[show abstract][hide abstract] ABSTRACT: The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways. p62 deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity in p62(-/-) mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity in p62(-/-) mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as in p62(-/-) mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobese p62(-/-) mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, in p62(-/-) mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome.
Journal of Neuroscience 09/2013; 33(37):14767-14777. · 6.91 Impact Factor
[show abstract][hide abstract] ABSTRACT: In gingival squamous cell carcinoma (GSCC), the association between survival and previous dental extraction (DE) is controversial. The purpose of this study was to investigate the prognosis for patients in whom GSCC was detected after DE was performed.
DE for GSCC tumor symptoms was performed in 19 patients before diagnosis (DE group) and not in 58 patients (non-DE group). The clinical features, characteristics, and prognosis were evaluated statistically between the 2 groups.
The interval from DE to the first hospital visit was 1.1 to 97 weeks (median, 7.3 weeks). There was no significant difference in tumor status, node status, local recurrence, pathologically positive lymph nodes, or distant metastasis between the DE and non-DE groups. Bone invasion was observed radiographically in 6 patients with mandibular GSCC in the DE group (100%) and 13 in the non-DE group (68.4%). There was a significant difference in bone invasion between the DE and non-DE groups (P < .01). Segmental mandibulectomy was performed in 11 patients (84.6%) in the DE group and 21 patients (61.8%) in the non-DE group. Extent of resection tended to be larger for the DE group. The 5-year overall survival rate was 84.6% for the DE group and 65.8% for patients with mandibular GSCC in the non-DE group. For maxillary GSCC, the survival rates differed significantly between groups (33.3% in DE group and 73.7% in non-DE group).
For mandibular GSCC, the resection field was appropriate for the extent of bone invasion after DE and the prognosis was similar to that in the non-DE group. For maxillary GSCC, a broad surgical field is suggested because of the potential for rapid spread in cancellous bony trabeculae.
Journal of oral and maxillofacial surgery: official journal of the American Association of Oral and Maxillofacial Surgeons 07/2013; · 1.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: Interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors including head and neck squamous cell carcinoma (HNSCC). We designed a novel IL-4Rα-lytic hybrid peptide composed of a binding peptide to IL-4Rα and a cell-lytic peptide. In the present study, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular-targeted therapy in HNSCC. Immunoblot analysis revealed that IL-4Rα was expressed in all tested HNSCC cell lines (HSC-2, HSC-3, HSC-4, Ca9-22 and OSC-19), but not in a human normal keratinocyte (HaCaT) cell line. Immunohistochemical expression levels of IL-4Rα in HNSCC tissues were higher compared to those in normal epithelial tissue. The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in all five cancer cell lines with a concentration that killed 50% of all cells (IC50) as low as 10 µM. HaCaT cells were less sensitive to this peptide with an IC50 of >30 µM. In addition, intratumoral administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human HNSCC in vivo. These results indicate that the IL-4Rα-lytic hybrid peptide may serve as a potent agent to provide a novel therapy for patients with HNSCC.
[show abstract][hide abstract] ABSTRACT: Radiation-induced carotid artery stenosis (RI-CS), a life-threatening condition, can occur after external radiation for head and neck cancer. We here describe a case of asymptomatic RI-CS in a 73-year-old patient treated with chemoradiotherapy and radical neck dissection for a basaloid squamous cell carcinoma of the oral floor. Stenosis of the left carotid artery, diagnosed as RI-CS, showed on an MRI performed 1.5 years after radiotherapy. Blood from the left side of the anterior cerebral artery and the middle anterior artery was flowing to the brain through the anterior and posterior communicating arteries, so no stent surgery or other treatment was necessary. The cancer has not recurred during approximately 5 years of followup after radiotherapy, and the patient has had no adverse effects from the RI-CS since it was diagnosed 3.5 years ago. This case emphasizes the necessity of early scrutiny for RI-CS in patients given radiotherapy for oral cancer.
Case reports in oncological medicine. 01/2013; 2013:379039.
[show abstract][hide abstract] ABSTRACT: Background. Neuroleptic malignant syndrome (NMS) is a rare but life-threatening complication of neuroleptic drugs, which are used widely in head and neck cancer (HANC) patients who develop delirium. Methods and Results. Postoperative delirium in a 39-year-old man with tongue cancer was treated with haloperidol and chlorpromazine. Three days after the first administration of antipsychotics, the patient exhibited elevated body temperature, autonomic and extrapyramidal symptoms, and impaired consciousness. A definitive diagnosis was made using the research diagnostic criteria for NMS in the DSM-IV, and the antipsychotics were immediately discontinued. The patient was given dantrolene and bromocriptine to treat the NMS. The patient's hyperthermia, elevated creatinin kinase (CK), and muscle rigidity improved gradually, with all symptoms of NMS resolving completely by 13 days after the diagnosis. Conclusions. HANC surgeons must be alert for early signs of NMS and use antipsychotics conservatively to avoid NMS and its potentially fatal outcome.
[show abstract][hide abstract] ABSTRACT: Cell division cycle associated 2 (CDCA2) recruits protein phosphatase 1 to chromatin to antagonize activation of ataxia telangiectasia mutated (ATM)-dependent signal transduction. ATM kinase plays a critical role in the DNA damage response and its phosphorylation cascade to inhibit the p53-MDM2 interaction, which releases p53 to induce p21 and G1 cell-cycle arrest. However, the relevance of CDCA2 to human malignancy including oral squamous cell carcinoma (OSCC) is unknown. In the current study, we found that CDCA2 expression was up-regulated in OSCC cell lines. Functional studies with shRNA system showed that knockdown of CDCA2 significantly (P<0.05) inhibited cellular proliferation compared with the control cells by arresting cell-cycle progression at the G1 phase and up-regulating the cyclin-dependent kinase inhibitors (p21(Cip1), p27(Kip1), p15(INK4B), and p16(INK4A)). CDCA2 knockdown also promoted apoptosis after treatment with the DNA damage reagent, cisplatin. In clinical samples, the CDCA2 protein expression level in primary OSCCs was significantly (P<0.05) greater than in matched normal oral tissues (67/85, 79%). Furthermore, CDCA2-positive cases were correlated significantly (P<0.05) with high cancer progression. Our results showed for the first time that CDCA2 frequently is overexpressed in OSCCs and might be associated closely with OSCC progression by preventing cell-cycle arrest and apoptosis.
PLoS ONE 01/2013; 8(2):e56381. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: PURPOSE: Cisplatin is one of the most potent chemotherapeutic agents used to treat cancer. However, cisplatin-induced nephrotoxicity, which is partly caused by oxidative damage, is a serious problem. We previously showed that murine embryonic fibroblasts deficient in Peroxiredoxin I (Prx I), a major Nrf2-linked anti-oxidant enzyme, are susceptible to cisplatin-induced cytotoxicity. In the present study, we examined the role of Prx I against cisplatin-induced renal injury in vivo using Prx I-null mice. METHODS: Prx I-null mice and wild-type (WT) mice were given an intraperitoneal injection of cisplatin, and tissues were removed and evaluated histopathologically. In addition, gene and protein expression of efflux transporters was analyzed. RESULTS: In contrast to an in vitro cell study, Prx I-null mice exhibited less cisplatin-induced renal damage than WT mice in histological and blood biochemical analyses. Moreover, Prx I-null mice showed a higher clearance rate of cisplatin than WT mice following intraperitoneal cisplatin injection. Consistent with these results, Prx I-null mice exhibited higher expression of renal efflux transporters Mrp2 and Mrp4 compared with WT mice under both basal and the cisplatin-induced conditions. We suggest the enhanced transcriptional activity of c-Myc in Prx I-null mice may partly contribute the enhanced expression of renal efflux transporters. CONCLUSION: In summary, the enhanced clearance rate of cisplatin significantly attenuates nephrotoxicity in Prx I-null mice.
Cancer Chemotherapy and Pharmacology 12/2012; · 2.80 Impact Factor
[show abstract][hide abstract] ABSTRACT: We evaluated the effects of presurgical nasoalveolar molding (NAM) with an orthopedic appliance and compared them with a passive orthopedic method (Hotz plate, HP), focusing on the naris morphology and width of the alveolar and palate cleft gap. The subjects were 28 unilateral complete cleft lip and palate patients treated with primary cheiloplasty at Tsukuba University Hospital from 2004 to 2011. Thirteen patients were treated preoperatively with NAM (NAM group), and 15 with HP (HP group). The surgical outcome was assessed according to left-right naris symmetry, as measured by the area ratio, perimeter ratio, aspect a/u ratio (aspect ratio of the affected side/aspect ratio of the unaffected side), and Hausdorff distance. In addition, the alveolar and palate cleft width was measured at the times of orthopedic plate setting and primary cheiloplasty. The aspect ratio was significantly smaller in the NAM group than in the HP group before the operation. In both groups, the aspect ratio, perimeter ratio, and Hausdorff distance were significantly smaller after the operation than before. The width of the alveolar and palate cleft gap was significantly narrowed in the NAM group, and the cleft gap at the initiation of NAM correlated significantly with the Hausdorff distance after cheiloplasty. We found that NAM improved the form of the naris after primary cheiloplasty and decreased the palate cleft gap more effectively than HP and that the width of the palate cleft gap was correlated with the surgical outcome of the naris.
The Journal of craniofacial surgery 11/2012; · 0.81 Impact Factor
[show abstract][hide abstract] ABSTRACT: We assessed the postoperative nasal form and symmetry after presurgical use of a Hotz plate (HP) in patients with unilateral complete cleft lip and palate (UCLP). The subjects were 28 infants with UCLP who underwent cheiloplasty. Of these subjects, 14 underwent presurgical orthopedic treatment using the HP (HP group) and 14 underwent the same treatment without the HP (non-HP group). Photographic records were obtained 1 and 6 months after cheiloplasty, and the results of anthropometric analysis were compared between the 2 groups. The nasal inclination and the ratio of the width of the nasal base to the total width of the nose were significantly improved in the HP group compared with the non-HP group at both postoperative time points. Thus, presurgical use of the HP significantly improved the nasal asymmetry and deformity in UCLP patients after primary cheiloplasty and nasal repair.
Annals of plastic surgery 11/2012; · 1.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: OBJECTIVE: To evaluate surgery results, we established a novel method to digitize nasal morphology with the use of Hausdorff distance and analyzed nose morphology after cheiloplasty. STUDY DESIGN: We evaluated the naris after primary cheiloplasty of 30 unilateral cleft lip and palate patients. Similarity between left and right sides was assessed by visual evaluation, area ratio, perimeter ratio, aspect a/u ratio, and Hausdorff distance. The postoperative naris morphology was also compared between 15 patients treated with a Hotz plate before surgery and 15 not treated. RESULTS: Significant correlation with visual evaluation was found for Hausdorff distance. For the groups with and without Hotz plate treatment, the visual evaluation was higher and Hausdorff distance significantly lower in the treated group. CONCLUSIONS: The morphologic measurement obtained using the Hausdorff distance was the closest to visual evaluation, and assessment using Hausdorff distance suggested that using a Hotz plate helps retain the symmetry of the nares after cheiloplasty.
Oral surgery, oral medicine, oral pathology and oral radiology. 08/2012;
[show abstract][hide abstract] ABSTRACT: Cell division cycle associated 3 (CDCA3), part of the Skp1-cullin-F-box (SCF) ubiquitin ligase, refers to a trigger of mitotic entry and mediates destruction of the mitosis inhibitory kinase. Little is known about the relevance of CDCA3 to human malignancy including oral squamous cell carcinoma (OSCC). We aimed to characterize the expression state and function of CDCA3 in OSCC.
We evaluated CDCA3 mRNA and protein expression in both OSCC-derived cell lines and primary OSCCs and performed functional analyses of CDCA3 in OSCC-derived cells using the shRNA system.
The CDCA3 expression at both the mRNA and protein levels was frequently up-regulated in all cell lines examined and primary tumors (mRNA, 51/69, 74 %; protein, 79/95, 83 %) compared to normal controls (p < 0.001). In contrast, no significant level of CDCA3 protein expression was seen in oral premalignant lesions (OPLs) (n = 20) compared with the expression in OSCCs. Among the clinical variables analyzed, the CDCA3 expression status was closely related to tumor size (p < 0.05). In addition, suppression of CDCA3 expression with shRNA significantly (p < 0.05) inhibited cellular proliferation compared with the control cells by arresting cell-cycle progression at the G1 phase. Further, there was up-regulation of the cyclin-dependent kinase inhibitors (p21(Cip1), p27(Kip1), p15(INK4B), and p16(INK4A)) in the knockdown cells.
The current results showed that overexpression of CDCA3 occurs frequently during oral carcinogenesis and this overexpression might be associated closely with progression of OSCCs by preventing the arrest of cell-cycle progression at the G1 phase via decreased expression of the cyclin-dependent kinase inhibitors.
[show abstract][hide abstract] ABSTRACT: While circulating tumor-derived molecules have been identified in a variety of malignant tumors, it is sometimes difficult to detect the molecular targets due to the lower serum concentration. We report that evaluation of circulating tumor-derived mitochondrial DNA (mtDNA) seems to have novel efficiency for detecting tumoral micrometastasis. In murine xenografting human oral cancer cells, human mtDNAs could be quantitatively detected from multiple organs and blood samples whereas human nucleic DNAs could not. We also determined if this mtDNA blood test was relevant for patients with oral cancer with no histologic evidence of tumoral cells in their surgical margins. For this, mtDNA from normal and tumorous tissues and serum mtDNA obtained pre and postoperatively was examined at three different regions including the displacement loop, 12S-rRNA, and 16S-rRNA. All non-recurring patients had significantly higher amounts of mutant mtDNAs in the tumoral tissues compared with the non-recurring group. More importantly, on the blood test with the cut-off point by receiver operating characteristic (ROC) curve analysis, while the vast majority of serum mtDNA samples obtained postoperatively in the recurring cases maintained significantly higher amounts of mutant mtDNAs, the non-recurring cases did not, and they showed good prognosis. This is the first report of this approach for managing patients after resection of oral tumors, and may have substantial diagnostic potential for other tumoral types.
[show abstract][hide abstract] ABSTRACT: Angiosarcoma is an uncommon malignancy, which spread out from the endothelial cells of vessels. Scalp angiosarcoma with cervical lymph node metastasis is particularly rare. This article describes a rare case of angiosarcoma of the scalp, presenting as neck inflammation. Imaging procedures such as computed tomography (CT), magnetic resonance image (MRI) and ultrasonography (US) were not sufficient to diagnose this case. A needle biopsy provided an effective and accurate diagnosis of cervical lymph node metastasis. Additional observation and physical examination was required to diagnose the origin of the primary cancerous lesion. Once the angiosarcoma diagnosis was confirmed histologically, sequential weekly and monthly docetaxel (DTX) treatment was effective in preventing reoccurrence. Nonetheless, the optimization of angiosarcoma treatment remains a future goal. Although patients generally describe pain and swelling at the primary lesion site, this patient complained only of painful neck inflammation, without any indication of pain or swelling of the scalp. A revised diagnostic protocol should note that cervical lymph node metastasis of unknown primary origin may result from angiosarcoma of the scalp.
International Journal of Oral Science 06/2012; 4(3):166-9. · 2.72 Impact Factor
[show abstract][hide abstract] ABSTRACT: We compared conventional ultrasound (US) B-mode, color Doppler and elastographic assessment of lymph node (LN) stiffness against pathological findings from surgical samples, to determine the most useful factors for identifying LN metastases. Seventy-one LNs in 19 patients with oral squamous cell carcinoma (OSCC) were examined. Using our new system, elastography images were scored from 1-5. The score 1-4 were correlated with the blue area of each LN, which indicated increased stiffness: (1) none; (2) < 50%; (3) 50%; or (4) > 50%. A score 5 indicated central necrosis and did not correlate with the blue area. We found significant differences in minimal diameter, shape index, margin, internal structure, hilus presence or absence, elastography score and percentage of blue area between metastatic and nonmetastatic LNs. Stepwise regression analysis identified elastography score 3-5 as an independent significant LN metastatic factor, suggesting that our scoring system may be useful for accurately diagnosing metastatic LNs.
Ultrasound in medicine & biology 03/2012; 38(3):389-95. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Oral mucositis (OM) is a frequent adverse effect of allogenic or autologous hematopoietic SCT. It results from direct toxic injury to the mucosal epithelial cells by the immunosuppressive regimen. Here, we compared the incidence and severity of OM between a group of 24 patients who received proper oral management during hematopoietic SCT and a group of 24 who did not. The oral management group received pre-hematopoietic SCT instruction on oral care and an oral examination in the clean room. Differences in the incidence and severity of OM between the two groups were examined statistically. OM was observed in 14 (58.3%) patients in the oral management group and 22 (91.6%) in the control group. The median of the OM score was 1 for the oral management group (range 0 to 3) and 2 for the control group (range 0 to 3). There was a significant difference in the OM score (P<0.05) and in the incidence of OM between the two groups (P<0.01). This study shows that oral management may decrease the occurrence of OM. Our results also suggest that it is important to include an oral management provider on the hematopoietic SCT team.
Bone marrow transplantation 08/2011; 47(5):725-30. · 3.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: Conventional therapies including radiation therapy cannot cure squamous cell carcinoma (SCC), and new treatments are clearly required. Our recent studies have shown that SCC cell lines exhibiting radioresistance show significant upregulation of the fibroblast growth factor receptor 3 (FGFR3) gene. We hypothesized that inhibiting FGFR3 would suppress tumor cell radioresistance and provide a new treatment approach for human SCCs. In the present study, we found that RNA interference-mediated FGFR3 depletion in HSC-2 cells, a radioresistant cell line, induced radiosensitivity and inhibited tumor growth. Use of an FGFR3 inhibitor (PD173074) obtained similar results with suppression of the autophosphorylation extracellular signal-regulated kinase pathway in HSC-2 cells and lung cancer cell lines. Moreover, the antitumor growth effect of the combination of PD173074 and radiation in vivo was also greater than that with either drug alone or radiation alone. Our results provided novel information on which to base further mechanistic study of radiosensitization by inhibiting FGFR3 in human SCC cells and for developing strategies to improve outcomes with concurrent radiotherapy.
[show abstract][hide abstract] ABSTRACT: Basal cell adenoma is a benign neoplasm of the salivary glands. This tumor usually arises in the major glands, with the parotid being the most frequent site of occurrence, while it is rare in the minor salivary glands. We report a case of basal cell adenoma of a minor salivary gland on the palate.
The patient was a 68-year-old man. Intraoral examination revealed a mass measuring 20 × 20 mm that was elastic-hard, dark violet, non-ulcerated, and covered the normal mucosa. Computed tomography scan and magnetic resonance imaging (MRI) both showed a mass situated in front of the soft palate. The T1-weighted MRI revealed tumor isointensity, and the T2-weighted image showed tumor hyperintensity. The clinical diagnosis was palate tumor, and excision was performed under general anesthesia. Histopathological examination revealed that an encapsulated mass had grown under the epithelium and indicated a diagnosis of basal cell adenoma.
Although no recurrence has been detected in the 3 years and 6 months of follow up, there was a case of malignant transformation of a basal cell adenoma reported. Therefore, careful follow-up observation will continue to be important.
Oral and Maxillofacial Surgery 02/2011; 16(1):111-4.