Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer.

Tissue inhibitor of metalloproteinase-1 (TIMP-1), a member of the TIMP family (TIMP-1 to 4), is highly expressed in various types of cancer and forms a complex with its receptor CD63 and Integrin ß1. However, the precise oncogenic mechanism of TIMP-1 remains unclear. Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) are transcription co-activators enhancing the transcription of specific genes related to cell proliferation. But the mechanism of aberrant YAP/TAZ activation in cancer is not fully understood. Here, we showed that TIMP-1 activates YAP/TAZ as novel downstream targets to promote cell proliferation. The TIMP-1-CD63-Integrin ß1 axis activates Src and promotes RhoA-mediated F-actin assembly, leading to LATS1/2 inactivation. This results in under-phosphorylation, protein stabilization and nuclear translocation of YAP/TAZ (YAP/TAZ activation); CTGF production; and cell proliferation. Furthermore, the TIMP-1-YAP/TAZ axis is aberrantly activated in various types of cancer cells or tissues. TIMP-1 knockdown inhibits cell proliferation through YAP/TAZ inactivation in cancer cells. This study found that TIMP-1 accelerates cell proliferation through YAP/TAZ activation in cancer, and suggests the TIMP-1-YAP/TAZ axis may be a novel potential drug target for cancer patients.

Lysosomal ceramide generated by acid sphingomyelinase triggers cytosolic cathepsin B-mediated degradation of X-linked inhibitor of apoptosis protein in natural killer/T lymphoma cell apoptosis.

We previously reported that IL-2 deprivation induced acid sphingomyelinase-mediated (ASM-mediated) ceramide elevation and apoptosis in an NK/T lymphoma cell line KHYG-1. However, the molecular mechanism of ASM-ceramide-mediated apoptosis during IL-2 deprivation is poorly understood. Here, we showed that IL-2 deprivation induces caspase-dependent apoptosis characterized by phosphatidylserine externalization, caspase-8, -9, and -3 cleavage, and degradation of X-linked inhibitor of apoptosis protein (XIAP). IL-2 re-supplementation rescued apoptosis via inhibition of XIAP degradation without affecting caspase cleavage. However, IL-2 deprivation induced ceramide elevation via ASM in lysosomes and activated lysosomal cathepsin B (CTSB) but not cathepsin D. A CTSB inhibitor CA-074 Me and knockdown of CTSB inhibited ceramide-mediated XIAP degradation and apoptosis. Inhibition of ceramide accumulation in lysosomes using an ASM inhibitor, desipramine, decreased cytosolic activation of CTSB by inhibiting its transfer into cytosol from the lysosome. Knockdown of ASM also inhibited XIAP degradation and apoptosis. Furthermore, cell permeable N-acetyl sphingosine (C2-ceramide), which increases mainly endogenous d18:1/16:0 and d18:1/24:1 ceramide-like IL-2 deprivation, induced caspase-dependent apoptosis with XIAP degradation through CTSB. These findings suggest that lysosomal ceramide produced by ASM mediates XIAP degradation by activation of cytosolic CTSB and caspase-dependent apoptosis. The ASM-ceramide-CTSB signaling axis is a novel pathway of ceramide-mediated apoptosis in IL-2-deprived NK/T lymphoma cells.

[German-Japanese scientific exchange in urology in the early 20th century]. / Deutsch-japanischer Wissenschaftsaustausch in der Urologie im frühen 20. Jahrhundert.

This paper analyzes the importance of the German language and German culture and institutional development of urology in Japan in the early 20th century, starting from the development of the medical school for Japanese in Germany and their function in the process of modernization of the Meiji period (1868-1912). Examples of bi-directional German-Japanese relations in medicine, which also included an integrated knowledge transfer, are shown. The study is based mainly on Japanese and German sources about Japanese physicians in Germany as well as contemporary publications in German and international medical journals. Methodologically, the article combines quantitative analysis with individual biographical aspects.

Improvement and quantitative performance estimation of the back support muscle suit.

We have been developing the wearable muscle suit for direct and physical motion supports. The use of the McKibben artificial muscle has opened the way to the introduction of "muscle suits" compact, lightweight, reliable, wearable "assist-bots" enabling manual worker to lift and carry weights. Since back pain is the most serious problem for manual worker, improvement of the back support muscle suit under the feasibility study and quantitative estimation are shown in this paper. The structure of the upper body frame, the method to attach to the body, and the axes addition were explained as for the improvement. In the experiments, we investigated quantitative performance results and efficiency of the back support muscle suit in terms of vertical lifting of heavy weights by employing integral electromyography (IEMG). The results indicated that the values of IEMG were reduced by about 40% by using the muscle suit.

American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort.

OBJECTIVE: We propose new classification criteria for Sjögren's syndrome (SS), which are needed considering the emergence of biologic agents as potential treatments and their associated comorbidity. These criteria target individuals with signs/symptoms suggestive of SS. METHODS: Criteria are based on expert opinion elicited using the nominal group technique and analyses of data from the Sjögren's International Collaborative Clinical Alliance. Preliminary criteria validation included comparisons with classifications based on the American­European Consensus Group (AECG) criteria, a model-based "gold standard"obtained from latent class analysis (LCA) of data from a range of diagnostic tests, and a comparison with cases and controls collected from sources external to the population used for criteria development. RESULTS: Validation results indicate high levels of sensitivity and specificity for the criteria. Case definition requires at least 2 of the following 3: 1) positive serum anti-SSA and/or anti-SSB or (positive rheumatoid factor and antinuclear antibody titer >1:320), 2) ocular staining score >3, or 3) presence of focal lymphocytic sialadenitis with a focus score >1 focus/4 mm2 in labial salivary gland biopsy samples. Observed agreement with the AECG criteria is high when these are applied using all objective tests. However, AECG classification based on allowable substitutions of symptoms for objective tests results in poor agreement with the proposed and LCA-derived classifications. CONCLUSION: These classification criteria developed from registry data collected using standardized measures are based on objective tests. Validation indicates improved classification performance relative to existing alternatives, making them more suitable for application in situations where misclassification may present health risks.

[From "schizophrenia" to "disturbance of the integrity of the self": causes and consequences of renaming schizophrenia in Japan in 2002]. / Von der "Schizophrenie" zur "Störung der Einheit des Selbst" : Ursachen und Folgen der Umbenennung der Schizophrenie in Japan im Jahre 2002.

In August 2002 the Japanese Society of Psychiatry and Neurology decided to rename the Japanese expression for schizophrenia from Sêshin Bunretsu Byô to Tôgô Shicchô Shô. Currently the psychiatric classification systems ICD-10 and DSM-IV are under revision. Against this background the Japanese process of renaming a psychiatric disorder is of high interest as far as the clinical, social and cultural implications of the new name are concerned.The authors give an overview of the Japanese process of renaming schizophrenia. Its background and realization are explained and the expectations of Japanese physicians, patients and their families related to the new name are analysed. Furthermore, its effects are evaluated. The aim of the paper is to clarify in how far the Japanese example may serve as a model for evaluating the possible implications that a renaming or nosological redefinition of schizophrenia might have in the course of the revision process of ICD 10 and DSM IV.

Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL-triggered cell death.

Ceramide can be converted into sphingomyelin by sphingomyelin synthases (SMS) 1 and 2. In this study, we show that in human leukemia Jurkat cells, which express mainly SMS1, Fas ligand (FasL) treatment inhibited SMS activity in a dose- and time-dependent manner before nuclear fragmentation. The SMS inhibition elicited by FasL (1) was abrogated by benzyloxycarbonyl valyl-alanyl-aspartyl-(O-methyl)-fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor; (2) did not occur in caspase-8-deficient cells and (3) was not affected in caspase-9-deficient cells. Western blot experiments showed SMS1 cleavage in a caspase-dependent manner upon FasL treatment. In a cell-free system, caspase-2, -7, -8 and -9, but not caspase-3 and -10, cleaved SMS1. In HeLa cells, SMS1 was Golgi localized and relocated throughout the cytoplasm in cells exhibiting an early apoptotic phenotype on FasL treatment. zVAD-fmk prevented FasL-induced SMS1 relocation. Thus, FasL-mediated SMS1 inhibition and relocation depend on caspase activation and likely represent proximal events in Fas signaling. FasL-induced ceramide production and cell death were enhanced in cells stably expressing an siRNA against SMS1. Conversely, in cells stably overexpressing SMS1, FasL neither increased ceramide generation nor efficiently induced cell death. Altogether, our data show that SMS1 is a novel caspase target that is functionally involved in the regulation of FasL-induced apoptosis.

Innervation of histamine neurons in the caudal part of the arcuate nucleus of hypothalamus and their activation in response to food deprivation under scheduled feeding.

It has been well established that histaminergic neurons innervate densely the anterior hypothalamus and regulate several functions through the histamine H1 receptor (H1R). However, the physiological function of the histaminergic neurons in other regions including the posterior hypothalamus has not been fully investigated. Recently, we have found a selective c-Fos expression in the caudal part of the arcuate nucleus of the hypothalamus (cARC) by food deprivation under scheduled feeding in rats. In this study, we histochemically examined the correlation of this c-Fos expression with the activation of histaminergic neurons in this region using an anti-H1R antibody. Strong H1R immunoreactivity was observed in the perikarya of the c-Fos positive cells. Abundant histamine-containing fibers were also found in the cARC and in the area between the cARC and the tuberomammillary nucleus (TM), where the histaminergic neuronal cell bodies are exclusively distributed. Our morphological observations suggest that c-Fos expression in the cARC by food deprivation under scheduled feeding is caused by the activation of histaminergic neurons projected from the TM.

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders.

BACKGROUND: Mikulicz's disease (MD) has been considered as one manifestation of Sjögren's syndrome (SS). Recently, it has also been considered as an IgG(4)-related disorder. OBJECTIVE: To determine the differences between IgG(4)-related disorders including MD and SS. METHODS: A study was undertaken to investigate patients with MD and IgG(4)-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG(4)-positive multiorgan lymphoproliferative syndrome (IgG(4)+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG(4) (>135 mg/dl) and infiltration of IgG(4)(+) plasma cells in the tissue (IgG(4)+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG(4)+MOLPS and 31 patients with typical SS were compared. RESULTS: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG(4)+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG(2), IgG(4) and IgE levels were significantly increased in IgG(4)+MOLPS. Histological specimens from patients with IgG(4)+MOLPS revealed marked IgG(4)+ plasma cell infiltration. Many patients with IgG(4)+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG(4)+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG(4)+MOLPS treated with glucocorticoids showed marked clinical improvement. CONCLUSION: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG(4)+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG(4)+MOLPS.

Analysis of disease-dependent sedative profiles of H(1)-antihistamines by large-scale surveillance using the visual analog scale.

Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.

Successful treatment of amegakaryocytic thrombocytopenia with anti-CD20 antibody (rituximab) in a patient with systemic lupus erythematosus.

Amegakaryocytic thrombocytopenia is an extremely rare disorder in systemic lupus erythematosus, and its mechanism and treatment are still largely unknown. We describe a 42-year-old woman with systemic lupus erythematosus who presented various clinical manifestations of life-threatening amegakaryocytic thrombocytopenia (10,000 platelets/mm3 with a marked decrease of megakaryocytes in the bone marrow), proteinuria, psychosis, refractory chylothorax, ascites, and type II diabetes caused by the anti-insulin receptor autoantibody. She was initially treated with prednisolone (25-50 mg/day) and cyclosporine A (200 mg/day) without any improvement in severe thrombocytopenia. However, her clinical symptoms, including platelet counts, dramatically improved, with a concurrent decrease in the anti-c-Mpl antibody, an autoantibody against the thrombopoietin receptor, after a subsequent treatment with rituximab (375 mg/m2 intravenously, weekly, for two consecutive weeks). Our case suggested that amegakaryocytic thrombocytopenia in patients with systemic lupus erythematosus might be mediated by the anti-c-Mpl antibody and could be treated with rituximab through elimination of pathogenic B cells producing autoimmune antibodies.

Clonality analysis of lymphoproliferative disorders in patients with Sjögren's syndrome.

The aim of this study was to clarify the nature of the clonal lymphocyte infiltration in Sjögren's syndrome (SS) patients associated with lymphoproliferative disorders. We examined B cell clonality in lymphoproliferative tissues from six primary SS patients associated with lymphoproliferative disorders or lymphoma by cloning and sequencing of the gene rearrangement of the immunoglobulin heavy chain complementarity determining region 3 (IgVH-CDR3). Three patients with sequential observation showed progressional clonal expansion with the presence of the same subclone in different tissues during the course of disease. Among them, one patient developed mucosa-associated lymphoid tissue (MALT) lymphoma in glandular parotid. The other three SS patients concomitant with malignant B cells lymphomas showed different clonal expansion of B cells between nodal sites and salivary glands. The cloanality analysis indicated that monoclonal B cell population could spread from one glandular site to another site during the course of SS, suggesting that the malignant clone may arise from the general abnormal microenvironment, not restricted to the glandular tissue, in some SS patients.

Activation of Akt signaling is sufficient to maintain pluripotency in mouse and primate embryonic stem cells.

Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates 'stemness' in a broad spectrum of stem cell systems.

Control of ceramide-induced apoptosis by IGF-1: involvement of PI-3 kinase, caspase-3 and catalase.

Insulin-like growth factor-1 (IGF-1) inhibited N-acetylsphingosine (C2-ceramide)-induced HL-60 cell apoptosis via relieving oxidative damage. This inhibitory action of IGF-1 was blocked by a phosphatidylinositol-3 (PI-3) kinase inhibitor wortmannin and enhanced by overexpression of the p110 catalytic subunit of PI-3 kinase. Either IGF-1 pretreatment or PI-3 kinase overexpression restored ceramide-depleted catalase function, and this restoration was inhibited by wortmannin. A catalase inhibitor 3-amino-1h-1, 2, 4-triazole (ATZ) blocked the inhibitory action of IGF-1 on ceramide-induced apoptosis, whereas exogenous purified catalase enhanced it. Ceramide-activated caspase-3 was inhibited by IGF-1/PI-3 kinase and enhanced by wortmannin, while the addition of a specific caspase-3 inhibitor DMQD-CHO significantly enhanced the restoration by IGF-1 of ceramide-depleted catalase function. Moreover, IGF-1 inhibited C2-ceramide-induced decrease of mitochondrial membrane potential, and increase of cytochrome c release, caspase-3 cleavage and caspase-3 activity as judged by PhiPhiLux cleaving method. In summary, these results suggest that IGF-1/PI-3 kinase inhibited C2-ceramide-induced apoptosis due to relieving oxidative damage, which resulted from the inhibition of catalase by activated caspase-3.

Fractalkine and vascular injury.

The vascular endothelium plays a central role in the recruitment and migration of circulating effector cells into sites of inflammation and immune responses. The unique CX(3)C-chemokine, fractalkine, is expressed on activated endothelial cells, and its receptor, CX(3)CR1, is expressed on natural killer cells, monocytes and some CD8+ T cells, all of which possess cytolytic function. Accumulating evidence that fractalkine is expressed on endothelial cells during glomerulonephritis and cardiac allograft rejection, as well as on cardiac endothelial cells activated by pro-inflammatory cytokines, might provide insight into the pathogenesis of vascular injury. Here, we propose a model in which fractalkine mediates vascular injury through the accumulation and activation of killer cells.

Fractalkine, a CX3C-chemokine, functions predominantly as an adhesion molecule in monocytic cell line THP-1.

A newly identified CX3C-chemokine, fractalkine, expressed on activated endothelial cells plays an important role in leucocyte adhesion and migration. Co-immobilized fractalkine with fibronectin or intercellular adhesion molecule-1 enhanced adhesion of THP-1 cells, which express the fractalkine receptor (CX3CR1), compared with that observed for each alone. That adherence was fractalkine-dependent and was confirmed in blocking studies. However, soluble fractalkine induced little chemotaxis in THP-1 cells in comparison to monocyte chemotactic protein-1 (MCP-1), which induced a strong chemotactic response. Moreover, the membrane form of fractalkine expressed on ECV304 cells reduced MCP-1 mediated chemotaxis of THP-1 cells. These results indicate that fractalkine may function as an adhesion molecule between monocytes and endothelial cells rather than as a chemotactic factor.

Down-regulation of alpha6 integrin, an anti-oncogene product, by functional cooperation of H-Ras and c-Myc.

BACKGROUND: The molecular basis of cooperation of H-Ras and c-Myc in regulating cellular behaviour, such as cell adhesiveness, is still poorly understood. To investigate the role of H-Ras and c-Myc in cell adhesiveness, a constitutively active H-RasV12 (H-RasV12) and c-Myc were stably expressed, singly or in combination in a haematopoietic cell line, and the expression and activity of cell adhesion molecules were monitored. RESULTS: We have shown that the ectopic expression of H-RasV12, but not c-Myc alone, in a haematopoietic cell line, induces the activation of very late antigen-6 (VLA-6, alpha6beta1) integrin. Co-expression of H-RasV12 and c-Myc in the same cells further resulted in the induction of expression of vascular cell adhesion molecule-1 (VCAM-1) and the inhibition of expression of alpha6 integrin, a candidate anti-oncogene product, leading to a loss of adhesiveness to laminin (Lm), a ligand for VLA-6. CONCLUSIONS: Cooperation of H-Ras and c-Myc reciprocally regulates expression of the adhesion molecules, alpha6 integrin and VCAM-1. Our results represent an unprecedented account of the cooperation of the oncogene products, H-Ras and c-Myc, to inhibit expression of an anti-oncogene product, alpha6 integrin.

Role of fractalkine in leukocyte adhesion and migration and in vascular injury.

Leukocyte adhesion and trafficking at the endothelium requires both cellular adhesion molecules and chemotactic factors. Fractalkine, a recently identified chemokine, has a unique architecture, a Cys-X-X-X-Cys chemokine domain presented on top of an extended mucin-like stalk as a part of transmembrane protein, and is expressed in a membrane-bound form on tumor necrosis factor-alpha and interleukin-1-activated endothelial cells. Fractalkine receptor CX3CR1 is expressed on natural killer (NK) cells, monocytes and some portions of CD8(+) T cells. Interactions between fractalkine and CX3CR1 can mediate not only chemotaxis but also cell adhesion in the absence of substrates for other adhesion molecules. Furthermore, fractalkine activates NK cells, resulting in enhanced cytolysis of fractalkine expressing endothelial cells. Since endothelial cells are primary targets of immunologic attack, fractalkine seems to be involved in pathogenesis of vascular injury.

Recurrent ischemic colitis in a patient with malignant rheumatoid arthritis (MRA).

Abstract A 63-year-old male with a 5-year history of malignant rheumatoid arthritis (MRA) developed recurrent massive melena and abdominal pain. Methylprednisolone pulse therapy and high doses of oral prednisolone markedly improved the clinical symptoms and normalized immunological disorders. However, he died of disseminated intra-vascular coagulation secondary to pneumonia caused by methicillin-resistant Staphylococcus aureus. Although a high dose of glucocorticoid therapy is effective for ischemic colitis complicated with MRA, intensive care to avoid any opportunistic infection is required.