Shinichiro Mine

Hypoxia-inducible factor-1alpha induces cell cycle arrest of endothelial cells.

Background: Hypoxia can induce tissue injury, including apoptosis of endothelial cells. However, little is known about the effects of hypoxia on endothelial cell function. We assessed the effects of hypoxia inducible factor (HIF)‐1α on the functional characteristics of endothelial cells, particularly on cell cycle regulators, by cationic liposome‐mediated transfection of HIF‐1α‐expression vector into the cells.

Oxidized low density lipoprotein-induced LFA-1-dependent adhesion and transendothelial migration of monocytes via the protein kinase C pathway

Inflammatory and immune responses are highly relevant processes in the pathogenesis of atherosclerosis, as illustrated by the central event of monocyte accumulation in atherosclerotic plaques. Integrin LFA-1-mediated adhesion of circulating monocytes to the endothelium is a prerequisite for recruitment of monocytes to these areas. Integrin-mediated adhesion is tightly regulated and integrins are only functional in response to particular monocyte activation stimuli. We investigated the role of oxidized low-density lipoprotein (LDL) in adhesion of resting monocytes prepared by elutriation from endothelium. Our results showed that: (1) oxidized LDL (and MCP-1) induced both LFA-1-mediated adhesion of monocytes to endothelial cells and transendothelial migration of monocytes; (2) oxidized LDL functionally transformed monocyte LFA-1 to an activated form; (3) oxidized LDL induced F-actin polymerization and cytoskeletal rearrangement within seconds; and (4) the LDL-associated antioxidant, alpha-tocopherol, but not beta-tocopherol, inhibited both F-actin polymerization and LFA-1-mediated adhesion of monocytes, which paralleled the effect of protein kinase C (PKC) inhibitors. Our results indicate that oxidized LDL plays a pivotal role in triggering LFA-1 activation and LFA-1-mediated adhesion and transmigration of monocytes to sites of atherosclerotic plaques, via the PKC pathway.

A Critical Role for Cyclin C in Promotion of the Hematopoietic Cell Cycle by Cooperation with c-Myc

ABSTRACT Cyclin C, a putative G1 cyclin, was originally isolated through its ability to complement a Saccharomyces cerevisiae strain lacking the G1 cyclin geneCLN1-3. Unlike cyclins D1 and E, the other two G1 cyclins obtained by the same approach and subsequently shown to play important roles during the G1/S transition, there is thus far no evidence to support the hypothesis that cyclin C is indeed critical for the promotion of cell cycle progression. In BAF-B03 cells, an interleukin 3 (IL-3)-dependent murine pro-B-cell line, cyclin C gene mRNA was induced at the G1/S phase upon IL-3 stimulation and reached a maximal level in the S phase. Enforced expression of exogenous cyclin C in this cell line failed to alter its growth properties. In the present study, we examined whether cyclin C is capable of cooperating with the cytokine-responsive immediate-early gene products c-Myc and c-Fos in the promotion of cell proliferation. We found that cyclin C is able to cooperate functionally with c-Myc, but not c-Fos, to induce both BAF-B03 cell proliferation in a cytokine-independent fashion and the formation of cell clusters. Furthermore, cyclin C was primarily responsible for the induction of cdc2 gene expression. Our data define a novel role for cyclin C in the regulation of both the G1/S and G2/M phases of the cell cycle, and this effect appears to be independent of the activity of CDK8 in the control of transcription.

Engagement of CD44 up-regulates Fas Ligand expression on T cells leading to activation-induced cell death

Activation-induced cell death (AICD) plays a pivotal role in self-tolerance by deleting autoreactive T cells, but a defect of AICD results in expansion of autoreactive T cells and is deeply involved in the pathogenesis of rheumatoid arthritis. Although the process of AICD is mainly mediated by Fas Ligand (FasL)/Fas signaling, it remains unclear what induces FasL expression on T cells. In the present study, we found that CD44 was the most potent stimulator of FasL expression on human peripheral T cells. CD44 cross-linking rapidly up-regulated FasL expression on the T cell surface by delivery from the cytoplasm without new FasL protein synthesis. This up-regulation of FasL was mediated by activation of a tyrosine kinase, IP3 receptor-dependent Ca2+ mobilization and actin cytoskeletal rearrangements. Furthermore, AICD induced by CD3 restimulation was inhibited by hyaluronidase as well as by soluble Fas, indicating an interaction between membrane-bound hyaluronan and the cell surface CD44 was involved in the up-regulation of FasL expression on T cells and subsequent AICD. We therefore propose that the engagement of CD44 on T cells can eliminate autoreactive T cells by expression of FasL and FasL-mediated AICD.

Management of symptoms in step‐down therapy of gastroesophageal reflux disease

Objective:  Majority of studies on gastroesophageal reflux disease (GERD) that include patients with or without erosive disease have documented the efficacy of proton pump inhibitors (PPIs) as well as their superiority to H2‐receptor antagonist (H2‐RA). The purpose of this study was to clarify the difference in quality of GERD treatment with PPIs and H2‐RA in step‐down protocol using lansoprazole.

Hepatic sarcoidosis associated with chronic hepatitis C.

A 57-year-old woman with sarcoidosis was referred because of the appearance of multiple small low-attenuation areas in the liver on computed tomography (CT). A liver biopsy specimen showed chronic active hepatitis accompanied by sarcoid granulomas. The patient received prednisolone and, later, interferon-alpha. CT at 5 months of prednisolone treatment showed disappearance of the hepatic low-attenuation nodules. During long-term follow-up, however, these nodules reappeared on CT and liver cirrhosis finally developed. We present this case for two reasons: (1) hepatic sarcoidosis was associated with chronic active hepatitis C; (2) hepatic nodular lesions were evaluated by CT throughout the entire course, with CT scans having been taken from 2 years prior to their appearance.

Parathyroid hormone-related peptide producing cholangiocellular carcinoma with a marked psammoma formation

Humoral hypercalcemia caused by parathyroid hormone‐related peptide (PTHrP), associated with cholangiocellular carcinoma (CCC), has rarely been documented. There have been no reports of CCC associated with extensive calcification of the tumor with psammoma body formation. A 66‐year‐old man was admitted with a large calcified tumor in the liver detected on an abdominal X‐ray. An ultrasound‐guided fine needle biopsy specimen of the liver tumor showed evidence of adenocarcinoma. He had hypercalcemia with an elevated PTHrP level. The patient died because of disseminated intravascular coagulation and progressive hepatic failure. A postmortem examination revealed a large poorly differentiated CCC in the liver. Immunohistochemical examination showed the presence of PTHrP‐positive tumor cells. The calcified lesion consisted of a number of accumulated psammoma bodies. We present a case of PTHrP producing CCC with a marked psammoma formation.

Ultrasonographic evaluation of lansoprazole-induced improvement of submucosal injury in patients with gastroesophageal reflux.

OBJECTIVE:Endoscopic ultrasonographic (EUS) changes in gastroesophageal reflux disease (GERD) after treatment with proton pump inhibitor have been poorly evaluated. We conducted a randomized, double-blind 12-wk clinical trial to compare the EUS effects of lansoprazole to histamine H2-receptor antagonist therapy in GERD.METHODS:Seventeen patients with reflux-related symptoms received 40 mg of famotidine for 6 wk or 30 mg of lansoprazole for 6 wk followed by 40 mg of famotidine or 30 mg of lansoprazole for another 6 wk, respectively. Patients underwent EUS before and at 6 and 12 wk after treatment.RESULTS:Before treatment, a variable degree of wall thickening was noted on EUS in the lower esophagus, compared with 20 normal subjects. After 6 wk of therapy, esophageal wall was significantly thicker in the famotidine group compared with the lansoprazole group (p < 0.01). Surprisingly, thickening of esophageal wall and abnormal architecture were also detected in endoscopically negative reflux disease. Lansoprazole was superior to famotidine in reducing the thickness of esophageal wall.CONCLUSIONS:EUS was very useful for evaluation of submucosal injury in patients with GERD. EUS showed that a 6-wk course of lansoprazole therapy reduced thickening of esophageal wall, which was resistant to histamine H2-receptor antagonist therapy. Our results also suggest that inflammatory damage to the submucosal and muscle layers of the lower esophagus is the underlying mechanism of heartburn and associated symptoms in patients with endoscopically negative reflux disease.

Increased esophageal mucosal/submucosal blood flow in patients with gastroesophageal reflux disease : Normalization by treatment with a proton pump inhibitor

Background and Aim:  Mucosal injury caused by gastroesophageal reflux may result in changes in esophageal mucosal blood flow. Little is known about esophageal mucosal blood flow in patients with gastroesophageal reflux disease (GERD). Here we examined esophageal mucosal blood flow and the effects of treatment in patients with GERD.

Ki-1 Lymphoma with Nodular Involvement in Liver and Spleen: Possible Role of Cytokines in Systemic Manifestation of Fever and Leukocytosis

Ki-1 lymphoma, a subset of non-Hodgkin’s lymphoma (NHL), usually presents with lymphadenopathy or skin involvement as the first manifestation (1–12). There are a few reports that described extranodal involvement; however, it is extremely rare that Ki-1 lymphoma presents with multiple nodular involvement in the liver and spleen in the early phase of the disease (5–15). Furthermore, there are only a few reports that have demonstrated increased cytokine levels in serum, such as interleukin (IL-6) and granulocyte colony-stimulating factor (G-CSF) and their contribution to certain clinical manifestations in patients with Ki-1 lymphoma (16–19). Here, we report a case of Ki-1 lymphoma with some unique onset features including tumor localization in the liver and spleen as well as the clinical manifestations suggestive of systemic inflammation, which were most likely attributable to increased levels of cytokines.