The development of statin-based therapy for patients with hepatitis C virus (HCV) infection using human induced pluripotent stem (iPS) cell technology.

Human induced pluripotent stem (iPS) cells may transform drug discovery. Here I show an example of the development of statin (HMG-CoA reductase inhibitors)-based therapy for patients with hepatitis C virus (HCV) infection using human iPS cell technology. When Shimada et al. considered the two reports on the antiviral effects of pitavastatin for HCV infection in vitro by Moriguchi et al., they conducted a randomized controlled trial. As a result, a proof-of-concept for the antiviral effect of pitavastatin against HCV infection using human iPS cell technology by Moriguchi et al. was confirmed in the randomized controlled trial by Shimada et al. in 2012. Therefore, above-mentioned a series of studies became to the first to report the clinical application of human iPS cells. Furthermore, here I propose that new clinical research methods using human iPS cell technology will be able to circumvent the limitations of conventional randomized controlled trials (RCTs) for the purpose of personalized medicine in the clinical setting.

The reprogramming therapy for a patient with advanced hepatocellular carcinoma by using human-induced pluripotent stem (iPS) cells technology.

Therapeutic methods to reprogramme and destroy human solid tumour cells have not been developed. We show a proof-of-concept for the direct reprogramming therapy of human solid tumour cells. Furthermore, our study is the first to report on the development of a new treatment by using human-induced pluripotent stem cells technology.

Stable expressions of nine genes within human oocytes and live birth by in vitro fertilisation.

The development of new methods to cryopreserve human ovarian cortex tissues without damage is needed for the improvement of quality of life of female cancer patients. Here, we show that stable expressions of nine genes within human oocytes by using a supercooling procedure are necessary in order to produce human mature eggs and experience live births with high safety profiles by in vitro fertilisation. Our method will be helpful in order to preserve the fertility of female cancer patients or healthy women.

Successful cryopreservation of human ovarian cortex tissues using supercooling.

The development of new method to cryopreserve human ovarian cortex tissues without damage is needed for the improvement of quality of life (QOL) of female cancer patients. Here we show novel cryopreservation method of human ovarian cortex tissues by using supercooling (S.C.) procedure. Our method will be helpful in order to preserve fertility of female cancer patients.

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.

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).

A new surgical technique of uterine auto-transplantation in cynomolgus monkey: preliminary report about two cases.

OBJECTIVE: Uterine transplantation experiments have been performed in various animal species for future clinical applications of uterine transplantation for permanent uterine factor infertility in humans. The aim of this study was to confirm the feasibility of uterine auto-transplantation in cynomolgus monkeys by developing new surgical techniques. METHODS: Two female cynomolgus monkeys underwent surgery under general anesthesia. The uterus with vascular grafts and the vaginal wall was removed, and back-table preparation was performed using heparinized saline. The uterus with vascular grafts and the vaginal wall was anastomosed with the vaginal stump and blood vessels in the pelvis, respectively. The auto-transplant uterine function was evaluated by confirming engraftment of the uterus by laparotomy, endometrial proliferation by transabdominal ultrasonography and periodical menstruation. RESULTS: The first animal died due to acute renal failure 2 days after the operation. Second-look laparotomy in the second animal at 40 days after the operation indicated there was no congestion in the uterus, and the uterus showed the typical red color of a normal uterus. Thereafter, endometrial proliferation was observed by transabdominal ultrasonography and periodical menstruation was confirmed, indicating re-established uterine function. CONCLUSION: This is the preliminary report of uterine auto-transplantation in cynomolgus monkeys. This study demonstrates the feasibility of uterine auto-transplantation by using new surgical technique in cynomolgus monkeys. Accumulation of basic experimental data in non-human primates is required prior to performing the procedure in humans.

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-2ß/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.

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.