Endoscopic examination of a 60-year-old man revealed multiple erosions in the gastric antrum. After 6 months, erosions also formed in the duodenal bulb and systemic lymph nodes become enlarged. After 20 months, the gastroduodenal erosions developed into mucosal ulcers, and the systemic lymph node swelling progressed. Histological examination of the neck lymph node showed mantle cell lymphoma (MCL). This result agreed with the results of the gastroduodenal biopsy. This case was diagnosed as recurrent primary gastric MCL in other areas, with systemic lymph node metastasis and bone marrow invasion. Hyper-CVAD (cyclophosphamide, doxorubicin, vincristine, and dexamethasone), high-dose methotrexate and cytarabine in combination with Rituximab and stem cell transplantation was performed. The gastroduodenal lesions and atypical cells in the bone marrow disappeared after 2 cycles of the chemotherapy. Metastatic lymph node swelling regressed after stem cell transplantation. We have had no evidence of recurrence for 50 months. Primary gastric MCL is very rare and cyclin D1 immunohistochemistry and FISH assay were very useful for the diagnosis of MCL.

A 57-year-old woman was diagnosed with acute myeloid leukemia (AML, M5a) with MLL rearrangement in August 2006. Cord blood transplantation (CBT) conditioned with a reduced-intensity regimen was carried out during second complete remission in March 2007. Marrow study on day 28 confirmed complete chimera and disappearance of minimal residual disease by RT-PCR. She complained of left chest pain around day 120. CT scan on day 127 showed left pleural effusion, tumors of the upper mediastinum and spleen, and pericardial effusion. She suddenly died of cardiogenic shock on day 129. Postmortem examination revealed systemic granulocytic sarcomas and infiltration of leukemic cells into the right atrium and epicardium without recurrence of leukemia in blood and marrow.

Progress in stem cell research reveals cancer stem cells to be present in a variety of malignant tumors. Since they exhibit resistance to anticancer drugs and radiotherapy, analysis of their properties has been rapidly carried forward as an important target for the treatment of intractable malignancies, including brain tumors. In fact, brain cancer stem cells (BCSCs) have been isolated from brain tumor tissue and brain tumor cell lines by using neural stem cell culture methods and isolation methods for side population (SP) cells, which have high drug-efflux capacity. Although the analysis of the properties of BCSCs is the most important to developing methods in treating BCSCs, the absence of BCSC purification methods should be remedied by taking it up as an important research task in the immediate future. Thus far, there are no effective treatment methods for BCSCs, and several treatment methods have been proposed based on the cell biology characteristics of BCSCs. In this article, I outline potential treatment methods damaging treatment-resistant BCSCs, including immunotherapy which is currently a topic of our research.

It has been reported that cancer initiating cells (cancer stem cells, CSCS) are present in human neoplasia. Although it is known that stem cells play a role in tumorigenesis, the early epigenetic events involved in the development of malignant precursors remain unknown. Here, we reviewed the epigenetic modifications involved in the induction of human brain tumors, particularly focusing on polycomb-repressive complex-mediated histone (H3) lysine (K) 27 tri-methylation (K27-3Me) and other DNA methylation patterns, which are known to act as transcriptional silencing machineries for tumor-suppressor genes, in brain tumor stem cells (BTSCs). Among the histone modifications associated with H3K27-3Me, the potential role of EZH2 histone methyltransferase, which is the catalytic subunit of polycomb repressive complex 2, in the formation of brain tumors has been discussed. In addition, we considered the prospects for developing epigenetic therapies.

The study of cancer stem cells (CSCs) is on the cutting edge of cancer research. Following the discovery of neural stem cells (NSCs), extensive studies on their characteristics led to the discovery of cancer stem cells (CSCs) in brain tumors: these cells are termed brain tumor stem cells (BTSCs). The study of NSCs provided insights into mechanisms underlying the maintenance of NSCs, and more recently, BTSCs. Adult NSCs exist in the subventricular zone (SVZ) of the lateral ventricle and in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Specific genes referred to as "stemness genes," combined with a specific microenvironment called the "stem cell niche" are important in maintaining NSC characteristics. Glioblastoma multiforme (GBM) is one of the most malignant forms of human cancer. Regardless of intensive treatment regimens, the mean survival time for GBM patients is approximately 12 months. Early cancer therapies for GBM primarily targeted the rapidly-dividing cells and not the slowly-dividing cells, which were minor populations of cells containing BTSCs. Identification of BTSCs yielded new insights regarding the chemo- and radio-resistant properties that facilitate their selective survival and ability to initiate tumor recurrence. Recent studies have focused on BTSCs as treatment targets for GBM. These investigations showed that inhibiting the pathway for stemness genes decreased the number of BTSCs in vitro and improved survival times of xenografted mice. Moreover, treatment with drugs that affect the stem cell niche in brain tumor-bearing mice prolonged their survival. We expect that the continued study of BTSCs, combined with the findings of past studies, will contribute to breakthroughs that will lead to novel treatments to cure GBM patients. In this review, we discuss recent progress in basic research on BTSCs as treatment targets.

A number of extrinsic factors and intracellular mechanisms have been revealed to be involved in oligodendrocyte development. For instance, sonic hedgehog induces the expression of basic helix-loop-helix (bHLH) transcription factors, Olig1 and Olig2, and a homeobox transcription factor Nkx2.2, both of which induce neural stem cells (NSCs) to differentiate into oligodendrocyte precursor cells when the factors work together. In contrast, Notch and bone morphogenic proteins (BMP) block oligodendrocyte differentiation by inducing the expression of the transcription inhibitors Hes5 and Id4, respectively. Moreover, it was shown that other extrinsic and intrinsic factors, including platelet derived growth factor, thyroid hormone (TH), TH receptors, p53, and Wnt, are also involved in the development, positively or negatively. It has been thought that oligodendroglioma, one of brain tumors, is generated from oligodendrocyte lineage cells as the tumor cells share characteristics of oligodendrocyte, such as the honeycomb structure, and the expression of oligodendrocyte-related factors, including Olig2 and NG2 proteoglycan. However, recent progress in the field revealed that oligodendroglioma might be generated from NSCs and astrocytes as well as oligodendrocyte lineage cells. Therefore, it is crucial to investigate the cell-of-origin of oligodendroglioma and to identify target genes and markers for the therapy. In this review, I summarize the mechanism of oligodendrocyte development and present how the oligodendrocyte research can help to understand and to investigate the mechanism of oligodendroglioma development.

Polydendrocytes or NG2 cells are the fourth major glial cell type observed in the mammalian central nervous system (CNS) that is distinct from neurons, mature oligodendrocytes, astrocytes, or microglia. They can be identified on the basis of the expression of NG2 proteoglycan and are distributed throughout the gray matter and white matter both in the developing and mature CNS. Although polydendrocytes were earlier regarded as oligodendrocyte progenitor cells, recent studies using Cre/loxP fate mapping provided the first direct evidence that endogenous polydendrocytes give rise to oligodendrocytes in vivo. In addition, the same technique showed that polydendrocytes differentiate into a subpopulation of astrocytes in a region-specific manner. On the other hand, it is highly debatable whether polydendrocytes generate neurons. Although some studies suggest the possibility that polydendrocytes produce neurons, other studies do not support this hypothesis. The possibility that polydendrocytes contribute to the formation of gliomas has been suggested in a number of clinical and basic experimental studies. In this review, we present both classical findings (and the latest reports on the basic characteristics of this cell type).

The current study was designed to investigate the role of circulating bone marrow (BM)-derived stem cells in the pathogenesis of polypoidal choroidal vasculopathy (PCV), a distinct type of neovascular age-related macular degeneration (AMD).

Regenerative medicine refers to research and treatments that restore damaged tissues. It consists of three factors: cells, chemical substances, and scaffolds. One of its purposes is rejuvenation, and from this point of view, it really resembles anti-aging medicine. Recently, studies concerning stem cells such as embryonic stem cells (ES) and induce pluripotent stem cells (iPS) have made remarkable progress and seem promising, but are still far from clinical use. In contrast, we introduce a few examples of anti-aging medicine using regenerative medicine methods that have been applied successfully in clinical use such as cultured fibroblast, adipose tissue derived stem cells and platelet rich plasma (PRP), and continue researching cultured dermal papilla cells.

A rare case of meningitis complicated by brainstem infarction is reported. A 64-year-old previously healthy female was admitted to our hospital because of a 1-week history of fever and headache. Cefdinir was orally administered for several days before admission. Analysis of cerebrospinal fluid (CSF) on admission showed a white blood cell (WBC) count of 9,013 cells/ micro/(97% polynuclear cells), a protein level of 212.8 mg/d/, and a glucose level of 3 mg/d/. CSF culture was negative for bacteria, including tubercle bacilli, and fungi. A brain computed tomography (CT) scan on admission showed acute hydrocephalus. Six hours after admission the patient developed tetraplegia. Diffusion-weighted magnetic resonance (MR) images on day 2 revealed elevated diffusion coefficients with high signal intensity in the pons and the medulla oblongata. MR angiography demonstrated a narrowing change of the cerebral arteries. Followup MR angiography two months after admission showed normalization of the cerebral arteries. The patient remained tetraplegic at eight months after admission. We speculated that brainstem infarction in our case might have been caused by vascultis or brain edema.

A genome-wide association study on diffuse-type gastric cancer identified the PSCA gene, whose exact function in the gastric epithelium has been unknown. Immunohistochemical analysis revealed that PSCA is expressed in the region in which gastric epithelial stem cells and precursors are considered to reside. Moreover, the PSCA was downregulated in gastric cancer tissues, and its product showed a cell-growth inhibition activity in vitro. We also identified a functional SNP, the risk allele of which suppressed a promoter activity of the PSCA gene. These findings suggest that the PSCA may contribute to carcinogenesis through the cell-growth regulation of the gastric epithelial precursors. The summary statistics of the 2-stage genome scan is available from a database, GeMDBJ (http://gemdbj.nibio.go.jp/).

Notch signaling regulates the self-renewal and differentiation of hematopoietic stem cells. Since acute myeloblastic leukemia (AML) originates from dysregulated hematopoietic cells, the Notch system may be involved in the abnormal growth. We found that AML cells express not only Notch proteins but also Notch ligand proteins, which suggests the possibility of autonomous Notch activation. It is known that more than half of T-cell acute lymphoblastic leukemia (T-ALL) cases have activating mutations of the NOTCH1 gene. We report that one out of 20 AML samples and none out of 20 MDS samples showed NOTCH1 mutation. We established an AML cell line, TMD7, which proliferates in response to a Notch ligand, Dll1 protein. Notch activation by ligand stimulation suppressed the cytokine-induced differentiation and apoptosis of U937 cells. For OCI/AML-6 and THP1 cells, Notch ligands suppressed the growth and self-renewal capacity while inducing differentiation into macrophage-like cells. For primary AML cells, the Notch ligands exhibited diverse effects on the short-term growth. The ligands reduced the self-renewal capacity and induced differentiation in some samples. For NOTCH1-mutated T ALL cells, gamma-secretase inhibitors(GSI), which block Notch activation, suppress the growth. We found that GSI suppressed the in vitro growth of some B-cell lymphoma and AML cell lines without NOTCH1 mutations through the induction of apoptosis. GSI may be useful as a novel molecular target therapy for various leukemias. For this purpose, we have to clarify the mechanism behind the effects. Laboratory tests regarding the expression and function of Notch will be important for individualized diagnosis and therapies.

Osteoblast lineage cells, which derive from mesenchymal stem cell, are an important target for development of bone anabolic agents. Osteoblasts synthesize bone matrix to execute bone formation, and play crucial roles in mineral metabolism, hematopoiesis and bone resorption as well. In the last decade, critical roles of several transcription factors in osteoblast differentiation have been demonstrated. The differentiation and fate of osteoblasts are also controlled by various extracellular signals, such as Hedgehog, Notch, Wnt and BMP. This short review describes recent advances, focusing on signaling molecules that affect bone mass through regulation of osteoblastic differentiation and function.