Tyrosine kinase inhibitors (TKIs) have dramatically improved the clinical outcomes of patients with chronic myeloid leukemia (CML) in the chronic phase. However, even if these patients achieve and maintain marked molecular responses such as a complete molecular response (BCR-ABL/ABL≤0.032% by international scale), discontinuation of TKI treatment results in early molecular relapse in most cases. Although several factors such as the Sokal score and the duration of TKI treatment have been identified as being related to treatment-free remission (TFR), identification of more definite factors or clinical conditions that would enable us to select patients who can maintain TFR is required. Relapse after TKI discontinuation is considered to be attributable to CML stem cells surviving even in patients who maintain marked molecular responses. A number of in vitro experiments have shown that TKI by itself cannot kill CML stem cells. Also, CML stem cells are resistant to TKI in a manner dependent on self-renewal factors (Hh, Wnt/β-catenin), cell cycle regulators (PML), metabotropic factors (FOXO3, Alox5), and adhesion molecules (CXCR4). In addition, surface markers specific for CML stem cells such as IL-1RAP and CD26 have been identified. New therapeutic strategies targeting these molecules in combination with TKI hold promise of achieving a more effective strategy for curing CML.

The bony skeleton enables the locomotive activity, the storage of calcium, and the harboring of the hematopoietic stem cells from which blood and immune cells are derived. The immune and skeletal systems share various molecules including cytokines, signaling molecules, transcription factors and membrane receptors. Investigation into rheumatoid arthritis (RA) as well as cloning of RANKL and various bone phenotypes found in immune-compromised gene deficient mice has highlighted the importance of the dynamic interplay between the both systems. These findings have recently led to both the emergence and subsequent rapid evolution of the field of osteoimmunology. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases related to the immune and skeletal systems.

Induced pluripotent stem cells(iPSCs)can be generated via reprogramming of somatic cells into pluripotent stem cells by introducing defined factors with appropriate culture conditions. iPSCs have 4 key properties. iPSCs have pluripotency and self-renewal ability, which are properties in common with embryonic stem cells. Additionally, iPSCs can be generated from various donor individuals with particular characteristics and also from various types of cells in a single donor. Regarding the medical applications of the technology, the best use of iPSCs should be based on a better understanding of these properties in accordance to different purposes. At present, the technology has been applied in various research fields. In cancer research, the technology has been expected to be useful, especially in immunotherapy, disease modeling, drug development. Thus, iPSC technology is a promising tool even in the field. Continuous challenges raise the hope for the development of novel cancer treatments using iPSC technologies in the future.

Recent advances in the field of radiation therapy (RT) have considerably improved treatment outcomes of various cancers. It is related to not only the technological progress in medical physics but also the analytical progress in radiation biological effectiveness. However, the treatment results of RT, especially in advanced cancer, are still insufficient, therefore it is necessary to establish a safety and more effective method for treating cancer. Understanding the radiation biology is essential to appreciate the effect of RT. Hence, we review the controversial point of RT for radiation biology and introduce the results of basic research.

The brain is particularly vulnerable to oxidative damage because of its high rate of oxygen consumption, abundant lipid content, and relative paucity of antioxidant enzymes compared with other organs. It has been well established that oxidative stress (OS) is involved in the pathogenesis of age-associated neurodegenerative disorders such as Alzheimer's disease (AD). Indeed, a large number of genetic and environmental factors of neurodegenerative disorders are associated with OS. Of note, studies on the levels of oxidative damage in patients with the prodromal stage of AD, transgenic animal models of AD, and induced pluripotent stem (iPS) cells derived from AD patients support the early-stage involvement of OS in the pathological cascade of the disorder. Recently, a growing body of evidence suggests that a considerable number of genetic and environmental factors of psychiatric disorders such as schizophrenia (SZ), bipolar disorders, and depression are associated with OS. Not only genetic polymorphisms in genes encoding antioxidant enzymes but also several known susceptible genes for psychiatric disorders, i. e., Disrupted-in-Schizophrenia-1 (DISC1), Neuregulin 1 (NRG1), proline dehydrogenase (PRODH), and G72, are all associated with increased levels of OS or decreased antioxidant capacities. Moreover, environmental factors such as infection, hypoxia, malnutrition, illicit substance use, and psychosocial stress are possibly associated with OS. In fact, increased levels of oxidized nucleic acids, proteins, and lipids have been described in the postmortem brains of patients with SZ and bipolar disorders, and decreased antioxidant capacities have been described in blood samples obtained from patients with first-episode psychosis. In concordance, iPS cells from SZ patients show an increased level of OS. Of particular interest is a conditional gene knockout mouse model of SZ with the functional elimination of NMDA receptors specifically from cortical interneurons. The NMDA receptor knockout mouse shows behavioral phenotypes resembling symptoms of human SZ. Importantly, a marked increase of OS, particularly in the cortical parvalbumin-positive interneurons, is rapidly exacerbated by post-weaning social isolation, but treatment with antioxidants abolishes OS and partially alleviates the SZ-like behavioral phenotypes. Therefore, it is suggested that OS is a convergence point for genetic and environmental susceptibilities to not only neurodegenerative but also psychiatric disorders. In other words, OS potentially plays a central role in the pathomechanisms that integrate gene-environment interactions in neuropsychiatric disorders. Further investigations into the development of useful OS biomarkers and efficacious OS-targeting interventions may shed light on a promising approach for establishing preemptive strategies against neuropsychiatric disorders.

Recent clinical neuroimaging studies have revealed a possible relationship between morphological brain changes and the manifestation of psychiatric disorders such as depression, schizophrenia, and alcoholism. Although its biological mechanism is still unclear, the emerging evidence suggests that the alteration of neurogenesis is the key factor for the morphological brain changes of these psychiatric disorders. In our previous work, we analyzed the mechanism of neural network disruption by ethanol using cultured cells, and found a suppressive effect of ethanol on neural stem cell (NSC) differentiation. While, we also demonstrated that antidepressants, mood stabilizers and atypical antipsychotics stimulate NSC differentiation which was inhibited by ethanol. In the present work, we have demonstrated that the usefulness of intravenous transplantation of NSCs to fetal alcohol spectrum disorder (FASD) model rat for the purpose of reconstructing the impaired neural network and investigating the possibility of regenerative therapy for patients with neurobehavioral deficits of FASD. We have shown the potential migration of transplanted NSCs into the brain by visualizing a fluorescent cell marker and radioisotope, as well as the possible recovery of behavioral abnormalities observed in FASD model rats, such as memory/cognitive function, and social interaction. We further assessed the characteristics of transplanted cells in the brain and found that the GABAergic interneurons were increased in amygdale, DG, cingulated cortex areas in the model rat. In the amygdala and cingulate Cortex of model rats, number of parvalbumin positive cells was reduced and the NSC transplantation recovered these disturbances. Moreover, in the amygdala and cingulate cortex, intravenous NSC transplantation appears to regenerate expression of post-synaptic density protein 95 (PSD95) in FASD model rats. These results indicate that intravenous NSC transplantation has the potential to become a therapeutic intervention for FASD patients.

Interaction of myeloma cells with bone marrow microenvironment underlies cell adhesion-mediated-drug resistance (CAM-DR). CAM-DR is exerted via not only direct adhesion to stromal cells, fibroblasts, mesenchymal stem cells, or macrophages but also indirect effects of IL-6, IGF-1, and SDF-1 in myeloma cells. Bortezomib overcomes CAM-DR via down-regulation of VLA-4, which is a key adhesion molecule in CAM-DR. Although bortezomib is indispensable for myeloma treatment, it is unclear which is the best drug to be combined. Using isobologram analysis, we show that not cyclophosphamide, adriamycin, and lenalidomide but melphalan exerts additive cytotoxicity under all culture conditions tested (stroma free and in contact with fibronectin or stromal cells). Melphalan is considered the best drug to be combined with bortezomib to overcome CAM-DR.

Multiple myeloma (MM) is characterized by the clonal expansion of malignant plasma cells. MM patients harbor phenotypic CD19+ B cells expressing the immunoglobulin gene sequence and the idiotype unique to the individual myeloma clone. However, in most MM patients CD19+ clonotypic B cells do not reconstitute MM disease upon transplantation into immune-deficient mice. In the SCID-rab and SCID-hu models, which enable engraftment of human MM in vivo, CD19-CD38++ plasma cells engrafted and rapidly propagated MM. These results indicate that MM-initiating cells are derived from plasma cells, which are terminally differentiated cells. It should be now clarified whether all MM plasma cells can exert as MM-initiating cells when located in the appropriate niche or only distinct myeloma stem cells can propagate MM.

For younger patients with relapsed or refractory lymphomas who respond to salvage therapy, autologous stem cell trans- plantation(ASCT)is the standard of care. Recently, it was demonstrated that the gemcitabine/dexamethasone/cisplatin (GDP) regimen for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma (NHL) prior to ASCT was not inferior to the standard dexamethasone/cytarabine/cisplatin (DHAP) regimen for patients with relapsed and refractory aggressive lymphoma. In Japan, most patients who receive CDDP-containing regimens are hospitalized because of the substantial transfusions required for preventing renal dysfunction. We initiated GDP therapy combined with a short period of hydration and the administration of a magnesium agent and mannitol for 5 patients with relapsed and refractory aggressive lymphoma. In 4 cases, GDP was safely administered on an outpatient basis. Furthermore, peripheral blood stem cells were successfully collected in 2 patients. After stem cell harvest, ASCT was performed in a patient with diffuse large B-cell lymphoma, with the patient remaining in complete remission (CR) after ASCT.

Intravenously administrated mesenchymal stem cells (MSCs) isolated and expanded from human bone marrow have been reported to ameliorate functional deficits in several CNS diseases in both experimental animal models and clinics. Therapeutic mechanisms may include replacement of damaged cells, neuroprotective effects, induction of axonal sprouting, and neovascularization. Here, we review the reparative and protective properties of transplanted MSCs in stroke, describe initial clinical studies on intravenous MSC delivery in stroke patients, and discuss a perspective on the prospects of MSCs for dementia.

The cancer stem cell (CSC) hypothesis shows that tumors contain a reservoir of self-renewing cells that maintain the tumor. Such cancer cells were first identified in leukemia in the 1990s. These cells appear to be resistant to various therapies and can survive to repopulate the tumor. Therefore, this concept has important therapeutic implications for recurrence and metastasis. In this review, we introduce the CSC hypothesis and the origin, method of identification and functions of prostate CSCs. In addition, we review the therapeutic challenges of targeting prostate CSCs.

Osteo/chondrogenic differentiation capabilities are seen after in vivo implantation of mesenchymal stem cells (MSCs), which are currently used for the patients having bone/cartilage defects. Importantly, the differentiation capabilities are induced by culturing technology, resulting in in vitro bone/cartilage formation. Especially, the in vitro bone tissue is useful for bone tissue regeneration. For cartilage regeneration, culture expanded chondrocytes derived from patient's normal cartilage are also used for the patients having cartilage damages. Recently, the cultured chondrocytes embedded in atelocollagen gel are obtainable as tissue engineered products distributed by Japan Tissue Engineering Co. Ltd. The products are available in the well-regulated hospitals by qualified orthopedic surgeons. The criteria for these hospitals/surgeons have been established. This review paper focuses on current status of bone/cartilage tissue engineering towards clinical applications in Japan.

Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The neurodegenerative condition of Parkinson's disease (PD) is the most common cause of parkinsonism. PD is classified as sporadic PD and familial PD. Whereas idiopathic PD is caused by a number of complex factors, familial PD is a result of mutations in PD-associated genes. Unraveling the mechanisms surrounding familial PD will offer pivotal clues in understanding etiology of not only familial PD but also sporadic PD. We have demonstrated neuroprotective effects with particular focus on DJ-1. On the other hand, idiopathic basal ganglia calcification, also known as Fahr disease (FD) is another condition characterized by parkinsonism. In 2012, solute carrier family 20A2 (SLC20A2) was identified as the causative gene for familial FD. Our analysis of patient samples revealed a novel mutation in SLC20A2. Type-III sodium-dependent phosphate transporter 2 (PiT-2), the protein encoded by SLC20A2, plays an important role in phosphate homeostasis. However, PiT-2's role in the pathology of FD remains largely unclear. We have established induced pluripotent stem (iPS) cells from FD patients and are investigating their usefulness in drug development. Here, we present some of our latest research findings.

  Tissue-resident mast cells are derived from circulating committed progenitors, which are originated from pluripotent hematopoietic stem cells in bone marrow. These progenitors migrate into extravascular tissues, where they undergo differentiation and maturation into tissue-specific mast cell phenotypes. When activated by antigen or microenvironmental factors, mast cells release various biologically active products, including pre-formed mediators stored in secretory granules, de novo synthesized lipid mediators, and newly transcribed cytokines and chemokines, thereby promoting anaphylactic inflammation as well as other acute and chronic inflammatory diseases. Here, I will highlight the newest understanding of the phospholipase A2 (PLA2)-driven lipid networks in the maturation and effector functions of mast cells and attendant allergic responses. Group III secreted PLA2, the sole mammalian homolog of the potent extrinsic anaphylaxis inducer bee venom PLA2, regulates mast cell maturation through the paracrine prostaglandin D2 (PGD2) circuit. While cytosolic PLA2α is essential for the generation of PGD2 and leukotriene C4 by mast cells, it is also functionally coupled, through the arachidonic acid transfer mechanism, with PGE2 synthase in stromal fibroblasts to provide anti-anaphylactic PGE2. In addition, the roles of two particular mast cell maturation-responsible genes, NDRG1 and NLRP3, in mast cells will be discussed.