Hypercholesterolemic Dysregulation of Calpain in Lymphatic Endothelial Cells Interferes With Regulatory T-Cell Stability and Trafficking.

Background: Although hypercholesterolemia reportedly counteracts lymphocyte trafficking across lymphatic vessels, the roles of lymphatic endothelial cells (LECs) in the lymphocyte regulations remain unclear. Previous studies showed that calpain-an intracellular modulatory protease-interferes with leukocyte dynamics in the blood microcirculation and is associated with hypercholesterolemic dysfunction in vascular endothelial cells.

Methods: This study investigated whether the calpain systems in LECs associate with the LEC-lymphocyte interaction under hypercholesterolemia using gene-targeted mice.

Calpain-mediated proteolytic production of free amino acids in vascular endothelial cells augments obesity-induced hepatic steatosis.

Free amino acids that accumulate in the plasma of patients with diabetes and obesity influence lipid metabolism and protein synthesis in the liver. The stress-inducible intracellular protease calpain proteolyzes various substrates in vascular endothelial cells (ECs), although its contribution to the supply of free amino acids in the liver microenvironment remains enigmatic. In the present study, we showed that calpains are associated with free amino acid production in cultured ECs.

Calpain-Associated Proteolytic Regulation of the Stromal Microenvironment in Cancer.

Background: Normalization of the stromal microenvironment is a promising strategy for cancer control. Cancer-associated fibroblasts, tumor-associated macrophages, and mesenchymal stromal cells have a central role in stromal functions. Accordingly, understanding these stromal cells is indispensable for the development of next-generation cancer therapies.

Calpain proteolytic systems counteract endothelial cell adaptation to inflammatory environments.

Vascular endothelial cells (ECs) make up the innermost surface of arteries, veins, and capillaries, separating the remaining layers of the vessel wall from circulating blood. Under non-inflammatory conditions, ECs are quiescent and form a robust barrier structure; however, exposure to inflammatory stimuli induces changes in the expression of EC proteins that control transcellular permeability and facilitate angiogenic tube formation. Increasing evidence suggests that dysfunction in intracellular proteolytic systems disturbs EC adaptation to the inflammatory environment, leading to vascular disorders such as atherosclerosis and pathological angiogenesis.

Mouse RanBPM is a partner gene to a germline specific RNA helicase, mouse vasa homolog protein.

Germ cell-specific ATP-dependent RNA helicase, the product of the mouse vasa homolog (Mvh), has been shown to play an essential role in the development of the male germ cell. In male Mvh knockout mice, premeiotic germ cells arrest at the zygotene stage. To investigate the role of MVH protein in the progression of meiosis, we searched for genes encoding partners that interact with MVH in testicular germ cells.

Embryonic stem cells can form germ cells in vitro.

Knock-in embryonic stem (ES) cells, in which GFP or lacZ was expressed from the endogenous mouse vasa homolog (Mvh), which is specifically expressed in differentiating germ cells, were used to visualize germ cell production during in vitro differentiation. The appearance of MVH-positive germ cells depended on embryoid body formation and was greatly enhanced by the inductive effects of bone morphogenic protein 4-producing cells. The ES-derived MVH-positive cells could participate in spermatogenesis when transplanted into reconstituted testicular tubules, demonstrating that ES cells can produce functional germ cells in vitro.

The mouse homolog of Drosophila Vasa is required for the development of male germ cells.

Restricted expression of a mouse Vasa homolog gene (Mvh) expression is first detected in primordial germ cells (PGCs) after colonization of the genital ridges. Subsequently, Mvh is maintained until postmeiotic germ cells are formed. Here, we demonstrate that male mice homozygous for a targeted mutation of Mvh exhibit a reproductive deficiency.

Generalized melanosis in metastatic malignant melanoma: the possible role of DOPAquinone metabolites.

Generalized melanosis occurs very rarely as a complication of malignant melanoma, and the pathogenesis of this condition is still unclear. Histological examination of pigmented skin and measurements of the DOPAquinone metabolites 5-S-cysteinyldopa (5-S-CD) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) in the patient's serum and urine were carried out. Histological examination revealed basal hyperpigmentation, discrete melanoma cells and melanophages around the blood vessels and an unusual melanin deposition within collagen bundles in the dermis.

Dermatoscopic and videomicroscopic features of melanocytic plantar nevi.

Nearly 10% of Japanese people have pigmented nevi on the soles. Since malignant melanoma also occurs on the plantar area in the Japanese, it would be very valuable to be able to differentiate benign and malignant lesions in the early clinical state. We have investigated the epiluminescence microscopic features of 500 melanocytic nevi on the soles of Japanese people using a dermatoscope and a videomicroscope that can magnify lesions from x 10 to x 200.

Characterization of the mononuclear infiltrate involved in regression of halo nevi.

Halo nevi are characterized by progressive degeneration of nevus cells surrounded by a mononuclear cell infiltrate. We studied the morphological features of the nevus cells and the composition of the mononuclear cell infiltrate in 15 cases of halo nevi using immunohistochemical techniques and a battery of antibodies to different subsets of lymphocytes and histiocytes. Regression could be divided into four more or less identifiable stages, associated with different subsets of lymphocytes and monocyte-macrophage lineage cells.

Lymphocyte and macrophage subsets in active and inactive lesions of lichen planus.

Lichen planus (LP) is a mucocutaneous disease for which the etiology and pathogenesis are poorly understood. We performed an immunohistochemical study on formalin-fixed tissue sections of 10 cases of LP using subsets of antibodies to lymphocytes (LCA, CD3, OPD4-CD4, L26, LN1 and Leu-7), and monocyte-macrophages [lysozyme, KP1-Mac, Factor XIIIa (FXIIIa) and S-100 protein]. Six cases showed typical histological features of active LP, two cases showed features of active and inactive LP, and two cases showed only inactive LP.

Reconstitution of severe combined immunodeficient mice with intrathyroidal lymphocytes of thyroid xenografts from patients with Hashimoto's thyroiditis.

Thyroid tissues from patients with Hashimoto's thyroiditis (HT) have been xenografted to both severe combined immunodeficiency (SCID) mice and nude mice to study the intrathyroidal lymphocytes which were expected to migrate from the xenografts in the SCID mice. Peripheral blood mononuclear cells from HT, Graves' disease, and normal donors have also been separately engrafted. SCID mice, but not nude mice with HT thyroid grafts produce human immunoglobulins.

Lymphocyte markers on formalin-fixed tissue in Jessner's lymphocytic infiltrate and lupus erythematosus.

Clinical and histological differentiation between Jessner's lymphocytic infiltration of the skin (JLI) and lupus erythematosus (LE) may be difficult. Previous immunohistochemical studies using monoclonal antibodies on frozen sections have shown that the majority of inflammatory cells in JLI and LE are T lymphocytes, whereas B lymphocytes are few or absent. We have performed an immunohistochemical study on formalin-fixed, paraffin-embedded tissue sections from seven patients with JLI and five with LE using monoclonal antibodies MT1 (pan T-cells), OPD4 (helper/inducer T-cells CD4), MT2 (mantle zone B and some T-cells), MB2 (pan B-cells), L26 (pan B-cells), and LN1 (germinal centre B-cells).

Localized myxedema on the nasal dorsum in a patient with Graves' disease: report of a case.

We report the case of a 56-year-old Japanese female with Graves' disease associated with localized myxedema on the nasal dorsum. The patient developed localized myxedema concomitantly with hyperthyroidism before antithyroid therapy was given. The lesion was totally removed surgically, as it was small and well circumscribed.