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Oral squamous cell carcinoma (OSCC) frequently invades nearby bone and bone involvement determines the prognosis of patients. Growth factors, stored in the bone matrix and released during bone destruction, are known as key components in the bone-tumor interaction. However, the coordination of growth factor signals and the precise mechanism of bone destruction in oral cancer are still unclear. In the study, we investigated the differential cytokine expression profile of oral cancer cells by TGF-β treatment and the function of altered expression of cytokines on the osteoclast differentiation. We established TGFBR2-knockdown cells using small hairpin RNA. TGF-β was treated to both TGFBR2 expressing and knockdown cells and the culture supernatants were analyzed using a cytokine array kit. We found that the TGF-β inhibited IGFBP3 level and enhanced MMP9 level. We confirmed this regulation of IGFBP3 and MMP9 by TGF-β using ELISA and zymography, respectively. IGFBP3 is known as to modulate the bioavailability of IGF1, which is abundant in the bone microenvironment and regulates osteoclast differentiation. Therefore, we further analyzed the function of IGFBP3 on osteoclastogenesis. Although IGFBP3 increased the viability of murine bone marrow macrophages, the osteoclast differentiation of these cells was blocked by IGFBP3 in a dose-dependent manner. These results revealed a novel pathway for the regulation of osteoclastogenesis by oral cancer cells, which may be a new therapeutic target for osteolysis induced by oral cancer infiltrating into the bone.

Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival. Here, we show that CCL28 functions as a negative regulator of OSCC bone invasion. CCL28 inhibited invasion and epithelial-mesenchymal transition (EMT), and its inhibition of EMT was characterized by induced E-cadherin expression and reduced nuclear localization of β-catenin in OSCC cells with detectable RUNX3 expression levels. CCL28 signaling via CCR10 increased retinoic acid receptor-β (RARβ) expression by reducing the interaction between RARα and HDAC1. In addition, CCL28 reduced RANKL production in OSCC and osteoblastic cells and blocked RANKL-induced osteoclastogenesis in osteoclast precursors. Intraperitoneally administered CCL28 inhibited tumor growth and osteolysis in mouse calvaria and tibia inoculated with OSCC cells. RARβ expression was also increased in tumor tissues. In patients with OSCC, low CCL28, CCR10, and RARβ expression levels were highly correlated with bone invasion. Patients with OSCC who had higher expression of CCL28, CCR10, or RARβ had significantly better overall survival. These findings suggest that CCL28, CCR10, and RARβ are useful markers for the prediction and treatment of OSCC bone invasion. Furthermore, CCL28 upregulation in OSCC cells or CCL28 treatment can be a therapeutic strategy for OSCC bone invasion.

The acute demise of stem cells following transplantation significantly compromises the efficacy of stem cell-based cell therapeutics for infarcted hearts. As the stem cells transplanted into the damaged heart are readily exposed to the hostile environment, it can be assumed that the acute death of the transplanted stem cells is also inflicted by the same environmental cues that caused massive death of the host cardiac cells. Pyroptosis, a highly inflammatory form of programmed cell death, has been added to the list of important cell death mechanisms in the damaged heart. However, unlike the well-established cell death mechanisms such as necrosis or apoptosis, the exact role and significance of pyroptosis in the acute death of transplanted stem cells have not been explored in depth. In the present study, we found that M1 macrophages mediate the pyroptosis in the ischemia/reperfusion (I/R) injured hearts and identified miRNA-762 as an important regulator of interleukin 1β production and subsequent pyroptosis. Delivery of exogenous miRNA-762 prior to transplantation significantly increased the post-transplant survival of stem cells and also significantly ameliorated cardiac fibrosis and heart functions following I/R injury. Our data strongly suggest that suppressing pyroptosis can be an effective adjuvant strategy to enhance the efficacy of stem cell-based therapeutics for diseased hearts.

Recent studies have shown that several upstream signaling elements of apoptosis and necroptosis are closely associated with acute injury in the heart. In our study, we observed that miR-105 was notably dysregulated in rat hearts with myocardial infarction (MI). Thus, the purpose of this study was to test the hypothesis that miR-105 participates in the regulation of RIP3/p-MLKL- and BNIP3-dependent necroptosis/apoptosis in H9c2 cells and MI rat hearts. Our results show that the RIP3/p-MLKL necroptotic pathway and BNIP3-dependent apoptosis signaling are enhanced in H9c2 cells under hypoxic conditions, whereas, compared with these pathways in the controls, those in miR-105-treated H9c2 cells are suppressed. Mechanistically, we identified miR-105 as the miRNA directly suppressing the expression of RIP3 and BNIP3, two important mediators involved in cell necroptosis and apoptosis. Furthermore, MI rat hearts injected with miR-105 had decreased infarct sizes, indicating that miR-105 is among three miRNAs that function simultaneously to suppress necroptotic/apoptotic cell death pathways and to inhibit MI-induced cardiomyocyte cell death at multiple levels. Taken together, miR-105 may constitute a new therapeutic strategy for cardioprotection in ischemic heart disease. Keywords: apoptosis, ischemic heart, microRNA-105, necroptosis, programmed cell death

Background/Aims: Bone metastasis of cancer cells decreases patient survival and quality of life. Hybridization via the covalent coupling of two bioactive natural products is a useful strategy for developing more potent anticancer agents by enhancing their bioavailability and avoiding drug resistance. Methods: The in vivo activities of artemisinin-daumone hybrid 15 (ARTD) were estimated in cancer cell-inoculated mice and ovariectomized mice. The viability, migration, and invasion of cancer cells were measured via MTT, wound-healing, and transwell invasion assays. ARTD-regulated transcription factors were detected with an RT2 profiler PCR array kit and Western blotting. Osteoclastogenesis and osteoclast activity were detected with tartrate-resistant acid phosphatase staining, a pit formation assay, gelatin zymography, and a cathepsin K ELISA assay. Results: ARTD blocked cancer-associated osteolysis more potently than artemisinin in mice with intratibially inoculated breast cancer or lung cancer cells. ARTD inhibited the viability, migration, and invasion of breast and lung cancer cells in the absence or presence of transforming growth factor-β1. ARTD treatment induced the expression of tumor suppressive activating transcription factor 3 and inhibited oncogenic E2F transcription factor 1 expression at the mRNA and protein levels. ARTD inhibited receptor activator of nuclear factor kappa-B ligand-induced osteoclast formation and bone resorbing activity by reducing the secreted levels of matrix metalloproteinase-9 and cathepsin K. Furthermore, ARTD prevented estrogen deficiency-induced bone loss in ovariectomized mice. Conclusion: ARTD may be a promising candidate for inhibiting cancer-induced bone destruction. The application of ARTD may be extended to patients with chemotherapy-induced ovarian failure or postmenopausal osteoporosis.

As a potent and selective allosteric inhibitor of MEK, TAK-733 has been shown to exert anti-cancer effects for a wide range of cancers both in vitro and in vivo. However, its effects on inhibiting growth have never been investigated in the cardiovascular system, where regulation of abnormal vascular smooth muscle cell growth in neointimal hyperplasia is an important area of focus. Angiotensin II was used to mimic inflammatory neointimal hyperplasia in an in vitro environment, and balloon catheter-induced injury with an infusion of angiotensin II was used to generate an in vivo rat restenosis model under inflammatory conditions. TAK-733 exerted anti-proliferative and anti-migratory effects on human vascular smooth muscle cells. These multiple effects of TAK-733 were evaluated using various assays, such as cell cycle analysis and wound healing. Interestingly, TAK-733 did not induce apoptosis in smooth muscle cells but only reduced the proliferation rate; additionally, it did not affect EC viability. TAK-733 also exhibited anti-inflammatory activity, as observed by attenuated monocyte adhesion to smooth muscle cells via inhibition of ICAM1 and VCAM1 overexpression. The in vivo study demonstrated that neointimal hyperplasia after balloon injury and angiotensin II stimulation was suppressed by TAK-733, and downregulation of the inflammatory signal and enhanced re-endothelialization were observed. TAK-733 may have therapeutic potential for treating neointimal hyperplasia by attenuating smooth muscle cell proliferation, migration, and inflammation. Thus, TAK-733 could be a promising drug candidate for treating patients with restenosis., Atherosclerosis: Potential therapy based on prospective cancer drug Drug undergoing trials as a cancer treatment shows promise in tackling the narrowing of blood vessels in other diseases. The thickening of arterial walls and consequent restriction of blood flow, typical of conditions like atherosclerosis, increases the risk of heart attacks and strokes. Soyeon Lim and Ki-Chul Hwang at the Catholic Kwandong University, South Korea, and co-workers have investigated the efficacy of a prospective cancer drug called TAK-733 against atherosclerosis both in cell culture and in trials on rat models of the disease. The team hypothesized that TAK-733’s anti-cancer effects could prove useful in treating other conditions. They demonstrated that TAK-733 successfully blocked the proliferation and migration of vascular smooth muscle cells, the overexpression of which is a dominant factor in the development of atherosclerosis.

// Junhee Park 1, 2 , Hyun-Jeong Kim 2 , Ki Rim Kim 3 , Sun Kyoung Lee 2 , Hyungkeun Kim 2, 4 , Kwang-Kyun Park 1, 2, 4 , Won-Yoon Chung 1, 2, 4 1 Department of Dentistry, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea 2 Department of Oral Biology, Oral Cancer Research Institute, and BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 120-752, Republic of Korea 3 Department of Dental Hygiene, Kyungpook National University, Sangju 742-711, Korea 4 Department of Applied Life Sciences, Graduate School, Yonsei University, Seoul 120-749, Republic of Korea Correspondence to: Won-Yoon Chung, email: wychung@yuhs.ac Kwang-Kyun Park, email: biochelab@yuhs.ac Keywords: oral squamous cell carcinoma, bone invasion, runt-related transcription factor 3, transforming growth factor-β Received: October 08, 2015 Accepted: December 15, 2016 Published: December 21, 2016 ABSTRACT High recurrence and lower survival rates in patients with oral squamous cell carcinoma (OSCC) are associated with its bone invasion. We identified the oncogenic role of RUNX3 during bone invasion by OSCC. Tumor growth and the generation of osteolytic lesions were significantly inhibited in mice that were subcutaneously inoculated with RUNX3-knockdown human OSCC cells. RUNX3 knockdown enhanced TGF-β-induced growth arrest and inhibited OSCC cell migration and invasion in the absence or presence of transforming growth factor-β (TGF-β), a major growth factor abundant in the bone microenvironment. RUNX3 knockdown induced cell cycle arrest at the G1 and G2 phases and promoted G2 arrest by TGF-β in Ca9.22 OSCC cells. RUNX3 knockdown also inhibited both the basal and TGF-β-induced epithelial-to-mesenchymal transition by increasing E-cadherin expression and suppressing the nuclear translocation of β-catenin. In addition, the expression and TGF-β-mediated induction of parathyroid hormone-related protein (PTHrP), one of key osteolytic factors, was blocked in RUNX3-knockdown OSCC cells. Furthermore, treating human osteoblastic cells with conditioned medium derived from RUNX3-knockdown OSCC cells reduced the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin ratio compared with treatment with conditioned medium from RUNX3-expressing cells. These findings indicate that RUNX3 expression in OSCC cells contributes to their bone invasion and the resulting osteolysis by inducing their malignant behaviors and production of osteolytic factors. RUNX3 alone or in combination with TGF-β and PTHrP may be a useful predictive biomarker and therapeutic target for bone invasion by oral cancer.

Background/aim Colorectal cancer (CRC) is one of the most common in the world and its prevalence is rapidly increasing. Jagged-1-activated Notch signaling by apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1) promotes CRC, and high expression of Jagged-1 is associated with poor prognosis. However, its clinical implication is unknown. The aim of this study was to investigate the clinical role of Jagged-1-activated Notch signaling by APEX1. Materials and methods The 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the anti-cancer efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan. Tissue from CRC patients was analyzed to assess the clinical specificity of Jagged-1 activated by APEX1. Results The half-maximal inhibitory concentration (IC50) in cells co-expressing APEX1 and Jagged-1 cells was higher than that in cells expressing only APEX1. These results indicated that the simultaneous expression of APEX1 and Jagged-1 might be associated with chemoresistance toward 5-FU, oxaliplatin, and irinotecan. Analysis of tissue from CRC patients revealed that high expression of Jagged-1 was associated with a statistically significantly low response to chemotherapy. Conclusion Overexpression of Jagged-1 by APEX1 might serve as a predictor of response to chemotherapy and of poor prognosis, and moreover may be a therapeutic target for chemotherapy of advanced CRC.

Objective Hearing loss is a major side effect of cisplatin chemotherapy. Although cell death in cisplatin-induced ototoxicity is primarily caused by apoptosis, the exact mechanism behind the ototoxic effects of cisplatin is not fully understood. Autophagy is generally known as a pro-survival mechanism that protects cells under starvation or stress conditions. However, recent research has reported that autophagy plays a functional role in cell death also. This study aimed to investigate the role of autophagy in cisplatin-induced ototoxicity in an auditory cell line. Methods Cultured HEI-OC1 cells were exposed to 30 μM cisplatin for 48 h, and cell viability was tested using MTT assays. To evaluate whether autophagy serves to cell death after cisplatin exposure, western blotting and immunofluorescence staining for LC3-II were performed. Markers of two autophagy-related pathways, mTOR and class III PI3K, were also investigated. Results The formation of the autophagic protein LC3-II in response to 30 μM cisplatin increased with time. The early upregulation of autophagy exerted cytoprotective activity via the class III PI3K pathway. But later increase in autophagy induced cell death by suppressing the mTOR pathway. Conclusion Our results prove that autophagy could induce cell death during cisplatin-induced ototoxicity, and modulating the autophagic pathway might be another strategy against cisplatin-induced ototoxicity.

Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre-invasive lesions. Here, we show that RUNX3 and RUNX3-regulated chemokines are linked to NSCLC-mediated bone resorption. Notably, the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3-knockdown NSCLC cells. We aimed to identify RUNX3-regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up-regulation and down-regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3-knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose-dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL-treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC-induced bone destruction.

Under distinct pathological heart conditions, the expression of a single miRNA can display completely opposite patterns. However, the mechanism underlying the bidirectional regulation of a single miRNA and the clinical implications of this regulation remain largely unknown. To address this issue, we examined the regulation of miR-1, one of the most abundant miRNAs in the heart, during cardiac hypertrophy and ischemia/reperfusion (I/R). Our data indicated that different magnitudes and chronicities of ROS levels in cardiomyocytes resulted in differential expression of miR-1, subsequently altering the expression of myocardin. In animal models, the administration of a miR-1 mimic attenuated cardiac hypertrophy by suppressing the transverse aortic constriction-induced increase in myocardin expression, whereas the administration of anti-miR-1 ameliorated I/R-induced cardiac apoptosis and deterioration of heart function. Our findings indicated that a pathologic stimulus such as ROS can bidirectionally alter the expression of miRNA to contribute to the development of pathological conditions exhibiting distinct phenotypes and that the meticulous adjustment of the pathological miRNA levels is required to improve clinical outcomes.

Breast cancer mainly spreads to bone, causing decreased survival of patient. Human antigen R (HuR) and chemokines are important molecules associated with mRNA stability and cell-cell interaction in cancer biology. Here, HuR knockdown inhibited bone metastasis and osteolysis of metastatic breast cancer cells in mice and HuR expression promoted the metastatic ability of cancer cells via CCL20 and GM-CSF. In contrast with the findings for GM-CSF, ELAVL1 and CCL20 expressions were markedly increased in breast tumor tissues and ELAVL1 expression showed a strong positive correlation with CCL20 expression in breast cancer subtypes, particularly the basal-like subtype. Metastasis-free survival and overall survival were decreased in the breast cancer patients with high CCL20 expression. We further confirmed the role of CCL20 in breast cancer bone metastasis. Intraperitoneal administration of anti-CCL20 antibodies inhibited osteolytic breast cancer bone metastasis in mice. Treatment with CCL20 noticeably promoted cell invasion and the secretion of MMP-2/9 in the basal-like triple-negative breast cancer cell lines, not the luminal. Moreover, CCL20 elevated the receptor activator of nuclear factors kappa-B ligand/osteoprotegerin ratio in breast cancer and osteoblastic cells and mediated the crosstalk between these cells. Collectively, HuR-regulated CCL20 may be an attractive therapeutic target for breast cancer bone metastasis.

Myocardial Ca(2+) overload induced by ischemia/reperfusion (I/R) is a major element of myocardial dysfunction in heart failure. Phospholipase C (PLC) plays important roles in the regulation of the phosphoinositol pathway and Ca(2+) homeostasis in various types of cells. Here, we investigated the protective role of PLCδ1 against myocardial I/R injury through the regulation of Ca(2+) homeostasis. To investigate its role, PLCδ1 was fused to Hph1, a cell-permeable protein transduction domain (PTD), and treated into rat neonatal cardiomyocytes and rat hearts under respective hypoxia-reoxygenation (H/R) and ischemia-reperfusion conditions. Treatment with Hph1-PLCδ1 significantly inhibited intracellular Ca(2+) overload, reactive oxygen species generation, mitochondrial permeability transition pore opening, and mitochondrial membrane potential elevation in H/R neonatal cardiomyocytes, resulting in the inhibition of apoptosis. Intravenous injections of Hph1-PLCδ1 in rats with I/R-injured myocardium caused significant reductions in infarct size and apoptosis and also improved systolic and diastolic cardiac functioning. Furthermore, a small ions profile obtained using time-of-flight secondary ion mass spectrometry showed that treatment with Hph1-PLCδ1 leads to significant recovery of calcium-related ions toward normal levels in I/R-injured myocardium. These results suggest that Hph1-PLCδ1 may manifest as a promising cardioprotective drug due to its inhibition of the mitochondrial apoptotic pathway in cells suffering from I/R injury.

Rationale:Intrahepatic adrenocortical adenoma (IAA) arising from adrenohepatic fusion (AHF) is rare and its imaging findings are not well established. Moreover, it is easily misdiagnosed as malignant hepatic tumor in patients at risk of malignancy. Its key finding is the connection between t

Salivary gland tumors, the second most common neoplasm of the mouth after squamous cell carcinoma, account for a significant proportion of tumors of the oral and perioral regions. An unusual case of adenoma presented as a solitary intraoral palatine mass in a 32-year-old woman is reported here. The tumor was interpreted as an unusual pleomorphic adenoma because of the presence of exuberant squamous metaplasia, clinically mimicking squamous cell carcinoma. Moreover, the presence of cystic structures filled with keratinized material was also salient feature. Pleomorphic adenomas may occasionally display focal squamous metaplastic changes; when extensive, it presents the potential for misinterpretation of the histology as indicative of well-differentiated squamous cell carcinoma.

Cervicogenic vertigo was known as Bow hunter's syndrome. Occlusion of vertebral artery causes vertebrobasilar insufficiency and we reported cervicogenic vertigo case which was treated by simple decompression of transverse foramen of C1. The patient was 48 years old female who had left side dominant vertebral artery and vertigo was provoked when she rotated her head to right side. Angiography showed complete obliteration of blood flow of left vertebral artery when her head was rotated to right side. The operation was decompression of left vertebral artery at C1 level. Posterior wall of transverse foramen was resected and vertebral artery was exposed and decompressed. After surgery, vertigo of the patient was disappeared, and angiography showed patent left vertebral artery when her head was rotated to right side. Vertigo caused by compression of cervical vertebral artery could be treated by decompression without fusion or instrumentation, especially in C1 transverse foramen.

Objectives The purpose of this study was to compare lymph node (LN) staging using 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) with contrast-enhancement (CE) PET/CT and contrast-enhanced neck CT (neck CT) in patients with thyroid cancer with level-by-level comparison with various factors. Methods This was a retrospective multicenter study. A total of 85 patients were enrolled. Patients who underwent a preoperative evaluation by CE PET/CT and neck CT for thyroid cancer were enrolled. The gold standard for LN was the combination of surgical pathology and clinical follow-up. We compared CE PET/CT with neck CT using a level-by-level method. Factors, including age, sex, camera, arm position, tumor size, extra-thyroidal extension, tumor location, number of primary tumors, primary tumor maximum standardized uptake value, and the interval from scan to operation were also analyzed. Results Overall accuracy was 81.2% for CE PET/CT and 68.2% for neck CT. CE PET/CT was more sensitive than neck CT (65.8% vs. 44.7%). Also, CE PET/CT showed higher negative predictive value (77.2% vs. 66.1%). CE PET/CT showed good agreement with the gold standard (weighted kappa [κ], 0.7) for differentiating N0, N1a, and N1b, whereas neck CT showed moderate agreement (weighted κ, 0.5). CE PET/CT showed better agreement for the number of levels involved with the gold standard (weighted κ, 0.7) than that of neck CT with the gold standard (weighted κ, 0.5). The accuracies for differentiating N0, N1a, and N1b were 81.2% for CE PET/CT and 68.2% for neck CT. Level-by-level analysis showed that CE PET/CT was more sensitive and has higher negative predictive value for detecting ipsilateral level IV and level VI LNs than neck CT. Other analyzed factors were not related to accuracies of both modalities. Conclusion CE PET/CT was more sensitive and reliable than neck CT for preoperative LN staging in patients with thyroid cancer.

Background Despite recent advances in the investigation of myeloproliferative neoplasms (MPN), the impact of genetic heterogeneity on its molecular pathogenesis has not been fully elucidated. Thus, in this study, we aim to characterize the genetic complexity in Korean patients with polycythemia vera (PV) and essential thrombocythemia (ET). Methods We conducted association studies using 84 single-nucleotide polymorphisms (SNPs) in 229 patients (96 with PV and 133 with ET) and 170 controls. Further, whole-genome sequencing was performed in six patients (two with JAK2 V617F and four with wild-type JAK2), and putative somatic mutations were validated in a further 69 ET patients. Clinical and laboratory characteristics were also analyzed. Results Several germline SNPs and the 46 haplotype were significantly associated with PV and ET. Three somatic mutations in MPDZ, IQCH, and CALR genes were selected and validated. The frequency of the CALR mutation was 58.0% (40/69) in ET patients, who did not carry JAK2/MPL mutations. Moreover, compared with JAK2 V617F-positive patients, those with CALR mutations showed lower hemoglobin and hematocrit levels (P = 0.004 and P = 0.002, respectively), higher platelet counts (P =0.008), and a lower frequency of cytoreductive therapy (P = 0.014). Conclusion This study was the first comprehensive investigation of the genetic characteristics of Korean patients with PV and ET. We found that somatic mutations and the 46 haplotype contribute to PV and ET pathogenesis in Korean patients.

Many osteopenic disorders, including a postmenopausal osteoporosis and lytic bone metastasis in breast and prostate cancers, are linked with a hyperosteoclast activity due to increased receptor activator of nuclear factor kappa-B ligand (RANKL) expression in osteoblastic/stromal cells. Therefore, inhibition of RANKL-induced osteoclastogenesis and osteoclast-induced bone resorption is an important approach in controlling pathophysiology of these skeletal diseases. We found that, of seven type I, II, and III saikosaponins isolated fromBupleurum falcatum, saikosaponins A and D, type I saikosaponins with an allyl oxide linkage between position 13 and 28 and two carbohydrate chains that are directly attached to the hydroxyl groups in position 3, exhibited the most potent inhibition on RANKL-induced osteoclast formation at noncytotoxic concentrations. The stereochemistry of the hydroxyl group at C16 did not affect their activity. Saikosaponins A and D inhibited the formation of resorptive pits by reducing the secreted levels of matrix metalloproteinase- (MMP-) 2, MMP-9, and cathepsin K in RANKL-induced osteoclasts. Additionally, saikosaponins A and D inhibited mRNA expression of parathyroid hormone-related protein as well as cell viability and invasion in metastatic human breast cancer cells. Thus, saikosaponins A and D can serve as a beneficial agent for the prevention and treatment of osteoporosis and cancer-induced bone loss.

Background Otolaryngologists encounter cases of various foreign bodies in the oral and pharyngeal regions. One commonly found foreign body is a fish bone, ingested in most cases by carelessness or an accident. These foreign materials are removed by endoscopy or through a simple procedure. However, hypopharyngeal damage is rarely caused by a foreign body in the pharynx following the swallowing of a toothbrush. Case presentation A 44-year-old Asian male visited the emergency room with chief complaints of intraoral pain and dysphagia that had started on the same day. The patient had paranoid-type schizophrenia that began 10 years ago; he had been hospitalized and was being treated at another clinic, and was transferred to the emergency room by the medical staff after swallowing a toothbrush. We successfully removed a toothbrush located within the pharynx of a patient with a history of a psychologic disorder via surgery and conservative treatment. Conclusion The case with this patient, and a rapid diagnosis as well as treatment is imperative. The presence and state of a foreign body must be determined through a careful physical examination and imaging, followed by the immediate removal of the foreign body, all while keeping in mind the possibility of accompanying damage to nearby tissues.

Perforation of the hypopharynx, which can occur after anterior cervical approach, is a very rare type of complication. If diagnosed late, it can lead to very fatal course, such as mediastinitis and hematosepsis. Therefore, a precise and prompt diagnosis is crucial. When conservative treatment alone is not expected to heal the perforated site or is likely to lead to serious complications, surgical treatment becomes necessary. This report demonstrates that surgical intervention performed immediately after an early diagnosis can lead to the successful treatment of a large perforation in the hypopharynx on a 58-year-old male patient.

Objective:Ototoxicity due to cisplatin therapy interferes with treatment and often forces a reduction in the dosage, duration and frequency of the cisplatin therapy. (-)-Epigallocatechin-3-gallate is known to have the highest antioxidant potency among all tea catechins. This study aimed to investigate the effect of (-)-epigallocatechin-3-gallate on cisplatin ototoxicity in an auditory cell line: House Ear Institute-Organ of Corti 1 cells.Methods:Cultured House Ear Institute-Organ of Corti 1 cells were exposed to cisplatin with or without pre-treatment with (-)-epigallocatechin-3-gallate. Cell viability was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Hoechst 33258 staining was used to identify cells undergoing apoptosis. Western blot analysis was conducted to determine whether (-)-epigallocatechin-3-gallate inhibited cisplatin-induced caspase activation. Intracellular reactive oxygen species production was examined to investigate whether (-)-epigallocatechin-3-gallate was capable of scavenging cisplatin-induced reactive oxygen species accumulation.Results:Cell viability significantly increased in cells pre-treated with (-)-epigallocatechin-3-gallate compared with cells exposed to cisplatin alone. Cisplatin increased cleaved caspase-3 on Western blot analysis; however, pre-treatment with (-)-epigallocatechin-3-gallate inhibited the expression of caspase-3. (-)-Epigallocatechin-3-gallate attenuated reactive oxygen species production and apoptosis in House Ear Institute-Organ of Corti 1 cells.Conclusion:(-)-Epigallocatechin-3-gallate protected against cisplatin cytotoxicity through anti-apoptotic and anti-oxidative effects. Therefore, (-)-epigallocatechin-3-gallate could play a preventive role in cisplatin-induced ototoxicity.

Objective To verify the clinical outcomes of posterior C2-C3 fixation for unstable Hangman's fracture compared with posterior C1-C3 fixation. Methods Twenty four patients for unstable Hangman's fracture were enrolled between July 2007 and June 2010 in this study. Thirteen patients underwent posterior C2-C3 fusion and 11 patients underwent posterior C1-C3 fusion. Clinical outcomes were evaluated using Neck Disability Index (NDI) scores and Visual Analogue Scale (VAS) scores during preoperative and postoperative follow up period. Plain radiographs were obtained on postoperative 1 day, 1 week, and then at 1, 2, 6, and 12 months. CT was done at postoperative 12 months in all patients for evaluation of bone fusion. The mean period of clinical follow-up was 15 months. Results The mean ages were 43.3 years in C2-C3 group and 50.0 years in C1-C3 group. Mean follow-up period was 17.2 months in C2-C3 group and 16.3 months in C1-C3 group. VAS scores and NDI scores in C2-C3 group were much less than those in C1-C3 group at each follow-up period. The differences of VAS score and NDI scores between C2-C3 and C1-C3 groups at each follow-up period were statistically significant (p

A lipoblastoma is a rare, benign tumor arising from embryonic white fat. The tumors occur primarily in infancy and early childhood and commonly arise from the limbs and the trunk, but neck involvement is extremely rare. Our case arose in a 22-month-old male presenting with a rapidly enlarging soft mass in the right submandibular area. Lipoblastoma was diagnosed by histologic evaluation, the mass was completely removed, and there was no recurrence at 1-year follow-up.

This paper describes a method and a platform for generating a treatment plan for a patient with a chronic disease such as diabetes. The planning process considers the user's living environment so the doctor's prescription can be easily implemented as a monitored activity. The process utilizes OWL representation for the knowledge modeling and Answer Set Programming for managing the patient's goals.

This paper describes user activity recognition for lifestyle disease patients at home: ways to define data mining system for sensing, logging, analyzing, mining, measuring and recognizing user's daily activities. Lifestyle disease patients spend most of the time at home. There are lots of sensing data that can be based on home devices with home networking (sensors, gadgets, appliances, cameras, smart phones and some software applications running on computers). Main problem is interoperability, there is no standard framework for logging, analyzing and utilizing the available data sources. In this paper, we will introduce our layered architecture to do data mining for user's activity recognition. Understand user's life pattern can help medical services to cure and prevent diseases from developing.

Second branchial cleft cysts are the most common neck masses found in adults. However, the parapharyngeal presence of branchial cleft cyst is very rare. We report three cases of parapharyngeal branchial cleft cyst in adults. They suffered from frequent oropharyngeal infection or abscess. We performed a transoral resection without any surgical complications. Biopsy revealed a squamous lined epithelial wall with lymphoid aggregation, which is characteristic of branchial cleft cyst. No evidence of recurrence was observed in 2 years. Korean J Otorhinolaryngol-Head Neck Surg 2016;59(2):140-4 Key WordsZZBranchial cleft cyst ㆍNeck mass ㆍParapharynx.

A possible prothrombotic effect of elevated thyrotropin (TSH) has been suggested. The mean platelet volume (MPV), which is used to measure the platelet size, can reflect platelet activity. Although limited and inconsistent data regarding the effects of thyroid function on the MPV are available from small-scale case-control studies, no study has been based on a general population, particularly in euthyroid states. The objective of the present study was to determine whether there is an association between the MPV and serum TSH concentrations in an apparently healthy Korean population without overt thyroid disease, but including subjects with unsuspected subclinical hypothyroidism (SCH).We retrospectively studied 6893 asymptomatic Korean adults who were 20 years of age or older and who underwent voluntary regular health check-ups at the Health Promotion Center of Chosun University Hospital. The subjects who met the inclusion and exclusion criteria were subdivided into four groups, such as tertile groups for the TSH reference range and an SCH (TSH ≥4 μIU/mL with a normal free T4 concentration) group according to the TSH level. We compared the mean values of the MPVs among the groups. Multivariate logistic regression analyses were used to identify associations between the highest tertile of the MPV and the TSH subgroups.The mean level of the MPV in all study subjects was 8.12±0.75 femtoliters (fL), and the mean value of the MPV was significantly different in each group. The mean MPV in SCH was significantly higher compared with those of the first tertile (T1) and second tertile (T2). Moreover, the mean MPV increased statistical significantly by increasing tertiles of the TSH concentration and was highest in SCH (T1, 8.08±0.81 fL; T2, 8.09±0.62 fL; T3, 8.13±0.77 fL; SCH, 8.21±0.81 fL; p for trend=0.012). After adjusting for risk factors associated with increasing MPVs and platelet counts, SCH was independently associated with the highest tertile of the MPV (all subjects, odds radio (OR) 1.58 [95% confidence interval (CI) 1.19-2.09]; men, OR 1.70 [CI 1.10-2.64]; women, OR 1.55 [CI 1.06-2.26]).The MPV was positively correlated with the TSH level. SCH is an independently associated factor with the highest tertile of MPV in a general Korean population. We propose that the MPV may contribute to the prothrombotic condition that is associated with SCH and perhaps even in putative euthyroid states where the TSH level is the higher part of the normal range.

Human bone marrow-derived mesenchymal stem cells (hMSCs) are an attractive candidate for cell therapy in heart disease. Low survival and incomplete electromechanical integration between resident cardiomyocytes and transplanted hMSCs remain unsolved. In order for an infarcted heart to tolerate transplantation, differentiation capacity in stem cells must be reinforced. In this study, we found that compound 56, an epidermal growth factor receptor (EGFR) inhibitor, promotes cardiogenic differentiation of hMSCs and the transplantation of hMSCs treated with compound 56 resulted in enhancement of heart functions. Furthermore, hMSCs transfected with microRNA-133a (miR-133a), which targets EGFR, were observed to express cardiac-specific markers. We also discovered that luciferase activity is exclusively decreased by targeting EGFR in hMSCs transfected with miR-133a mimic. These results suggest that EGFR plays a key role in the regulation of cardiogenic differentiation in hMSCs.

Clear cell myoepithelial carcinoma is a very rare disease which develops primarily in the parotid gland. To date, only 17 cases of clear cell myoepithelial carcinoma have been reported worldwide. Among them, only three cases developed in the minor salivary gland in the oral cavity. No cases developed in the base of the tongue. Here, we report a new case of clear cell myoepithelial carcinoma that developed in the tongue base of a 52-year-old female patient. A mass was discovered on the left side of the tongue base. We successfully removed the mass through suprahyoid pharyngotomy approach. The light microscopy examination and various immunohistochemical stainings revealed clear cell myoepithelial carcinoma. During a two year follow-up period, there was no recurrence or local or distant metastasis.

Objectives Despite the ongoing development of treatment protocols for laryngeal squamous cell carcinoma (LSCC), the patients suffering with this malady have shown only a modestly improved outcome. This poor outcome has been attributed to the lack of therapy that's individualized to the tumor's biological properties. Various studies have showed that galectin-8 is widely expressed in tumor tissues as well as in normal tissues, and the level of the galectin-8 expression may correlate with the malignancy of human squamous cell carcinoma. The purpose of this study is to evaluate the expression of galectin-8 and to investigate its correlations with the primary stage, the nodal involvement, the clinical stage and the histologic grade of squamous cell carcinoma of the larynx. Methods The paraffin-embedded tissue specimens from 77 patients who were diagnosed as LSCC between 1993 and 2007 were immunohistochemically stained for galectin-8. Results Immunohistochemical analysis showed that a strong positive expression of galectin-8 was correlated with the T-stages, the nodal stages and the clinical stages. However, the histopathologic grades were not correlated with the galectin-8 expression in LSCC. Conclusion The expression of galectin-8 protein can be used as a prognostic factor for patients with LSCC.

Proinflammatory genotypes of the IL-1 (interleukin-1) gene have been associated with an increased gastric cancer risk in Caucasians, whereas some studies in Asian populations did not find such association. Furthermore, the risk genotypes differed somewhat between Caucasian and Asian populations. These findings might reflect more complex genetic mechanisms in Asian compared with Caucasian populations. Therefore, we examined a polymorphism (rs1864169) in the general transcription factor 2A1 (GTF2A1) gene as a test of the hypothesis that this transcription factor and IL-IB gene polymorphisms interact in the effects on the gastric cancer risk due to the possible biological relationship between the two genes. Genotyping of the 515 control and 342 case samples was performed by primer extension assay and SNaPshot assays. We found an association between carriage of the IL1B-31C allele and gastric cancer among Koreans, which was observed only in subjects with GTF2A1 GG genotype. The GTF2A1GG/IL1B-31C carrier genotype combination showed stronger association with diffuse type gastric cancer cases. These findings indicate that the effect of the two genetic polymorphisms on risk of gastric cancer is synergistic. Our results also suggest that an additional host genetic factor acting epistatically may differentially contribute to the histogenesis of the diffuse and intestinal subtypes.

Oral cancer ranks among the top 10 commonly diagnosed cancers. It easily invades underlying jaw bones and causes severe psychological and physical problems. When oral cancer cells infiltrate into jaw bones, survival rate of the patient is significantly decreased. Therefore, attention has been focused on molecular diagnostics and targeted therapy for oral cancer-induced bone destruction. However, there remains a lack of reliable biomarkers that can distinguish between bone-invasive and non-invasive oral cancers despite the recent advances in the field. The Runt domain transcription factor, RUNX3, has been found to be a tumor suppressor in many cancers through promoting transforming growth factor-β (TGF-β)-induced growth inhibition. However, the role of RUNX3 in oral cancer remains controversial. Here, we investigated whether RUNX3 has a critical role in oral cancer-induced bone destruction. In mice inoculated with RUNX3 knockdown oral cancer cells, tumor growth and bone destruction were significantly reduced. In oral cancer cells, RUNX3 knockdown significantly reduced cell viability in TGF-β-stimulated cells compared to unstimulated cells. Cell cycle analysis revealed that RUNX3 knockdown induced G1-specific cell-cycle arrest in the cancer cells without TGF-β treatment but G2-specific cell-cycle arrest in response to TGF-β treatment. RUNX3 knockdown inhibited cell migration and invasion in the absence or presence of TGF-β by changing both basal and TGF-β-induced level of epithelial-to-mesenchymal transition-related proteins. Furthermore, RUNX3 knockdown reduced parathyroid hormone-like protein expression, a major osteolytic factor, in oral cancer cells with or without TGF-β. We confirmed that RUNX3 knockdown in cancer cells decreased receptor activator of nuclear factor-kappaB ligand/osteoprotegerin ratio in osteoblastic hFOB1.19 cells treated with cancer cell-derived conditioned media. In summary, RUNX3 promotes oral cancer-induced bone destruction by enhancing interactions between cancer cells and bone cells as well as promoting malignant behavior of cancer cells. Therefore, RUNX3 may be a useful biomarker and potential therapeutic target for bone invasion of oral cancer. Citation Format: Junhee Park, Won-Yoon Chung, Kwang-Kyun Park. RUNX3 knockdown inhibited oral cancer-induced bone destruction via reducing TGF-β-dependent responses. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2028. doi:10.1158/1538-7445.AM2015-2028

Objective The aim of this study is to evaluate the clinical course of intracranial aneurysm in patients aged 65 years and older and the immediate outcome after its aggressive management. Materials and Methods We performed a retrospective analysis using the medical records of 159 elderly patients managed at our institute from September 2008 to December 2013. Obtained clinical information included age, sex, Hunt and Hess grade (HHG), aneurysm location, Fisher grade (FG) and the treatment modality. Concomitant clinical data aside from cerebrovascular condition (hypertension, diabetes, previous medication) were evaluated to determine risk factors that might affect the functional outcomes. Results A total of 108 patients (67.9%) presented with subarachnoid hemorrhage (SAH), and 51 (32.1%) with unruptured intracranial aneurysms (UIAs). Coiling was performed in 101 patients and 58 patients underwent clipping. In the SAH population, 62 patients (57.4%) showed favorable outcomes, with a mortality rate of 11.3% (n = 18). In the UIAs population, 50 (98%) patients achieved 'excellent' and one (2%) achieved 'good' outcome. Factors including high-grade HHG (p < 0.001), advanced age (p = 0.014), and the presence of intraventricular hematoma (IVH) (p = 0.017) were significant predictors of poor outcome. Conclusion SAH patients with high grade HHG and IVH are associated with poor outcome with statistical significance, all the more prominent the older the patient is. Therefore, the indication for aggressive therapy should be considered more carefully in these patients. However, as the outcomes for elderly patients with UIAs were excellent regardless of the treatment modality, aggressive treatment could always be considered in UIAs cases.

Carcinosarcoma, or true malignant mixed tumor of the salivary gland, is a very rare malignant tumor comprised of both carcinomatous and sarcomatous elements and accounts for only 0.040.16% of all salivary gland tumors. Carcinosarcoma usually occurs in the parotid gland. Other locations including submandibular gland, minor salivary gland, uterus, bladder or lung have been reported. We report a rare case of carcinosarcoma of the parotid gland in an 85-year-old female. The tumor was large, about 19×17 cm in size, and was successfully excised. � Korean J Otorhinolaryngol-Head Neck Surg 2014;57:38-41 Key WordsZZCarcinosarcoma ㆍMalignant mixed tumor ㆍParotid gland.

Objective The beneficial effect of decompressive craniectomy in the treatment of severe traumatic brain injury (TBI) is controversial, but there is no debate that decompression should be performed before irreversible neurological deficit occurs. The aim of our study was to assess the value of ultra-early decompressive craniectomy in patients with severe TBI. Methods Total of 127 patients who underwent decompressive craniectomy from January 2007 to December 2013 was included in this study. Among them, 60 patients had underwent ultra-early (within 4 hours from injury) emergent operation for relief of increased intracranial pressure. Initial Glasgow coma scale, brain computed tomography (CT) scan features by Marshall CT classification, and time interval between injury and craniectomy were evaluated retrospectively. Clinical outcome was evaluated, using the modified Rankin score. Results The outcomes of ultra-early decompressive craniectomy group were not better than those in the comparison group (p=0.809). The overall mortality rate was 68.5% (87 patients). Six of all patients (4.7%) showed good outcomes, and 34 patients (26.8%) remained in a severely disabled or vegetative state. Forty of sixty patients (66.7%) had died, and two patients (3.3%) showed good outcomes at last follow-up. Conclusion Ultra-early decompressive craniectomy for intracranial hypertension did not improve patient outcome when compared with "early or late" decompressive craniectomy for managing severe TBI.

A 39-year-old female was suffering from cold-induced Raynaud's attacks in both hands and feet, with symptoms being most severe in her left foot. The patient did not respond to medical treatments and was referred to our department of pain medicine. We performed sequential bipolar radiofrequency lumbar sympathectomy to the patient, which offered a long duration of symptom relief. Sequential bipolar radiofrequency lesions could create continuous strip lesion, and thus, could achieve better results, while the potential risk of liquid neurolytic agents could be avoided.

Granular cell tumors (GCTs) are uncommon neoplasm. They can originate in any part of the body. The most common sites of origin are in the head and neck, while the larynx is a relatively uncommon location. Patients affected with a laryngeal GCT typically present with persistent hoarseness, stridor, hemoptysis, dysphagia, and otalgia but, the tumor may be asymptomatic. Care must be taken to differentiate this lesion from others due to the presence of pseudo-epitheliomatous hyperplasia which overlies the GCT and may occasionally mimic squamous cell carcinoma. Therefore, a confirmative diagnosis should be made histopathologically and should be supported by immunohistochemical staining. These tumors are treated by complete surgical resection. Examining the complete removal of the tumor through securing a negative free margin is considered to be a consequential procedure. We experienced a 64-yr-old man with a laryngeal granular cell tumor involving the right true vocal cord. He was treated by surgical resection under a fine dissection laryngomicroscope. Here we present this case and a review of literature.

Hiccups are common benign and usually transient phenomenon that occur in nearly everyone. However, persistent or intractable hiccups can cause multiple problems including malnutrition, weight loss, fatigue, dehydration, insomnia, and wound dehiscence. We have experienced a case of postoperative persistent hiccup. The patient was formerly diagnosed tongue cancer and developed persistent hiccup after partial glossectomy with modified radical neck dissection and a radial forearm free-flap operation. He was unsuccessfully managed using pharmacologic methods, and then we tried phrenic nerve block guided by ultrasonography and a nerve stimulator because the surface anatomy of neck was deformed by the previous operation. Thirty minutes after the block, the hiccups disappeared.

Background Epithelial-myoepithelial carcinoma is an extremely rare disease that usually occurs in the parotid gland but can occur in a variety of sites such as the nasal cavity, paranasal sinus, and base of the tongue. Case presentation We report a rare case of epithelial-myoepithelial carcinoma, which developed in the subglottic region. A 78-year-old Korean woman visited our hospital complaining of hoarseness, which had developed 1 month previously. Flexible laryngoscopy showed a round mass that blocked approximately 80 % of the tracheal diameter. Complete excision of the mass was carried out under general anesthesia, using a transoral approach. Epithelial-myoepithelial carcinoma was diagnosed following immunohistochemical analysis. Conclusions We report a rare case of epithelial-myoepithelial carcinoma that occurred in the subglottic region. To the best of our knowledge, only one other case has been reported since this disease was first identified approximately 40 years ago.