A 57-year-old man presented with subacute progression of cognitive impairment (MMSE 22/30). He had been diagnosed as AIDS two years before and taking atazanavir, abacavir, and lamivudine. HIV RNA of plasma had been negative. On admission, HIV RNA was 4,700 copy/ml and 5,200 copy/ml in plasma and in cerebrospinal fluid respectively, suggesting treatment failure of cART. The brain magnetic resonance imaging showed high intensity areas in the white matter of the both frontal lobes and brain stem. The drug-resistance test revealed the resistance of lamivudine and abacavir. We introduced the CNS penetration effectiveness (CPE) score to evaluate the drug penetration of HIV drugs. As the former regimen had low points (7 points), we optimized the regimen to raltegravir, zidovudine, and darunavir/ritonavir (scoring 10 points). His cognitive function improved as normal (MMSE 30/30) in 2 weeks and HIV-RNA became undetectable both in plasma and CSF in a month. In spite of the cognitive improvement, the white matter hyperintensity expanded. To rule out malignant lymphoma or glioblastoma, the brain biopsy was performed from the right frontal lobe. It revealed microglial hyperplasia and diffuse perivascular infiltration by CD8+/CD4-lymphocytes. No malignant cells were found and the polymerase chain reaction analyses excluded other viruses. Considering the drug penetration to the central nervous system is important for treating HIV encephalopathy.

Allogeneic hematopoietic stem cell transplantation is performed in patients with hematologic malignancies refractory to chemotherapy. However, its efficacy is often limited by the development of graft-versus-host disease (GVHD) secondary to the allogeneic interaction of donor T cells with host dendritic cells. On the other hand, the antihost cytotoxicity of donor T cells enhances the graft-versus-tumor (GVT) effect. Extracellular adenosine generated by CD73/ecto-5'-nucleotidase from ATP via AMP plays pleiotropic roles under physiological and pathological conditions by engaging four adenosine receptors. One study recently demonstrated that ATP released from damaged cells exacerbates GVHD by activating the P2X7 receptor on host dendritic cells. In this review, we summarize our recent findings on the immunosuppressive role of extracellular adenosine in GVHD and the GVT effect. We have shown that in MHC-mismatched bone marrow transplantation, CD73 deficiency, particularly in the recipient, enhanced GVHD severity because of excessive donor T-cell expansion. Severe GVHD was enhanced by repeated administration of a CD73 inhibitor or an adenosine receptor antagonist. A competitive engraftment assay identified endogenous A2AAR signaling in donor T cells as part of a regulatory mechanism by CD73-generated adenosine. Pharmacological inhibition of CD73 enhanced the GVT effect against B-cell lymphoma and improved survival in tumor-relapsing mice after transplantation. Along with our findings, we herein introduce a novel concept that CD73-generated adenosine counteracts the ATP-evoked allogeneic immune reaction as a negative regulatory mechanism in GVHD. Pharmacological manipulation of CD73 activity could be a therapeutic strategy to limit GVHD and to preserve the GVT effect against hematopoietic malignancy.

Sarcopenia, an age-related decline in skeletal muscle mass and strength, causes the decline of the quality of life in the elderly. The age-related alteration in the differentiation potency of satellite cells, myogenic tissue specific stem cells in skeletal muscle, and preadipocytes in skeletal muscle is possibly involved in the disruption of homeostasis in skeletal muscle. The differentiation of the cells is affected by the microenvironment surrounding the cells, called niche. Here, we focused on SPARC (secreted protein acidic and rich in cysteine) as a secreted glycoprotein existing in the niche. We review the roles of SPARC on the differentiation of satellite cells and preadipocytes in the muscle and their alteration with age.

Skeletal muscle has a high degree of plasticity. The mass of skeletal muscle maintains owing to muscle protein synthesis and the regeneration by satellite cells. Skeletal muscle atrophy with aging (sarcopenia) is developed by decline of muscle protein synthesis and dysfunction of satellite cells. It is urgently necessary for today's highly aged society to elucidate the mechanism of sarcopenia and to establish prevention measure. This review shows that the positive effects of "exercise" on muscle protein synthesis and satellite cell function including their main molecular mechanism.

During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT-70, isolated from the stem bark of Calophyllum Brasiliense collected in Brazil, significantly inhibited the growth of leukemic cells via the induction of caspase-mediated and p53-independent apoptosis. Furthermore, we synthesized BNS-22 as a derivative of GUT-70, which showed more antiproliferative activity against human cancer cells than GUT-70. GUT-70 and BNS-22 commonly inhibited ubiquilin-1, suggesting that a GUT-70 derivative might become a First in Class agent. In addition, GUT-70 and BNS-22 inhibited HSP90 and topoisomerase II, respectively. Recently, we also found that GUT-70 inhibited HIV replication. These findings indicated that GUT-70 could serve as a lead compound to develop novel therapeutic agents against cancer and HIV-1 infection.

We report a case of a 38-year-old man who was diagnosed with a mediastinal germ cell tumor. After induction chemotherapy, the tumor marker levels normalized, but the tumor itself continued to grow. Surgical resection was performed successfully, but the patient developed acute megakaryoblastic leukemia 6 months later, and induction and consolidation therapies failed to achieve remission. Leukemia cells invaded the central nervous system following hematopoietic stem cell transplantation, and the patient died 5 months after being diagnosed with leukemia. This very rare case of a mediastinal germ cell tumor met the criteria for "growing teratoma syndrome", against a background of acute megakaryoblastic leukemia.

There are two main types of therapy for hematologic malignancies: intensive cytotoxic chemotherapy and hematopoietic stem cell transplantation(HSCT). The roles of granulocyte colony-stimulating factor(G-CSF)in patients receiving HSCT are the mobilization of hematopoietic stem cells/progenitor cells into peripheral blood and the enhancement of neutrophil recovery as therapy or prophylaxis for fatal complications following HSCT. In the treatment of acute leukemias, G-CSF is used as therapy or prophylaxis for febrile complications during remission induction and post-remission therapies. In the treatment of lymphomas, primary prophylactic G-CSF is recommended during all cycles of chemotherapy when the expected incidence of neutropenic fever is more than 20% or when the patient is treated with potentially curative regimens. G-CSF is used as secondary prophylaxis to maintain dose intensity in patients with lymphomas treated in settings where reductions in chemotherapy dose intensity or dose density are associated with poorer prognosis. In the treatment of multiple myelomas, prophylactic G-CSF can be used when there is a high estimated risk of neutropenic fever(e. g., in patients receiving high-dose chemotherapy). For all cases, the appropriate use of G-CSF is recommended in accordance with the guidelines of the American Society of Clinical Oncology(ASCO), European Organisation for Research and Treatment of Cancer(EORTC), Infectious Diseases Society of America(IDSA), National Comprehensive Cancer Network(NCCN), and our JSCO-2013.

Both glutamic (Glu) and gamma-aminobutyric (GABA) acids are believed to play roles as neurotransmitters released from particular neurons into synaptic clefts in the mammalian central nervous system. Although GABA has been shown to act as an extracellular signal outside the brain, little attention has been paid to the possible expression of machineries required for neuronal glutamatergic signaling in cells other than central neurons. We first demonstrated the presence of Glu receptors in peripheral tissues such as the adrenal and pituitary glands three decades ago. In this review, I will outline our experimental findings accumulated since then on the physiological and pathological significance of neuronal amino acids as an extracellular signal for the maintenance of homeostasis in a variety of plasma cells. For example, Glu is released upon stimulation in a Ca2+-dependent manner for signal output in osteoblasts, where Glu is essential for the expression of the master regulator of osteoblastogenesis through a particular inotropic receptor subtype. In contrast, GABA plays a role in mechanisms underlying the suppression of cellular differentiation and maturation through a particular metabotropic receptor subtype in osteoblasts. Taken together, osteoblastic maturation proceeds as a delicate balancing between excitatory glutamatergic and inhibitory GABAergic signals, as seen in the brain. Re-evaluation of drugs currently used could be beneficial for the efficient discovery and development of innovative drugs useful for the prophylaxis and/or therapy of a variety of diseases relevant to the disturbance of glutamatergic and GABAergic signaling in diverse plasma cells.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system inflammatory disease characterized by the punctate gadolinium enhancement peppering the pons and the cerebellar peduncles as neuroimaging. We report the case of a 66-year-old woman who presented with CLIPPERS associated with swelling in the brainstem. She was hospitalized because of gait ataxia and consciousness disturbance. MRI of the brain showed FLAIR hyperintense lesions in the pons, cerebellar peduncles, cerebellum and the subcortical white matter lesion in the right occipital lobe with significant swelling in the brainstem. Diffusion-weighted MRI did not show an abnormal signal, indicating vasogenic edema. Post-contrast T1-weighted MRI showed enhanced area in the right occipital lobe and panctate gadolinium enhancement peppering brainstem. Treatment with steroids led to rapid improvement. However, she showed exacerbation of clinical and radiological findings during the tapering schedule of steroid. The biopsy from the occipital lobe revealed intense perivascular and parenchymal lymphocytic infiltrates composed of primarily T cells, B cells and macrophages. The patient was diagnosed with CLIPPERS, and treatment with increased dose of corticosteroid induced a clinical improvement. Previous reports well described a characteristic MRI finding of punctate enhancement peppering the pons. In addition, the pons and cerebellar peduncles swelling can occur in this disorder.

The author proposes the "D-cell hypothesis" for molecular basis of the mesolimbic dopamine (DA) hyperactivity of schizophrenia. D-neurons, which were defined as "non-monoaminergic aromatic L-amino acid decarboxylase (AADC)-containing cells", produce trace amines (TAs), such as tyramine, phenylethylamine (PEA) and tryptamine. D-neurons may also take up amine precursors, and may convert them to amines by decarboxylation. The author's preliminary report showed that the number of AADC-containing neurons, that is D-neurons, was reduced in the striatum and nucleus accumbens of patients with schizophrenia. TA-associated receptor type 1 (TAAR1) has been shown to have a number of ligands, such as tyramine, PEA, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), and lysergic acid diethylamide (LSD), that may change human mental states. In patients with schizophrenia, the reduction of striatal D-neurons and possible decrease of striatal TA, is caused by neural stem cell dysfunction in the subventricular zone of the lateral ventricle. The reduced stimulation of TAAR1 on terminals of ventral tegmental area (VTA) DA neurons increases the firing frequency of VTA DA neurons, as recently published reports have shown, resulting in mesolimbic DA hyperactivity. In addition, increased DA D2 receptor stimulation, caused by striatal DA hyperactivity, may suppress forebrain neural stem cell proliferation, and would cause an additional decrease of D-neurons.

Recent studies revealed that the subventricular zone (SVZ) in the developing mammalian cerebrum is a source of cortical neurons along with the ventricular zone (VZ), and especially in human SVZ, abundant self-renewal stem cells exist and are thought to largely contribute to the development of huge brain. These studies suggested that the regulations of the number of progenitors or stem cells in the SVZ and their stemness are important issues for understanding the final output of the cortical neurons. We previously reported the migratory difference between the direct progeny of the VZ and the further dividing cells in the SVZ in mice. The former population finishes the cell division in the VZ, stays there for more than 10 hours, and then accumulates in the lower SVZ as multipolar cells. The other exits the VZ earlier than former, distributes widely in the SVZ and divides. These observations showed that the SVZ is divided into two regions; the lower postmitotic cell accumulation region and upper dividing cell-rich region. This model provides the framework for understanding the nature of the SVZ.

The mice with a disruption of Rank or Rankl exhibit normal mammary development during puberty, but their mammary epithelium fails to proliferate and form lobuloalveolar structures during pregnancy, resulting in the death of newborns. Hormone replacement therapy is associated with an increased risk of breast cancer. Importantly, specific deletion of RANK in mammary epithelium cells prevents both the onset and progression of medroxyprogesterone acetate (MPA) -driven mammary cancer and impairs self-renewal of breast cancer stem cells. Furthermore, RANK is highly expressed in several cancer cells. Functionally, it has been shown that RANKL can stimulate the directed migration of mammary epithelial cells as well as prostate cancer and melanoma cells toward a source of RANKL. In an in vivo metastasis model, OPG reduced the tumor burden in bones and ameliorated clinical paralysis, but did not affect the frequency of the spread of metastases into other tissues. These findings show that the RANK/RANKL system is crucial for mammary development, breast tumorigenesis and bone metastasis.

Myelodysplastic syndromes (MDS) are a group of related disorders in which bone marrow stem cells malfunction, while the type is diagnosed based on the WHO classification revised in 2008. Although the diagnosis largely depends on the cytomorphology, it is difficult to diagnose MDS based on the morphology alone, particularly in patients with < 5% blasts in the bone marrow and a normal karyotype. In Japan, a grading system for the diagnostic accuracy of MDS was proposed in 2007, and evaluation of dysplasia (high, intermediate, low, minimal) is a characteristic part. Morphologic dysplastic changes are classified into highly specific category A (pseudo-Pelger-Huet anomaly, degranulation of neutrophils, micro-megakaryocytes, ringed sideroblasts) and less specific category B (dysplasia other than category A). With the use of this grading system, diagnostic problems should be reduced. Flow cytometry has also been proposed as a tool to improve the evaluation of marrow dysplasia, because immunophenotyping is an accurate method for quantitative and qualitative evaluations of hematopoietic cells, and MDS specimens have been found to exhibit abnormal expressions of several cellular antigens. In addition, the molecular classification of MDS has received marked attention in recent years. New molecular markers including RPS14, TET2, IDH1/2, SF3B1, ASXL1, RUNX1, TP53, EZH2, JAK2, and WT1 have been revealed to be important for the prognosis, as well as diagnosis and classification. In this report, we review MDS diagnostic approaches from the viewpoints of cytomorphology, immunophenotyping, and cytogenetics.