Hsiang Yang

Topical photodynamic therapy is very effective for oral verrucous hyperplasia and oral erythroleukoplakia

BACKGROUND Oral verrucous hyperplasia (OVH) and oral erythroleukoplakia (OEL) are two oral precancerous lesions with relatively high malignant transformation potential. One of the best cancer prevention strategies is to use a conservative and effective treatment modality to eliminate oral precancers to stop their further malignant transformation. Our previous studies have shown that the topical 5-aminolevulinic acid-mediated photodynamic therapy (topical ALA-PDT) using the 635-nm light-emitting diode (LED) light is very effective for OVH and OEL lesions. METHODS Because the laser machine is a more-popular light source than the LED device in PDT clinics, in this study 40 OVH and 40 OEL lesions were treated once a week with the same PDT protocol but using the 635-nm laser light to evaluate whether this laser light-mediated topical ALA-PDT was also effective for OVH and OEL lesions. RESULTS We found that all the 40 OVH lesions exhibited complete response (CR) after an average of 3.6 PDT treatments. Of the 40 OEL lesions, 38 showed CR after an average of 3.4 PDT treatments and two showed partial response (PR). Better PDT outcomes were significantly associated with OVH and OEL lesions with the smaller size, pink to red color, epithelial dysplasia, or thinner surface keratin layer. CONCLUSION This study indicates that the laser light-mediated topical ALA-PDT is also very effective for OVH and OEL lesions. Therefore, we suggest that topical ALA-PDT using either the LED or laser light may serve as the first-line treatment of choice for OVH and OEL lesions.

Comparison of clinical outcomes of oral erythroleukoplakia treated with photodynamic therapy using either light‐emitting diode or laser light

Topical 5‐aminolevulinic acid‐mediated photodynamic therapy (topical ALA‐PDT) using a 635‐nm light‐emitting diode (LED) light is an effective treatment modality for oral verrucous hyperplasia. This study tested whether topical ALA‐PDT using either the LED or laser light was also an effective treatment modality for oral erythroleukoplakia (OEL) lesions.

5-aminolevulinic acid induce apoptosis via NF-κB/JNK pathway in human oral cancer Ca9–22 cells

BACKGROUND 5-aminolevulinic acid-based photodynamic therapy (5-ALA-PDT) is being used to treat oral pre-cancerous and cancerous lesions with some encouraging clinical outcomes. However, the exact mechanisms behind the photodynamic treatment are still not fully elucidated. METHOD   Flow cytometry, TdT-mediated dUTP nick end labeling assay and Western blot analysis were used to investigate the effects of 5-ALA-PDT on human oral cancer Ca9-22 cells. RESULTS We found that 5-ALA-PDT induces apoptosis in Ca9-22 cells. Western blotting showed that 5-ALA-PDT activates both the caspase-8 and caspase-9 pathways, which differed from previous studies conducted in other cell types. Activation of JNK was evident as early as 30 min. The caspases activation was inhibited by JNK inhibitor SP600125. Treatment with NF-κB inhibitor Bay 11-7082 (Bay) completely abrogated ALA-PDT-induced JNK activation. In addition, Bay and SP600125 almost completely abolished ALA-PDT-induced apoptosis. CONCLUSION These results demonstrate significant involvement of caspase-8 and -9 and their upstream NF-κB-JNK pathways in ALA-PDT-induced apoptosis. Future studies on how NF-κB and JNK activity regulate ALA-PDT response should provide a better strategy for the treatment of oral cancer.

Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: A therapeutic benefit for arthritis

OBJECTIVE To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis. METHODS Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB. Interaction between CREB and the Cyr61 promoter was evaluated by electrophoretic mobility shift assay and chromatin immunoprecipitation. CCL2 expression was examined by Northern blotting and enzyme-linked immunosorbent assay. In rats with collagen-induced arthritis (CIA), osteoblastic expression of Cyr61 was examined by immunohistochemistry, and disease progression was assessed by clinical, radiographic, and histologic examination. RESULTS In primary human osteoblasts and U2OS cells, Cyr61 expression stimulated by tumor necrosis factor α, interleukin-1β (IL-1β), oncostatin M (OSM), and other IL-6-family cytokines was suppressed by simvastatin. In U2OS cells, simvastatin inhibited OSM-induced CREB phosphorylation and CREB-DNA binding. Knockdown of CREB by short hairpin RNA reduced Cyr61 synthesis. OSM-induced Cyr61 promoter activation was dependent on CRE-CREB interaction and inhibited by simvastatin. Cyr61 enhanced CCL2 expression by U2OS cells. Intraarticular injection of simvastatin inhibited CIA progression and diminished the number of Cyr61+ osteoblasts and infiltrating macrophages. CONCLUSION Simvastatin inhibited cytokine-stimulated Cyr61 expression in osteoblastic cells and suppressed disease progression and osteoblastic expression of Cyr61 in inflammatory arthritis. This finding indicates that simvastatin may have potential as a therapeutic agent for inflammatory arthritis.

Odontogenic Fibroma: A Clinicopathological Study of 15 Cases

BACKGROUND/PURPOSE Odontogenic fibroma (ODF) is a rare odontogenic tumor. It can be further divided into peripheral odontogenic fibroma (PODF) and central odontogenic fibroma (CODF). This retrospective study evaluated the clinical and histopathological features of 15 ODFs in Taiwanese patients. METHODS Fifteen consecutive cases of ODF were collected from 1984 to 2009. The clinical data and microscopic features of these cases were reviewed and analyzed. RESULTS Twelve PODFs were excised from six male and six female patients (mean age: 35 years) and three CODFs from two male and one female patients (mean age: 11 years). Eight of the 12 PODFs were found on the mandibular gingiva and four on the maxillary gingiva, with the most common site being the mandibular anterior and premolar region (5 cases). Two CODFs were located in the molar region of the mandible and one in the anterior maxilla. Two CODFs showed a mixed lesion and one a radiolucent lesion. No recurrence of the 15 ODFs was found after total excision or enucleation. Microscopically 58.3% of the PODFs showed surface ulcèration. Calcified foci composed of osteoid, cementoid, or cementicle-like materials were noted in all 15 ODFs. Nests or strands of odontogenic epithelium were found in all 15 ODFs. The stromal component was mainly fibro-collagenous in nine of the 12 PODFs, whereas two of the three CODFs contained predominantly myxomatous stroma. CONCLUSION PODFs occurred more commonly than CODFs. PODF showed an equal sex distribution and was found more frequently in patients in the third to fourth decades of life. The most commonly affected site was the mandibular gingiva, especially the anterior and premolar gingiva. Only three CODFs were found; therefore, we could not draw any conclusions about CODF in Taiwanese patients.

Expression of Vascular Endothelial Growth Factor is Significantly Associated With Progression and Prognosis of Oral Squamous Cell Carcinomas in Taiwan

BACKGROUND/PURPOSE Expression of vascular endothelial growth factor (VEGF) correlates with progression and prognosis of several human cancers. The main purposes of this study were to assess expression of VEGF in specimens of oral squamous cell carcinoma (OSCC) and to evaluate the possible influence of VEGF on the progression and prognosis of OSCC in Taiwan. METHODS An immunohistochemical technique was used to examine the expression of VEGF in 100 specimens of OSCC, 66 specimens of oral epithelial dysplasia, and 36 specimens of normal oral mucosa. RESULTS We found that the mean labeling indices (Lis) of VEGF increased significantly from normal oral mucosa (13 ± 6%), through mild (22 ± 8%), moderate (24 ± 13%), and severe oral epithelial dysplasia (32 ± 14%), to OSCC samples (50 ± 18%, p < 0.001). The higher mean VEGF LI was significantly related to OSCC with positive lymph node metastasis (p = 0.022) and with more advanced clinical stages (p = 0.046). In addition, positive lymph node metastasis (p = 0.008) and VEGF LI > 40% (p = 0.046) were identified as independent unfavorable prognosis factors for OSCC patients by multivariate analysis with the Cox regression model. Moreover, the Kaplan-Meier curve showed that OSCC patients with a VEGF LI > 40% had a significantly poorer cumulative survival than those with a VEGF LI ≤ 40% (log-rank test, p = 0.016). CONCLUSION We conclude that VEGF may be a biomarker for prediction of the progression and prognosis of OSCC in Taiwan.

Simvastatin suppresses osteoblastic expression of Cyr61 and progression of apical periodontitis through enhancement of the transcription factor Forkhead/winged helix box protein O3a.

INTRODUCTION In this study, the role of transcription factor Forkhead/winged helix box protein O3a (FoxO3a) in Cyr61 expression and its modulation by simvastatin were investigated in cultured murine osteoblasts and a rat model of induced apical periodontitis. We also examined the effects of simvastatin on the synthesis of chemokine CCL2 and chemotaxis of macrophages in vitro. METHODS We assessed tumor necrosis factor (TNF)-α-stimulated expression of Cyr61 and phosphorylated inactive FoxO3a (p-FoxO3a) in MC3T3-E1 murine osteoblasts by Western analysis. Forced expression of FoxO3a by lentiviral-based gene transduction was performed, and its effect on Cyr61 expression was evaluated. The modulation of CCL2 secretion and macrophage chemotaxis by simvastatin were examined by enzyme-linked immunosorbent assay and transwell migration assay, respectively. In a rat model of induced apical periodontitis, the relation between disease progression and osteoblastic expression of Cyr61, p-FoxO3a, and CCL2 and macrophage recruitment were studied by radiographic and immunohistochemistry analyses. RESULTS Western blot analysis showed enhanced expression of Cyr61 and p-FoxO3a after TNF-α treatment in a time-dependent manner. Simvastatin significantly counteracted the actions of TNF-α. Forced expression of FoxO3a reduced TNF-α-stimulated Cyr61 synthesis. Simvastatin and FoxO3a diminished TNF-α-induced CCL2 secretion and macrophage recruitment, whereas Cyr61 partially restored the stimulating action. In rat periapical lesions, simvastatin significantly attenuated bone resorption, reduced osteoblastic expressions of Cyr61, p-FoxO3a, and CCL2, and suppressed macrophage recruitment. CONCLUSIONS Simvastatin may alleviate periapical lesions by enhancing FoxO3a activity to suppress the synthesis of Cyr61 in osteoblasts. Moreover, the downstream effector mechanism of Cyr61 may involve CCL2 production and macrophage recruitment.

Successful treatment of an early invasive oral squamous cell carcinoma with topical 5-aminolevulinic acid-mediated photodynamic therapy

Our previous studies showed successful treatment of a series of 36 oral verrucous hyperplasia lesions and of an extensive oral verrucous carcinoma with a topical 5-aminolevulinic acid (ALA)-mediated photodynamic therapy (topical ALA-PDT) protocol (with a fluence rate of 100 mW/cm 2 and a light exposure dose of 100 J/cm 2 ) using a 635-nm light-emitting diode (LED) light source. In this case report, we tested whether an enhanced topical ALA-PDT protocol (with a fluence rate of 200 mW/cm 2 and a light exposure dose of 200 J/cm 2 ) could be used to treat an early invasive oral squamous cell carcinoma (OSCC) with a verrucous appearance of the left lower posterior edentulous alveolar mucosa of a 67-year-old male former areca-quid chewer and ex-smoker. The main verrucous lesion showed complete regression after eight treatments with PDT. However, 10 extra treatments were needed to eradicate the multiple residual leukoplakia lesions on the edentulous alveolar mucosa. Moderate to severe post-PDT pain was noted during the initial eight treatments, and the patient needed analgesics (codeine phosphate, 30 mg three times daily) to control the pain. No recurrence of the OSCC lesion was found after a follow-up period of 4 years. We suggest that our enhanced topical ALA-PDT protocol may have good potential to be used as a treatment of choice for a superficially invasive OSCC without regional or distant metastasis before the commencement of other effective therapies.

Epigallocatechin-3-gallate diminishes cytokine-stimulated Cyr61 expression in human osteoblastic cells: a therapeutic potential for arthritis

OBJECTIVE To assess the effects of epigallocatechin-3-gallate (EGCG) on cytokine-induced Cyr61 synthesis in human osteoblastic cells and the associated signalling pathways. The therapeutic effect of EGCG on CIA in rats was also studied. METHODS The expression of Cyr61 and NF-κB pathway molecules was examined by western blotting. CCL2 expression was assessed by northern blotting and ELISA. Interaction between NF-κB and Cyr61 promoter was evaluated by electrophoretic mobility shift assay. In rat CIA, osteoblastic expression of Cyr61 was examined by immunohistochemistry and disease progression was assessed by clinical, radiographic and histological examinations. RESULTS EGCG inhibited Cyr61 expression stimulated by cytokines in primary human osteoblasts and human osteoblastic cell line U2OS. In U2OS, oncostatin M (OSM) induced IκB-α degradation through the mTOR/rictor/Akt pathway, and EGCG attenuated the action. Electrophoretic mobility shift assay revealed that the OSM-enhanced NF-κB/DNA binding was reduced by EGCG, possibly through abrogating nucleus localization of p65 and p50. Cyr61 enhanced OSM-induced expression of CCL2. Moreover, EGCG diminished OSM-stimulated CCL2 expression at least partially via suppressing Cyr61 induction. Co-distribution of CD68(+) macrophages and Cyr61(+) osteoblasts in osteolytic areas was obvious in the CIA model. Clinical, radiographic and immunohistochemical analyses revealed that administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the number of Cyr61-synthesizing osteoblasts. CONCLUSION By modulating the mTOR/rictor/Akt/NF-κB pathway, EGCG attenuated Cyr61 production in osteoblastic cells and in turn diminished macrophage chemotaxis. Our data support the therapeutic potential of EGCG on arthritis.

Physiologic and behavioral effects of papoose board on anxiety in dental patients with special needs

BACKGROUND/PURPOSE Anxiety induced by dental treatment can become a serious problem, especially for patients with special needs. Application of deep touch pressure, which is a sensory adaptation technique, may ameliorate anxiety in disabled patients. However, few empiric studies have investigated the possible links between the clinical effects of deep touch pressure and its behavioral and physiologic aspects. Equally little progress has been made concerning theoretical development. The current study is a crossover intervention trial to investigate the behavioral and physiological effects of deep touch pressure for participants receiving dental treatment. METHODS Nineteen disabled participants, who were retrospectively subclassified for positive trend or negative trend, were recruited to receive the papoose board as an application of deep touch pressure. Quantitative analyses of behavioral assessments and physiological measurements, including electrodermal activity and heart rate variability, were conducted. We sought to understand the modulation of the autonomic nervous system and the orchestration of sympathetic and parasympathetic (PsNS) nervous systems. RESULTS Behavioral assessments reported that higher levels of anxiety were induced by the dental treatment for participants with both groups of positive and negative trends. Although no significant differences were found in the SNS activity, physiologic responses indicated that significantly changes of PsNS activity were observed under the stress condition (dental treatment) when deep touch pressure intervention was applied, especially for participants in the group of positive trend. CONCLUSION Our results suggest that the PsNS activation plays a critical role in the process of ANS modulation. This study provides not only physiologic evidence for the modulation effects of deep touch pressure on stressful conditions in dental environments but also the evidence that the application of papoose board, as a sensory adaptation technique, is not harmful for dental patients with special needs.