Comparison of Partial Versus Superficial or Total Parotidectomy for Superficial T1-2 Primary Parotid Cancers.

OBJECTIVES: This study aimed to compare the oncological outcomes of partial versus superficial or total parotidectomy for superficial T1 or T2 primary parotid cancers and investigate their prognostic factors and recurrence patterns. METHODS: The medical records of 77 patients with T1-2 primary parotid malignancies between May 2003 and March 2022 were retrospectively reviewed. Univariate and multivariate analyses were performed to evaluate the prognostic factors associated with overall survival, disease-free survival, and local and distant recurrence. RESULTS: The average follow-up duration was 70.2 months (range, 12-202 months). The 5-year overall and disease-free survival rates were 88.7% and 77.1%, respectively. Twenty-two patients underwent partial parotidectomy, and 55 underwent superficial or total parotidectomy. There were no significant differences in the disease recurrence (P=0.320) and mortality rates (P=0.884) of the partial and superficial or total parotidectomy groups. The mean duration of surgery was shorter and the overall complication rates were significantly lower in the partial group than in the superficial or total parotidectomy group (P=0.049). Sixteen cases of recurrence occurred during the study period (20.8%). Univariate analyses showed that high-grade tumors (P=0.006), lymphovascular invasion (P=0.046), and regional lymph node metastasis (P=0.010) were significant risk factors for disease recurrence. Multivariate analysis identified regional lymph node metastasis as an independent prognostic factor for disease recurrence (P=0.027), and lymphovascular invasion as an independent prognostic factor for overall survival (P=0.033). CONCLUSION: The conservative surgical approach of partial parotidectomy can yield oncological outcomes comparable to those of superficial or total parotidectomy with careful patient selection in T1-2 parotid cancers.

Somatic anxiety in patients with laryngopharyngeal reflux.

Objective: This study aimed to evaluate the relationship between laryngopharyngeal reflux (LPR) and anxiety in patients with LPR. Design: Prospective, case-control study. Setting: This study was conducted at a tertiary care center. Participants: Sixty-four patients with LPR and 60 healthy controls. Methods: Patients with LPR and healthy individuals (N = 64 and N = 60) were enrolled in this study. The Beck Anxiety Inventory (BAI) and reflux symptom index (RSI) were used to evaluate anxiety and reflux-related symptoms, respectively. The BAI can be classified into somatic and subjective symptom scales. The prevalence of anxiety was compared between patients with LPR and healthy individuals. This study evaluated the relationship between BAI and RSI scores. Results: No statistical difference was found in the prevalence of anxiety between patients with LPR and healthy individuals (42.2% vs. 33.3%). However, the somatic anxiety symptom score was statistically higher in patients with LPR than in healthy individuals (p = .047). We observed a correlation between RSI and somatic anxiety scores of BAI in patients with LPR (rho = 0.286, p = .021). Conclusion: Patients with LPR had more severe somatic anxiety symptoms, and somatic anxiety was associated with their LPR-related symptoms.

Association between Metabolic Syndrome and Risk of Hypopharyngeal Cancer: A Nationwide Cohort Study from Korea.

This study evaluated the relationship between metabolic syndrome (MS) and the risk of hypopharyngeal cancer. This retrospective cohort study used data from the Korean National Health Insurance Research Database. A total of 4,567,890 participants who underwent a health checkup in 2008 were enrolled. The participants were followed until 2019, and the incidence of hypopharyngeal cancer was analyzed. We evaluated the risk of hypopharyngeal cancer according to the presence of MS, including obesity, dyslipidemia, hypertension, and diabetes, using a multivariate Cox proportional hazards model adjusted for age, sex, alcohol consumption, and smoking. During the follow-up period, 821 were newly diagnosed with hypopharyngeal cancer. MS was inversely associated with the risk of hypopharyngeal cancer (hazard ratio (HR), 0.83 [95% confidence interval (CI), 0.708-0.971]). Large waist circumference and high triglyceride levels among MS elements were both inversely related to the risk of hypopharyngeal cancer (HR: 0.82 [95% CI, 0.711-0.945] and 0.83 [95% CI, 0.703-0.978], respectively). The risk of hypopharyngeal cancer decreased with increasing comorbidity of MS in women (N = 0 vs. N = 1-2 vs. N ≥ 3; HR = 1 vs. HR = 0.511 [95% CI, 0.274-0.952] vs. HR = 0.295 [95% CI, 0.132-0.66]), but not in men. This study may improve our etiological understanding of hypopharyngeal cancer.

Assessment of the Mutation Profile of Tonsillar Squamous Cell Carcinomas Using Targeted Next-Generation Sequencing.

Data regarding driver mutation profiles in tonsillar squamous cell carcinomas (TSCCs) remain scarce, limiting the understanding of its pathogenesis and unexpected behavior in the updated staging system. We investigated the incidence of clinically relevant mutations and their contribution in the prognosis of the condition, and their association with human papillomavirus (HPV) infection and adjuvant therapy. We subjected 43 surgically resected TSCC samples to targeted next-generation sequencing, determined their HPV status using polymerase chain reaction, and performed The Cancer Genomic Atlas and Gene Set Enrichment analyses. Thirty-five TSCC samples (81.4%) showed at least one oncogenic/likely oncogenic mutation among twenty-nine cancer-related genes. The top five mutated genes were TP53 (46.5%), PIK3CA (25.6%), PTEN (18.6%), EGFR (16.3%), and SMAD4 (14.0%). The EGFR pathway was the most frequently affected (51.2%), followed by the p53 (48.8%), PI3K (39.5%), and RTK (34.9%) pathways. The gene set enrichment analysis confirmed that the genes involved in signal transduction, such as growth factor receptors and second messengers, EGFR tyrosine kinase inhibitors, and PI3K signaling pathways, were mostly related with TSCCs. TP53 mutation was an independent prognostic factor predicting worse overall survival in the adjuvant therapy group. RTK mutations were related to survival in all patients and in the HPV-positive group, but multivariate analyses showed no significance. In conclusion, oncogenic/likely oncogenic mutations were relatively high in TSCCs, and TP53 and RTK mutations may be candidate predictors for poor prognosis in the adjuvant therapy and HPV-positive groups, respectively, under the updated staging system.

The key timing of pharyngeal reflux in patients with laryngopharyngeal reflux.

OBJECTIVE: To analyze the incidence of pharyngeal reflux in laryngopharyngeal reflux patients over a 24-hour period and find out the key timing of pharyngeal reflux. METHODS: We reviewed 69 patients who visited our clinic with LPR-related symptoms and were proven to have pharyngeal reflux via 24-hour multichannel intraluminal impedance-pH (24hr MII-pH) monitoring. Quantitative analysis was conducted for the LPR profiles, such as the acidity of reflux, nighttime reflux, and positional reflux. The time series of pharyngeal reflux episodes and mealtimes were analyzed over a 24-hour period. Also, we recruited 26 normal controls. We compared the timing of pharyngeal reflux between LPR patients and asymptomatic controls. RESULTS: The quantitative analysis revealed that pharyngeal reflux occurred 4.88 ± 4.59 times over 24 hours. Weakly acidic pharyngeal reflux was more abundant than acidic or weakly alkaline reflux. Pharyngeal reflux occurred mainly during daytime in the upright position. The most frequent timing of pharyngeal reflux episodes was within 2 hours after meals. Additionally, there was no significant difference of the timing of post-prandial reflux between LPR patients and asymptomatic controls. CONCLUSION: The key timing of pharyngeal reflux in patients with LPR was post-prandial 2 hours.

Prediction of survival in oropharyngeal squamous cell carcinoma using machine learning algorithms: A study based on the surveillance, epidemiology, and end results database.

Background: We determined appropriate survival prediction machine learning models for patients with oropharyngeal squamous cell carcinoma (OPSCC) using the "Surveillance, Epidemiology, and End Results" (SEER) database. Methods: In total, 4039 patients diagnosed with OPSCC between 2004 and 2016 were enrolled in this study. In particular, 13 variables were selected and analyzed: age, sex, tumor grade, tumor size, neck dissection, radiation therapy, cancer directed surgery, chemotherapy, T stage, N stage, M stage, clinical stage, and human papillomavirus (HPV) status. The T-, N-, and clinical staging were reconstructed based on the American Joint Committee on Cancer (AJCC) Staging Manual, 8th Edition. The patients were randomly assigned to a development or test dataset at a 7:3 ratio. The extremely randomized survival tree (EST), conditional survival forest (CSF), and DeepSurv models were used to predict the overall and disease-specific survival in patients with OPSCC. A 10-fold cross-validation on a development dataset was used to build the training and internal validation data for all models. We evaluated the predictive performance of each model using test datasets. Results: A higher c-index value and lower integrated Brier score (IBS), root mean square error (RMSE), and mean absolute error (MAE) indicate a better performance from a machine learning model. The C-index was the highest for the DeepSurv model (0.77). The IBS was also the lowest in the DeepSurv model (0.08). However, the RMSE and RAE were the lowest for the CSF model. Conclusions: We demonstrated various machine-learning-based survival prediction models. The CSF model showed a better performance in predicting the survival of patients with OPSCC in terms of the RMSE and RAE. In this context, machine learning models based on personalized survival predictions can be used to stratify various complex risk factors. This could help in designing personalized treatments and predicting prognoses for patients.

Metabolic Diseases and Risk of Head and Neck Cancer: A Cohort Study Analyzing Nationwide Population-Based Data.

The aim of the study was to investigate the association between metabolic diseases and the risk of head and neck cancer (HNC) using nationwide population-based big data. This retrospective cohort study was conducted using the Korean National Health Insurance Service health checkup database. A total of 4,575,818 participants aged >40 years who received a health checkup in 2008 were enrolled, and we studied the incidence of HNC until 2019. We analyzed the risk of HNC according to the presence of metabolic diseases, such as obesity, dyslipidemia, hypertension, and diabetes. Although metabolic syndrome itself was not associated with HNC, each component of metabolic syndrome was associated with HNC. Underweight and diabetes were risk factors for HNC (HR: 1.694). High total cholesterol and high low-density lipoprotein cholesterol levels were factors that decreased the risk (HR 0.910 and 0.839). When we analyzed men and women separately, low total cholesterol level, low low-density lipoprotein cholesterol level, and hypertension were risk factors only in men. In addition, pre-obesity, obesity, and central obesity decreased the risk only in men. Each metabolic disease affects HNC in different ways. Underweight and diabetes increased the risk of HNC, whereas high total cholesterol and high low-density lipoprotein cholesterol levels decreased the risk of HNC.

The association between laryngopharyngeal reflux and insomnia.

OBJECTIVES: To evaluate the prevalence of insomnia in patients with laryngopharyngeal reflux (LPR) and to analyze the relationship between the severity of insomnia and LPR-related symptoms. METHODS: We analyzed 69 patients with LPR and 61 healthy controls. The LPR was confirmed via the 24-h hypopharyngeal-esophageal multichannel intraluminal impedance pH monitoring. Reflux symptoms and sleep disturbances were assessed using the Reflux Symptom Index and Insomnia Severity Index. We compared the prevalence of insomnia between the two groups. We analyzed the relationship between reflux symptoms and severity of insomnia. RESULTS: The prevalence of insomnia was significantly higher in patients with LPR than in healthy controls (46.3% vs. 29.5%; p = 0.049). The severity of reflux-related symptoms was correlated with insomnia severity (rho = 0.44; p < 0.001). Patients with LPR with nighttime reflux were more likely to have sleep disturbances than patients with LPR without nighttime reflux. CONCLUSION: Patients with LPR are more likely to experience insomnia than healthy controls, and the severity of reflux symptoms was related to the severity of insomnia.

Ideal Reference Lines for Assessment of Facial Asymmetry in Rhinoplasty Patients.

BACKGROUND: Assessing facial asymmetry is important to prevent unsatisfactory results in rhinoplasty. There has yet to be a consensus on reference lines for determining asymmetry. This study aimed to determine ideal reference lines to assess facial asymmetry and identify predictors of subjective perceptions of facial asymmetry. METHODS: Preoperative photographs of 47 patients who underwent rhinoplasty were adjusted according to two reference lines (vertical line from the mid-glabella to Cupid's bow and horizontal interpupillary line). In total, 94 photographs were generated, randomly ordered, and evaluated by two independent observers for anthropometric measurements including six distances (distances from the midline to the medial and lateral canthi, ala, oral commissure, width of midface at maximum distance, and mandible width) and three angles (lateral canthal, lateral alar, and lip margin angles). Photographs were rated by 18 independent observers for subjective perceptions of facial asymmetry. RESULTS: Observers perceived faces as asymmetric if accompanied by nasal deviation, irrespective of the reference line (p < 0.001). Based on the horizontal reference line, subjective perceptions of asymmetry were correlated with the midline to lateral alar margin distance (r = 0.489, p = 0.003) and sum of the distance ratios (r = 0.354, p = 0.037). None of the objective parameters correlated with subjective perceptions when adopting the vertical reference line. A deviated nose and lateral alar angle were significant predictors of subjective perceptions of facial asymmetry. CONCLUSION: To assess facial asymmetry, the horizontal reference line should be determined first followed by the perpendicular vertical line. The nose is the most important feature determining overall facial asymmetry. LEVEL OF EVIDENCE V: "This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ."

Diagnostic Value of Salivary miRNA in Head and Neck Squamous Cell Cancer: Systematic Review and Meta-Analysis.

Several studies have highlighted the diagnostic potential of salivary microRNA (miRNA) in head and neck squamous cell cancer (HNSCC). The purpose of this meta-analysis was to summarize published studies and evaluate the diagnostic accuracy of salivary miRNA in HNSCC detection. In this meta-analysis, we systematically searched PubMed, EMBASE, and Cochrane Library databases for studies on miRNA and HNSCC diagnosis. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) with a summary receiver-operating characteristic curve were calculated using a bivariate random-effect meta-analysis model. Furthermore, subgroup analyses were conducted to explore the main sources of heterogeneity. Seventeen studies from ten articles, including 23 miRNA and a total of 759 subjects, were included in this meta-analysis. The pooled sensitivity and specificity of salivary miRNA in the diagnosis of HNSCC were 0.697 (95% CI: 0.644-0.744) and 0.868 (95% CI: 0.811-0.910), respectively. The overall area under the curve was 0.803 with a DOR of 12.915 (95% CI: 9.512-17.534). Salivary miRNAs are a promising non-invasive diagnostic biomarker with moderate accuracy for HNSCC. These results must be verified by large-scale prospective studies.

A nationwide population-based study in South Korea on a relationship between height and anosmia.

The relationship between anosmia and anthropometric factor has not been investigated sufficiently yet. Thus, the purpose of this study was to evaluate anthropometric risk factors of anosmia in an Asian population. Claims data of subjects over 20 years old who underwent a national health examination conducted by the Korean National Insurance Program between 2005 and 2008 were analyzed. They were followed up through the Korean National Insurance Service database. Individuals newly diagnosed with anosmia were identified after the initial health examination until the last follow-up date (December 31, 2016). The incidence of anosmia was high in females younger than 70 years old. The hazard ratio of anosmia was found to be higher in taller groups. The tallest quintile had higher risk than the shortest quintile (hazard ratio = 1.185, 95% confidence interval: 1.147-1.225) after adjusting for age, sex, BMI, income, smoking status, alcohol consumption, regular physical activity, hypertension, diabetes mellitus, and dyslipidemia. This study showed that the incidence of anosmia had a positive association with height. However, careful interpretation is needed to generalize our result because of the limitation of the study population. Further studies are needed to clarify the genetic or environmental causes of anosmia.

Gene signature for prediction of radiosensitivity in human papillomavirus-negative head and neck squamous cell carcinoma.

PURPOSE: The probability of recurrence of cancer after adjuvant or definitive radiotherapy in patients with human papillomavirus-negative (HPV(-)) head and neck squamous cell carcinoma (HNSCC) varies for each patient. This study aimed to identify and validate radiation sensitivity signature (RSS) of patients with HPV(-) HNSCC to predict the recurrence of cancer after radiotherapy. MATERIALS AND METHODS: Clonogenic survival assays were performed to assess radiosensitivity in 14 HNSCC cell lines. We identified genes closely correlated with radiosensitivity and validated them in The Cancer Genome Atlas (TCGA) cohort. The validated RSS were analyzed by ingenuity pathway analysis (IPA) to identify canonical pathways, upstream regulators, diseases and functions, and gene networks related to radiosensitive genes in HPV(-) HNSCC. RESULTS: The survival fraction of 14 HNSCC cell lines after exposure to 2 Gy of radiation ranged from 48% to 72%. Six genes were positively correlated and 35 genes were negatively correlated with radioresistance, respectively. RSS was validated in the HPV(-) TCGA HNSCC cohort (n = 203), and recurrence-free survival (RFS) rate was found to be significantly lower in the radioresistant group than in the radiosensitive group (p = 0.035). Cell death and survival, cell-to-cell signaling, and cellular movement were significantly enriched in RSS, and RSSs were highly correlated with each other. CONCLUSION: We derived a HPV(-) HNSCC-specific RSS and validated it in an independent cohort. The outcome of adjuvant or definitive radiotherapy in HPV(-) patients with HNSCC can be predicted by analyzing their RSS, which might help in establishing a personalized therapeutic plan.

Epidemiology of Anosmia in South Korea: A Nationwide Population-Based Study.

Research about the epidemiology of olfactory dysfunction in Asians was not enough. The purpose of this study was to assess the prevalence and incidence rate of olfactory disorders in Koreans and to evaluate demographic risk factors. We analyzed clinical data of patients with anosmia using Korean National Health Insurance Service data from 2006 to 2016. The data includes medical insurance claim data and medical records of almost 50,000,000 people in Korea. The 30-39 age group showed the highest prevalence (19.25 per 10,000 per year). Their incidence rate was also high comparing other age groups (13.30 per 10,000 per year). The prevalence and the incidence increased from 7.10 to 13.74 and from 5.66 to 9.54 between 2006 and 2016. In the seasonal analysis, the incidence rate was high in spring and autumn. The high-income population showed about 1.4-folds higher incidence rate than the low-income population. We thought that the socioeconomic status could generally affect the rate of hospital visit in the anosmia population. Anosmia can be frequently underdiagnosed in the clinical environment because the elderly and the low-income people easily underestimate their anosmia symptom and ignore the severity due to their economic problem. Therefore careful attention and further studies for anosmia are needed.

Effects of exercise training and detraining on atheromatous matrix metalloproteinase activity in mice.

BACKGROUND AND AIMS: Exercise training (ET) helps treat atherosclerosis. However, many patients stop regular ET for various reasons. The effect of detraining on atherosclerosis is not well studied. We examined the effects of ET vs. short-term detraining on atheromatous matrix-metalloproteinase (MMP) activity in preexisting plaque and circulating cytokines/lipids. METHODS AND RESULTS: Eighteen-week-old apolipoprotein-E-/- mice (n = 56) on a Western diet underwent: 1) ET for 6-weeks (ET5+1), 2) ET for 5-weeks and detraining for 1-week (ET5+0), 3) ET for the last 1-week (ET0+1), or 4) no treadmill ET at all for 6-weeks (ET0+0). Atheromatous MMP-activity was visualized using molecular imaging with an MMP-2/9-activatable near-infrared-fluorescent probe. Compared with no ET (ET0+0), regular ET (ET5+1) decreased carotid atheromatous MMP activity, but this protective effect was significantly blunted by short-term detraining (ET5+0). Short-term detraining after longer-term ET showed a reduction in MMP-activity similar to short-term ET (ET0+1). Blood levels of lipids and cytokines paralleled the molecular imaging results: exercise caused higher levels of high-density lipoprotein, adiponectin, and interleukin-10 and lower levels of vascular cell adhesion molecule, monocyte chemoattractant protein-1, interleukin-1ß, and low-density lipoprotein. However, this beneficial effect was short-lived, with the ET5+0 group being similar to the ET0+0 group, and the ET0+1 group being similar to the ET5+1 group. The effect of exercise can be modeled with an exponential-decay of the protective factor of about 15%/day. CONCLUSIONS: Even short-term detraining reduces atheroprotective effects, and tips the balance towards atherosclerosis. This suggests that ET, to be effective, needs to be prolonged and regular, and that detraining should be avoided.

Neutrophil-lymphocyte ratio as a valuable prognostic marker in idiopathic sudden sensorineural hearing loss.

Background: Neutrophil-to-lymphocyte ratio (NLR) has emerged as a marker for degree of inflammation. Inflammation has been regarded as one of the causes of idiopathic sudden sensorineural hearing loss.Objectives: This study investigated the potential association between neutrophil-to-lymphocyte ratio (NLR) and prognosis in patients with idiopathic sudden sensorineural hearing loss (ISSNHL).Material and methods: This retrospective, case-control clinical trial analyzed data from 186 subjects diagnosed with ISSNHL and admitted to Kyung-Hee Medical Center between March 2016 and February 2019. Hematologic and audiometric parameters were measured.Results: NLR showed a linear correlation with hearing recovery in patients with ISSNHL, with hearing gain (dB) = 56.698 - 3.718 × NLR (r2 = 0.451, p = .001). Hearing recovery at all frequencies was numerically higher in patients with low (<6.661) than higher (≥6.661) NLR at all frequencies and was significantly higher at 500, 1000, 2000, 3000, and 4000 Hz. Hearing thresholds at 250, 500, 1000, 2000, 3000, and 4000 Hz in the low NLR group were significantly lower after treatment.Conclusions and significance: The ability to recover from ISSNHL decreases as NLR increases. NLR may be a valuable prognostic marker in patients with ISSNHL.

Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3.

BACKGROUND/AIMS: Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis. METHODS: Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson's trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF). RESULTS: The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFß in vitro. CONCLUSIONS: The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.

Cytokine Response to Diet and Exercise Affects Atheromatous Matrix Metalloproteinase-2/9 Activity in Mice.

BACKGROUND: The aim of this study is to identify the principal circulating factors that modulate atheromatous matrix metalloproteinase (MMP) activity in response to diet and exercise.Methods and Results:Apolipoprotein-E knock-out (ApoE-/-) mice (n=56) with pre-existing plaque, fed either a Western diet (WD) or normal diet (ND), underwent either 10 weeks of treadmill exercise or had no treatment. Atheromatous MMP activity was visualized using molecular imaging with a MMP-2/9 activatable near-infrared fluorescent (NIRF) probe. Exercise did not significantly reduce body weight, visceral fat, and plaque size in either WD-fed animals or ND-fed animals. However, atheromatous MMP-activity was different; ND animals that did or did not exercise had similarly low MMP activities, WD animals that did not exercise had high MMP activity, and WD animals that did exercise had reduced levels of MMP activity, close to the levels of ND animals. Factor analysis and path analysis showed that soluble vascular cell adhesion molecule (sVCAM)-1 was directly positively correlated to atheromatous MMP activity. Adiponectin was indirectly negatively related to atheromatous MMP activity by way of sVCAM-1. Resistin was indirectly positively related to atheromatous MMP activity by way of sVCAM-1. Visceral fat amount was indirectly positively associated with atheromatous MMP activity, by way of adiponectin reduction and resistin elevation. MMP-2/9 imaging of additional mice (n=18) supported the diet/exercise-related anti-atherosclerotic roles for sVCAM-1. CONCLUSIONS: Diet and exercise affect atheromatous MMP activity by modulating the systemic inflammatory milieu, with sVCAM-1, resistin, and adiponectin closely interacting with each other and with visceral fat.

Sirt1 Regulates DNA Methylation and Differentiation Potential of Embryonic Stem Cells by Antagonizing Dnmt3l.

Embryonic stem cell (ESC) abnormalities in genome methylation hamper the utility of their therapeutic derivatives; however, the underlying mechanisms are unknown. Here, we show that the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, Sirt1, selectively prevents abnormal DNA methylation of some developmental genes in murine ESCs by antagonizing Dnmt3l. Transcriptome and DNA methylome analyses demonstrated that Sirt1-null (Sirt1-/-) ESCs repress expression of a subset of imprinted and germline genes concomitant with increased DNA methylation of regulatory elements. Dnmt3l was highly expressed in Sirt1-/- ESCs, and knockdown partially rescued abnormal DNA methylation of the Sirt1 target genes. The Sirt1 protein suppressed transcription of Dnmt3l and physically interacted with the Dnmt3l protein, deacetylating and destabilizing Dnmt3l protein. Sirt1 deficiency delayed neurogenesis and spermatogenesis. These differentiation delays were significantly or partially abolished by reintroduction of Sirt1 cDNA or Dnmt3l knockdown. This study sheds light on mechanisms that restrain DNA methylation of developmentally vital genes operating in ESCs.