The Molecular Pathogenesis and Clinical Implications of Hepatocellular Carcinoma

The prognosis of hepatocellular carcinoma (HCC) is affected by tumoral factors and liver functions; therefore it is often difficult to select the appropriate therapeutic methods for HCC. Recently, two global phase III trials showed that sorafenib, which is a tyrosine kinase inhibitor, improved the prognosis of patients with advanced HCC. As a new therapeutic strategy for HCC, sorafenib is expected to expand the indication for HCC in the future. However, it alone is insufficient for the molecular-targeted treatment of HCC because the signaling pathway exists not only in cancer cells but also in normal cells. Recently, cancer stem cells (CSCs) have attracted attention as a novel therapeutic target for HCC. There is now much evidence that stem cell properties such as self-renewal, unlimited proliferation, and differentiation are highly relevant to cancer recurrence and the drug resistance of HCC. In this review, we describe the molecular pathogenesis and the current state and future development of molecular- and CSC-therapeutic targeted agents for HCC, citing various reports

The Role of T-Cell Leukemia Translocation-Associated Gene Protein in Human Tumorigenesis and Osteoclastogenesis

Synovial tissues of patients with rheumatoid arthritis (RA) include factors regulating bone resorption, such as receptor activator NF-κB ligand (RANKL), TNF-α, IL-6, IL-17, and IFN-γ. However, in addition to these cytokines, other factors expressed in synovial tissues may play a role in regulating bone resorption. In 2009, we demonstrated that novel peptides from T-cell leukemia translocation-associated gene (TCTA) protein expressed in synovial tissues from patients with RA inhibit human osteoclastogenesis, preventing cellular fusion via the interaction between TCTA protein and a putative counterpart molecule. Only a few studies on the role of TCTA protein have been reported. Genomic Southern blots demonstrated a reduced TCTA signal in three of four small cell lung cancer cell lines, suggesting the loss of one of the two copies of the gene. In the current paper, we reviewed the roles of TCTA protein in lung cancer cell lines and human osteoclastogenesis

Prevention of growth arrest-induced cell death of vascular smooth muscle cells by a product of growth arrest-specific gene, gas6

AbstractWe have purified Gas6 as a growth-potentiating factor for vascular smooth muscle cells (VSMCs) [Nakano, T. et al. (1995) J. Biol. Chem. 270, 5702-57051. However, specific production of Gas6 in growth-arrested cells raises an intriguing question as to the physiological function of Gas6. In this study, we found that serum-starved VSMCs secreted some survival factors and depletion of the factors induced cell death of VSMCs. Finally, we demonstrated that cell death was prevented by the addition of Gas6, suggesting that one of the major biological activity of Gas6 is protection of growth-arrested VSMCs from death

IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis

HIP KINEMATICS AND MUSCLE ACTIVITY DURING INSIDE SOCCER KICK IN PLAYERS WITH A HISTORY OF GROIN PAIN

The purpose of this study was to clarify the kinematic characteristics of groin pain (GP). In addition, we investigated the correlations between the kinematics of inside soccer kick movement and muscle activities in the lower extremities. Twenty-four male soccer players (control group, 13; GP group, I1 ) were instructed to perform maximum inside kick. Our results showed that the adductor muscle activity was maintained from the back swing to the leg acceleration phase in the in GP group but was decreased from the peak value at the back swing to the leg acceleration phase in the control group. In the leg acceleration phase, the adductor muscle activity was significantly higher in the GP group than in the control group. The GP group showed faster adduction/abduction velocity of the kicking leg in all kicking phases than the control group

Molecular and virulence characteristics of an outer membrane-associated RTX exoprotein in Pasteurella pneumotropica

<p>Abstract</p> <p>Background</p> <p><it>Pasteurella pneumotropica </it>is a ubiquitous bacterium that is frequently isolated from laboratory rodents and causes various clinical symptoms in immunodeficient animals. Currently two RTX toxins, PnxIA and PnxIIA, which are similar to hemolysin-like high-molecular-weight exoproteins are known in this species. In this study, we identified and analyzed a further RTX toxin named PnxIIIA and the corresponding type I secretion system.</p> <p>Results</p> <p>The RTX exoprotein, PnxIIIA, contains only a few copies of the RTX repeat-like sequence and 3 large repeat sequences that are partially similar to the outer membrane protein found in several prokaryotes. Recombinant PnxIIIA protein (rPnxIIIA) was cytotoxic toward J774A.1 mouse macrophage cells, whereas cytotoxicity was attenuated by the addition of anti-CD11a monoclonal antibody. rPnxIIIA could bind to extracellular matrices (ECMs) and cause hemagglutination of sheep erythrocytes. Binding was dependent on the 3 large repeat sequences in PnxIIIA. Protein interaction analyses indicated that PnxIIIA is mainly localized in the outer membrane of <it>P. pneumotropica </it>ATCC 35149 in a self-assembled oligomeric form. PnxIIIA is less cytotoxic to J774A.1 cells than PnxIA and PnxIIA.</p> <p>Conclusions</p> <p>The results implicate that PnxIIIA is located on the cell surface and participates in adhesion to ECMs and enhanced hemagglutination in the rodent pathogen <it>P. pneumotropica</it>.</p

Complete Dissection of a Hepatic Segment after Blunt Abdominal Injury Successfully Treated by Anatomical Hepatic Lobectomy: Report of a Case

A 21-year-old male patient was transferred to the emergency room of our hospital after suffering seat belt abdominal injury in a traffic accident. Abdominal computed tomography revealed a massive hematoma in the abdominal cavity associated with deep hepatic lacerations in the right lobe. The presence of a solid tissue possibly containing pneumobilia was observed above the greater omentum. These findings were consistent with a tentative diagnosis of hepatic laceration due to blunt trauma; therefore, this prompted us to perform emergency laparotomy. The operative findings revealed a massive hematoma and pulsatile bleeding from the lacerated liver and a retroperitoneal hepatoma, which was most likely due to subcapsular injury of the right kidney. In accordance with the preoperative imaging studies, a pale liver fragment on the greater omentum was observed, which was morphologically consistent with the defect in the posterior segment of the liver. Since the damaged area of the liver broadly followed the course of the middle hepatic vein, we carefully inspected and isolated the inflow vessels and eventually performed a right hepatic lobectomy. The patient's postoperative course was uneventful, and he was doing well at 10 months after surgery