The kinase-deficient Src acts as a suppressor of the Abl kinase for Cbl phosphorylation

The kinase activity of Abl is known to be regulated by a putative trans-acting inhibitor molecule interacting with the Src homology (SH) 3 domain of Abl. Here we report that the kinase-deficient Src (SrcKD) directly inhibits the tyrosine phosphorylation of Cbl and other cellular proteins by Abl. We found that both the SH2 and SH3 domains of SrcKD are necessary for the suppressor activity toward the Abl kinase phosphorylating Cbl. To suppress the Cbl phosphorylation by Abl, the interaction between the SH3 domain of SrcKD and Cbl is required. This interaction between SrcKD and Cbl is regulated by a closed structure of Cbl. The binding of Abl to the extreme carboxyl-terminal region of Cbl unmasks the binding site of SrcKD to Cbl. This results in a ternary complex that inhibits the Abl-mediated phosphorylation of Cbl by steric hindrance. These results illustrate a mechanism by which the enzymatically inactive Src can exert a biological function in vivo.     

Bismuth-free Triple Therapy for Eradicating Helicobacter pylori and Reducing the Gastric Ulcer Recurrence Rate

Objectives: The goals of this study were to assess the effectiveness of a new triple therapy consisting of amox–icillin and metronidazoie with plaunotol in the eradication of Helicobacter pylori infection in hnmans, and to determine whether this treatment regimen reduces the rate of recurrence of gastric ulcer in patients infected with H. pylori , without instituting maintenance therapy with H2–receptor antagonists. Methods: Thirty patients with active gastric ulcer who were infected with H. pylori were first treated with omeprazole until scarring occurred. Patients then received plaunotol for 4 wk, with amoxicillin and metronidazoie for 7 days. Results: This triple therapy resulted in the safe eradication of H. pylori in 26 (86.7%) of 30 patients, with no recurrence of ulcer seen during a 12-month follow-up period in patients who tested negative for the presence of H. pylori . In addition, histological inflammatory changes improved in these patients. Of the four patients with persistent H. pylori infection, in three (75%), ulcers recurred. Conclusion: This new triple therapy was very effective in eradicating H. pylori in infected patients and in reducing the rate of recurrence of gastric ulcer in these patients.     

Immunomodulatory aspects in the progression and treatment of oral malignancy

Inflammation substantially affects the risk of oral malignancy. Pro-inflammatory cytokine, interferon (IFN)-γ, confers anti-tumor activity using several different mechanisms. Conversely, higher expression of interleukin (IL)-17 is associated with worse prognosis. Monocyte chemotactic protein (MCP)-1 correlates positively with poor long-term survival of head and neck squamous cell carcinoma (HNSCC) patients. IL-1α affects cancer associated fibroblasts and macrophages, and promote several malignant phenotypes including immune suppression. Some anti-inflammatory cytokines, including IL-10 and transforming growth factor (TGF)-β, relate to pro-tumoral activities.Among immune checkpoint modulators, programmed death (PD-)1 and PD-ligand (L)1 facilitate oral squamous cell carcinoma (OSCC) cell evasion from immune surveillance, and the expression status of these has a prognostic value.OSCCs contain tumor associated macrophages (TAMs) as major stromal cells of their tumor microenvironment. Among the two distinctive states, M2 macrophages support tumor invasion, metastasis and immune suppression. Crosstalk between TAMs and OSCC or cancer-associated fibroblasts (CAF) plays an important role in the progression of OSCC.Clinical trials with blocking antibodies against IL-1α or melanoma-associated antigens have been reported as therapeutic approaches against OSCCs. The most promising approach activating antitumor immunity is the blockade of PD-1/PD-L1 axis. Manipulating the polarization of pro-tumorigenic macrophages has been reported as a novel therapeutic approach.     

Immunohistochemical expression of podoplanin in so-called hard α-keratin-expressing tumors, including calcifying cystic odontogenic tumor, craniopharyngioma, and pilomatrixoma

Podoplanin, a transmembrane sialomucin-like glycoprotein, is a specific marker of lymphatic vessels, and its expression is also considered to be associated with tumor invasion and tooth development. In this study, we examined the expression of podoplanin in calcifying cystic odontogenic tumor (CCOT) in comparison with that in other so-called hard α-keratin-expressing tumors such as craniopharyngioma (CP) and pilomatrixoma (PM). Immunohistochemical staining for podoplanin was carried out using surgical specimens of 15 CCOTs of the jaw, 19 CPs of the pituitary gland, and 15 PMs of the skin. Positivity for hard α-keratin was evident in ghost, shadow and transitional cells in all of these tumors (100%). The podoplanin expression in CCOTs was evident in the periphery of ameloblastoma-like epithelium (86.6%) and the epithelial cells adjacent to ghost cells (60%). On the other hand, in adamantinomatous-type CPs, podoplanin expression was observed in epithelial components corresponding to the stratum intermedium (100%), but not in the periphery of ameloblastoma-like epithelium (0%). In squamous-type CPs podoplanin was expressed in basal cells (100%), but all of the PMs were podoplanin-negative (0%). In the periphery of the ameloblastoma-like epithelium or basophilic cell layer, podoplanin was expressed more strongly in CCOTs than in CPs or PMs. These findings suggest that the expression of podoplanin in CCOTs may reflect rapid turnover of cytoskeletal filaments and local invasiveness.     

Possible involvement of angiotensin-converting enzyme 2 and Mas activation in inhibitory effects of angiotensin II Type 1 receptor blockade on vascular remodeling

We explored the roles of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7), and Mas activation in angiotensin II type 1 receptor blockade-mediated attenuation of vascular remodeling. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. After cuff placement, the mRNA level of both ACE2 and Mas was markedly decreased in wild-type mice, whereas ACE mRNA was not changed. Immunostaining of ACE2 and Mas was observed mainly in the media and was reduced in the injured artery. Administration of angiotensin-(1-7) decreased neointimal formation after cuff placement, whereas administration of [D-Ala(7)] angiotensin-(1-7), a Mas antagonist, increased it. Consistent with these results, we also demonstrated that neointimal formation induced by cuff placement was further increased in ACE2 knockout mice. In angiotensin II type 1a receptor knockout mice, mRNA expression and immunostaining of ACE2 and Mas in the injured artery were greater, with less neointimal formation than in wild-type mice. Increased ACE2 expression in the injured artery was also observed by treatment of wild-type mice with an angiotensin II type 1 receptor blocker, olmesartan. These results suggested that activation of the ACE2-angiotensin-(1-7)-Mas axis is at least partly involved in the beneficial effects of angiotensin II type 1 receptor blockade on vascular remodeling.     

Perspectives On the Role of the Lateral Pterygoid Muscle and the Sphenomandibular Ligament in Temporomandibular Joint Function

The lateral pterygoid muscle plays an important role in the movement of the mandible and has been studied from several points of view, including structural and functional anatomy. What matters clinically is the relative position of the muscle fibers attached medially to the mandibular condyle. In the following study, we observed not only the attachment of the lateral pterygoid muscle fibers to the articular disk, but also the relative position of the mandibular condyle to a base line set up on the mandibular condyle. According to our observations, the lateral pterygoid muscle fibers attach to the articular disk at the inner point of the medial pole. Based on this finding, we can say that the muscle fibers can both draw the articular disk anteriorly and balance it by supporting it posteriorly. That is to say, the lateral pterygoid muscle has two actions: to elevate the articular disk anteriorly and to support the articular disk. Furthermore, the sphenomandibular ligament has continuity with the articular disk tissue medially. This relationship suggests that the ligament fibers attached to the articular disk draw the disk posteriorly in its course of mandibular closing, thus enabling the articular disk to move smoothly.