Influence of sleep stages on determining positional dependency in patients with obstructive sleep apnea.

Objective: Supine sleep position and rapid eye movement (REM) stage are widely known to aggravate the severity of obstructive sleep apnea (OSA). In general, position-dependent OSA is defined as an apnea-hypopnea index (AHI) at least twice as high in the supine position as in other sleep positions, but it can be misdiagnosed if a certain sleep stage, REM or NREM, is dominant in a specific sleep position. In this study, we investigated the influences of the sleep stages on positional dependency. Methods: The polysomnographic data from 111 OSA patients aged ≥ 18 years (AHI > five events/hour) who slept in both supine and non-supine positions (each ≥ 5% of the total sleep time) were retrospectively analyzed. The overall ratio of non-supine AHI/supine AHI (NS/S AHI ratio) during the entire sleep was compared between specific sleep stages, i.e., REM or NREM sleep. Additionally, the weighted NS/S AHI ratio reflecting the proportion of each sleep time was created and compared with the original NS/S AHI ratio. Results: The mean value of the NS/S AHI ratio did not differ between the entire sleep and the specific sleep stages. However, those ratios in the individual patients showed poor agreement of the NS/S AHI ratios between the entire sleep and the specific sleep stages. The weighted NS/S AHI ratio also demonstrated poor agreement with the original NS/S AHI ratio, mainly due to the discrepancy in mild to moderate OSA patients. Conclusion: The weighted NS/S AHI ratio might help assess precise positional dependency.

Sirt6-Mediated Cell Death Associated with Sirt1 Suppression in Gastric Cancer.

BACKGROUND: Gastric cancer, one of the leading causes of cancer-related death, is strongly associated with H. pylori infection, although other risk factors have been identified. The sirtuin (Sirt) family is involved in the tumorigenesis of gastric cancer, and sirtuins can have pro- or anti-tumorigenic effects. METHODS: After determining the overall survival rate of gastric cancer patients with or without Sirt6 expression, the effect of Sirt6 upregulation was also tested using a xenograft mouse model. The regulation of Sirt6 and Sirt1, leading to the induction of mouse double minute 2 homolog (MDM2) and reactive oxygen species (ROS), was mainly analyzed using Western blotting and immunofluorescence staining, and gastric cancer cell (SNU-638) death associated with these proteins was measured using flow cytometric analysis. RESULTS: Sirt6 overexpression led to Sirt1 suppression in gastric cancer cells, resulting in a higher level of gastric cancer cell death in vitro and a reduced tumor volume. ROS and MDM2 expression levels were upregulated by Sirt6 overexpression and/or Sirt1 suppression according to Western blot analysis. The upregulated ROS ultimately led to gastric cancer cell death as determined via Western blot and flow cytometric analysis. CONCLUSION: We found that the upregulation of Sirt6 suppressed Sirt1, and Sirt6- and Sirt1-induced gastric cancer cell death was mediated by ROS production. These findings highlight the potential of Sirt6 and Sirt1 as therapeutic targets for treating gastric cancer.

Delayed Horner's Syndrome After Multiple Penetrating Stab Injury of the Neck.

Horner's syndrome is characterized by a triad of symptoms (ipsilateral miosis, ptosis, and anhidrosis) with damage of the sympathetic nervous system. The condition may be congenital or acquired from traumatic conditions including cardiovascular surgery. Horner's syndrome can be also caused by neck trauma especially when cervical vital structures such as blood vessels, the aerodigestive tract, and nerves are disrupted. This report describes a 16-year-old woman with delayed Horner's syndrome who initially presented with internal jugular vein injury caused by multiple penetrating stab injury to the neck. To the best of our knowledge, this is the first reported case of Horner's syndrome resulting from neck trauma of which symptoms were presented after a couple of weeks after initial trauma. Understanding this rare clinical course may help surgeons pay attention to not only early hospital course but also long-term complications of patients with neck trauma.

Two cases of extraluminal migration of fishbones into the thyroid gland and submandibular gland.

Laryngopharyngeal or cervical pain following ingestion of foreign bodies is one of the most frequently encountered emergencies in otolaryngologic practice. Although most of these foreign bodies can be easily removed under laryngoscopic examination without any complications, surgical removal may be required when foreign bodies migrate extraluminally. This report describes two rare cases of ingested fishbones that had migrated, one each to the thyroid gland and submandibular gland. Extraluminal migration fishbones should always be considered in otolaryngologic clinics.

MDM2-dependent Sirt1 degradation is a prerequisite for Sirt6-mediated cell death in head and neck cancers.

Sirt6 is involved in multiple biological processes, including aging, metabolism, and tumor suppression. Sirt1, another member of the sirtuin family, functionally overlaps with Sirt6, but its role in tumorigenesis is controversial. In this study, we focused on cell death in association with Sirt6/Sirt1 and reactive oxygen species (ROS) in head and neck squamous cell carcinomas (HNSCCs). Sirt6 induced cell death, as widely reported, but Sirt1 contributed to cell death only when it was suppressed by Sirt6 via regulation of MDM2. Sirt6 and Sirt6-mediated suppression of Sirt1 upregulated ROS, which further led to HNSCC cell death. These results provide insight into the molecular roles of Sirt6 and Sirt1 in tumorigenesis and could therefore contribute to the development of novel strategies to treat HNSCC.

Periostin Plays a Key Role in Radioresistance of Head and Neck Cancer Cells Via Epithelial-to-Mesenchymal Transition.

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) is an aggressive head and neck malignancy. The aim of this study was to elucidate the role of periostin (POSTN) in the epithelial-to-mesenchymal transition (EMT) process mediating the acquisition of radioresistance in HNSCC. MATERIALS AND METHODS: The expression levels of EMT hallmark genes including POSTN and Erk/Akt signaling pathways were compared between radiosensitive and radioresistant HNSCC cells. RESULTS: POSTN mRNA expression was higher in radioresistant HNSCC cells, and silencing POSTN significantly impaired their invasiveness under the effect of EMT process represented by up-regulation of mesenchymal markers and down-regulation of an epithelial marker. Expression levels of Erk and Akt were higher in radioresistant cells. CONCLUSION: POSTN in association with the Erk and Akt signaling pathways was up-regulated during the EMT process, leading to the conversion of radiosensitive to radioresistant HNSCC cells. POSTN may be a key marker for predicting the radioresistance and therapeutic target of HNSCC.

Mesenchymal stem cells in suppression or progression of hematologic malignancy: current status and challenges.

Mesenchymal stem cells (MSCs) are known for being multi-potent. However, they also possess anticancer properties, which has prompted efforts to adapt MSCs for anticancer therapies. However, MSCs have also been widely implicated in pathways that contribute to tumor growth. Numerous studies have been conducted to adapt MSCs for further clinical use; however, the results have been inconclusive, possibly due to the heterogeneity of MSC populations. Moreover, the conflicting roles of MSCs in tumor inhibition and tumor growth impede their adaptation for anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in hematologic malignancies are not as well established as they are for solid malignancies, and data comparing them are still limited. Herein the effect of MSCs on hematologic malignancies, such as leukemia and lymphoma, their mechanisms, sources of MSCs, and their effects on different types of cancer, have been discussed. This review describes how MSCs preserve both antitumorigenic and protumorigenic effects, as they tend to not only inhibit tumor growth by suppressing tumor cell proliferation but also promote tumor growth by suppressing tumor cell apoptosis. Thus clinical studies trying to adapt MSCs for anticancer therapies should consider that MSCs could actually promote hematologic cancer progression. It is necessary to take extreme care while developing MSC-based cell therapies in order to boost anticancer properties while eliminating tumor-favoring effects. This review emphasizes that research on the therapeutic applications of MSCs must consider that they exert both antitumorigenic and protumorigenic effects on hematologic malignancies.

Anti-leukemic effects of PPARγ ligands.

The peroxisome proliferator-activated receptor (PPAR) γ, a subtype of PPARs, is a member of the nuclear receptor family. PPARγ and its ligands contribute to various types of diseases including cancer. Given that currently developed therapies against leukemia are not very effective or safe, PPARγ ligands have been shown to be a new class of compounds with the potential to treat hematologic malignancies, particularly leukemia. The capability of PPARγ ligands to induce apoptosis, inhibit proliferation, and promote differentiation of leukemia cells suggests it has significant potential as a drug against leukemia. However, the specific mechanisms and molecules involved are not well-understood, although a number of PPARγ ligands with anti-leukemic effects have been identified. This may explain why PPARγ ligands have not been widely evaluated in clinical trials. To fill the gaps in the lack of understanding of specific anti-leukemic processes of PPARγ ligands and further adapt these molecules as anti-leukemic agents, this review describes previous studies of the anti-leukemic effects of PPARγ ligands.

Strategies to improve the immunosuppressive properties of human mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are of particular interest for the treatment of immune-related diseases because of their immunosuppressive capacities. However, few clinical trials of MSCs have yielded satisfactory results. A number of clinical trials using MSCs are currently in progress worldwide. Unfortunately, protocols and methods, including optimized culture conditions for the harvest of MSCs, have not been standardized. In this regard, complications in the ex vivo expansion of MSCs and MSC heterogeneity have been implicated in the failure of clinical trials. In this review, potential strategies to obtain MSCs with improved immunosuppressive properties and the potential roles of specific immunomodulatory genes, which are differentially upregulated in certain culture conditions, will be discussed.

Effect of ex vivo culture conditions on immunosuppression by human mesenchymal stem cells.

A microarray analysis was performed to investigate whether ex vivo culture conditions affect the characteristics of MSCs. Gene expression profiles were mainly influenced by the level of cell confluence rather than initial seeding density. The analysis showed that 276 genes were upregulated and 230 genes downregulated in MSCs harvested at ~90% versus ~50% confluence (P < 0.05, FC > 2). The genes that were highly expressed in MSCs largely corresponded to chemotaxis, inflammation, and immune responses, indicating direct or indirect involvement in immunomodulatory functions. Specifically, PTGES and ULBP1 were up-regulated in MSCs harvested at high density. Treatment of MSCs with PTGES or ULBP1 siRNA reversed their inhibition of T-cell proliferation in vitro. The culture conditions such as cell confluence at harvest seem to be important for gene expression profile of MSCs; therefore, the results of this study may provide useful guidelines for the harvest of MSCs that can appropriately suppress the immune response.

Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, independently of PPARγ in human glioma cells.

Peroxisome proliferator-activated receptor γ (PPARγ) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPARγ in CGZ-induced cell death was examined. At concentrations of greater than 30 µM, CGZ, a synthetic PPARγ agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 µM CGZ effectively induced cell death after pretreatment with 30 µM of the PPARγ antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPARγ was down-regulated cells by siRNA, lower concentrations of CGZ (<30 µM) were sufficient to induce cell death, although higher concentrations of CGZ (≥30 µM) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPARγ. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPARγ in glioma cells, by down-regulating Akt activity and inducing MMP collapse.