Hisashi Moriguchi

Uterine autotransplantation in cynomolgus macaques: the first case of pregnancy and delivery

BACKGROUND For women with congenital uterine infertility, or for those who have undergone hysterectomy, uterine transplantation is one of the potential treatments to regain fertility. In this study, we utilized a primate model of uterine transplantation, and evaluated the patency of our microsurgical anastomoses, and the perfusion of the transplanted uterus. METHODS Two female cynomolgus monkeys underwent surgery. We anastomosed two arteries and one vein in Case 1 and two arteries and two veins in Case 2. The arteries used were the uterine arteries and the anastomosis was done to the external iliac artery. We used one of the ovarian veins in both animals, but resected the ovary from the Fallopian tube. Uterine arterial blood flow and uterine size were determined by intraoperative indocyanine green (ICG) angiography and ultrasonography. The biopsy of the uterine cervix was performed after surgery. RESULTS ICG angiography showed that the unilateral uterine artery perfused the bilateral uterine bodies and cervix. In Case 1, ICG angiography showed the occlusion of one of the anastomosed arteries during the operation and the uterus appeared atrophied 2 months after operation. In Case 2, the transplanted uterus survived and normal menstruation occurred. The animal achieved a natural pregnancy and was delivered by the Caeserean section due to early separation of the placenta. The newborn suffered fetal distress. CONCLUSIONS These results show the anastomosis of at least the bilateral uterine arteries and the unilateral ovarian vein is required for uterus transplantation. This is the first report of a natural pregnancy in a primate following uterine autotransplantation.

Uterus autotransplantation in cynomolgus macaques: intraoperative evaluation of uterine blood flow using indocyanine green

BACKGROUND Uterus transplantation may be the only theoretical option for some women, for example, those with congenital uterine infertility or who have undergone hysterectomy. In this study, we evaluated the intra- and post-operative blood flow conditions of vascular anastomosed regions and the blood-perfused area of the transplanted uterus in a cynomolgus macaque model of uterus autotransplantation. METHODS Female cynomolgus monkeys (n = 6) underwent surgery: the first two animals were used to study the pelvic vascular anatomy and the remaining four animals were used for uterus autotransplantation. We used indocyanine green (ICG) fluorescent angiography during surgery to assess blood perfusion in the vascular anastomosed region and uterine area. After surgery, the uterine size, presence or absence of the endometrium and blood flow rates in the uterine artery and vein were evaluated using Doppler ultrasonography. RESULTS; Uterine arterial and venous anastomoses succeeded in all four animals that underwent autotransplantation. Intraoperative ICG fluorescence angiography showed favorable blood flow in the vascular anastomosed regions and the entire uterus received a sufficient blood supply from a single uterine artery. Favorable blood flow in the uterine artery and vein immediately after surgery was shown by Doppler ultrasonography. Ultimately, three out of four animals died within 3 months following surgery because of reduced feeding and loss of body strength. CONCLUSIONS ICG fluorescence angiography can be used for simple evaluation of real-time blood flow conditions in the anastomosed uterine artery, vein and uterine area and can facilitate the success rate of uterus transplantation.

Lymphaticovenous anastomosis for facial lymphoedema after multiple courses of therapy for head-and-neck cancer

Lymphaticovenous anastomosis (LVA) is a treatment for lymphoedema that can improve lymph circulation by the anastomosis of lymph vessels and veins. A therapeutic effect of LVA for lymphoedema has been shown in limbs, but efficacy for other regions has not been shown. Lymphoedema in the head-and-neck region following cancer resection and radiotherapy is mainly treated with manual lymphatic drainage. However, there is no alternative when this treatment is ineffective because application of compression treatment using a bandage is difficult in this region. We used LVA for lymphoedema in the head-and-neck region and achieved a good outcome. Functional and dilating lymph vessels were identified using pre- and intra-operative fluorescent lymphography, and a lymph vessel with a diameter of about 0.2-1.0 mm was anastomosed with a vein using supermicrosurgery. The outcome of this case suggests that LVA is applicable for treatment of lymphoedema in the head-and-neck region.

Chromatin remodeling system, cancer stem-like attractors, and cellular reprogramming.

The cancer cell attractors theory provides a next-generation understanding of carcinogenesis and natural explanation of punctuated clonal expansions of tumor progression. The impressive notion of atavism of cancer is now updated but more evidence is awaited. Besides, the mechanisms that the ectopic expression of some germline genes result in somatic tumors such as melanoma and brain tumors are emerging but are not well understood. Cancer could be triggered by cells undergoing abnormal cell attractor transitions, and may be reversible with “cyto-education”. From mammals to model organisms like Caenorhabditis elegans and Drosophila melanogaster, the versatile Mi-2β/nucleosome remodeling and histone deacetylation complexes along with their functionally related chromatin remodeling complexes (CRCs), i.e., the dREAM/Myb-MuvB complex and Polycomb group complex are likely master regulators of cell attractors. The trajectory that benign cells switch to cancerous could be the reverse of navigation of embryonic cells converging from a series of intermediate transcriptional states to a final adult state, which is supported by gene expression dynamics inspector assays and some cross-species genetic evidence. The involvement of CRCs in locking cancer attractors may help find the recipes of perturbing genes to achieve successful reprogramming such that the reprogrammed cancer cell function in the same way as the normal cells.

Tumorigenicity of human induced pluripotent stem cells depends on the balance of gene expression between p21 and p53

1. Lok ASF, McMahon B. Chronic hepatitis B: Update 2009. HEPATOLOGY 2009;50:661-662. 2. Núñez M, Rı́os P, Pérez-Olmeda M, Soriano V. Lack of ‘occult’ hepatitis B virus infection in HIV-infected patients AIDS 2002;16:2099-2101. 3. Neau D, Winnock M, Jouvencel AC, Faure M, Castéra L, Legrand E, et al. Occult hepatitis B virus infection in HIV-infected patients with isolated antibodies to hepatitis B core antigen: Aquitaine cohort 20022003. Clin Infect Dis 2005;40:750-753. 4. Rodrı́guez-Torres M, Gonzales-Garcia J, Bräu N, Solá R, Moreno S, Rockstroh J, et al. APRICOT Investigators Occult Hepatitis B virus infection in the setting of hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co-infection: clinically relevant or a diagnostic problem? J Med Virol 2007;79:694-700. 5. Shire NJ, Rouster SD, Rajicic N, Sherman KE. Occult hepatitis B in HIV-infected patients. J Acquir Immune Defic Syndr 2004;36:869-875. 6. Lo Re VL 3rd, Frank I, Gross R, Reddy KR, Mounzer K, Zemel BS, et al. Prevalence, risk factors, and outcomes of occult hepatitis B virus infection among HIV-infected patients. J Acquir Immune Defic Syndr 2007;44:315-320. 7. Pogany K, Zaajier HL, Prins JM, Wit FW, Lange JM, Beld MG. Occult hepatitis B virus infection before and 1 year after start of HAART in HIV type-1 positive patients. AIDS Res Hum Retroviruses 2005;21:922-926. 8. Hofer M, Joller-Jemelka HI, Grob PJ, Luthy R, Opravil M. Frequent chronic hepatitis B virus infection in HIV infected patients positive for antibody to hepatitis B core antigen only. Swiss HIV cohort study. Eur J Clin Microbiol Infect Dis 1998;17:6-13. 9. Piroth L, Binquet C, Vergne M, Minello A, Livry C, Bour JB, et al. The evolution of hepatitis B virus serological patterns and the clinical relevance of isolated antibodies to hepatitis B core antigen in HIV infected patients. J Hepatol 2002;36:681-686. 10. Morsica G, Ancarani F, Bagaglio S, Maracci M, Cicconi P, Cozzi AL, et al. Occult hepatitis B virus infection in a cohort of HIV-positive patients: correlation with hepatitis C virus coinfection, virological and immunological features. Infection 2009;37:445-449.

An identification of the novel combination therapy for hepatitis C virus 1b infection by using a replicon system and human induced pluripotent stem cells

1. Yeoman AD, Westbrook RH, Al-Chalabi T, Carey I, Heaton ND, Portmann BC, et al. Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group (IAIHG) criteria in acute and chronic liver disease. HEPATOLOGY 2009;50:538-545. 2. Hennes EM, Zeniya M, Czaja AJ, Parés A, Dalekos GN, Krawitt EL, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. HEPATOLOGY 2008;48:169-176. Copyright

An identification of novel therapy for human hepatocellular carcinoma by using human induced pluripotent stem cells.

PVT. In other words, the gap among patency of various portal venous segments would have disappeared, if the data were stratified according to complete or partial obstruction. In contrast, degree stratification is consistently involved in the studies about outcome of invasive therapies for PVT due to its close associations with operability and prognosis. Herein, diverse classifications of PVT were listed in Table 2, except for simple classification into complete and partial thrombus. Further, some classical images in our patients are demonstrated (Fig. 1) for a clear distinction between partial and complete occlusion, which are mainly characterized by partial and complete absence of flow within portal vein on color Doppler ultrasound or angiography, or a filling defect and ‘‘train track’’ appearance of enhancement on computed tomography. From our perspectives, it is necessary for prediction of recanalization to accurately distinguish between complete and partial thrombosis in any study on management of PVT. XINGSHUN QI GUOHONG HAN JIANHONG WANG KAICHUN WU DAIMING FAN Department of Digestive Interventional Radiology, Department of Ultrasound, and State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China

A therapeutic method for the direct reprogramming of human liver cancer cells with only chemicals.

Various methods for the direct reprogramming of human somatic cells have been developed. However, a therapeutic method to reprogram and eliminate human solid tumor cells has not been developed. Here we show a novel therapeutic method to reprogram and eliminate human solid tumor cells with chemicals. This therapeutic method may be applicable to various human solid tumor cells that express aldo-keto reductase family 1 member B10 (AKR1B10) and retinoid X receptors (RXRs).

New translational research on novel drugs for hepatitis C virus 1b infection by using a replicon system and human induced pluripotent stem cells

1. Corey KE, Kane E, Munroe C, Barlow LL, Zheng H, Chung RT. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. HEPATOLOGY 2009;50:1030-1037. 2. Maggi G, Bottelli R, Gola D, Perricone G, Posca M, Zavaglia C, et al. Serum cholesterol and chronic hepatitis C. Ital J Gastroenterol 1996;28: 436-440. 3. Fabris C, Federico E, Soardo G, Falleti E, Pirisi M. Blood lipids of patients with chronic hepatitis: differences related to viral etiology. Clin Chim Acta 1997;261:159-165. 4. Dai CY, Chuang WL, Ho CK, Hsieh MY, Huang JF, Lee LP, et al. Associations between hepatitis C viremia and low serum triglyceride and cholesterol levels: a community-based study. J Hepatol 2008;49:9-16. 5. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-1389. 6. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C; American College of Cardiology; American Heart Association; National Heart, Lung and Blood Institute. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002;106:1024-11028. 7. Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 2009;49:225-232. 8. Alyan O, Kacmaz F, Ozdemir O, Deveci B, Astan R, Celebi AS, et al. Hepatitis C infection is associated with increased coronary artery atherosclerosis defined by modified Reardon severity score system. Circ J 2008;72:1960-1965.

An indicator for evaluating the risk of cancerous transformations of human induced pluripotent stem cells.

the not entirely characterized lysosomal complex of metallothionein polymers with a glycoprotein component, as supported by periodic acid–Schiff staining. We realized that copper-metallothionein autofluorescence was well-known in earlier literature, and wondered about its possible practical use and the potential role of autofluorescence in liver pathology as quoted in an excellent review on the subject. We thought it was worth sharing this matter in the Image of the Month forum and remain glad to have generated some academic debate.