Publications by authors named "Ming-Hsui Tsai"

164 Publications

Metformin Increases Survival in Hypopharyngeal Cancer Patients with Diabetes Mellitus: Retrospective Cohort Study and Cell-Based Analysis.

Pharmaceuticals (Basel) 2021 Feb 26;14(3). Epub 2021 Feb 26.

Department of Life Sciences, and Ph.D. program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan.

Hypopharyngeal squamous cell carcinoma (HSCC) is usually diagnosed at an advanced stage, leading to a poor prognosis. Even after improvement of surgical techniques, chemotherapy, and radiation technology, the survival rate of HSCC remains poor. Metformin, which is commonly used for type 2 diabetes mellitus (DM), has been suggested to reduce the risk of various cancer types. However, only a few clinical studies mentioned the relationship between metformin use and HSCC. Hence, the aim of this study was to elucidate the specific effect and mechanism of action of metformin in hypopharyngeal cancer. We first assessed whether metformin use has an effect on hypopharyngeal cancer patients with DM by conducting a retrospective cohort study. Our results showed that DM hypopharyngeal cancer patients who used metformin exhibited significantly better overall survival rates than that without metformin treatment. The cell-based analysis further indicated that metformin treatment regulated p38/JNK pathway to reduce Cyclin D1 and Bcl-2 expressions. In addition, metformin activated the pathways of AMPKα and MEK/ERK to phosphorylate p27(Thr198) and reduce mTOR phosphorylation in cells. These actions direct cells toward G1 cell cycle arrest, apoptosis, and autophagy. Our results, through combining a clinical cohort analysis with an in vitro study, demonstrate that metformin can be used for drug repositioning in the treatment of DM patients with hypopharyngeal cancer.
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http://dx.doi.org/10.3390/ph14030191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996771PMC
February 2021

Arecoline N-oxide initiates oral carcinogenesis and arecoline N-oxide mercapturic acid attenuates the cancer risk.

Life Sci 2021 Apr 3;271:119156. Epub 2021 Feb 3.

Environment-Omics-Disease Research Center, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address:

Arecoline N-oxide (ANO), an oxidative metabolite of the areca nut, is a predictable initiator in carcinogenesis. The mechanisms of arecoline metabolites in human cancer specimens is still limited. This present study aims to estimate the oral squamous cell carcinoma (OSCC) inductive activity between arecoline metabolites in human cancer specimens/OSCC cells. We have collected 22 pairs (tumor and non-tumor part) of patient's specimens and checked for clinical characteristics. The identification of arecoline and its metabolites levels by using LC-MS/MS. The NOD/SCID mice model was used to check the OSCC inductive activity. The tumor part of OSCC samples exhibited higher levels of arecoline and ANO. Besides, ANO treated mice accelerates the NOTCH1, IL-17a and IL-1β expressions compared to the control mice. ANO exhibited higher cytotoxicity, intracellular ROS levels and decline in antioxidant enzyme levels in OC-3 cells. The protein expression of NOTCH1 and proliferation marker levels are significantly lower in NOM treated cells. Overall, ANO induced initial stage carcinogenesis in the oral cavity via inflammation, ROS and depletion of antioxidant enzymes. Arecoline N-oxide mercapturic acid (NOM) attenuates the initiation of oral carcinogenesis.
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http://dx.doi.org/10.1016/j.lfs.2021.119156DOI Listing
April 2021

Monocyte Chemoattractant Protein 1 Promotes VEGF-A Expression in OSCC by Activating ILK and MEK1/2 Signaling and Downregulating miR-29c.

Front Oncol 2020 27;10:592415. Epub 2020 Nov 27.

School of Medicine, China Medical University, Taichung, Taiwan.

Oral squamous cell carcinoma (OSCC) is an aggressive tumor that has a poor prognosis, with high levels of local invasion and lymph node metastasis. Vascular endothelial growth factor A (VEGF-A) plays essential roles in OSCC tumor angiogenesis and metastasis. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is implicated in various inflammatory conditions and pathological processes, including oral cancer. The existing evidence has failed to confirm any correlation between MCP-1 or VEGF-A expression and OSCC angiogenesis. In this study, high expression levels of MCP-1 and VEGF-A were positively correlated with disease stage in patients with OSCC. In oral cancer cells, MCP-1 increased VEGF-A expression and subsequently promoted angiogenesis; miR-29c mimic reversed MCP-1 activity. We also found that MCP-1 modulated VEGF-A expression and angiogenesis through CCR2/ILK/MEK1/2 signaling. results of the chick embryo chorioallantoic membrane (CAM) assay revealed the angiogenic qualities of MCP-1, with increased numbers of visible blood vessel branches. Our data suggest that MCP-1 is a new molecular therapeutic target for the inhibition of angiogenesis and metastasis in OSCC.
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http://dx.doi.org/10.3389/fonc.2020.592415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729166PMC
November 2020

Chronic rhinosinusitis and premorbid autoimmune diseases: a population-based case-control study.

Sci Rep 2020 10 29;10(1):18635. Epub 2020 Oct 29.

Department of Otorhinolaryngology, China Medical University Hospital, Taichung, 40447, Taiwan.

Evidence shows that chronic rhinosinusitis (CRS) is associated with prior presence of autoimmune diseases; however, large-scale population-based studies in the literature are limited. We conducted a population-based case-control study investigating the association between CRS and premorbid autoimmune diseases by using the National Health Insurance Research Database in Taiwan. The CRS group included adult patients newly diagnosed with CRS between 2001 and 2013. The date of diagnosis was defined as the index date. The comparison group included individuals without CRS, with 1:4 frequency matching for gender, age, and index year. Premorbid diseases were forward traced to 1996. Univariate and multivariate logistic regression was performed to estimate odds ratios (ORs) and 95% confidence intervals. The CRS group consisted of 30,611 patients, and the comparison group consisted of 122,444 individuals. Patients with CRS had a higher significant association with premorbid autoimmune diseases (adjusted OR 1.39 [1.28-1.50]). Specifically, patients with CRS had a higher significant association with ankylosing spondylitis, polymyositis, psoriasis, rheumatoid arthritis, sicca syndrome, and systemic lupus erythematosus (adjusted OR 1.49 [1.34-1.67], 3.47 [1.12-10.8], 1.22 [1.04-1.43], 1.60 [1.31-1.96], 2.10 [1.63-2.72], and 1.69 [1.26-2.25]). In subgroup analysis, CRS with and without nasal polyps demonstrated a significant association with premorbid autoimmune diseases (adjusted OR 1.34 [1.14-1.58] and 1.50 [1.38-1.62]). In addition, CRS with fungal and non-fungal infections also demonstrated a significant association with premorbid autoimmune diseases (adjusted OR 2.02 [1.72-2.49] and 1.39 [1.28-1.51]). In conclusion, a significant association between CRS and premorbid autoimmune diseases has been identified. These underlying mechanisms need further investigation.
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http://dx.doi.org/10.1038/s41598-020-75815-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596473PMC
October 2020

ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs.

Nat Commun 2020 10 28;11(1):5453. Epub 2020 Oct 28.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.
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http://dx.doi.org/10.1038/s41467-020-19145-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595232PMC
October 2020

Noise Induced Hearing Loss and Tinnitus-New Research Developments and Remaining Gaps in Disease Assessment, Treatment, and Prevention.

Brain Sci 2020 Oct 13;10(10). Epub 2020 Oct 13.

School of Medicine, China Medical University, Taichung City 40402, Taiwan.

Long-term noise exposure often results in noise induced hearing loss (NIHL). Tinnitus, the generation of phantom sounds, can also result from noise exposure, although understanding of its underlying mechanisms are limited. Recent studies, however, are shedding light on the neural processes involved in NIHL and tinnitus, leading to potential new and innovative treatments. This review focuses on the assessment of NIHL, available treatments, and development of new pharmacologic and non-pharmacologic treatments based on recent studies of central auditory plasticity and adaptive changes in hearing. We discuss the mechanisms and maladaptive plasticity of NIHL, neuronal aspects of tinnitus triggers, and mechanisms such as tinnitus-associated neural changes at the cochlear nucleus underlying the generation of tinnitus after noise-induced deafferentation. We include observations from recent studies, including our own studies on associated risks and emerging treatments for tinnitus. Increasing knowledge of neural plasticity and adaptive changes in the central auditory system suggest that NIHL is preventable and transient abnormalities may be reversable, although ongoing research in assessment and early detection of hearing difficulties is still urgently needed. Since no treatment can yet reverse noise-related damage completely, preventative strategies and increased awareness of hearing health are essential.
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http://dx.doi.org/10.3390/brainsci10100732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602100PMC
October 2020

Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers.

medRxiv 2020 May 12. Epub 2020 May 12.

Baxter Laboratory, Department of Microbiology & Immunology, Stanford University School of Medicine, Stanford, California, USA.

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.
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http://dx.doi.org/10.1101/2020.05.08.20092866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273284PMC
May 2020

Low-grade albuminuria is associated with hearing loss in non-diabetic US males: A cross-sectional analysis of 1999-2004 national health and nutrition examination survey.

Medicine (Baltimore) 2020 Mar;99(11):e19284

School of Medicine, College of Medicine, China Medical University, Taichung.

High levels of albuminuria have been demonstrated to associate with hearing loss in non-diabetic people, while the clinical impact of low-grade albuminuria has attracted less attention. This cross-sectional population-based study aimed to examine whether hearing loss in non-diabetic United States (US) adults is independently associated with low-grade albuminuria or reduced estimated glomeruli filtration rate (eGFR).A total of 2518 participants aged 20 to 69 years were selected from the US National Health and Nutritional Examination Survey database. Participants with diabetes or high-grade albuminuria were excluded. Hearing loss was assessed using low-frequency pure-tone average (LFPTA) thresholds (0.5, 1.0, 2.0 kHz) and high-frequency pure-tone average (HFPTA) thresholds (3.0, 4.0, 6.0, 8.0 kHz). Logistic and linear regression analyses were used to evaluate associations between renal function indicators and hearing loss.The median age of included participants was 37.4 years, and 55% of them were female. Multivariate analysis revealed that participants with urinary albumin-to-creatinine ratio (UACR) in the highest tertile had a significantly higher risk of hearing loss (OR, 1.79; 95% CI, 1.01-3.19) and higher HFPTA thresholds (β: 2.23; SE: 0.77). Participants with eGFR <60 mL/min/1.73 m had higher LFPTA thresholds (β: 4.31; SE: 1.79). After stratification by sex, a significant risk remained only for males in the highest UACR tertile, with 2.18 times the risk of hearing loss (95% CI, 1.06-4.48).Non-diabetic US males with low-grade albuminuria are at increased risk of hearing loss, independent of eGFR.
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http://dx.doi.org/10.1097/MD.0000000000019284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220087PMC
March 2020

Adult Lymphangioma of the Oropharynx: A Case Report.

Anticancer Res 2020 Mar;40(3):1631-1636

Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan, R.O.C

Lymphangioma insults in adults are uncommon and the occurrence in the oropharynx is extremely rare. Although disease history and clinical symptoms may help in distinguishing it from malignant tumors, the pathophysiology of lymphangioma via histological examinations should be established for convenient and precise diagnosis. We present a 20-year-old male with lymphangioma in the right oropharynx, and the multiple-angle examination and treatment plan used. The case further emphasizes the need to consider lymphangioma in the differential diagnosis of an oropharyngeal mass. Awareness that lymphangioma can occur in adults is important for its proper management, which includes complete surgical removal to prevent recurrence.
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http://dx.doi.org/10.21873/anticanres.14112DOI Listing
March 2020

Assessment of the Risk of Oral Cancer Incidence in A High-Risk Population and Establishment of A Predictive Model for Oral Cancer Incidence Using A Population-Based Cohort in Taiwan.

Int J Environ Res Public Health 2020 01 20;17(2). Epub 2020 Jan 20.

Department of Health Services Administration, China Medical University, Taichung 40402, Taiwan.

We aimed to assess the risk of oral cancer incidence in a high-risk population, establish a predictive model for oral cancer among these high-risk individuals, and assess the predictive ability of the constructed model. Individuals aged ≥30 years who had a habit of smoking or betel nut chewing and had undergone oral cancer screening in 2010 or 2011 were selected as study subjects. The incidence of oral cancer among the subjects at the end of 2014 was determined. The annual oral cancer incidence among individuals with a positive screening result was 624 per 100,000 persons, which was 6.5 times that of the annual oral cancer incidence among all individuals screened. Male sex, aged 45-64 years, divorce, low educational level, presence of diabetes, presence of other cancers, high comorbidity severity, a habit of smoking or betel nut chewing, and low monthly salary were high-risk factors for oral cancer incidence ( < 0.05). The area under the curve of the predictive model for oral cancer incidence was 0.73, which indicated a good predictive ability. Therefore, the oral cancer screening policy for the high-risk population with a habit of smoking and/or betel nut chewing is beneficial for the early diagnosis of oral cancer.
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http://dx.doi.org/10.3390/ijerph17020665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014279PMC
January 2020

Combination of celecoxib and calyculin-A inhibits epithelial-mesenchymal transition in human oral cancer cells.

Biotech Histochem 2020 Jul 15;95(5):341-348. Epub 2020 Jan 15.

Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan.

Expression of cyclo-oxygenase-2 (COX-2) and protein phosphatase 2A (PP2A) deactivation occurs frequently in oral squamous cell carcinoma (OSCC). We initially assessed COX-2 and PP2A protein expression in OSCC specimens using immunohistochemical (IHC) staining and western blot analysis. We found strong COX-2 and phosphorylated PP2A (p-PP2A) expression in OSCC samples. No significant difference in total PP2A expression was observed between cancer and nontumor tissues. The effect of combining COX-2 inhibitor and celecoxib (CXB) with the PP2A inhibitor, calyculin-A (CLA) on the OSCC cell line, HSC3, was evaluated in vitro. We found that a combination of 1 nM CLA and 50 µM CXB significantly inhibited cell viability, and migration and invasion of HSC3 cells. Western blots for AKT, p-AKT, ERK, p-ERK, E-cadherin, vimentin and β-catenin were conducted after treatment with CXB and/or CLA. Increased E-cadherin and decreased β-catenin expression were found in CXB or CLA treated hsc-3 cells, whereas the combined CXB and CLA treatment showed no difference in E-cadherin or β-catenin expression. Our findings suggest that CLA alone was more effective than CXB alone, but not in the combined drug treatment.
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http://dx.doi.org/10.1080/10520295.2019.1700429DOI Listing
July 2020

Cigarette smoking increases the risk of nasopharyngeal carcinoma through the elevated level of IgA antibody against Epstein-Barr virus capsid antigen: A mediation analysis.

Cancer Med 2020 03 10;9(5):1867-1876. Epub 2020 Jan 10.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: The study aims are to evaluate the associations between nasopharyngeal carcinoma (NPC) risk and cigarette smoking and to explore the effects of cigarette smoking on Epstein-Barr virus (EBV) infection for NPC risk.

Methods: 1235 male NPC cases and 1262 hospital-based male controls matched to cases were recruited across six collaborative hospitals between 2010 and 2014. Using a standardized questionnaire, information on cigarette smoking and other potential risk factors for NPC was obtained. Blood was collected and used for anti-EBV VCA IgA and anti-EBV EA-EBNA1 IgA testing using standard methods. Unconditional logistic regression analysis was used to estimate odds ratio (OR) with 95% confidence interval (CI) for each risk factor after adjusting for confounders.

Results: 63.6% of cases and 44.0% of controls reported ever smoking cigarettes. After full adjustment, current smokers had a significant 1.60-fold (95% CI = 1.30-1.97) and former smokers a borderline significant 1.27-fold (95% CI = 1.00-1.60) increased NPC risk compared to never smokers. NPC risk increased with increasing duration, intensity, and pack-years of cigarette smoking but not with age at smoking initiation. Among controls, anti-EBV VCA IgA seropositivity rate was higher in current smokers than never smokers (14.0% vs 8.4%; OR = 1.82; 95% CI = 1.19-2.79). Mediation analyses showed that more than 90% of the cigarette smoking effect on NPC risk is mediated through anti-EBV VCA IgA.

Conclusion: This study confirms the association between long-term cigarette smoking and NPC and demonstrates that current smoking is associated with seropositivity of anti-EBV VCA IgA antibodies.
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http://dx.doi.org/10.1002/cam4.2832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050088PMC
March 2020

Clinical Features of Head and Neck Solitary Extramedullary Plasmacytoma in Taiwan.

In Vivo 2020 Jan-Feb;34(1):261-265

Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan, R.O.C

Background/aim: Solitary extramedullary plasmacytoma (SEP) is a rare, malignant plasma-cell tumor, which mainly occurs in the head and neck regions. Globally the disease has been rarely happening up to 2019, with only about ten papers focused on SEP cases reported in English. Thus, a literature collectively reviewing the characteristics of the patients would be valuable.

Patients And Methods: We enrolled 10 SEP patients, and recorded their primary sites and the treatment modality, and analyzed their survival rates and outcomes. We also reviewed previous studies and compared their findings with ours.

Results: No gender or age disparity has been observed, and younger patients had a better local control with RT compared to surgery among our patients.

Conclusion: Further investigations with more patients and long-time follow-up may provide more information for treatment determination and the recurrence and progression from SEP to MM.
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http://dx.doi.org/10.21873/invivo.11769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984109PMC
June 2020

WISP-1 Promotes Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Cells Via the miR-153-3p/Snail Axis.

Cancers (Basel) 2019 Nov 29;11(12). Epub 2019 Nov 29.

School and Medicine, China Medical University, Taichung 404, Taiwan.

Around half of all patients with oral squamous cell carcinoma (OSCC) present with lymphatic metastasis, a strong predictor of poor survival. Improving survival rates depends on preventing the first step in the "invasionmetastasis cascade," epithelialtomesenchymal transition (EMT), and developing antilymphangiogenesis therapies that antagonize lymphatic metastasis. The extracellular matrixrelated protein WISP1 (WNT1inducible signaling pathway protein1) stimulates bone remodeling and tumor progression. We have previously reported that WISP1 promotes OSCC cell migration and lymphangiogenesis induced by vascular endothelial growth factor C (VEGFC). This investigation sought to determine the role of WISP1 in regulating EMT in OSCC. Our analysis of oral cancer data from The Cancer Genome Atlas (TCGA) database revealed significant and positive associations between levels of WISP1 expression and clinical disease stage, as well as regional lymph node metastasis. We also found higher levels of WISP1 expression in serum samples obtained from patients with OSCC compared with samples from healthy controls. In a series of in vitro investigations, WISP1 activated EMT signaling via the FAK/ILK/Akt and Snail signaling transduction pathways and downregulated miR1533p expression in OSCC cells. Our findings detail how WISP1 promotes EMT via the miR1533p/Snail axis in OSCC cells.
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http://dx.doi.org/10.3390/cancers11121903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966565PMC
November 2019

Trans-oral robotic surgery versus coblation tongue base reduction for obstructive sleep apnea syndrome.

PeerJ 2019 2;7:e7812. Epub 2019 Oct 2.

Department of Otolaryngology Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan.

Objectives: To compare the efficacy of trans-oral robotic surgery (TORS) with that of coblation assisted tongue base reduction surgery in patients with obstructive sleep apnea syndrome (OSAS).

Subjects And Methods: The medical charts were retrospectively reviewed for all OSAS patients admitted to one institution for surgical intervention between 2012 and 2017. We analyzed 33 cases; 16 patients received TORS and 17 received coblation surgery for tongue base reduction. Both groups received concomitant uvulopalatoplasty. Surgical outcomes were evaluated by comparing the initial polysomnography (PSG) parameters with the follow-up PSG data (at least 3 months after the surgery). Epworth sleepiness scale (ESS) and complications were also compared between the 2 groups.

Results: The success rate (≥50% reduction of pre-operative AHI and post-operative AHI <20) in the TORS group and coblation group were 50% and 58%, respectively, and there was no significant difference ( = .611). The AHI (mean ± SD) reduction in the TORS and coblation groups were 24.9 ± 26.5 events/h and 19.4 ± 24.8 events/h, respectively; the between-group difference was not significant ( = .631). ESS improvement did not differ significantly between the TORS and coblation groups (3.8 ± 6.6 and 3.1 ± 9.2, respectively,  = .873). The rates of minor complication were higher in the TORS group (50%) than that of the coblation group (35.3%) without statistical significance ( = .393).

Conclusion: TORS achieved comparable surgical outcomes compared to coblation assisted tongue base reduction surgery in OSAS patients. Multilevel surgery using either TORS or coblation tongue base reduction combined with uvulopalatoplasty is an effective approach for the management of OSAS.
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http://dx.doi.org/10.7717/peerj.7812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778434PMC
October 2019

The effect of metformin use on hypopharyngeal squamous cell carcinoma in diabetes mellitus patients.

BMC Cancer 2019 Aug 30;19(1):862. Epub 2019 Aug 30.

Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan.

Background: Metformin is proven to improve the prognosis of various cancers, but it is unknown if metformin could ameliorate hypopharyngeal cancer in diabetes mellitus patients. This was a retrospective cohort study, and the effect and survival outcome of metformin on hypopharyngeal cancer with diabetes mellitus was investigated.

Methods: There were 141 hypopharyngeal cancer patients collected in a tertiary referral center from December 1st, 2011 to December 31st, 2013. There were 49 patients without diabetes mellitus (DM) and 92 patients with DM. In the 92 DM patients, there were 43 patients with metformin used and 49 patients without metformin used. All received patients followed up until September 1st, 2015.

Results: There was no significant difference in patients' characteristics between the non-DM and DM groups, and also no significant difference in clinical T stage, N stage, metastatic condition, and disease stage between the non-DM and DM groups. DM with metformin patients had lower metastasis rates and better overall survival (OS) (p = 0.011) and disease-free survival (DFS) (p = 0.004) compared to non-DM and DM without metformin. Multivariate analysis also showed a better OS and DFS in DM-Met (+) with advanced hypopharyngeal cancer but not in early stage.

Conclusion: There was less distant metastasis and better survival outcomes in hypopharyngeal cancer DM patients who use metformin.
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http://dx.doi.org/10.1186/s12885-019-6083-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716861PMC
August 2019

Evaluation of Rare and Common Variants from Suspected Familial or Sporadic Nasopharyngeal Carcinoma (NPC) Susceptibility Genes in Sporadic NPC.

Cancer Epidemiol Biomarkers Prev 2019 10 3;28(10):1682-1686. Epub 2019 Jul 3.

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Background: Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC.

Methods: We conducted targeted gene sequencing of 20 genes [16 identified from the study of multiplex families, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one identified from both studies] among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted.

Results: We found that NPC was associated with combined common and rare variants in ( = 1.3 × 10), ( = 1.6 × 10), ( = 4.0 × 10), and ( = 5.4 × 10). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g., for common variants of = 4.6 × 10; for rare variants, = 0.04). We also observed a suggestive association with rare variants in ( = 3.8 × 10) for NPC risk. In addition, we validated four previously reported NPC risk-associated SNPs.

Conclusions: Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC.

Impact: NPC-associated genes, including , and , suggest a role for telomere length maintenance in NPC etiology.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774819PMC
October 2019

Regulation of miRNA Biogenesis and Histone Modification by K63-Polyubiquitinated DDX17 Controls Cancer Stem-like Features.

Cancer Res 2019 05 15;79(10):2549-2563. Epub 2019 Mar 15.

Research Center for Tumor Medical Science, China Medical University, Taichung, Taiwan.

Markers of cancer stemness predispose patients to tumor aggressiveness, drug and immunotherapy resistance, relapse, and metastasis. DDX17 is a cofactor of the Drosha-DGCR8 complex in miRNA biogenesis and transcriptional coactivator and has been associated with cancer stem-like properties. However, the precise mechanism by which DDX17 controls cancer stem-like features remains elusive. Here, we show that the E3 ligase HectH9 mediated K63-polyubiquitination of DDX17 under hypoxia to control stem-like properties and tumor-initiating capabilities. Polyubiquitinated DDX17 disassociated from the Drosha-DGCR8 complex, leading to decreased biogenesis of anti-stemness miRNAs. Increased association of polyubiquitinated DDX17 with p300-YAP resulted in histone 3 lysine 56 (H3K56) acetylation proximal to stemness-related genes and their subsequent transcriptional activation. High expression of HectH9 and six stemness-related genes (, and ) predicted poor survival in patients with head and neck squamous cell carcinoma and lung adenocarcinoma. Our findings demonstrate that concerted regulation of miRNA biogenesis and histone modifications through posttranslational modification of DDX17 underlies many cancer stem-like features. Inhibition of DDX17 ubiquitination may serve as a new therapeutic venue for cancer treatment. SIGNIFICANCE: Hypoxia-induced polyubiquitination of DDX17 controls its dissociation from the pri-miRNA-Drosha-DCGR8 complex to reduce anti-stemness miRNA biogenesis and association with YAP and p300 to enhance transcription of stemness-related genes.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-2376DOI Listing
May 2019

Novel K6-K14 keratin fusion enhances cancer stemness and aggressiveness in oral squamous cell carcinoma.

Oncogene 2019 06 13;38(26):5113-5126. Epub 2019 Mar 13.

Human Genetic Center, China Medical University Hospital, Taichung, 40447, Taiwan.

Keratin intermediate filament (IF) is one component of cellular architectures, which provides necessary mechanical support to conquer environmental stresses. Recent findings reveal its involvement in mechano-transduction and the associated stem cell reprogramming, suggesting the possible roles in cancer development. Here, we report t(12;17)(q13.13;q21.2) chromosomal rearrangement as the most common fusion event in OSCC, resulting in a variety of inter-keratin fusions. Junction site mapping verified 9 in-frame K6-K14 variants, three of which were correlated with lymph node invasion, late tumor stages (T3/T4) and shorter disease-free survival times. When expressed in OSCC cells, those fusion variants disturbed wild-type K14 organization through direct interaction or aggregate formation, leading to perinuclear structure loss and nuclear deformation. Protein array analyses showed the ability of K6-K14 variant 7 (K6-K14/V7) to upregulate TGF-β and G-CSF signaling, which contributed to cell stemness, drug tolerance, and cell aggressiveness. Notably, K6-K14/V7-expressing cells easily adapted to a soft 3-D culture condition in vitro and formed larger, less differentiated tumors in vivo. In addition to the anti-mechanical-stress activity, our data uncover oncogenic functionality of novel keratin filaments caused by gene fusions during OSCC development.
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http://dx.doi.org/10.1038/s41388-019-0781-yDOI Listing
June 2019

Free flap reconstruction for early stage tongue squamous cell carcinoma: surgical margin and recurrence.

Acta Otolaryngol 2018 Oct;138(10):945-950

a Department of Otolaryngology-Head and Neck Surgery , China Medical University Hospital , Taichung , Taiwan.

Background: To identify the difference of surgical margin and recurrence status of early stage tongue carcinoma via wide excision in a single institution with and without free flap reconstruction.

Objective: Survey whether the reconstruction methods for early tongue cancer affects disease control, survival outcomes.

Methods: This was a retrospective study and patients with early tongue cancer underwent surgery via tumor ablation with (group 1 = 56) or without free flap reconstruction (group 2 = 291).

Results: The percentage of patients with free margin less than 5 mm was higher in the group 2 than in group 1 (49.48% vs. 19.64%, p < .001), as the mean free margin was significantly larger in group 1 than in group 2 (7.88 mm vs. 5.68 mm; p < .001). Despite higher number of T2 stage patients in group 1 (89.29%), the group 1 resulted in a significant lower recurrence rate (p = .024).

Conclusions: The utilization of free flap reconstruction for early stage tongue cancer achieved a large pathologic free margin and had relative lower recurrence and good survival rates.
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http://dx.doi.org/10.1080/00016489.2018.1490030DOI Listing
October 2018

Development and preliminary validation of a mandarin Chinese language questionnaire measuring betel quid dependency among adults in Taiwan.

Psychiatry Res 2019 01 22;271:153-160. Epub 2018 Nov 22.

School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan; Department of Medical Research, China Medical University Hospital, Taichung, Taiwan; Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan. Electronic address:

The purposes of this study were to develop the Chinese-version betel quid dependence instrument (BQDI) and to test its reliability and validity. An item pool relevant to betel quid dependence was generated. A panel of three experts assessed content validity including content relevance, clarity, and domain coverage. A cross-sectional study was conducted, consisting of 113 participants from a construction site, betel quid stalls, and a teaching hospital in Taichung, Taiwan. Construct validity was assessed by hypothesizing a significant correlation between the BQDI score and number of pieces-years for betel quid chewing and betel quid biomarkers. The overall Cronbach's alpha coefficient was 0.94. Factor analysis indicated the BQDI consisted of a three-factor structure, including physical and psychological cravings, lack of resistance to betel quid, and maladaptive use. We observed significant associations of BQDI total and factor scores with arecaidine (adjusted odds ratio [OR] for medium total BQDI score: 12.87, 95% CI: 1.45-114.5; high total BQDI score: 28.9, 3.53-236.6) and N-methylnipecotate (medium total BQDI score: 6.18, 1.21-31.62; high total BQDI score: 13.10, 2.72-63.03, respectively). Our results provide preliminary good internal consistency and construct validation of the Chinese-version BQDI as a measure of betel quid dependence in community adults.
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http://dx.doi.org/10.1016/j.psychres.2018.11.027DOI Listing
January 2019

ALPK1 Expression Is Associated with Lymph Node Metastasis and Tumor Growth in Oral Squamous Cell Carcinoma Patients.

Am J Pathol 2019 01 11;189(1):190-199. Epub 2018 Oct 11.

Environment-Omics-Diseases Research Centre, China Medical University Hospital, Taichung, Taiwan. Electronic address:

Oral squamous cell carcinoma (OSCC) is the most common malignant cancer, with high mortality rates in advanced stages. Recent studies have shown that the expression of ALPK1 mRNA and its inhibitory differentiation function are associated with cancer progression. However, the expression and clinicopathologic features of ALPK1 in OSCC remain unexplored. Herein, the authors investigated the expression patterns of ALPK1 in 39 matched OSCC patients and examined the relationship between ALPK1 protein expression and clinicopathologic factors using immunohistochemical scores. Using Western blot analysis, ALPK1 expression was found to be significantly higher in tumor tissues than that in nontumor tissues. Through an immunoreactive scoring system, a significantly higher number of advanced-stage tumor size T4 and lymph node metastasis N2 exhibited higher ALPK1 expression levels than that exhibited by T1/T2/T3 tumors and N0/N1. In addition, ALPK1 protein expression was aberrant in malignant oral cancer cell lines compared with that in pre-malignant oral epithelial cells, whereas minimal expression was observed in normal oral epithelial cells. Knockdown of ALPK1 resulted in a significant reduction in cell growth, migration, and invasion capacity in vitro. Consequently, expression of N-cadherin and vimentin decreased in ALPK1-deficient cells. Thus, these results suggest that ALPK1 serves as a potential biomarker and target for OSCC development in late stages.
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http://dx.doi.org/10.1016/j.ajpath.2018.09.003DOI Listing
January 2019

The Role of BPIFA1 in Upper Airway Microbial Infections and Correlated Diseases.

Biomed Res Int 2018 3;2018:2021890. Epub 2018 Sep 3.

Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan.

The mucosa is part of the first line of immune defense against pathogen exposure in humans and prevents viral and bacterial infection of the soft palate, lungs, uvula, and nasal cavity that comprise the ear-nose-throat (ENT) region. Bactericidal/permeability-increasing fold containing family A, member 1 (BPIFA1) is a secretory protein found in human upper aerodigestive tract mucosa. This innate material is secreted in mucosal fluid or found in submucosal tissue in the human soft palate, lung, uvula, and nasal cavity. BPIFA1 is a critical component of the innate immune response that prevents upper airway diseases. This review will provide a brief introduction of the roles of BPIFA1 in the upper airway (with a focus on the nasal cavity, sinus, and middle ear), specifically its history, identification, distribution in various human tissues, function, and diagnostic value in various upper airway infectious diseases.
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http://dx.doi.org/10.1155/2018/2021890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6140130PMC
January 2019

Biomarkers of Oxidative Stress Associated with the Risk of Potentially Malignant Oral Disorders.

Anticancer Res 2018 Sep;38(9):5211-5216

School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan, R.O.C

Aim: To investigate the effect of oxidative stress biomarkers on the risk of potentially malignant oral disorders (PMODs).

Materials And Methods: A total of 208 male adults with PMODs and an equal number of same-age control patients were enrolled. Plasma biomarkers of oxidative stress, measured with 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), were determined using enzyme-linked immunosorbent assay (ELISA) kits. PMODs were diagnosed in accordance with the World Health Organization (WHO) guidelines.

Results: A significant association between a high level of 8-ISO and an increased risk of PMODs was identified [odds ratio (OR)=1.71, 95% confidence interval (CI)=1.12-2.63; p=0.013]. This positive association was stronger among patients with PMOD subtype of leukoplakia (OR=1.94, 95% Cl=1.24-3.06; p=0.004). However, no significant association was observed between plasma 8-OHdG levels and overall risk of PMODs or subtypes.

Conclusion: Increased plasma 8-ISO levels may indicate the prominence of lipid peroxidation in the development of PMODs, particularly leukoplakia.
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http://dx.doi.org/10.21873/anticanres.12844DOI Listing
September 2018

Biomarkers of Oxidative Stress Associated with the Risk of Potentially Malignant Oral Disorders.

Anticancer Res 2018 Aug;38(8):4661-4666

School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan, R.O.C

Aim: To investigate the effect of oxidative stress biomarkers on the risk of potentially malignant oral disorders (PMODs).

Materials And Methods: A total of 208 male adults with PMODs and an equal number of same-age control patients were enrolled. Plasma biomarkers of oxidative stress, measured with 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-isoprostane (8-ISO), were determined using enzyme-linked immunosorbent assay kits. PMODs were diagnosed in accordance with the World Health Organization (WHO) guidelines.

Results: A significant association between a high level of 8-ISO and an increased risk of PMODs was identified [odds ratio (OR)=1.71, 95% confidence interval (CI)=1.12-2.63; p=0.013]. This positive association was stronger among patients with PMOD subtype of leukoplakia (OR=1.94, 95% Cl=1.24-3.06; p=0.004). However, no significant association was observed between plasma 8-OHdG levels and overall risk of PMODs or subtypes.

Conclusion: Our findings suggest that increased plasma 8-ISO levels may indicate the prominence of lipid peroxidation in the development of PMODs, particularly leukoplakia.
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http://dx.doi.org/10.21873/anticanres.12771DOI Listing
August 2018

Associations Between Polymorphisms and the Risk of Potentially Malignant Oral Disorders.

Anticancer Res 2018 Jul;38(7):4021-4026

School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan, R.O.C.

Aim: The study aimed to investigate the role of two polymorphisms of methylenetetrahydrofolate reductase (MTHFR), C677T and A1298C, in the risk of potentially malignant oral disorders (PMODs).

Materials And Methods: Genotypes of the MTHFR C677T and A1298C polymorphisms were determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) for 224 PMOD cases and 485 age-matched controls.

Results: The C677T T allele-carrying genotypes were significantly associated with a decreased risk of PMODs [odds ratio (OR)=0.62, 95% confidence interval (CI)=0.44-0.86]. Haplotype analysis also indicated that the 677T/1298A haplotype was associated with a decreased risk of PMODs (OR=0.56, 95%CI=0.40-0.80). No significant interaction was observed between MTHFR polymorphisms and lifestyle factors.

Conclusion: Our findings suggest that the T-allele-carrying MTHFR C677T genotype or haplotype may reduce the risk of PMODs. However, these observations require further confirmation using larger samples.
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http://dx.doi.org/10.21873/anticanres.12690DOI Listing
July 2018

Adjuvant radiotherapy after curative surgery for oral cavity squamous cell carcinoma and treatment effect of timing and duration on outcome-A Taiwan Cancer Registry national database analysis.

Cancer Med 2018 Jun 14. Epub 2018 Jun 14.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population-based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra-nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause-specific survival (CSS), local-regional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P < .001). Extreme RT dose (>70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.
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http://dx.doi.org/10.1002/cam4.1611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051157PMC
June 2018

Chemokine CCL4 Induces Vascular Endothelial Growth Factor C Expression and Lymphangiogenesis by miR-195-3p in Oral Squamous Cell Carcinoma.

Front Immunol 2018 2;9:412. Epub 2018 Mar 2.

Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.

The inflammatory chemokine (C-C motif) ligand 4 (CCL4) plays an important role in the pathogenesis and progression of cancer. In particular, higher serum CCL4 levels in patients with oral squamous cell carcinoma (OSCC) are associated with a more advanced stage of disease. OSCC accounts for approximately 95% of oral cancer in Taiwan and has a poor prognosis, due to aggressive local invasion and metastasis, leading to recurrence. OSCC spreads preferentially through lymphatic vessels and has the propensity to metastasize to the cervical lymph nodes even in the early stage of disease. Vascular endothelial growth factor C (VEGF-C) is an essential regulator of lymphangiogenesis. In particular, VEGF-C is specific to lymphatic vessel development, and VEGF-C expression levels have been found to directly correlate with lymph node metastasis in OSCC. However, it is unclear as to whether CCL4 correlates with VEGF-C expression and lymphangiogenesis in OSCC. We found that CCL4 increased VEGF-C expression and promoted lymphangiogenesis in oral cancer cells and . miR-195-3p mimic reversed CCL4-enhanced VEGF-C expression. CCL4 stimulation of oral cancer cells augmented JAK2 and STAT3 phosphorylation. Thus, CCL4 may be a new molecular therapeutic target for inhibition of lymphangiogenesis and metastasis in OSCC.
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http://dx.doi.org/10.3389/fimmu.2018.00412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863517PMC
June 2019

Comparison of Balloon Dilation and Laser Eustachian Tuboplasty in Patients with Eustachian Tube Dysfunction: A Meta-analysis.

Otolaryngol Head Neck Surg 2018 04 20;158(4):617-626. Epub 2018 Mar 20.

1 Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan.

Objective We aimed to perform a meta-analysis examining balloon dilatation and laser tuboplasty for the treatment of eustachian tube dysfunction (ETD). Data Sources PubMed, Cochrane, and Embase search up to April 18, 2016, with the following keywords: eustachian, middle-ear, eustachian tuboplasty, balloon tuboplasty, laser tuboplasty, laser dilatation, and balloon dilatation. Review Methods Randomized controlled trials and prospective, retrospective, and 1-arm studies of patients with ETD treated with balloon dilatation or laser tuboplasty were included. Outcome measures were improvement of eustachian tube score (ETS) and tympanometry and Valsalva maneuver results. Results Two retrospective and 11 prospective studies were included (1063 patients; 942 treated with balloon and 121 with laser tuboplasty). Balloon tuboplasty resulted in a significant improvement of ETS (pooled standardized mean difference [SMD], 0.94; 95% confidence interval [CI], 0.23-1.66; P = .009) and, compared with laser tuboplasty, a greater tympanometry improvement rate (pooled event rate = 73% vs 13%; P = .001). Valsalva maneuver improvement rate was not different between the group results (pooled event rate = 67% vs 50%; P = .472). The maximum number of studies that provided outcome data for any one measure was only 4, and sensitivity analysis indicated ETS results may have been overly influenced by 2 studies. No balloon tuboplasty studies reported ETS data, preventing comparison between the 2 procedures. Conclusion Both procedures can improve symptoms of ETD; however, because of the limited numbers of studies reporting data of the outcomes of interest, it remains unclear if one procedure provides greater benefits.
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http://dx.doi.org/10.1177/0194599817753609DOI Listing
April 2018

Interaction Between Rare Variants in NOTCH1 and Betel Quid Chewing in Oral Squamous Cell Carcinoma.

Genet Test Mol Biomarkers 2017 Oct 14;21(10):608-612. Epub 2017 Sep 14.

1 Graduate Institute of Clinical Medical Science, China Medical University , Taichung, Taiwan .

Background: In this study, we investigated rare variants of the NOTCH1 gene located near somatic mutations as surrogate markers, as well as the relationship of these rare variants with betel quid (BQ) chewing and the occurrence of oral squamous cell carcinoma (OSCC).

Materials And Methods: A total of 410 patients diagnosed with OSCC and 282 unrelated, healthy subjects without cancer were recruited from two medical centers in Taiwan. Odds ratios (OR) and 95% confidence intervals (CI) were assessed by logistic regression. The Cox proportional hazard model was used to assess the interaction between rare NOTCH1 variants and BQ chewing in OSCC.

Results: The genetic variant rs139994842 in exon15 of NOTCH1 was significantly associated with an increased risk of OSCC (OR = 2.88 95% CI: 1.07-7.79), and the association between rs202133782 in exon13 of NOTCH1 with OSCC was borderline significant (p = 0.0627). Moreover, a combination of four rare variants was significantly associated with OSCC (p = 0.012). Patients who carried these NOTCH1 variants were at a higher risk of recurrence (OR = 18.95; 95% CI, 1.01-326.74; p = 0.0428). Furthermore, of the mean 24-year BQ exposure period, the OSCC incidence rate was significantly higher in OSCC patients who chewed BQ and had a NOTCH1 variant (p < 0.0001).

Conclusion: This information is applicable to prevention; the surveillance of patients at risk; and for early detection to reduce morbidity and mortality from OSCC.
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http://dx.doi.org/10.1089/gtmb.2017.0013DOI Listing
October 2017