Review, safety, and relief services of the Pharmaceuticals and Medical Devices Agency are primarily focused on scientifically evaluating pharmaceuticals, medical devices, and cellular and tissue-based products referring to their quality, efficacy, and safety, which requires a variety of scientific knowledge and methods. Pharmaceutical regulation should be established based on the most advanced scientific expertise at all times. In order to evaluate products that use cutting-edge technology such as induced pluripotent stem cells and information and communication technology adequately, since fiscal year 2012 the Science Committee has been established as a platform to exchange opinions among members from top-ranking domestic and international academia and to enhance personnel exchanges through the Initiative to Facilitate Development of Innovative Drugs. In addition, the Regulatory Science Center will be established in 2018 to increase the integrity of our services for product reviews and safety measures. In particular, requiring electronic data submissions for clinical trial applications followed by an advanced approach to analysis should not only enhance the quality of reviews of individual products but should also support the development of pharmaceuticals and medical devices by providing pharmaceutical affairs consultations on research and development strategies with various guidelines based on new insights resulting from product-bridging data analysis. Moreover, a database including electronic health records with comprehensive medical information collected mainly from 10 cooperating medical institutions will be developed with the aim of developing safety measures in a more timely manner using methods of pharmacoepidemiological analysis.

Despite the marked progress in the procedure of allogeneic hematopoietic stem cell transplantation (allo- HCT) as a curative therapy for hematological malignancy, we still need to resolve issues in clinical laboratory testing for the assessment of transplant patients. For example, minimal residual disease (MRD) negativity before transplantation is known to be associated with good survival, but the widespread use of the multi-color flow cytometry system is needed for the routine assessment of MRD. In addition, we should apply an appropriate testing system for counting harvested bone marrow cells with careful consideration of the meas- urement principle of testing equipment because bone marrow is different from peripheral blood in its compo- sition of cells and components. It is also a problem that the short tandem repeat-polymerase chain reaction (PCR) for the evaluation of donor chimerism is not covered by Japanese national health insurance. Tissue biopsy is useful for the diagnosis of graft-versus-host disease, transplantation-associated microangi- opathy, and sinusoidal obstruction syndrome. It is, however, potentially dangerous for patients who have thrombocytopenia after allo-HCT to undergo a biopsy. Non-invasive tests including surrogate makers for the diagnosis of those complications are highly desirable, but they have been not established. Moreover, limitations in the diagnosis of infection after allo-HCT by laboratory tests include the poor clinical utility of the viral antibody test after allo-HCT and the fact that quantitative virus PCR tests after allo-HCT are not covered by Japanesehational health insurance. The number of long-term transplant survivors has increased in recent years. We therefore need to focus on treatment strategies against long-term complications after allo-HCT and the improvement of the quality of life. Further progress in laboratory medicine in the allo-HCT field may contribute to the prevention of late complications and/or improvement of the quality of life. I.

Recent advances in the treatment of inflammatory bowel diseases has raised its therapeutic goal up to completely repairing the damaged intestinal tissue and achieve "mucosal healing". To improve and further facilitate the tissue repair process in inflammatory bowel disease patients, stem cell based therapy using mesenchymal stem cells is under development. Also, transplantation of ex-vivo cultured intestinal stem cells is another regenerative therapy that may become an alternative choice to treat refractory ulcers in inflammatory bowel disease patients. Therefore, the present review summarizes the present achievement as well as future prospects of stem cell based therapy in inflammatory bowel disease.

The newt switches the cellular mechanism for limb regeneration from a stem/progenitor-based mechanism(larval mode)to a dedifferentiation-based one(adult mode)as it grows beyond metamorphosis. When it comes to muscle, larval newts regenerate muscle from muscle stem/progenitor cells such as satellite cells, but after metamorphosis the animals recruit muscle fibers for the same purpose by means of dedifferentiation in which muscle fibers(multinucleated cell)at the stump are fragmented to produce mononucleated cells, the primary cell source for new muscle. Dedifferentiation of muscle fibers may have been advantageous for the newt, during its evolution, to quickly regenerate the limbs by supplementing satellite cells whose number and potency become restricted by metamorphosis(transformation to adapt to terrestrial environments)or aging. The ability of dedifferentiation may have been invented in this animal through modifications of the molecular mechanism(or program)which runs in dying or degenerating muscle fibers.

Skeletal muscle has its stem cell named satellite cell. The absence of satellite cells does not allow muscle regeneration, it is unquestionable that satellite cell is indispensable for muscle regeneration processes. A certain number of satellite cells appear to be necessary for the successful muscle regeneration, meaning the maintenance of the satellite cells is essential for the functional homeostasis of skeletal muscle. Recent studies have revealed the molecular mechanism underlying satellite cell maintenance in a steady state. A loss of those molecules responsible for the maintenance often results in decreased satellite cell pool and reduced regeneration ability. On the other hand, the contribution of satellite cells to muscle hypertrophy or aged-related atrophy(sarcopenia)is controversial. In this review, we will introduce the molecules that regulate satellite cells homeostasis in the dormant state and then further discuss the recent results on the roles of satellite cell in sarcopenia.

A 62-year-old man with CHOP refractory adult T-cell leukemia/lymphoma (ATLL) received anti-CC chemokine receptor 4 antibody (mogamulizumab) combined with CHOP and achieved complete remission. At 71 days after the final administration of mogamulizumab, he received umbilical cord blood transplantation (CBT) using reduced intensity conditioning. Umbilical cord blood engraftment was confirmed on day16. Grade II acute graft-versus-host disease (GVHD) was diagnosed on day60 and was controlled by administration of methylprednisolone. There was no evidence of relapse at 9 months after CBT. Ratios of regulatory T cells in CD4 positive T cells were remarkably low during all of these periods. Since mogamulizumab reduces regulatory T cells, the frequency and severity of acute GVHD were reported to be increased in patients administered mogamulizumab before allogenic stem cell transplantation. Further experiences are needed for selecting optimal donor sources, the portability period and GVHD prophylaxis for patients using mogamulizumab before allogeneic stem cell transplantation.

A 75-year-old woman was referred to our hospital with suspected leukemia. Complete blood count demonstrated WBC 3,810/µl with 26% blasts, Hb of 11.7 g/dl and Plt of 18.0×104/µl. Bone marrow aspiration revealed blasts (86.3%) with expressions of CD34, CD7, TdT, CD33, and CD117. MPO was negative. Chromosomal analysis of the bone marrow showed isolated trisomy 10 in all leukemic cells (20/20). Swelling of superficial lymph nodes was also observed. Cervical lymph node biopsy revealed leukemic blasts which had the same phenotype as those in the bone marrow except that proliferation of Langerhans cell-like cells (LCs) was observed in the paracortex. LCs had pale cytoplasm and grooved nuclei, and were positive for both CD1a and S100 protein. Trisomy 10 was detected in both the leukemic blasts and the LCs by fluorescence in situ hybridization. This rare case strongly suggests leukemic cells to differentiate into LCs.

Heart failure is a life-threatening disorder worldwide, and the current end-stage therapies for severe heart failure are replacement therapies such as ventricular-assist devices and heart transplantation. Although these therapies have been reported to be useful, there are many issues in terms of the durability, complications, limited donors, adverse effect of continuous administration of immunosuppressive agents, and high costs involved. Recently, regenerative therapy based on genetic, cellular, or tissue engineering techniques has gained attention as a new therapy to overcome the challenges encountered in transplantation medicine. We focused on skeletal myoblasts as the source of progenitor cells for autologous cell transplantation and the cell-sheet technique for site-specific implantation. In vitro studies have reported that myoblast sheets secrete cytoprotective and angiogenic cytokines such as hepatocyte growth factor (HGF). Additionally, in vivo studies using large and small animal models of heart failure, we have shown that myoblast sheets could improve diastolic and systolic performance and enhance angiogenesis and antifibrosis as well as the expression of several cytokines including HGF and vascular endothelial growth factor(VEGF) in the tissues at the transplanted site. Based on the results of these studies, we performed clinical trials using autologous myoblast sheets in ischemic cardiomyopathy (ICM) and dilated cardiomyopathy patients. Some patients showed left ventricular reverse remodeling and improved symptoms and exercise tolerance. Recently, multiple medical institutions including our institution successfully conducted an exploratory, uncontrolled, open-label phase II study in subjects with ICM to validate the efficacy and safety of autologous myoblast sheets. Moreover, as a novel cell source for regenerative medicine, our recent studies demonstrated that induced pluripotent stem cell-derived cardiomyocyte sheets showed electrical and microstructural homogeneity with heart tissue in vitro and in vivo, thus establishing proof of concept in small and large animal models of heart failure.

Ephedra Herb is defined in the 17th edition of the Japanese Pharmacopoeia as the terrestrial stem of Ephedra sinica STAPF., Ephedra intermedia SCHRENK et C.A. MEYER, or Ephedra equisetina BUNGE (Ephedraceae) which contains more than 0.7% ephedrine alkaloids (ephedrine and pseudoephedrine). The primary effects and adverse effects of Ephedra Herb are traditionally believed to be mediated by ephedrine alkaloids. We recently reported that Ephedra Herb extract (EHE) exhibits antimetastatic and antitumor effects by suppressing the hepatocyte growth factor-c-Met signaling pathway through the inhibition of c-Met tyrosine kinase activity. We confirmed that the non-alkaloidal fraction of EHE had c-Met-inhibitory activity. Moreover, we discovered herbacetin glycosides in EHE and demonstrated that herbacetin, the aglycone of the glycosides, shows c-Met-inhibitory activity and analgesic action. These findings suggest that some pharmacological actions of EHE may be produced by its non-alkaloidal fraction, which does not cause the adverse effects of ephedrine alkaloids. Therefore, we prepared ephedrine alkaloids-free EHE (EFE) by removing ephedrine alkaloids from EHE using ion-exchange column chromatography. EFE had c-Met-inhibitory action, analgesic effects, and antiinfluenza activity similar to EHE but had no toxicity. Now, we are evaluating the safety of EFE in healthy volunteers and its efficacy in patients to obtain licensing approval for its therapeutic use in the future.

Aberrant activation of Wnt/β-catenin canonical signaling is observed in multiple malignant tumors, and is recognized as an attractive therapeutic target for molecular targeted drugs. This signaling pathway is also involved in maintaining pluripotency in adult stem cells. Therefore, lowering potential stem cell toxicity is a key factor for the development of a Wnt/β-catenin signaling inhibitor. Here, we show Wnt/β-catenin pathway inhibitors with low toxicity, identified through phenotype-based screening using zebrafish embryos. Artificial activation of the Wnt/β-catenin pathway in fertilized eggs, which are often considered the "ultimate stem cells", results in an "eyeless" phenotype in zebrafish embryos. Screening for compounds that rescue this "eyeless" phenotype and have no effects on normal embryogenesis could help us identify Wnt/β-catenin pathway inhibitors with minimal stem cell toxicities, at least at a concentration that suppresses aberrant signaling. Chemical suppressors of the "eyeless" phenotype include novel and known compounds with different modes of action. Some of these compounds diminish the activation of crosstalk between other signaling pathways and the Wnt/β-catenin pathway. These inhibitors reduced tumor growth in ApcMin/+ mice and did not show apparent toxicities. Thus, our screening for chemical suppressors of the "eyeless" phenotype allowed us to successfully identify inhibitors for the Wnt/β-catenin pathway with low toxicity.

The emergence of drug resistance is a major obstacle to the successful pharmacological treatment of cancer. Tumor heterogeneity is one of the key factors underlying drug resistance. Cancer cell heterogeneity in tumors is caused by genetic mutation and by the existence of cancer stem cells (CSCs). CSCs are defined as a subpopulation of highly tumorigenic cancer cells with self-renewal activity. It has been reported that various types of cancer involve CSCs, and that CSCs are generally resistant to anticancer drugs. Therefore, CSC-targeting agents could allow for more effective pharmacological treatment of cancer. Using a comprehensive gene expression study and functional genomic approach, we are trying to identify CSC-specific survival factors, as well as candidate compounds that interfere with CSC-selective survival signaling. These CSC-targeting drugs could be promising new therapeutic agents which would suppress the emergence of drug-resistant cells and enhance the effect of antitumor agents.

A haplobank of induced pluripotent stem cell (iPSC) lines derived from healthy donors with homozygous human leukocyte antigen(HLA), which is called "an iPSC stock", has been under construction in Japan. The iPSC stock is expected to enable HLA matching of a majority of recipients and reduce the risk of trans- plant rejection. Full-scale operations began in FY2013, with the aim of covering 30-50% of the Japanese population by FY2017 and most of the population by FY2022 with the iPSC stock. A novel feeder-free and xeno-free culture system for iPSCs was developed to comply with regulatory safety standards. In 2015, a clinical-grade iPSC line with homozygous HLA of the highest-frequency haplotype was released as a first in the world. Other clinical-grade lines are being generated successively. If all goes to plan, the first clinical research using the iPSC stock will start in 2017. However, many challenges remain to ensuring the future of iPSC stock. In accordance with the progress of the latest research, safety issues regarding iPSC-based cell therapy are being monitored with much interest, and one of the major concerns is tumorigenicity. We have to continue to discuss the extent of genomic abnormalities that would or would not be acceptable in not only iPSC-derived products but also iPSC stock, taking into account the risks and benefits of cell therapy. It is also necessary to demonstrate the clinical efficacy of HLA matching, which is indicated to promote graft survival and reduce immunosuppressive drug use.

Clinical results have shown promising therapeutic potential of engineered T cell express- ing TCR (T cell antigen receptor) or CAR (chimeric antigen receptor). However, high cost, donor cell availability, complicated procedure of genetic engineering prevent their wider ap- plication. iPSCs (induced pluripotent stem cells) are attractive source of immune cells includ- ing T cells and dendritic cells, and may provide an unlimited cell source for adoptive immune cell therapy. Genetic engineering of iPSCs may confer enhanced anti-tumor activity and ena- ble the escape from immune rejection. Here, we discuss the potential of iPSCs as a novel source of anti-tumor immune cells.

Identification of tumor-associated antigens (TAAs) recognized by T cells has enabled clinical peptide vaccination trials targeting TAAs to be performed for patients with carcinoma or sarcoma. Although peptide vaccination could elicit specific immunological responses, clinical objective responses were not frequently observed, especially in end-stage patients with large tumor burdens who were receiving high-dose chemotherapy. The key points for developing effective peptide vaccination therapy are (i) targeting cancer stem-like cell antigens that are expressed in cancer cells but not in normal cells and regulating tumorigenesis and (ii) manip- ulating memory T stem cells that have the capacity of long-living and resistance to chemo- therapeutic drugs. The combination of a peptide vaccination and immune checkpoint inhibi- tors might also be attractive.

The intestinal epithelium constitutes a physical barrier between inner and outer side of our body. It also functions as a "hub" which connects factors that determine the development of inflammatory bowel disease, such as microbiota, susceptibility genes, and host immune response. Accordingly, recent studies have implicated and further featured the role of intestinal epithelial cell dysfunction in the pathophysiology of inflammatory bowel disease. For example, mucin producing goblet cells are usually "depleted" in ulcerative colitis patients. Studies have shown that those goblet cells exhibit various immune-regulatory functions in addition to mucin production, such as antigen presentation or cytokine production. Paneth cells are another key cell lineage that has been deeply implicated in the pathophysiology of Crohn's disease. Several susceptibility genes for Crohn's disease may lead to impairment of anti-bacterial peptide production and secretion by Paneth cells. Also, other susceptibility genes may determine the survival of Paneth cells, which leads to reduced Paneth cell function in the patient small intestinal mucosa. Further studies may reveal other unexpected roles of the intestinal epithelium in the pathophysiology of inflammatory bowel disease, and may help to develop alternative therapies targeted to intestinal epithelial cell functions.

Since the discovery of induced pluripotent stem cells (iPSCs) generation, much progress has been made in the fields of medical and pharmaceutical research, such as cell transplantation therapy. We have generated retinal cells and tissues, including retinal pigment epithelia (RPE), from human iPSCs. The ability to produce iPSCs from patients allows for autologous transplantation without causing immune rejection. The autologous transplantation of iPSC-derived retinal pigment epithelial sheets to a patient with age-related macular degeneration was carried out in Japan in 2014 as a first-in-human clinical study. Biotechnology has enabled the development of a wide range of drugs, including cell-based drugs. We are currently developing iPSC-derived RPE sheets as next-generation cell-based drugs aimed at allogeneic transplantation utilizing iPSC banks of homozygotes of human leukocyte antigen at 3 loci. Regulatory science concerning cellular and tissue-based products is a vital matter associated with the realization of regenerative medicine. Here we review the most recent progress in retinal regeneration and drug development, as well as its future prospects.

FMS-like tyrosine kinase 3 (FLT3), a class III tyrosine kinase receptor, plays an important role in the pro- liferation, survival, and differentiation of hematopoietic stem/progenitor cells. Approximately 30% of pa- tients with cytogenetically normal acute myeloid leukemia (CN-AML) harbor FLT3 mutations. The most frequent FLT3 mutations are internal tandem duplications (ITDs) in the juxtamembrane domain. FLT3-ITD mutations cause ligand-independent dimerization of FLT3 and the constitutive activation of its downstream signaling pathways, such as PI3K/AKT, A4APK/ERK, and STAT5, leading to dysregulated cellular prolifera- tion. The relapse risk of CN-AML patients with FLT3-ITD is higher and the overall survival (OS) of such patients is shorter than those of patients with wild-type FLT3. Recently genome-wide studies with next-generation sequencing have suggested that mutational combinations of genes related to signal transduction, transcription, splicing, cancer suppressors, and epigenetics contribute to the pathogenesis of AML. These mutations including FLT3-ITD may be prognostic factors facilitating the risk stratification for CN-AML. The point mutations D835/I836 in the tyrosine kinase domain (TKD) are detected in 5-7% of AML patients. The clinical relevance of these FLT3-TKD mutations remains unclear. FLT3-TKD mutations are detected even in patients treated with FLT3 inhibitors as secondary mutations, suggesting that the mutations are as- sociated with the resistance. Therefore, the detection of these mutations might provide us with the opportunity to consider appropriate treatment for patients. The molecular abnormalities in AML patients give us insights into the pathology of AML and clinically significant information required for the diagnosis, prognosis, and treatment decisions. [Review].