Relationship of computed tomography-verified degenerative condylar morphology with temporomandibular joint disk displacement and sex.

OBJECTIVE: This study investigated the association of computed tomography (CT)-verified degenerative condylar changes with disk displacement (DD) and sex. STUDY DESIGN: Multidetector CT and cone beam CT scans of 165 condyles were evaluated for erosion, osteophyte formation, flattening, subcortical sclerosis, generalized sclerosis, subcortical defects, and loose joint bodies. Disk position was determined using magnetic resonance imaging. The association of degenerative alterations with disk position and sex was analyzed. RESULTS: The risks of erosion, osteophyte formation, and flattening were significantly increased by 3.72, 9.00, and 6.35 times, respectively, in the joints with DD without reduction (DDNR); however, the risks of these changes did not increase significantly in joints with DD with reduction. The risks of extensive erosion and slight and moderate osteophyte formation significantly increased only in the joints with DDNR. The degenerative changes were more likely to exist together in the joints with DDNR than in those with a normal disk position. The association of DD and most degenerative morphologies was not significantly influenced by sex. CONCLUSIONS: Erosion, osteophyte formation, and flattening were significantly associated with DDNR, regardless of sex.

Effects of molecular weight and structural conformation of multivalent-based elastin-like polypeptides on tumor accumulation and tissue biodistribution.

In order to improve clinical outcomes for novel drug delivery systems, distinct optimization of size, shape, multifunctionality, and site-specificity are of utmost importance. In this study, we designed various multivalent elastin-like polypeptide (ELP)-based tumor-targeting polymers in which multiple copies of IL-4 receptor (IL-4R)-targeting ligand (AP1 peptide) were periodically incorporated into the ELP polymer backbone to enhance the affinity and avidity towards tumor cells expressing high levels of IL-4R. Several ELPs with different molecular sizes and structures ranging from unimer to micelle-forming polymers were evaluated for their tumor accumulation as well as in vivo bio-distribution patterns. Different percentages of cell binding and uptake were detected corresponding to polymer size, number of targeting peptides, or unimer versus micelle structure. As compared to low molecular weight polypeptides, high molecular weight AP1-ELP showed superior binding activity with faster entry and efficient processing in the IL-4R-dependent endocytic pathway. In addition, in vivo studies revealed that the high molecular weight micelle-forming AP1-ELPs (A86 and A100) displayed better tumor penetration and extensive retention in tumor tissue along with reduced non-specific accumulation in vital organs, when compared to low molecular weight non-micelle forming AP1-ELPs. It is suggested that the superior binding activities shown by A86 and A100 may depend on the multiple presentation of ligands upon transition to a micelle-like structure rather than a larger molecular weight. Thus, this study has significance in elucidating the different patterns underlying unimer and micelle-forming ELP-mediated tumor targeting as well as the in vivo biodistribution.

Targeting of Cisplatin-Resistant Melanoma Using a Multivalent Ligand Presenting an Elastin-like Polypeptide.

Acquired drug resistance is a common occurrence and the main cause of melanoma treatment failure. Melanoma cells frequently developed resistance against cisplatin during chemotherapy, and thus, targeting delivery systems have been devised to decrease drug resistance, increase therapeutic efficacy, and reduce side effects. We genetically engineered a macromolecular carrier using the recursive directional ligation method that specifically targets cisplatin-resistant (Cis-R) melanoma. This carrier is composed of an elastin-like polypeptide (ELP) and multiple copies of Cis-R melanoma-targeting ligands (M-peptide). The designed M16E108 contains 16 targeting ligands incorporated within an ELP and has an ideal thermal phase transition at 39 °C. When treated to melanoma cells, M16E108 specifically accumulated in Cis-R B16F10 melanoma cells and accumulated to a lesser extent in parental B16F10 cells. Consistently, M16E108 exhibited efficient homing and longer retention in tumor tissues in Cis-R melanoma-bearing mice than in parental B16F10 melanoma-bearing mice. Thus, M16E108 was found to display considerable potential as a novel agent that specifically targets cisplatin-resistant melanoma.

Changes in condylar dimensions in temporomandibular joints with disk displacement.

OBJECTIVES: The aim of this study was to investigate the condylar dimensions of the temporomandibular joint (TMJ) with respect to disk displacements and sex by using computed tomography (CT) and magnetic resonance imaging (MRI). STUDY DESIGN: Disk displacements were divided into 3 groups based on MRI findings: normal disk position (NR), disk displacement with reduction (DDR), and disk displacement without reduction (DDNR). After the angular and linear condylar dimensions were calculated from CT images, differences in condylar dimensions with respect to disk displacements and sex were analyzed with 2-way analysis of variance. RESULTS: Condylar depth and condylar height were significantly smaller in condyles with DDNR compared with those with NR or DDR (NR = DDR > DDNR). Condylar width gradually decreased significantly from NR to DDNR (NR > DDR > DDNR). The anterior condylar angle was significantly larger in condyles with NR compared with those with DDR or DDNR (NR > DDR = DDNR). Condyles with DDNR exhibited significantly larger horizontal condylar angles than those with NR or DDR (NR = DDR < DDNR). Altered condylar dimensions associated with disk displacement were not significantly different between men and women. CONCLUSIONS: Condylar dimensions may be significantly associated with disk displacements of the TMJ, irrespective of sex.

Benzylideneacetone Derivatives Inhibit Osteoclastogenesis and Activate Osteoblastogenesis Independently Based on Specific Structure-Activity Relationship.

(E)-3,4-Dihydroxybenzylideneacetone (compound 1) inhibited receptor activator of NF-κB ligand-induced osteoclastogenesis of C57BL/6 bone marrow monocyte/macrophages with IC50 of 7.8 µM (IC50 of alendronate, 3.7 µM) while stimulating the differentiation of MC3T3-E1 osteoblastic cells, accompanied by the induction of Runt-related transcription factor 2, alkaline phosphatase, and osteocalcin. (E)-4-(3-Hydroxy-4-methoxyphenyl)-3-buten-2-one (compound 2c) showed a dramatically increased osteoclast-inhibitory potency with IC50 of 0.11 µM while sustaining osteoblast-stimulatory activity. (E)-4-(4-Hydroxy-3-methoxyphenyl)-3-buten-2-one (compound 2g) stimulated alkaline phosphatase production 2-fold at 50 µM without changing osteoclast-inhibitory activity, compared with compound 1. Oral administration of compounds 1, 2c, and 2g prevented ovariectomy-induced osteoporosis in ddY mice to a degree proportional to their osteoclastogenesis-inhibitory potencies. The administration of 1 (mg/kg)/d compound 2c ameliorated histomorphometry of osteoporotic bone to a degree comparable with 10 (mg/kg)/d alendronate. Conclusively, the in vitro capacity of a few benzylideneacetone derivatives to inhibit osteoclastogenesis supported by independent osteoblastogenesis activation was convincingly reflected in in vivo management of osteoporosis, suggesting a potential novel therapeutics for osteopenic diseases.

A Selective FGFR inhibitor AZD4547 suppresses RANKL/M-CSF/OPG-dependent ostoclastogenesis and breast cancer growth in the metastatic bone microenvironment.

Aberrant activation of fibroblast growth factor receptor (FGFR) signalling contributes to progression and metastasis of many types of cancers including breast cancer. Accordingly, FGFR targeted tyrosine kinase inhibitors (TKIs) are currently under development. However, the efficacy of FGFR TKIs in the bone microenvironment where breast cancer cells most frequently metastasize and also where FGFR is biologically active, has not been clearly investigated. We investigated the FGFR-mediated interactions among cancer and the bone microenvironment stromal cells (osteoblasts and osteoclasts), and also the effects of FGFR inhibition in bone metastasis. We showed that addition of culture supernatant from the MDA-MB-134-VI FGFR-amplified breast cancer cells-activated FGFR siganalling in osteoblasts, including increased expression of RANKL, M-CSF, and osteoprotegerin (OPG). Further in vitro analyses showed that AZD4547, an FGFR TKI currently in clinical trials for breast cancer, decreased RANKL and M-CSF, and subsequently RANKL and M-CSF-dependent osteoclastogenesis of murine bone marrow monocytes. Moreover, AZD4547 suppressed osteoclastogenesis and tumor-induced osteolysis in an orthotopic breast cancer bone metastasis mouse model using FGFR non-amplified MDA-MB-231 cells. Collectively, our results support that FGFR inhibitors inhibit the bone microenvironment stromal cells including osteoblasts and osteoclasts, and effectively suppress both tumor and stromal compartments of bone metastasis.

Interleukin-7 Contributes to the Invasiveness of Prostate Cancer Cells by Promoting Epithelial-Mesenchymal Transition.

Precise mechanisms underlying interleukin-7 (IL-7)-mediated tumor invasion remain unclear. Thus, we investigated the role of IL-7 in tumor invasiveness using metastatic prostate cancer PC-3 cell line derivatives, and assessed the potential of IL-7 as a clinical target using a Janus kinase (JAK) inhibitor and an IL-7-blocking antibody. We found that IL-7 stimulated wound-healing migration and invasion of PC-3 cells, increased phosphorylation of signal transducer and activator of transcription 5, Akt, and extracellular signal-regulated kinase. On the other hand, a JAK inhibitor and an IL-7-blocking antibody decreased the invasiveness of PC-3 cells. IL-7 increased tumor sphere formation and expression of epithelial-mesenchymal transition (EMT) markers. Importantly, lentiviral delivery of IL-7Rα to PC-3 cells significantly increased bone metastasis in an experimental murine metastasis model compared to controls. The gene expression profile of human prostate cancer cells from The Cancer Genome Atlas revealed that EMT pathways are strongly associated with prostate cancers that highly express both IL-7 and IL-7Rα. Collectively, these data suggest that IL-7 and/or IL-7Rα are promising targets of inhibiting tumor metastasis.

Gap arthroplasty with active mouth opening exercises using an interocclusal splint in temporomandibular joint ankylosis patients.

BACKGROUND: Temporomandibular joint (TMJ) ankylosis during early childhood may lead to disturbances in growth and facial asymmetry and to serious difficulties in eating as well as in breathing during sleep. The purpose of this study is to describe the effectiveness of an interocclusal splint (IOS) for active mouth opening exercises in the treatment of TMJ ankylosis. METHODS: A total of nine patients with 13 instances of TMJ ankylosis from 2008 to 2010 were included in this study, of which five patients were male and four patients were female. Five patients demonstrated unilateral ankylosis, while five patients showed bilateral symptoms. Ankylosed mass resection with coronoidectomy, fibrotic scar release, and resection of stylohyoid ligament calcification was performed with gap arthroplasty without an interpositional graft, and all patients were assessed for maximum mouth opening (MMO) during a mean 6.6-year follow-up period. RESULTS: All patients were subjected to postoperative mouth opening exercises from the day of the operation with the help of an IOS, which was based on an impression taken during surgery. All patients were sufficiently comfortable moving their mandible according to the IOS's guiding plane and impingement, and satisfactory results were achieved, in which MMO was improved by 35 mm more than 6 years after surgery. CONCLUSIONS: Complete and adequate resection of the ankylosed mass and postoperative active mouth opening exercises are essential in the treatment of TMJ ankylosis. Moreover, a more comfortable mouth opening guide and interdigitation can be achieved using an IOS, and newly organized fibrosis in the gap space between the newly made resected condylar head and temporal fossa can be suggested.

Multivalent Targeting Based Delivery of Therapeutic Peptide using AP1-ELP Carrier for Effective Cancer Therapy.

Elastin-like polypeptide (ELP)-based drug delivery has been utilized for various applications including cancer therapies for many years. Genetic incorporation of internalization ligands and cell-targeting peptides along with ELP polymer enhanced tumor accumulation and retention time as well as stability and activities of the drug conjugates. Herein, we described a unique delivery system comprised of genetically engineered ELP incorporated with multiple copies of IL-4 receptor targeting peptide (AP1) periodically and proapoptotic peptide (KLAKLAK)2 referred to as AP1-ELP-KLAK. It triggered thermal-responsive self-assembly into a nanoparticle-like structure at physiological body temperature and stabilized its helical conformation, which is critical for its membrane-disrupting activities. Increased IL-4 receptor specific cellular internalization was associated with the enhanced cytotoxic effect of (KLAKLAK)2 peptide. Additionally, multivalent presentation of targeting ligands by AP1-ELP-KLAK significantly enhanced intratumoral localization and prolonged the retention time compared to ELP-KLAK, non-targeted control. Systemic administration of AP1-ELP-KLAK significantly inhibited tumor growth by provoking cell apoptosis in various tumor xenograft models without any specific organ toxicity. Thus, our newly designed AP1-ELP-KLAK polymer nanoparticle is a promising candidate for effective cancer therapy and due to the simple preparative procedures of ELPs, this platform can be used as a good carrier for tumor-specific delivery of other therapeutics.