Flow-induced hardening of endothelial nucleus as an intracellular stress-bearing organelle

The mechanical contribution of nucleus in adherent cells to bearing intracellular stresses remains unclear. In this paper, the effects of fluid shear stress on morphology and elastic properties of endothelial nuclei were investigated. The morphological observation suggested that the nuclei in the cytoplasm were being vertically compressed under static conditions, whereas they were elongated and more compressed with a fluid shear stress of 2 Pa (20 dyn/cm(2)) onto the cell. The elongated nuclei remained the shape even after they were isolated from the cells. The micropipette aspiration technique on the isolated nuclei revealed that the elastic modulus of elongated nuclei, 0.62 +/- 0.15 kPa (n = 13, mean +/- SD), was significantly higher than that of control nuclei, 0.42 +/- 0.12 kPa (n = 11), suggesting that the nuclei remodeled their structure due to the shear stress. Based of these results and a transmission electron microscopy, a possibility of the nucleus as an intracellular compression-bearing organelle was proposed, which will impact interpretation of stress distribution in adherent cells. (C) 2005 Elsevier Ltd. All rights reserved

Cyclic phosphatidic acid and lysophosphatidic acid induce hyaluronic acid synthesis via CREB transcription factor regulation in human skin fibroblasts

AbstractCyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator and an analog of the growth factor-like phospholipid lysophosphatidic acid (LPA). cPA has a unique cyclic phosphate ring at the sn-2 and sn-3 positions of its glycerol backbone. We showed before that a metabolically stabilized cPA derivative, 2-carba-cPA, relieved osteoarthritis pathogenesis in vivo and induced hyaluronic acid synthesis in human osteoarthritis synoviocytes in vitro. This study focused on hyaluronic acid synthesis in human fibroblasts, which retain moisture and maintain health in the dermis. We investigated the effects of cPA and LPA on hyaluronic acid synthesis in human fibroblasts (NB1RGB cells). Using particle exclusion and enzyme-linked immunosorbent assays, we found that both cPA and LPA dose-dependently induced hyaluronic acid synthesis. We revealed that the expression of hyaluronan synthase 2 messenger RNA and protein is up-regulated by cPA and LPA treatment time dependently. We then characterized the signaling pathways up-regulating hyaluronic acid synthesis mediated by cPA and LPA in NB1RGB cells. Pharmacological inhibition and reporter gene assays revealed that the activation of the LPA receptor LPAR1, Gi/o protein, phosphatidylinositol-3 kinase (PI3K), extracellular-signal-regulated kinase (ERK), and cyclic adenosine monophosphate response element-binding protein (CREB) but not nuclear factor κB induced hyaluronic acid synthesis by the treatment with cPA and LPA in NB1RGB cells. These results demonstrate for the first time that cPA and LPA induce hyaluronic acid synthesis in human skin fibroblasts mainly through the activation of LPAR1-Gi/o followed by the PI3K, ERK, and CREB signaling pathway

Cyclooxygenase-2 is Involved in the Progression of Thyroid Cancer

Although the inducible form of cyclooxygenase (COX), COX-2, is highly expressed in various cancers and it is also involved in cancer progression, its role in thyroid cancer is not fully understood. We assessed in the situ cyclooxygenase expression in normal thyroids (n=6), Graves\u27 thyroids (n=6), thyroid adenomas (n=12), thyroid follicular (n=15) and papillary carcinomas (n=30). In comparison to the constitutive expression of COX-1, COX-2 was highly expressed in thyroid cancers (90.0% of thyroid papillary carcinomas and 73.3% of thyroid follicular carcinomas) and moderately in thyroid adenomas (25.5%), but barely expressed in normal and Graves\u27 thyroid tissues. This quantitative assessment employed immunohistochemical methods. Thereafter we compared the effect of COX-2 inhibition on a human follicular thyroid carcinoma cell line (WRO), and a human papillary carcinoma cell line (NPA), using selective COX-2 inhibitor(NS-398). The treatment with 50 μM NS-398 suppressed the growth of the COX-2 expressing cells, NPA cells (37.7%;p<0.01) and WRO cells (10.1%;p<0.05). Moreover, at concentrations ? 100 μM, NS-398 induced cell death a mitochondrial dysfunction. In addition, 50 μM of NS-398 inhibited the activation of extracellular signal-regulated kinase in NPA cells after the stimulation with fetal bovine serum. Our results indicate that COX-2 is involved in the progression of thyroid cancer

Shoulder and elbow pain in elementary school baseball players : The results from a nation-wide survey in Japan

Background: Despite recommendations on how to prevent baseball injuries in youths by the Japanese Society of Clinical Sports Medicine, shoulder and elbow pain still frequently occurs in young baseball players. We conducted a questionnaire survey among baseball players at elementary schools across the country to understand the practice conditions of players, examining the risk factors of shoulder and elbow pain in baseball players. Methods: The questionnaire survey was conducted among elementary school baseball players as members of the Baseball Federation of Japan in September 2015. Results: A total of 8354 players belonging to 412 teams (average age: 8.9) responded to the survey. Among 7894 players who did not have any shoulder and/or elbow pain in September 2014, elbow pain was experienced in 12.3% of them, shoulder pain in 8.0% and shoulder and/or elbow pain in 17.4% during the previous one year. A total of 2835 (39.9% of the total) practiced four days or more per week and 97.6% practiced 3 h or more per day on Saturdays and Sundays. The risk factors associated shoulder and elbow pain included a male sex, older age, pitchers and catchers, and players throwing more than 50 balls per day. Conclusions: It has been revealed that Japanese elementary school baseball players train too much. Coaches should pay attention to older players, male players, pitchers and catchers in order to prevent shoulder and elbow pain. Furthermore, elementary school baseball players should not be allowed to throw more than 50 balls per day. Study design: Retrospective cohort study

Some Factors Concerning the Distribution of Bronchial Glands

It is well known that the secretion from bronchial glands play an important role to make the airway clean up against sticky bronchial secret. The aim of the present study was to evaluate the relationship between the functional modality of bronchial glands and occurrence of postoperative pulmonary complication due to difficulty of expectoration. However, the noteworthy development of bronchial glands was proved histologically with a distribution index (DI) in each circumstances of either the elderly more than 40 of age or existing inflammation of bronchial trees. Based on histochemical examination by means of PAS stain, the almost same attitudes in regard to magnitude of secretion were not necessarily documented even among bronchial glands with marked development. It was of note that the intimate correlation between secretory behavior of bronchial glands and development of bronchial glands was not certified in the series of this study and that secretory function of bronchial glands did not compatible with pronounced distribution and marked development of them. As a result of this study, the preventive role of bronchial glands from occurrence of postoperative pulmonary complication has not been substantiated by morphological and biochemical study

Clinical Evaluation of Immune Response in Patients with Lung Cancer

In patients with lung cancer, the immune response was observed with an analysis of various factors which mostly related to its prognosis. Its response was extremly depressed in the course of following surgery in advanced cases of stage III and IVas well as in unresectable cases for lung cancer, compared with those of stage I and II . Furthermore, it showed that the high levels of immune response were seen in those of long term survivors given OK-432 during follow-up period. It was obvious from this study that the use of OK-432 was suitable for activation of the immune reaction against host as one of the immunopotentiators. Meanwhile, from the immunological mechanism of view, the hyperactivity of immune response enable the patient to be free from recurrence of cancer for a long term following surgery, in contrast the low level of the immune response showed to be poor prognosis owing to early appearance of recurrence. Furthermore, the effectiveness in use of OK-432 was clinically presented in patients with malignant pleural effusion, which showed direct cytocidal action of OK-432 given intrapleurally with a 10 or 14 days interval

Suppressing TGFβ signaling in regenerating epithelia in an inflammatory microenvironment is sufficient to cause invasive intestinal cancer

Genetic alterations in the TGFβ signaling pathway in combination with oncogenic alterations lead to cancer development in the intestines. However, the mechanisms of TGFβ signaling suppression in malignant progression of intestinal tumors have not yet been fully understood. We have examined ApcΔ716 TGFβr2ΔIEC compound mutant mice that carry mutations in Apc and TGFβr2 genes in the intestinal epithelial cells. We found inflammatory microenvironment only in the invasive intestinal adenocarcinomas but not in noninvasive benign polyps of the same mice. We thus treated simple TGFβr2ΔIEC mice with dextran sodium sulfate (DSS) that causes ulcerative colitis. Importantly, these TGFβr2ΔIEC mice developed invasive colon cancer associated with chronic inflammation.Wealso found that TGFβ signaling is suppressed in human colitis-associated colon cancer cells. In the mouse invasive tumors, macrophages infiltrated and expressed MT1-MMP, causingMMP2activation. These results suggest that inflammatory microenvironment contributes to submucosal invasion of TGFβ signaling-repressed epithelial cells through activation of MMP2. We further found that regeneration was impaired in TGFβr2ΔIEC mice for intestinal mucosa damaged by DSS treatment or X-ray irradiation, resulting in the expansion of undifferentiated epithelial cell population. Moreover, organoids of intestinal epithelial cells cultured from irradiated TGFβr2ΔIEC mice formed "long crypts" in Matrigel, suggesting acquisition of an invasive phenotype into the extracellular matrix. These results, taken together, indicate that a simple genetic alteration in the TGFβ signaling pathway in the inflamed and regenerating intestinal mucosa can cause invasive intestinal tumors. Such a mechanism may play a role in the colon carcinogenesis associated with inflammatory bowel disease in humans

An Experimental Evaluation of Tracheal Blood Flow with Special Referrence to Operative Procedure of Tracheal Mobilization

Based on the study with special referrence to blood flow in the trachea, the factors influential on the operative procedure of tracheal mobilization were carefully evaluated to ensure optimal surgical results. It has already been assumed with an aid of microangiographic technique that the main trancheal blood flow comprise two routes, namely, adventitial and submucosal layers. The amount of blood flow in the trachea divided into individual two layers were measured by hydrogen clearance test with wire electrodes placed in either adventitial or submucosal layer. When employed the procedure of extensive mobilization of the trachea, the level of tracheal blood flow reduced in adventitial layer rather lthan in submucosal layer. Blood flow in submucosal layer, however, remain closely near the normal level, which is thought to compensate a decreased blood supply in the tracheal adventitia. Meanwhile, when proposed an excessive tension of more than 800g at the site of anastomosis, a decrease in submucosal blood flow has become manifest despite of a slight decrease in adventitial blood flow simultaneously. Greater emphasis has been focused upo