lymphoma.
*Clinical, pathological, epidemiological, and bacteriological study for Helicobacter pylori infection in collaboration with Clinical Laboratories of Shinshu University Hospital.
*Long-time follow-up study of patients with early gastric cancer that were treated using endoscopic mucosal resection and/or endoscopic submucosal dissection.
*Clinical study of pancreatic cancer.
* Basic and Clinical study of autoimmune pancreatitis and IgG4-related diseases.

Hematology
*Development of new therapies for the hematological malignancies with multicenter clinical trials as a member of Japan Adult Leukemia study group(JALSG)
*Novel therapeutic approach for NK cell lymphoma with multicenter clinical trial as a member of NK tumor study group(NKTSG)
*Pathobiology of aggressive NK-cell leukemia
*Characterization and classification of granular lymphocyte-proliferative disorders (GLPD)
*Prevalence of Celiac disease and  its complications among non Caucasian populations
*Molecular basis of macrothormbocytopnic disorders

Nephrology
*Reaction of cultured mesangial cells after the stimulation of high glucose state and the addition of immune-complex
*Expression of hepatocyte growth factor induced by the interaction between human mesangial cells and monocytes
*Role of nitric oxide in diabetic nephropathy rats
*Interaction between parietal and visceral epithelial cells in experimental nephritis models
*Role of peroxisome proliferator-activated receptor α (PPARα) in rat renal proximal tubular cells
*Role of macrophage in uremic condition
*Incidence and prevalence of several hepatic virus infection in hemodialysis and CAPD patients  
*Relationship between effluent levels of β2-microglobulin and peritoneal injury markers in 7.5 % icodextrin-based peritoneal dialysis solution
*Investigation of clinical and histological progressive factors in IgA nephropathy
*Search for more adequate equation about estimated glomerular filtration rate (eGFR)
*Case-based clinical research in renal transplantation
*Pharmacokinetics and Pharmakodynamics of mitiglinide calcium hydrate in end-stage renal failure patients

Major Publications

◎Selected Articles
Division of Hepatology
1. Matsumoto A, Tanaka E. (2009) Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in patients with chronic hepatitis C, using viral and host factors: some concerns (reply). Hepatology 49: 2125-2126.

2. Okiyama W, Tanaka N, Nakajima T, Tanaka E, Kiyosawa K, Gonzalez FJ, Aoyama T. (2009) Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress. J Hepatol 50: 1236-1246.

3. Umemura T, Ichijo T, Yoshizawa K, Tanaka E, Kiyosawa K. (2009) Epidemiology of hepatocellular carcinoma in Japan. J Gastroenterol 44: 102- 107.

4. Umemura T, Katsuyama Y, Hamano H, Kitahara K, Takayama M, Arakura N, Kawa S, Tanaka E, Ota M. (2009) Association analysis of Toll-like receptor 4 polymorphisms with autoimmune pancreatitis. Hum Immunol 70: 742- 746.

5. Komatsu M, Yazaki M, Tanaka N, Sano K, Hashimoto E, Takei Y, Song YZ, Tanaka E, Kiyosawa K, Saheki T, Aoyama T, Kobayashi K.(2008) Citrin deficiency as a cause of chronic liver disorder mimicking non-alcoholic fatty liver disease. J Hepatol.49: 810-820.

6. Shirakawa H, Matsumoto A, Joshita S, Komatsu M, Tanaka N, Umemura T, Ichijo T, Yoshizawa K, Kiyosawa K, Tanaka E (2008) Nagano Interferon Treatment Research Group: Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology 48: 1753-1760.

7. Tanaka E, Umemura T. (2008) History and prevention of de novo hepatitis B virus-related hepatitis in Japan and the world. Clin J Gastroenterol 1: 83-86.

8. Tanaka N, Nagaya T, Komatsu M, Horiuchi A, Tsuruta G, Shirakawa H, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K, Aoyama T, Kiyosawa K, Tanaka E. (2008) Insulin resistance and hepatitis C virus: a case-control study of non-obese, non-alcoholic and non-steatotic hepatitis virus carriers with persistently normal serum aminotransferase. Liver Int 28: 1104-1111.

9. Umemura T, Ota M, Hamano H, Katsuyama Y, Muraki T, Arakura N, Kawa S, Kiyosawa K. (2008)Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol 103: 588-594.

10. Umemura T, Ota M, Yoshizawa K, Katsuyama Y, Ich Tanaka E, Kiyosawa K.ijo T. (2008) Association of cytotoxic T-lymphocyte antigen 4 gene polymorphisms with type 1 autoimmune hepatitis in Japanese. Hepatol Res 38: 689-695.

11. Umemura T, Tanaka E, Kiyosawa K, Kumada H; Japan de novo Hepatitis B Research Group. (2008) Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan. Clin Infect Dis 47: e52-56.

12. Yoshizawa K, Shirakawa H, Ichijo T, Umemura T, Tanaka E, Kiyosawa K, Imagawa E, Matsuda K, Hidaka E, Sano K, Nakazawa Y, Ikegami T, Hashikura Y, Miyagawa S, Ota M, Nakano M.(2008) De novo autoimmune hepatitis following living-donor liver transplantation for primary biliary cirrhosis. Clin Transplant 22: 385-390.

13. Yokosawa S, Yoshizawa K, Ota M, Katsuyama Y, Kawa S, Ichijo T, Umemura T, Tanaka E, Kiyosawa K. (2007) A genomewide DNA microsatellite association study of Japanese patients with autoimmune hepatitis type 1. Hepatology 45: 384-90.

14. Umemura T, Muto H, Tanaka E, Matsumoto A, Ichijo T, Yoshizawa K, Akamatsu T, Kiyosawa K, and the Nagano Interferon Treatment Research Group. (2007) Anti-Helicobacter seropositivity: influence on severity and treatment response in patients with chronic hepatitis C. J Viral Hepatitis 14: 48-54.

15. Umemura T, Ota M, Yoshizawa K, Katsuyama Y, Ichijo T, Tanaka E, Kawa S, Kiyosawa K. (2007) Lack of association between FCRL3 and FcγRII polymorphisms in Japanese type 1 autoimmune hepatitis. Clin Immunol 122: 338-342.

16. Tanaka N, Horiuchi A, Yamaura T, Komatsu M, Tanaka E, Kiyosawa K. (2007) Efficacy and safety of 6-month iron reduction therapy in patients with hepatitis C virus-related cirrhosis: a pilot study. J Gastroenterol 42: 49-55.

17. Matsumoto A, Tanaka E, Minami M, TOkanoue T, Yatsuhashi H, Nagaoka S, Suzuki F, Kobayashi M, Chayama K, Imamura M, Yotsuyanagi H, Nakaoka S, Maki N, Kawata S, Kumada H, Iino S, Kiyosawa K. (2007) Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy. Hepatol Res 37: 661-666.

18. Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. (2007) Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology 46: 463-471.

19. Umemura T, Zen Y, Hamano H, Ichijo T, Kawa S, Nakanuma Y, Kiyosawa K. (2007) IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis. Gut. 56: 1471-1472.

20. Tanaka E, Matsumoto A, Suzuki F, Kobayashi M, Mizokami M, Tanaka Y, Okanoue T, Minami M, Chayama K, Imamura M, Yatsuhashi H, Nagaoka S, Yotsuyanagi H, Kawata S, Kimura T, Maki N, Iino S, Kiyosawa K. (2006) HBV Core-Related Antigen Study Group. Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance. Liver Int 26(1): 90-96.

21. Misawa N, Matsumoto A, Tanaka E, Rokuhara A, Yoshizawa K, Umemura T, Maki N, Kimura T, Kiyosawa K. (2006) Patients with and without loss of hepatitis B virus DNA after hepatitis B e antigen seroconversion have different virological characteristics. J Med Virol 78: 68-73.

22. Tanaka N, Tanaka E, Sheena Y, Komatsu M, Okiyama W, Misawa N, Muto H, Umemura T, Ichijo T, Matsumoto A, Yoshizawa K, Horiuchi A, Kiyossawa K. (2006) Useful parameters for distinguishing nonalcoholic steatohepatitis with mild steatosis from cryptogenic chronic hepatitis in the Japanese population. Liver Int 26:956-963.

23. Rokuhara A, Matsumoto A, Tanaka E, Umemura T, Yoshizawa K, Kimura T, Maki N, Kiyosawa K. (2006) Hepatitis B virus RNA is measurrable in serum and can be a new marker for monitoring lamivudine therapy. J Gastroenterol 41: 785-790.

24. Matsumoto A, Tanaka E, Rokuhara A, Kiyosawa K, Kumada H, Omata M, Okita K, Hayashi N, Okanoue T, Iino S, Tanikawa K; the Inuyama Hepatitis Study Group. (2005) Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients. Hepatol Res 14: 173-184

25. Tanaka E, Matsumoto A, Takeda N, Li TC, Umemura T, Yoshizawa K, Miyakawa Y, Miyamura T, Kiyosawa K (2005) Age-specific antibody to hepatitis E virus has remained constant during the past 20 years in Japan. J Viral Hepat 12: 439-442.

26. Yoshizawa K, Ota M, Katsuyama Y, Ichijo T, Matsumoto A, Tanaka E, Kiyosawa K. (2005) Genetic analysis of the HLA region of Japanese patients with type 1 autoimmune hepatitis. J Hepatol. 42: 578-584.

Division of Gastroenterology
1. Umemura T, Joshita S, Ichijo T, Yoshizawa K, Katsuyama Y, Tanaka E, Ota M; The Shinshu PBC Study Group.　HLA class II molecules confer both susceptibility and progression in Japanese patients with primary biliary cirrhosis.　 Hepatology 2012;55:506-511.

2. Yoshizawa K, Matsumoto A, Ichijo T, Umemura T, Joshita S, Komatsu M, Tanaka N, Tanaka E, Ota M, Katsuyama Y, Kiyosawa K, Abe M, Onji M.  Long-term outcome of Japanese patients with type 1 autoimmune hepatitis. Hepatology 2012;56:668-76.

3. Umemura T, Tanaka E, Kiyosawa K, Kumada H, the Japan de novo Hepatitis B Research Group. Mortality secondary to fulminant hepatic failure in patients with prior resolution of hepatitis B virus infection in Japan. Clinical Infectious Diseases 2008;47:e52-56.

4. Shirakawa H, Matsumoto A, Joshita S, Komatsu M, Tanaka N, Umemura T, Ichijo T, Yoshizawa K, Kiyosawa K, Tanaka E. Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology 2008;48:1753-1760.

5. Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. ImmunoglobulinG4-hepatopathy: Association of IgG4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology 2007;46:463-471.

6. Suzawa K, Kobayashi M, Sakai Y, Hoshino H, Watanabe M, Harada O, Ohtani H, Fukuda M, Nakayama J：Preferential induction of peripheral lymph node addressin on high endothelial venule-like vessels in the active phase of ulcerative colitis.：Am J Gastroenterol. 102(7):1499-509, 2007

7. Hamano H, Kawa S, Uehara T, Ochi Y, Takayama M, Komatsu K, Muraki T, Umino J, Kiyosawa K, Miyagawa S. Immunoglobulin G4-related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis. Gastrointest Endosc. 2005 Jul;62(1):152-7

8. Hamano H, Kawa S, Ochi Y, Unno H, Shiba N, Wajiki M, Nakazawa K, Shimojo H, Kiyosawa K. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet. 2002 Apr 20;359(9315):1403-4.

9. Suga T, Akamatsu T, Kawamura Y, Saegusa H, Kajiyama M, Nakamura N, Takei M, Matsumoto A : Actual behaviour of N-butyl-2-cyanoacrylate (histoacryl) in a blood vessel: a model of the varix. Endoscopy 34 : 73-77, 2002.

10. Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, Fukushima M, Nikaido T, Nakayama K, Usuda N, Kiyosawa High serum IgG4 concentrations in patients with sclerosing pancreatitis. K.N Engl J Med. 2001 Mar 8;344(10):732-8.


Division of Nephrology
1. Hashimoto K, Kamijo Y, Nakajima T, Harada M, Higuchi M, Ehara T, Shigematsu H, Aoyama T. PPARα Activation Protects against Anti-Thy1 Nephritis by Suppressing Glomerular NF-κB Signaling. PPAR Res. 976089, 2012

2. Kamijo Y, Wang L, Matsumoto A, Nakajima T, Hashimoto K, Higuchi M, Kyogashima M, Aoyama T, Hara A: Long-term improvement of oxidative stress via kidney transplantation ameliorates serum sulfatide levels. Clin Exp Nephrol 16: 959-967, 2012

3. Sheng X, Nakajima T, Wang L, Zhang X, Kamijo Y, Takahashi K, Tanaka N, Sugiyama E, Kyogashima M, Aoyama T, Hara A. Attenuation of kidney injuries maintains serum sulfatide levels dependent on hepatic synthetic ability: a possible involvement of oxidative stress. Tohoku J Exp Med 227;1-12, 2012

4. Shimada K, Tomita T, Kamijo Y, Higuchi M, Ito K, Koizumi Y, Yamamoto K, Aizawa K, Koshikawa M, Kasai H, Izawa A, Miyashita Y, Kumazaki S, Koyama J, Ikeda U. Hemodialysis-induced P-wave signal-averaged electrocardiogram alterations are indicative of vulnerability to atrial arrhythmias. Circ J 76;612-617, 2012

5. Kamijo Y, Hashimoto K, Takahashi K, Ehara T, Shigematsu H, Higuchi M: Treatment with cyclosporine A improves SLE disease activity of Japanese patients with diffuse proliferative lupus nephritis. Clin Nephrol 76: 136-143, 2011

6. Takahashi K, Kamijo Y, Hora K, Hashimoto K, Higuchi M, Nakajima T, Ehara T, Shigematsu H, Gonzalez FJ, Aoyama T: Pretreatment by low-dose fibrates protects against acute free fatty acid-induced renal tubule toxicity by counteracting PPARalpha deterioration. Toxicol Appl Pharmacol 252: 237-249, 2011

7. Kono K, Kamijo Y, Hora K, Takahashi K, Higuchi M, Kiyosawa K, Shigematsu H, Gonzalez F. J, Aoyama T: PPAR{alpha} attenuates the proinflammatory response in activated mesangial cells. Am J Physiol Renal Physiol. 296: F328-336, 2009

8. Kamijo Y, Hora K, Kono K, Takahashi K, Higuchi M, Ehara T, Kiyosawa K, Shigematsu H, Gonzalez FJ, Aoyama T. PPARα protects proximal tubular cells from acute fatty acid toxicity. J Am Soc Nephrol 18: 3089-3100, 2007

9. Hu R, Li G, Kamijo Y, Aoyama T, Nakajima T, Inoue T, Node K, Kannagi R, Kyogashima M, Hara A. Serum sulfatides as a novel biomarker for cardiovascular disease in patients with end-stage renal failure. Glycoconj J. 2007 Dec;24(9):565-71.

10. Kamijo Y, Hora K, Nakajima T, Kono K, Takahashi K, Ito Y, Higuchi M, Kiyosawa K, Shigematsu H, Gonzalez FJ, Aoyama T. Peroxisome proliferator-activated receptor alpha protects against glomerulonephritis induced by long-term exposure to the plasticizer di-(2-ethylhexyl)phthalate. J Am Soc Nephrol. 18:176-88, 2007


Division of Hematology
1. Sekiguchi N, Asano N, Ito T, Momose K, Momose M, Ishida F: Elevated serum granulysin and its clinical relevance in mature NK-cell neoplasms. Int J Hematol 96: 461-468, 2012

2. Ito T, Makishima H, Nakazawa H, Senoo Y, Senoo N, Ishida F: Donor lymphocyte infusion for extranodal NK/T cell lymphoma, nasal type, relapsed after allogeneic hematopoietic SCT. Bone Marrow Transplant 46: 1270-1271, 2011

3. Asano N, Suzuki R, Ohshima K, Kagami Y, Ishida F, Yoshino T, Ogawa H, Morishima Y, Nakamura S: Linkage of expression of chemokine receptors (CXCR3 and CCR4) and cytotoxic molecules in peripheral T cell lymphoma, not otherwise specified and ALK-negative anaplastic large cell lymphoma. Int J Hematol. 91: 426-435; 2010

4. Ishida F, Kwong YL: Diagnosis and management of natural killer-cell malignancies. Expert Rev Hematol. 3: 593-602; 2010

5. Ishida F, Nishina S, Asano N, Sasaki S, Sekiguchi N, Nakazawa H, Ito T, Shikama N: Late relapse of extranodal natural killer/T cell lymphoma, nasal type, after more than ten years. Leuk Lymphoma. 51: 171-173; 2010

6. Ishida F, Okubo K, Ito T, Okumura N, Souri M, Ichinose A: Spontaneous regression of the inhibitor against the coagulation factor XIII A subunit in acquired factor XIII deficiency. Thromb Haemost. 104: 1284-1285; 2010

7. Asano N, Yamamoto K, Tamaru J, Oyama T, Ishida F, Ohshima K, Yoshino T, Nakamura N, Mori S, Yoshie O, Shimoyama Y, Morishima Y, Kinoshita T, Nakamura S: Age-related Epstein-Barr virus (EBV)-associated B-cell lymphoproliferative disorders: comparison with EBV-positive classic Hodgkin lymphoma in elderly patients. Blood. 113: 2629-2636, 2009

8. Ito T., Makishima H., Nakazawa H., Kobayashi H., Shimodaira S., Nakazawa Y., Kitano K., Matsuda K., Hidaka E.,Ishida F. Promising approach for aggressive NK cell leukaemia with allogeneic haematopoietic cell transplantation. Eur J Haematol 2008; 81(2): 107-111.

9. Makishima H., Komiyama Y., Asano N., Momose K., Nakamura S.,Ishida F. Peripheral T-cell lymphoma following diffuse large B-cell lymphoma associated with celiac disease. Intern Med 2008; 47(4): 295-298.